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Sample records for leptin glucose insulin

  1. Leptin rapidly improves glucose homeostasis in obese mice by increasing hypothalamic insulin sensitivity.

    Science.gov (United States)

    Koch, Christiane; Augustine, Rachael A; Steger, Juliane; Ganjam, Goutham K; Benzler, Jonas; Pracht, Corinna; Lowe, Chrishanthi; Schwartz, Michael W; Shepherd, Peter R; Anderson, Greg M; Grattan, David R; Tups, Alexander

    2010-12-01

    Obesity is associated with resistance to the actions of both leptin and insulin via mechanisms that remain incompletely understood. To investigate whether leptin resistance per se contributes to insulin resistance and impaired glucose homeostasis, we investigated the effect of acute leptin administration on glucose homeostasis in normal as well as leptin- or leptin receptor-deficient mice. In hyperglycemic, leptin-deficient Lep(ob/ob) mice, leptin acutely and potently improved glucose metabolism, before any change of body fat mass, via a mechanism involving the p110α and β isoforms of phosphatidylinositol-3-kinase (PI3K). Unlike insulin, however, the anti-diabetic effect of leptin occurred independently of phospho-AKT, a major downstream target of PI3K, and instead involved enhanced sensitivity of the hypothalamus to insulin action upstream of PI3K, through modulation of IRS1 (insulin receptor substrate 1) phosphorylation. These data suggest that leptin resistance, as occurs in obesity, reduces the hypothalamic response to insulin and thereby impairs peripheral glucose homeostasis, contributing to the development of type 2 diabetes.

  2. Central insulin and leptin-mediated autonomic control of glucose homeostasis.

    Science.gov (United States)

    Marino, Joseph S; Xu, Yong; Hill, Jennifer W

    2011-07-01

    Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular play a crucial role in the development of insulin resistance. This review discusses the neuronal crosstalk between the hypothalamus, autonomic nervous system, and tissues associated with the pathogenesis of type 2 diabetes, and how hypothalamic insulin and leptin signaling are integral to maintaining normal glucose homeostasis. Copyright © 2011 Elsevier Ltd. All rights reserved.

  3. Central insulin and leptin-mediated autonomic control of glucose homeostasis

    OpenAIRE

    Marino, Joseph S.; Xu, Yong; Hill, Jennifer W.

    2011-01-01

    Largely as a result of rising obesity rates, the incidence of type 2 diabetes is escalating rapidly. Type 2 diabetes results from multi-organ dysfunctional glucose metabolism. Recent publications have highlighted hypothalamic insulin- and adipokine-sensing as a major determinant of peripheral glucose and insulin responsiveness. The preponderance of evidence indicates that the brain is the master regulator of glucose homeostasis, and that hypothalamic insulin and leptin signaling in particular...

  4. Insulin elevates leptin secretion and mRNA levels via cyclic AMP in 3T3-L1 adipocytes deprived of glucose

    Directory of Open Access Journals (Sweden)

    Tomomi Tsubai

    2016-11-01

    Conclusion: Insulin alone stimulates leptin secretion and elevates leptin mRNA levels via cAMP under the lack of glucose metabolism, while glucose is a significant and ambivalent effector on the insulin effects of leptin.

  5. Clinical significance of determination of serum leptin, insulin levels and blood sugar in pregnant women with glucose metabolism disturbances

    International Nuclear Information System (INIS)

    Yu Suqing; Li Yusheng; Wang Lin; Chu Kaiqiu

    2006-01-01

    Objective: To investigate the changes of serum leptin, insulin levels and blood sugar contents in pregnant women with gestational glucose metabolism disturbances. Methods: Fasting and 3h after oral 50g glucose serum levels of leptin were measured with RIA in 36 pregnant women with glucose metabolism disturbances (gestational diabetes mellitus or gestational impaired glucose tolerance) and 34 controls. Also, fasting serum insulin levels (with CLIA) and blood sugar contents 1h after oral 50 glucose (with glucose oxidase method) were determined in all these subjects. Results: 1. Serum levels of leptin in pregnant women with glucose metabolism disturbances were 14.9 ± 4.3 μg/L (vs controls 9.8 ± 1.7 μg/L, P<0.01). 2. The serum levels of insulin and 1 h post - 50g glucose blood sugar contents in pregnant women with glucose metabolism disturbances were 12.9±4.3mU/L and 11.0±1.4mmol/L respectively, which were both significantly positively correlated with the serum leptin levels (r=0.835, r=0.758 respectively) (vs levels in controls: 8.45±3.0mU/L and 7.84±1.3mmol/L). Conclusion: Elevation of fasting serum levels of leptin was demonstrated in pregnant women with glucose metabolism disturbances and the level of leptin was positively correlated with that of insulin and blood sugar. (authors)

  6. Insulin and leptin induce Glut4 plasma membrane translocation and glucose uptake in a human neuronal cell line by a phosphatidylinositol 3-kinase- dependent mechanism.

    Science.gov (United States)

    Benomar, Yacir; Naour, Nadia; Aubourg, Alain; Bailleux, Virginie; Gertler, Arieh; Djiane, Jean; Guerre-Millo, Michèle; Taouis, Mohammed

    2006-05-01

    The insulin-sensitive glucose transporter Glut4 is expressed in brain areas that regulate energy homeostasis and body adiposity. In contrast with peripheral tissues, however, the impact of insulin on Glut4 plasma membrane (PM) translocation in neurons is not known. In this study, we examined the role of two anorexic hormones (leptin and insulin) on Glut4 translocation in a human neuronal cell line that express endogenous insulin and leptin receptors. We show that insulin and leptin both induce Glut4 translocation to the PM of neuronal cells and activate glucose uptake. Wortmannin, a specific inhibitor of phosphatidylinositol 3-kinase, totally abolished insulin- and leptin-dependent Glut4 translocation and stimulation of glucose uptake. Thus, Glut4 translocation is a phosphatidylinositol 3-kinase-dependent mechanism in neuronal cells. Next, we investigated the impact of chronic insulin and leptin treatments on Glut4 expression and translocation. Chronic exposure of neuronal cells to insulin or leptin down-regulates Glut4 proteins and mRNA levels and abolishes the acute stimulation of glucose uptake in response to acute insulin or leptin. In addition, chronic treatment with either insulin or leptin impaired Glut4 translocation. A cross-desensitization between insulin and leptin was apparent, where exposure to insulin affects leptin-dependent Glut4 translocation and vice versa. This cross-desensitization could be attributed to the increase in suppressor of cytokine signaling-3 expression, which was demonstrated in response to each hormone. These results provide evidence to suggest that Glut4 translocation to neuronal PM is regulated by both insulin and leptin signaling pathways. These pathways might contribute to an in vivo glucoregulatory reflex involving a neuronal network and to the anorectic effect of insulin and leptin.

  7. INFLUENCE OF DIETARY FAT ON LEPTIN AND INSULIN IN MALE ALBINO RATS

    International Nuclear Information System (INIS)

    KASSAB, F.M.A.; ABDEL-KHALEK, L.G.; KAMAL, A.M.

    2008-01-01

    Sixty male albino rats were arranged into 5 equal groups which were used in this study to investigate the relation between leptin and insulin hormones under high fat intake and to assess the role of fresh vegetable intake on minimizing dyslipidemia.The results denoted that dietary fat caused significant increase in the levels of blood glucose and leptin hormone with significant decrease in insulin concentration and with prolonged high fat intake, insulin level was increased. However, the increased leptin and glucose indicated that prolonged fatty diet may cause insulin resistance. Addition of green vegetables to the diet normalized to a great extent the level of cholesterol, triglycerides, VLDL, glucose and insulin

  8. Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance.

    Science.gov (United States)

    Connelly, Margery A; Wolak-Dinsmore, Justyna; Dullaart, Robin P F

    2017-05-01

    Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the extent to which the association of BCAA with insulin resistance is attributable to altered leptin and adiponectin levels in individuals with varying degrees of glucose tolerance. BCAA were measured by nuclear magnetic resonance, whereas leptin and adiponectin were measured by immunoassay, in subjects with normal fasting glucose (n = 30), impaired fasting glucose (n = 25), and T2DM (n = 15). Insulin resistance was estimated by homeostasis model assessment (HOMAir). BCAA were higher in men than in women (P BCAA were correlated with HOMAir (r = 0.46; P  0.05). Multivariable linear regression analysis, adjusting for age, sex, T2DM, and body mass index (BMI), demonstrated that BCAA were positively associated with HOMAir (β = 0.242, P = 0.023). When BCAA, leptin, and adiponectin were included together, the positive relationship of HOMAir with BCAA (β = 0.275, P = 0.012) remained significant. Insulin resistance was associated with BCAA. This association remained after adjusting for age, sex, T2DM, BMI, as well as leptin and adiponectin. It is unlikely that the relationship of insulin resistance with BCAA is to a major extent attributable to effects of leptin and adiponectin.

  9. Pivotal role of leptin in insulin effects

    Directory of Open Access Journals (Sweden)

    R.B. Ceddia

    1998-06-01

    Full Text Available The OB protein, also known as leptin, is secreted by adipose tissue, circulates in the blood, probably bound to a family of binding proteins, and acts on central neural networks regulating ingestive behavior and energy balance. The two forms of leptin receptors (long and short forms have been identified in various peripheral tissues, a fact that makes them possible target sites for a direct action of leptin. It has been shown that the OB protein interferes with insulin secretion from pancreatic islets, reduces insulin-stimulated glucose transport in adipocytes, and increases glucose transport, glycogen synthesis and fatty acid oxidation in skeletal muscle. Under normoglycemic and normoinsulinemic conditions, leptin seems to shift the flux of metabolites from adipose tissue to skeletal muscle. This may function as a peripheral mechanism that helps control body weight and prevents obesity. Data that substantiate this hypothesis are presented in this review.

  10. Some metabolic and anthropometric variables in obes children by measuring serum insulin, and leptin

    International Nuclear Information System (INIS)

    Nour Eldin, A.M.

    2004-01-01

    The present study aimed to assess serum leptin level in obese children to study its correlation with some metabolic variables as serum insulin and serum glucose. The study was conducted on 30 obese children of age from 9-14 years with body mass index (BMI) > 27.8 Kg/m 2 . All children were subjected to history taking, clinical examination, anthropometric measurements and laboratory investigations including fasting serum leptin, insulin and blood glucose. Serum leptin was significantly higher in obese children (102.3± 56.2 ng/ml) compared to non-obese ones (48.15±26.1 ng/ml). The relation between serum leptin and anthropometric measurements and laboratory investigations including fasting serum insulin and blood glucose. Serum leptin was significantly higher in obese children (102.3± 56.2 ng/ml)compared to non-obese ones (48.15±26.1 ng/ml). The relation between serum leptin and anthropometric variables was positively correlated with BMI r s = 0.68, (p s = 0.59.(p<0.01). It is concluded that serum leptin is increased in obesity and its concentration effects the size of the body. Moreover, the relation of leptin and insulin suggests a positive role of leptin in insulin resistance, which are common metabolic disorders associated with obesity

  11. Leptin and insulin pathways in POMC and AgRP neurons that modulate energy balance and glucose homeostasis

    Science.gov (United States)

    Varela, Luis; Horvath, Tamas L

    2012-01-01

    With the steady rise in the prevalence of obesity and its associated diseases, research aimed at understanding the mechanisms that regulate and control whole body energy homeostasis has gained new interest. Leptin and insulin, two anorectic hormones, have key roles in the regulation of body weight and energy homeostasis, as highlighted by the fact that several obese patients develop resistance to these hormones. Within the brain, the hypothalamic proopiomelanocortin and agouti-related protein neurons have been identified as major targets of leptin and insulin action. Many studies have attempted to discern the individual contributions of various components of the principal pathways that mediate the central effects of leptin and insulin. The aim of this review is to discuss the latest findings that might shed light on, and lead to a better understanding of, energy balance and glucose homeostasis. In addition, recently discovered targets and mechanisms that mediate hormonal action in the brain are highlighted. PMID:23146889

  12. Effect of leptin gene methylation on glucose metabolism in pregnant rats

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    Zhen LI

    2011-11-01

    Full Text Available Objective To examine the dynamic level of progesterone,insulin,and leptin,as well as the change in the features of leptin gene methylation in the promoter region of pregnant rats during different gestation stages and to analyze the correlation and effect of these conditions on glucose metabolism during gestation.Methods C57BL/6J pregnant rats are divided to four different groups,namely,early,mid-,and late gestation,as well as seven days postpartum(five rats for each group.Five C57BL/6J non-pregnant rats are taken as the control group.The change in glucose metabolism during gestation was determined by measuring the glucose tolerance of rats in different groups and by testing the level of progesterone,insulin,and leptin in the sera and the level of the methylation of leptin gene promoters during different stages of gestation.Results The levels of insulin [(13.70±0.70,14.78±0.91,and 16.07±0.55mU/L],progesterone [(10.10±0.37,11.41±0.50,and 15.34±0.65μg/L],and leptin [(1356.73±100.41,1628.02±53.03,and 1954.12±39.71ng/L] in pregnant rats in the three groups(early,mid-,and late gestation are apparently higher than that of the non-pregnant rats [(12.25±1.62mU/L,(7.14±0.38μg/L,and(934.38±62.29ng/L] and the postpartum group [(12.46±0.93mU/L,(9.74±0.82μg/L,and(1259.19±105.74ng/L].The difference among the different stages of gestation has statistical significance(P < 0.01,but the difference between the non-pregnant and postpartum groups is statistically insignificant.Fasting blood glucose during gestation is low.The level of blood glucose in mid-gestation and late-gestation rats after being injected with glucose is apparently higher than that of the non-pregnant group(P < 0.01.The level of methylation in the leptin gene promoter zone of the placenta drops along with gestation.Conclusions High levels of progesterone,insulin,and leptin contribute to physiological insulin resistance during gestation,resulting in reduced fasting blood glucose

  13. Leptin responses to bovine interferon- α and insulin in cattle

    African Journals Online (AJOL)

    Egyptian Journal of Biochemistry and Molecular Biology ... IFN- α injection produced a rapid increase in glucose and insulin levels but leptin levels did not show any alteration after the injection. ... Insulin levels rapidly increased in the blood and consequently a significant decrease in blood glucose level was recorded.

  14. Leptin Is Required for Glucose Homeostasis after Roux-en-Y Gastric Bypass in Mice.

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    Mohamad Mokadem

    Full Text Available Leptin, the protein product of the ob gene, increases energy expenditure and reduces food intake, thereby promoting weight reduction. Leptin also regulates glucose homeostasis and hepatic insulin sensitivity via hypothalamic proopiomelanocortin neurons in mice. Roux-en-Y gastric bypass (RYGB induces weight loss that is substantial and sustained despite reducing plasma leptin levels. In addition, patients who fail to undergo diabetes remission after RYGB are hypoletinemic compared to those who do and to lean controls. We have previously demonstrated that the beneficial effects of RYGB in mice require the melanocortin-4 receptor, a downstream effector of leptin action. Based on these observations, we hypothesized that leptin is required for sustained weight reduction and improved glucose homeostasis observed after RYGB.To investigate this hypothesis, we performed RYGB or sham operations on leptin-deficient ob/ob mice maintained on regular chow. To investigate whether leptin is involved in post-RYGB weight maintenance, we challenged post-surgical mice with high fat diet.RYGB reduced total body weight, fat and lean mass and caused reduction in calorie intake in ob/ob mice. However, it failed to improve glucose tolerance, glucose-stimulated plasma insulin, insulin tolerance, and fasting plasma insulin. High fat diet eliminated the reduction in calorie intake observed after RYGB in ob/ob mice and promoted weight regain, although not to the same extent as in sham-operated mice. We conclude that leptin is required for the effects of RYGB on glucose homeostasis but not body weight or composition in mice. Our data also suggest that leptin may play a role in post-RYGB weight maintenance.

  15. Leptin and insulin engage specific PI3K subunits in hypothalamic SF1 neurons

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    Jong-Woo Sohn

    2016-08-01

    Full Text Available Objective: The ventromedial hypothalamic nucleus (VMH regulates energy balance and glucose homeostasis. Leptin and insulin exert metabolic effects via their cognate receptors expressed by the steroidogenic factor 1 (SF1 neurons within the VMH. However, detailed cellular mechanisms involved in the regulation of these neurons by leptin and insulin remain to be identified. Methods: We utilized genetically-modified mouse models and performed patch-clamp electrophysiology experiments to resolve this issue. Results: We identified distinct populations of leptin-activated and leptin-inhibited SF1 neurons. In contrast, insulin uniformly inhibited SF1 neurons. Notably, we found that leptin-activated, leptin-inhibited, and insulin-inhibited SF1 neurons are distinct subpopulations within the VMH. Leptin depolarization of SF1 neuron also required the PI3K p110β catalytic subunit. This effect was mediated by the putative transient receptor potential C (TRPC channel. On the other hand, hyperpolarizing responses of SF1 neurons by leptin and insulin required either of the p110α or p110β catalytic subunits, and were mediated by the putative ATP-sensitive K+ (KATP channel. Conclusions: Our results demonstrate that specific PI3K catalytic subunits are responsible for the acute effects of leptin and insulin on VMH SF1 neurons, and provide insights into the cellular mechanisms of leptin and insulin action on VMH SF1 neurons that regulate energy balance and glucose homeostasis. Author Video: Author Video Watch what authors say about their articles Keywords: Cellular mechanism, Conditional knockout mouse, Patch clamp technique, Functional heterogeneity, Homeostasis

  16. Effects of high-fructose corn syrup and sucrose consumption on circulating glucose, insulin, leptin, and ghrelin and on appetite in normal-weight women.

    Science.gov (United States)

    Melanson, Kathleen J; Zukley, Linda; Lowndes, Joshua; Nguyen, Von; Angelopoulos, Theodore J; Rippe, James M

    2007-02-01

    Fructose has been implicated in obesity, partly due to lack of insulin-mediated leptin stimulation and ghrelin suppression. Most work has examined effects of pure fructose, rather than high-fructose corn syrup (HFCS), the most commonly consumed form of fructose. This study examined effects of beverages sweetened with HFCS or sucrose (Suc), when consumed with mixed meals, on blood glucose, insulin, leptin, ghrelin, and appetite. Thirty lean women were studied on two randomized 2-d visits during which HFCS- and Suc-sweetened beverages were consumed as 30% of energy on isocaloric diets during day 1 while blood was sampled. On day 2, food was eaten ad libitum. Subjects rated appetite at designated times throughout visits. No significant differences between the two sweeteners were seen in fasting plasma glucose, insulin, leptin, and ghrelin (P > 0.05). The within-day variation in all four items was not different between the two visits (P > 0.05). Net areas under the curve were similar for glucose, insulin, and leptin (P > 0.05). There were no differences in energy or macronutrient intake on day 2. The only appetite variable that differed between sweeteners was desire to eat, which had a higher area under the curve the day after Suc compared with HFCS. These short-term results suggest that, when fructose is consumed in the form of HFCS, the measured metabolic responses do not differ from Suc in lean women. Further research is required to examine appetite responses and to determine if these findings hold true for obese individuals, males, or longer periods.

  17. Control of blood pressure, appetite, and glucose by leptin in mice lacking leptin receptors in proopiomelanocortin neurons.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Cai, Zhengwei; Lin, Shuying; Dubinion, John H; Hall, John E

    2011-05-01

    Although the central nervous system melanocortin system is an important regulator of energy balance, the role of proopiomelanocortin (POMC) neurons in mediating the chronic effects of leptin on appetite, blood pressure, and glucose regulation is unknown. Using Cre/loxP technology we tested whether leptin receptor deletion in POMC neurons (LepR(flox/flox)/POMC-Cre mice) attenuates the chronic effects of leptin to increase mean arterial pressure (MAP), enhance glucose use and oxygen consumption, and reduce appetite. LepR(flox/flox)/POMC-Cre, wild-type, LepR(flox/flox), and POMC-Cre mice were instrumented for MAP and heart rate measurement by telemetry and venous catheters for infusions. LepR(flox/flox)/POMC-Cre mice were heavier, hyperglycemic, hyperinsulinemic, and hyperleptinemic compared with wild-type, LepR(flox/flox), and POMC-Cre mice. Despite exhibiting features of metabolic syndrome, LepR(flox/flox)/POMC-Cre mice had normal MAP and heart rate compared with LepR(flox/flox) but lower MAP and heart rate compared with wild-type mice. After a 5-day control period, leptin was infused (2 μg/kg per minute, IV) for 7 days. In control mice, leptin increased MAP by ≈5 mm Hg despite decreasing food intake by ≈35%. In contrast, leptin infusion in LepR(flox/flox)/POMC-Cre mice reduced MAP by ≈3 mm Hg and food intake by ≈28%. Leptin significantly decreased insulin and glucose levels in control mice but not in LepR(flox/flox)/POMC-Cre mice. Leptin increased oxygen consumption in LepR(flox/flox)/POMC-Cre and wild-type mice. Activation of POMC neurons is necessary for the chronic effects of leptin to raise MAP and reduce insulin and glucose levels, whereas leptin receptors in other areas of the brain other than POMC neurons appear to play a key role in mediating the chronic effects of leptin on appetite and oxygen consumption.

  18. Is fasting leptin associated with insulin resistance among nondiabetic individuals? The Miami Community Health Study

    DEFF Research Database (Denmark)

    Donahue, R P; Prineas, R J; Donahue, R D

    1999-01-01

    Whether serum leptin levels are associated with insulin resistance independent of the effects of hyperinsulinemia and adiposity is an important unanswered question. We examined the relationship between the rate of insulin-mediated glucose uptake and serum leptin concentrations among nondiabetic men...

  19. Impact of risperidone on leptin and insulin in children and adolescents with autistic spectrum disorders.

    Science.gov (United States)

    Srisawasdi, Pornpen; Vanwong, Natchaya; Hongkaew, Yaowaluck; Puangpetch, Apichaya; Vanavanan, Somlak; Intachak, Boontarika; Ngamsamut, Nattawat; Limsila, Penkhae; Sukasem, Chonlaphat; Kroll, Martin H

    2017-08-01

    To evaluate the influence of dose and duration of risperidone treatment on cardiovascular and diabetes risk biomarkers in children and adolescents with autistic spectrum disorders (ASDs). In this cross-sectional analysis, a total of 168 ASDs patients (89% male) treated with a risperidone-based regimen for ≥12months were included. Blood samples were analyzed for glucose and lipid metabolic markers, adiponectin, leptin, prolactin, cortisol and high sensitive C-reactive protein. The mean concentrations of glucose, insulin, prolactin and leptin and HOMA-IR significantly rose with risperidone dosage (all P<0.025), but those of adiponectin and cortisol did not. Using regression analysis, insulin, leptin, prolactin and glucose concentrations and HOMA-IR show significant association with dosage. None of the markers except adiponectin showed dependence on duration of treatment. However, insulin and leptin concentrations and HOMA-IR clearly increased with increasing both dosage and duration. Dosage and duration of treatment had minimal effect on standard lipid profile and lipoprotein subclasses. Risperidone treatment disturbed glucose homeostasis and endocrine regulation (particularly leptin) in children and adolescents with ASDs, in a dose- and duration-dependent manner, being suggestive of leptin and insulin resistance mechanisms. Metabolic adverse effects, especially development of type 2 diabetes mellitus should be closely monitored, particularly in individuals receiving high doses and/or long-term risperidone treatment. Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.

  20. Living without insulin: the role of leptin signaling in the hypothalamus

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    Teppei eFujikawa

    2015-03-01

    Full Text Available Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we review the neuronal and peripheral mechanisms by which leptin signaling in the central nervous system (CNS regulates glucose metabolism in an insulin-independent manner.

  1. Leptin, adiponectin, leptin to adiponectin ratio and insulin resistance in depressive women.

    Science.gov (United States)

    Zeman, Miroslav; Jirak, Roman; Jachymova, Marie; Vecka, Marek; Tvrzicka, Eva; Zak, Ales

    2009-01-01

    Depressive disorder (DD) is associated with an increased risk of type 2 diabetes mellitus (DM2) and cardiovascular disease (CVD). It was suggested, that metabolic syndrome (MetS), cluster of metabolic and hormonal changes, such as insulin resistence (IR), abdominal obesity, dyslipidemia, arterial hypertension and elevated fasting glycaemia, could stand behind the connection. Recent findings have shown, that adipocytokines leptin and adiponectin might play a role in both depression and MetS. The aim of this pilot study was to observe the plasma concentrations of leptin, adiponectin, leptin-to-adiponectin ratio and indices of IR in women with depressive disorder. The plasma leptin, adiponectin, parameters of lipid and glucose homeostasis and indices of IR were investigated in a group of 38 women with DD. The results were compared with those of 38 healthy women of the control group, matched for age. Depressive women differed significantly from the controls in higher concentrations of plasma leptin (p insulin (p insulin sensitivity was lower (p <0.01). HAM-D score of DD cases correlated negatively with adiponectin (r = - 0.3505; p < 0.05), independently of HOMA-IR. We have not found in DD group any differences between the drug free patients and those treated either with escitaloprame alone or in the combination with mirtazapine. The results of the pilot study presented support the hypothesis that at least part of DD cases has increased leptin serum levels and certain features of MetS. It could be the factor connecting depression with an increased risk of either DM2 or CVD.

  2. Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

    Science.gov (United States)

    Kalra, Satya P

    2013-10-01

    Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable glycemia for lifetime.

  3. Should leptin replace insulin as a lifetime monotherapy for diabetes type 1 and 2?

    Directory of Open Access Journals (Sweden)

    Satya P Kalra

    2013-01-01

    Full Text Available Evidence accumulated during the last decade has affirmed that adipocyte leptin insufficiency in the hypothalamus is the primary etiological factor in the pathogenesis of diabetes type 1 and 2 and related metabolic morbidities. Leptin insufficiency disrupts the relay of hypothalamic regulatory information along three descending pathways to the organs in the periphery that normally participate in maintenance of glucose homeostasis on a minute-to-minute basis throughout lifetime. Reinstatement of leptin sufficiency in the hypothalamus by either systemic or central injections, or its provision selectively in the hypothalamus with the aid of gene therapy extinguished hyperglycemia and normalized blood glucose stably during the entire course of treatment in a variety of animal models of diabetes type 1 and 2. In follow-up clinical trials, twice daily leptin treatment in leptinopenic and insulinopenic type 1 diabetics and leptinopenic and hyperinsulinemic type 2 diabetics with congenital lipodystrophy or acquired lipoatrophy normalized blood glucose without any discernible adverse effects during the extended course of treatment. Taken together, these findings have amply endorsed the efficacy of leptin therapy to restore glucose homeostasis in insulin-deficient as well as hyperinsulinemic diabetic patients. Consequently, restoration of optimal hypothalmic signaling to reinstate glucose homeostasis with leptin is a highly suitable new therapeutic strategy to ameliorate diabetes type 1 and 2 for the lifetime and to replace the currently in vogue insulin monotherapy. In view of the relentless challenges posed by the worldwide epidemic of diabetes and soaring treatment costs, taken together with the well-known shortcomings of therapies based on restoring insulin signaling, it is highly critical and timely to undertake new clinical trials that ascertain appropriate dosage and route of leptin delivery to the hypothalamus capable of safely sustaining stable

  4. An acute bout of whole body passive hyperthermia increases plasma leptin, but does not alter glucose or insulin responses in obese type 2 diabetics and healthy adults.

    Science.gov (United States)

    Rivas, Eric; Newmire, Dan E; Crandall, Craig G; Hooper, Philip L; Ben-Ezra, Vic

    2016-07-01

    Acute and chronic hyperthermic treatments in diabetic animal models repeatedly improve insulin sensitivity and glycemic control. Therefore, the purpose of this study was to test the hypothesis that an acute 1h bout of hyperthermic treatment improves glucose, insulin, and leptin responses to an oral glucose challenge (OGTT) in obese type 2 diabetics and healthy humans. Nine obese (45±7.1% fat mass) type 2 diabetics (T2DM: 50.1±12y, 7.5±1.8% HbA1c) absent of insulin therapy and nine similar aged (41.1±13.7y) healthy non-obese controls (HC: 33.4±7.8% fat mass, Pwhole body passive hyperthermia treatment via head-out hot water immersion (1h resting in 39.4±0.4°C water) that increased internal temperature above baseline by ∆1.6±0.4°C or a control resting condition. Twenty-four hours post treatments, a 75g OGTT was administered to evaluate changes in plasma glucose, insulin, C-peptide, and leptin concentrations. Hyperthermia itself did not alter area under the curve for plasma glucose, insulin, or C-peptide during the OGTT in either group. Fasting absolute and normalized (kg·fat mass) plasma leptin was significantly increased (P<0.01) only after the hyperthermic exposure by 17% in T2DM and 24% in HC groups (P<0.001) when compared to the control condition. These data indicate that an acute hyperthermic treatment does not improve glucose tolerance 24h post treatment in moderate metabolic controlled obese T2DM or HC individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

  5. Enhanced leptin sensitivity and improved glucose homeostasis in mice lacking suppressor of cytokine signaling-3 in POMC-expressing cells.

    Science.gov (United States)

    Kievit, Paul; Howard, Jane K; Badman, Michael K; Balthasar, Nina; Coppari, Roberto; Mori, Hiroyuki; Lee, Charlotte E; Elmquist, Joel K; Yoshimura, Akihiko; Flier, Jeffrey S

    2006-08-01

    Suppressor of cytokine signaling-3 (Socs-3) negatively regulates the action of various cytokines, as well as the metabolic hormones leptin and insulin. Mice with haploinsufficiency of Socs-3, or those with neuronal deletion of Socs-3, are lean and more leptin and insulin sensitive. To examine the role of Socs-3 within specific neurons critical to energy balance, we created mice with selective deletion of Socs-3 within pro-opiomelanocortin (POMC)-expressing cells. These mice had enhanced leptin sensitivity, measured by weight loss and food intake after leptin infusion. On chow diet, glucose homeostasis was improved despite normal weight gain. On a high-fat diet, the rate of weight gain was reduced, due to increased energy expenditure rather than decreased food intake; glucose homeostasis and insulin sensitivity were substantially improved. These studies demonstrate that Socs-3 within POMC neurons regulates leptin sensitivity and glucose homeostasis, and plays a key role in linking high-fat diet to disordered metabolism.

  6. Serum leptin and insulin tests in obesity

    International Nuclear Information System (INIS)

    Yang Yin; Jiang Xiaojin; Leng Xiumei

    2001-01-01

    Objective: To study the clinical significance and the relations of leptin and insulin on obesity group. Methods: Leptin and insulin were tested with radioimmunoassay (RIA) in pre-obesity group and obesity group respectively. Results: Serum leptin and insulin levels were significantly elevated in obesity group compare with the controls (P<0.01). Conclusion: Changing with insulin, the elevation of leptin in obesity group has been identified as an important agent of diabetes mellitus (DM)

  7. Regulation of leptin and insulin signaling by the t cell protein tyrosine phosphatase

    OpenAIRE

    Loh, Kim Yong

    2017-01-01

    The prevalence of obesity and diabetes are increasing at alarming rates. Both are major health concerns worldwide. Food intake, energy expenditure and hepatic glucose production are regulated by hypothalamic neuronal circuits that respond to peripheral signals including leptin and insulin. Leptin is produced by adipose tissue and acts in the hypothalamus via the JAK2/STAT3 signaling pathway to decrease food intake and increase energy expenditure. It is now also widely appreciated that insulin...

  8. The Effects of Reduction Mammaplasty on Serum Leptin Levels and Insulin Resistance

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    Hakan Uzun

    2015-01-01

    Full Text Available Background. The reduction mammaplasty has been a well-executed and known procedure in which considerable amount of fatty tissue is removed from the body. The authors aimed to show the effects of the reduction mammaplasty on serum leptin levels and insulin resistance. Methods. 42 obese female patients who had gigantomastia were operated on. We recorded patients’ demographic and preoperative data, including age, weight, height, and body mass index. Fasting serum leptin, glucose, and insulin levels were noted. Homeostasis model assessment scores were calculated. At the postoperative 8th week, patients were reevaluated in terms of above parameters assessing the presence of any difference. Results. Serum leptin levels were decreased postoperatively and the decrease was statistically significant. We were able to show a decrease in homeostasis model assessment score, which indicated an increase in insulin sensitivity, and this change was statistically significant. A significant correlation between body mass index and leptin change was found postoperatively. Conclusion. Reduction mammaplasty is not solely an aesthetic procedure but it decreases serum leptin levels and increases insulin sensitivity, which may help obese women to reduce their cardiovascular risk.

  9. Association of leptin and insulin resistance in PCOS: A case-controlled study.

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    Namavar Jahromi, Bahia; Dabaghmanesh, Mohammad Hassan; Parsanezhad, Mohammad Ebrahim; Fatehpoor, Faranak

    2017-07-01

    Endocrine abnormalities related to polycystic ovary Syndrome (PCOS) are important problems. To compare serum leptin levels between infertile women with and without PCOS. To rank sensitivity of six indirect methods for detection of insulin resistance (IR) and to evaluate the association between leptin and IR in PCOS group. This Case-controlled study performed on 189 infertile women referred to Shiraz Mother and Child Hospital during 2012-2015. Ninety-nine PCOS cases according to Rotterdam criteria were compared to 90 cases without PCOS. Serum leptin, body mass index (BMI), several hormones, and their correlation coefficients with leptin were compared. IR in PCOS women was measured by indirect methods, including fasting blood sugar (FBS), fasting insulin (FI), glucose/insulin, homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), and MacAuley index. Association between IR and leptin was evaluated. Independent sample t-test and Pearson's test were used. Infertile women with PCOS had higher BMI (26.47±3.62 vs. 24.82±5.18 kg/m 2 ) and serum leptin levels (41.79±187.89 vs. 19.38±12.57 ng/mL). Leptin showed significant association with weight and BMI in both groups (pPCOS group. HOMA-IR showed the highest rate of IR followed by FI and QUICKI methods. The mean leptin levels had positive association with IR assessed by HOMA-IR (pPCOS infertile women. HOMA-IR followed by FI and QUICKI is the most sensitive test for detection of IR.

  10. Insulin and leptin levels in overweight and normal-weight Iranian adolescents: The CASPIAN-III study

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    Ehsan Bahrami

    2014-01-01

    Full Text Available Background: In this study, we aim to compare insulin and leptin levels in adolescents with or without excess weight and in those with or without abdominal obesity. Materials and Methods : This case-control study was conducted among 486 samples. We randomly selected 243 overweight and an equal number of normal-weight adolescents from among participants of the third survey of a national surveillance program entitled "Childhood and Adolescence Surveillance and PreventIon of Adult Non-communicable diseases study." Serum insulin and leptin were compared between two groups and their correlation was determined with other variables. Results: The mean age and body mass index (BMI of participants were 14.10 ± 2.82 years and 22.12 ± 6.49 kg/m 2 , respectively. Leptin and insulin levels were higher in overweight than in normal-weight adolescents (P < 0.05. Leptin level was higher in children with abdominal obesity than in their other counterparts (P < 0.001. Leptin level was correlated with age, fasting blood glucose, BMI, and insulin level. Conclusion: Insulin and leptin levels were higher among overweight and obese children, which may reflect insulin and leptin-resistance. Given the complications of excess weight from early life, prevention and controlling childhood obesity should be considered as a health priority.

  11. Relationship of insulin, glucose, leptin, IL-6 and TNF-α in human breast milk with infant growth and body composition.

    Science.gov (United States)

    Fields, D A; Demerath, E W

    2012-08-01

    Numerous appetite, growth, obesity-related hormones and inflammatory factors are found in human breast-milk, but there is little evidence on their relationship with infant body composition. OBJECTVIE: The purpose of the present cross-sectional pilot study was to assess the cross-sectional associations of appetite-regulating hormones and growth factors (leptin, insulin and glucose) and inflammatory factors (interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-α)) in human breast-milk with infant size, adiposity, and lean tissue at 1-month of age in healthy term infants. Human breast-milk was collected from nineteen exclusively breast-feeding mothers using one full breast expression between 8:00 and 10:00 a.m. The milk was then mixed, aliquoted, stored at -80°C and then centrifuged to remove the milk fat, prior to analyses using commercially available immunoassay kits; milk analytes were natural log transformed prior to analysis. Infant body composition was assessed using a Lunar iDXA v11-30.062 scanner (Infant whole body analysis enCore 2007 software, GE, Fairfield, CT). Maternal pre-pregnancy BMI was positively associated with milk leptin concentration (P = 0.0027), and so maternal-BMI-adjusted Spearman correlations were examined between breast-milk analytes and infant growth and body composition variables. As previously reported, greater milk leptin was associated with lower BMIZ (BMI-for-age z-score based on WHO 2006 growth charts; r = -0.54, P = 0.03). Glucose was positively associated with relative weight (r = 0.6, P = 0.01), and both fat and lean mass (0.43-0.44, P milk insulin were associated with lower infant weight, relative weight, and lean mass (r = -0.49-0.58, P milk IL-6 was associated with lower relative weight, weight gain, percent fat, and fat mass (r = -0.55-0.70, P milk concentrations of insulin, glucose, IL-6 and TNF-α, in addition to leptin, may be bioactive and differentially influence the accrual of fat and lean body mass. © 2012

  12. Plasma resistin, adiponectin and leptin levels in relation to insulin resistance

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.E.T.

    2010-01-01

    Adipose tissue regulates insulin sensitivity via the circulating adipo cytokines, adiponectin, resistin and leptin. The objective of this study was to compare the levels of resistin, adiponectin and leptin in lean and obese subjects and determine the relationship between circulating adipocytokines and insulin resistance. We examined plasma levels of resistin, adiponectin and leptin in 20 lean subjects with mean body mass index (BMI) of 24, and, 36 nondiabetic obese individuals with mean BMI 34. Insulin resistance was assessed using the homeostasis model assessment ratio (HOMA-R) formula derived from fasting insulin and glucose levels. Resistin levels were not significantly different between the two groups but were significantly higher in women compared with men, 30.4±6.5 vs. 14.4±2.9 mg/l, P<0.01. Resistin did not correlate with BMI but did significantly correlate with HOMA-R, P < 0.01, and this correlation remained significant after adjustment for gender and BMI. Adiponectin levels were significantly reduced in obese compared with lean subjects, P < 0.005 and higher in women, P< 0.001. Adiponectin levels showed significant correlation with HOMA-R and this correlation remained significant after adjustment for gender and BMI. Leptin levels were significantly higher in obese subjects and women and correlated with resistin, but, didn't correlate with HOMA-R. In this small group of patients we demonstrated that insulin resistance correlated most strongly and reciprocally with adiponectin levels. Significant correlation between resistin levels and insulin resistance was also observed. Although a similar trend was apparent for leptin, the correlation with insulin resistance did not achieve statistical significance

  13. Insulin and Leptin Signaling Interact in the Mouse Kiss1 Neuron during the Peripubertal Period.

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    Xiaoliang Qiu

    Full Text Available Reproduction requires adequate energy stores for parents and offspring to survive. Kiss1 neurons, which are essential for fertility, have the potential to serve as the central sensors of metabolic factors that signal to the reproductive axis the presence of stored calories. Paradoxically, obesity is often accompanied by infertility. Despite excess circulating levels of insulin and leptin, obese individuals exhibit resistance to both metabolic factors in many neuron types. Thus, resistance to insulin or leptin in Kiss1 neurons could lead to infertility. Single deletion of the receptors for either insulin or the adipokine leptin from Kiss1 neurons does not impair adult reproductive dysfunction. However, insulin and leptin signaling pathways may interact in such a way as to obscure their individual functions. We hypothesized that in the presence of genetic or obesity-induced concurrent insulin and leptin resistance, Kiss1 neurons would be unable to maintain reproductive function. We therefore induced a chronic hyperinsulinemic and hyperleptinemic state in mice lacking insulin receptors in Kiss1 neurons through high fat feeding and examined the impact on fertility. In an additional, genetic model, we ablated both leptin and insulin signaling in Kiss1 neurons (IR/LepRKiss mice. Counter to our hypothesis, we found that the addition of leptin insensitivity did not alter the reproductive phenotype of IRKiss mice. We also found that weight gain, body composition, glucose and insulin tolerance were normal in mice of both genders. Nonetheless, leptin and insulin receptor deletion altered pubertal timing as well as LH and FSH levels in mid-puberty in a reciprocal manner. Our results confirm that Kiss1 neurons do not directly mediate the critical role that insulin and leptin play in reproduction. However, during puberty kisspeptin neurons may experience a critical window of susceptibility to the influence of metabolic factors that can modify the onset of

  14. Adipocytokines and insulin resistance across various degrees of glucose tolerance in pregnancy.

    Science.gov (United States)

    Skvarca, A; Tomazic, M; Krhin, B; Blagus, R; Janez, A

    2012-01-01

    Gestational diabetes mellitus is characterized by progressive insulin resistance. Adipocytokines are thought to be associated with insulin resistance. This cross-sectional study evaluated the associations between serum concentrations of several adipocytokines and insulin resistance at different stages of glucose tolerance in pregnancy, using the homeostasis model assessment of insulin resistance (HOMA-IR) as a reference. According to oral glucose tolerance test results, 74 pregnant women were divided into three groups: normal glucose tolerance (n = 25); intermediate glucose tolerance (n = 19); gestational diabetes mellitus (n = 30). Adiponectin, leptin, resistin, visfatin and retinol-binding protein 4 (RBP4) concentrations were measured using enzyme-linked immuno sorbent assays. Groups were comparable regarding age, week of gestation and body mass index before gestation. There were statistically significant between-group differences in HOMA-IR, but no significant differences regarding serum adipocytokine concentrations. Adipo nectin, leptin, resistin, visfatin and RBP4 were not associated with the degree of glucose tolerance in pregnancy. Concentrations of these adipocytokines are not sufficiently sensitive to replace HOMA- IR in pregnancy.

  15. The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.Et

    2012-01-01

    We aimed to study how smoking influences the relationship between fat mass ,soluble tumor necrosis factor-α, (TNF?) receptors 1 and 2 (sTNFR1 and sTNFR2),highly sensitive C-reactive protein(hs-CRP), adiponectin, leptin and insulin resistance.A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m 2 ), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNF α) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs- CRP and insulin sensitivity index.Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9 ±0.8 ng/ml, π=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (π = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (π = 0.18) and between IR and IS subjects (π = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

  16. The Relationship among Smoking, Plasma Adiponectin, Leptin, Inflammatory Markers and Insulin Resistance

    International Nuclear Information System (INIS)

    Shousha, M.A.; Soliman, S.Et.

    2011-01-01

    The study aimed to investigate how smoking influences the relationship between fat mass, soluble tumor necrosis factor-α , (TNFα ) receptors 1 and 2 (sTNFR1 and sTNFR2), highly sensitive C-reactive protein (hs-CRP), adiponectin, leptin and insulin resistance. A total of 60 healthy men (age: 27-53 years, body mass index (BMI): 20-35 kg/m2), 30 of whom were never-smokers and 30 smokers, matched for age, BMI and waist-to-hip ratio were included in this study. Those were subdivided into insulin resistant (IR) and insulin sensitive (IS) subgroups. Measures included circulating soluble fractions of the tumor necrosis factor α (TNFα ) receptors (sTNFR1 and sTNFR2) and their relationship to fat mass, fasting plasma adiponectin, leptin, hs-CRP and insulin sensitivity index. Smokers had significantly lower fat mass, lower fasting glucose, insulin and leptin concentrations than nonsmokers. Despite lower fat mass, insulin and leptin, smokers showed significantly increased circulating sTNFR2 levels (3.7±0.8 vs. 2.9±0.8 ng/ml, P=0.03). Being either a smoker or having insulin resistance was independently associated with lower adiponectin concentrations (P = 0.046 and 0.001, respectively). No difference was detected in average hs- CRP concentrations between smokers and nonsmokers (P = 0.18) and between IR and IS subjects (P = 0.13).Both fat mass and smoking are related to increased activity of the TNFα axis. Plasma adiponectin concentrations are lower in smokers and IR subjects. These two mechanisms could be associated with increased cardiovascular risk in smokers

  17. Leptin recruits Creb-regulated transcriptional coactivator 1 to improve hyperglycemia in insulin-deficient diabetes

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    Geun Hyang Kim

    2015-03-01

    Conclusions: Our study reveals that Crtc1 functions as a conduit for leptin's glucoregulatory actions in insulin-dependent diabetes. This study also highlights a new role for Crtc1 in modulating peripheral glucose metabolism.

  18. Flurbiprofen ameliorates glucose deprivation-induced leptin resistance

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    Toru Hosoi

    2016-09-01

    Full Text Available Leptin resistance is one of the mechanisms involved in the pathophysiology of obesity. The present study showed that glucose deprivation inhibited leptin-induced phosphorylation of signal transducer and activator of transcription 3 (STAT3 and signal transducer and activator of transcription 5 (STAT5 in neuronal cells. Flurbiprofen reversed glucose deprivation-mediated attenuation of STAT3, but not STAT5 activation, in leptin-treated cells. Glucose deprivation increased C/EBP-homologous protein (CHOP and glucose regulated protein 78 (GRP78 induction, indicating the activation of unfolded protein responses (UPR. Flurbiprofen did not affect the glucose deprivation-induced activation of UPR, but did attenuate the glucose deprivation-mediated induction of AMP-activated protein kinase (AMPK phosphorylation. Flurbiprofen may ameliorate glucose deprivation-induced leptin resistance in neuronal cells.

  19. Metabolic health assessment of zoo elephants: Management factors predicting leptin levels and the glucose-to-insulin ratio and their associations with health parameters.

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    Kari A Morfeld

    Full Text Available Screening for metabolic-related health problems can enhance animal welfare, so the purpose of this study was to conduct the first metabolic health assessment of zoo elephants and use epidemiological methods to determine how factors in the captive environment were associated with metabolic hormone concentrations. In addition, we examined relationships between metabolic status and several fitness parameters: foot health, musculoskeletal health, reproductive cyclicity, and body condition. Two blood samples were collected 2 weeks apart from 87 Asian (Elephas maximus and 105 African (Loxodonta africana elephants managed by zoos accredited by the Association of Zoos and Aquariums for analysis of serum leptin, insulin, glucose and the glucose-to-insulin ratio (G:I. In females, mean (± SD leptin concentrations and the G:I were lower (P0.05. As mean leptin concentration increased there was an increase in the odds of a female being non-cycling (P = 0.0083. The G:I was associated inversely with body condition (P = 0.0002; as the G:I increased there was a decreased risk of BCS = 4 or 5 as compared to the ideal, or BCS = 3. Neither leptin nor G:I were predictive of foot or musculoskeletal health scores. Factors related to walking and feeding practices were most influential in predicting metabolic status, whereas social and housing factors showed smaller, but significant effects. The metabolic health benefits of walking were detected if the time spent in staff-directed walking was 7 hours or more per week. The most protective feeding practices included implementing a random rather than predictable feeding schedule and limiting the number of methods presentation methods. Results indicate that leptin levels and G:I can be used as predictors of both ovarian cycle function and body condition, and are affected by zoo management in elephants.

  20. Plasma leptin concentration in donkeys.

    Science.gov (United States)

    Díez, E; López, I; Pérez, C; Pineda, C; Aguilera-Tejero, E

    2012-01-01

    Donkeys appear to be more predisposed than large breed horses to suffer from hyperlipemia. The reason for that predisposition is unknown but anorexia is a consistent feature of the disease. Leptin, a protein synthesized in fat tissue, is one of the major inhibitors of appetite in mammals. We hypothesized that donkeys could have elevated plasma leptin concentrations compared to horses. Blood samples were obtained from 50 donkeys for measurement of leptin, triglycerides (TGs), glucose, and insulin. Glucose/insulin ratio, modified insulin to glucose ratio, and reciprocal of the square root of insulin were calculated. Based on their body condition score (BCS), donkeys were classified as lean (n = 18), normal (n = 16), or overweight (n = 16). The results were compared with reference values from our laboratory and with a group of horses (n = 25) used as an internal control. Values of both leptin and TGs in donkeys were above the horse reference range and also significantly higher than those of the control horses: leptin (11.2 ± 1.7 versus 5.8 ± 0.5 µg/L, p donkeys had leptin (19.3 ± 2.9 µg/L) and TG (1.3 ± 0.2 mmol/L) concentrations that were significantly (p donkeys. A significant positive correlation (p Donkeys have higher plasma leptin concentrations than horses and leptin is correlated with BCS.

  1. Adiponectin, Leptin, and Leptin Receptor in Obese Patients with Type 2 Diabetes Treated with Insulin Detemir

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    Paweł Olczyk

    2017-07-01

    Full Text Available The aim of the present study is to quantitatively assess the expression of selected regulatory molecules, such as leptin, leptin receptor, and adiponectin in the blood of obese patients with type 2 diabetes both before treatment and after six months of pharmacological therapy with the long-lasting insulin analogue, insulin detemir. A significant decrease in the analysed regulatory molecules, i.e., leptin receptor and adiponectin, was found in blood plasma of the patients with untreated type 2 diabetes. These changes were accompanied by an increase in plasma leptin concentrations. Insulin treatment resulted in the normalization of plasma leptin receptor and adiponectin concentrations. The circulating leptin level did not change following anti-diabetic therapy with insulin detemir. Gender was a significant factor modifying the circulating level of all the analysed regulatory active compounds. Bioinformatic analysis was performed using Matlab with the Signal Processing Toolbox. The conducted discriminant analysis revealed that the leptin receptor, Δw(19, and adiponectin, Δw(21, were the parameters undergoing the most significant quantitative changes during the six-month therapy with insulin detemir. The conducted examinations indicated the contribution of adipocytokines—the biologically-active mediators of systemic metabolism, such as leptin and adiponectin in the pathomechanism of disorders being the basis for obesity which leads to development of insulin resistance, which, in turn, results in the occurrence of type 2 diabetes.

  2. Changes of serum leptin and their relationships with insulin resistance in patients with simple obesity and patients with type 2 diabetes mellitus complicated with obesity

    International Nuclear Information System (INIS)

    Zhang Lei; Changzhou Wujin People's Hospital of Jiangsu Province, Changzhou; Shi Linlin; Lu Dan; Zhang Lei; Wang Qing; Yao Wenhua

    2005-01-01

    Objective: To study the changes of serum leptin in patients with simple obesity and patients with type 2 diabetes mellitus complicated with obesity in order to explore the relationship of leptin and insulin resistance and the role of leptin in the occurrence of type 2 diabetes mellitus. Methods: 60 cases of simple obesity, 60 cases of type 2 diabetes mellitus and 30 cases of normal control were included according to the diagnostic criteria of obesity and type 2 diabetes mellitus. the levels of fasting serum leptin, fasting serum insulin, fasting glucose, fasting blood lipid were measured in all cases. The body mass index (BMI) and insulin action index were calculated. Results: The level of BMI, serum leptin, serum insulin, blood lipid were significantly higher in patients with simple obesity and with type 2 diabetes mellitus complicated with obesity than in normal control cases, while (IAI) was significantly lower. The levels of free serum leptin, serum insulin, free glucose, and blood lipid were significantly higher in patients with type 2 diabetes mellitus complicated with obesity than in patients with simple obesity, while IAI was significantly lower. The level of serum leptin was positively correlated with BMI (r=0.48, P<0.55) and fasting serum leptin (r=0.55, P<0.05) and negatively correlated with IAI (r=-0.47, P<0.05) in patients with type 2 diabetes complicated with obesity. Conclusion: The overexpression of serum leptin may play an important role in the occurrence of the insulin resistance and type 2 diabetes mellitus in obesity patients. (authors)

  3. Plasma levels of leptin, omentin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26 and adiponectin before and after oral glucose uptake in slim adults

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    Schäffler Andreas

    2007-02-01

    Full Text Available Abstract Background Adipose tissue secreted proteins are collectively named adipocytokines and include leptin, adiponectin, resistin, collagenous repeat-containing sequence of 26-kDa protein (CORS-26 and omentin. Several of these adipocytokines influence insulin sensitivity and glucose metabolism and therefore systemic levels may be affected by oral glucose uptake. Whereas contradictory results have been published for leptin and adiponectin, resistin has not been extensively investigated and no reports on omentin and CORS-26 do exist. Methods Therefore the plasma levels of these proteins before and 120 min after an oral glucose load were analyzed in 20 highly-insulin sensitive, young adults by ELISA or immunoblot. Results Circulating leptin was reduced 2 h after glucose uptake whereas adiponectin and resistin levels are not changed. Distribution of adiponectin and CORS-26 isoforms were similar before and after glucose ingestion. Omentin is highly abundant in plasma and immunoblot analysis revealed no alterations when plasma levels before and 2 h after glucose intake were compared. Conclusion Taken together our data indicate that only leptin is reduced by glucose uptake in insulin-sensitive probands whereas adiponectin and resistin are not altered. CORS-26 was demonstrated for the first time to circulate as high molecular weight form in plasma and like omentin was not influenced by oral glucose load. Omentin was shown to enhance insulin-stimulated glucose uptake but systemic levels are not correlated to postprandial blood glucose.

  4. Comparative Study of Serum Leptin and Insulin Resistance Levels Between Korean Postmenopausal Vegetarian and Non-vegetarian Women.

    Science.gov (United States)

    Kim, Mi-Hyun; Bae, Yun-Jung

    2015-07-01

    The present study was conducted to compare serum leptin and insulin resistance levels between Korean postmenopausal long-term semi-vegetarians and non-vegetarians. Subjects of this study belonged to either a group of postmenopausal vegetarian women (n = 54), who maintained a semi-vegetarian diet for over 20 years or a group of non-vegetarian controls. Anthropometric characteristics, serum leptin, serum glucose, serum insulin, insulin resistance (HOMA-IR; Homeostasis Model Assessment of Insulin Resistance), and nutrient intake were compared between the two groups. The vegetarians showed significantly lower body weight (p vegetarians. The HOMA-IR of the vegetarians was significantly lower than that of the non-vegetarians (p vegetarian diet might be related to lower insulin resistance independent of the % of body fat in postmenopausal women.

  5. Leptin Production by Encapsulated Adipocytes Increases Brown Fat, Decreases Resistin, and Improves Glucose Intolerance in Obese Mice.

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    David J DiSilvestro

    Full Text Available The neuroendocrine effects of leptin on metabolism hold promise to be translated into a complementary therapy to traditional insulin therapy for diabetes and obesity. However, injections of leptin can provoke inflammation. We tested the effects of leptin, produced in the physiological adipocyte location, on metabolism in mouse models of genetic and dietary obesity. We generated 3T3-L1 adipocytes constitutively secreting leptin and encapsulated them in a poly-L-lysine membrane, which protects the cells from immune rejection. Ob/ob mice (OB were injected with capsules containing no cells (empty, OB[Emp], adipocytes (OB[3T3], or adipocytes overexpressing leptin (OB[Lep] into both visceral fat depots. Leptin was found in the plasma of OB[Lep], but not OB[Emp] and OB[3T3] mice at the end of treatment (72 days. The OB[Lep] and OB[3T3] mice have transiently suppressed appetite and weight loss compared to OB[Emp]. Only OB[Lep] mice have greater brown fat mass, metabolic rate, and reduced resistin plasma levels compared to OB[Emp]. Glucose tolerance was markedly better in OB[Lep] vs. OB[Emp] and OB[3T3] mice as well as in wild type mice with high-fat diet-induced obesity and insulin resistance treated with encapsulated leptin-producing adipocytes. Our proof-of-principle study provides evidence of long-term improvement of glucose tolerance with encapsulated adipocytes producing leptin.

  6. Central infusion of leptin improves insulin resistance and suppresses beta-cell function, but not beta-cell mass, primarily through the sympathetic nervous system in a type 2 diabetic rat model.

    Science.gov (United States)

    Park, Sunmin; Ahn, Il Sung; Kim, Da Sol

    2010-06-05

    We investigated whether hypothalamic leptin alters beta-cell function and mass directly via the sympathetic nervous system (SNS) or indirectly as the result of altered insulin resistant states. The 90% pancreatectomized male Sprague Dawley rats had sympathectomy into the pancreas by applying phenol into the descending aorta (SNSX) or its sham operation (Sham). Each group was divided into two sections, receiving either leptin at 300ng/kgbw/h or artificial cerebrospinal fluid (aCSF) via intracerebroventricular (ICV) infusion for 3h as a short-term study. After finishing the infusion study, ICV leptin (3mug/kg bw/day) or ICV aCSF (control) was infused in rats fed 30 energy % fat diets by osmotic pump for 4weeks. At the end of the long-term study, glucose-stimulated insulin secretion and islet morphometry were analyzed. Acute ICV leptin administration in Sham rats, but not in SNSX rats, suppressed the first- and second-phase insulin secretion at hyperglycemic clamp by about 48% compared to the control. Regardless of SNSX, the 4-week administration of ICV leptin improved glucose tolerance during oral glucose tolerance tests and insulin sensitivity at hyperglycemic clamp, compared to the control, while it suppressed second-phase insulin secretion in Sham rats but not in SNSX rats. However, the pancreatic beta-cell area and mass were not affected by leptin and SNSX, though ICV leptin decreased individual beta-cell size and concomitantly increased beta-cell apoptosis in Sham rats. Leptin directly decreases insulin secretion capacity mainly through the activation of SNS without modulating pancreatic beta-cell mass.

  7. Central insulin action in energy and glucose homeostasis.

    Science.gov (United States)

    Plum, Leona; Belgardt, Bengt F; Brüning, Jens C

    2006-07-01

    Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin's role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body's energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level.

  8. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

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    Kentaro Kaneko

    2016-09-01

    Full Text Available The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.

  9. Correlation of insulin resistance with serum C-reactive protein, adiponectin and leptin levels in patients with type 2 diabetes

    International Nuclear Information System (INIS)

    Duan Yangqiang; Wang Zuobing; Yu Hui

    2012-01-01

    Objective: To explore the relationship between serum C-reactive protein (CRP), adiponectin (APN), leptin (Leptin) levels, insulin resistance index (HOMA-IR) and type 2 diabetes mellitus (T2DM) disease susceptibility. Methods: The plasma leptin and insulin (FINS) levels in the DM patients were determined by RIA, and the serum ANP levels were determined by ELSIA. The CRP, conventional serum fasting plasma glucose (FPG) levels were determine by automatic biochemistry analyzer. The insulin resistance index (HOMA-IR, FPG x FINS/22.5) was calculated. The result was analyzed with normal healthy control group. Results: The serum CRP and leptin, HOMA-IR levels in T2DM group were significantly higher than that of in control group (P< 0.01), and the serum ANP was significantly lower than in control group (P<0.01). The HOMA-IR in T2DM was positively correlated with serum CRP (r= 0.36, P<0.05) and leptin(r= 0.39, P<0.05), and was negatively correlated with serum APN (r=0.32, P<0.05). Conclusion: The high serum CRP and leptin and low APN levels hyperlipidaemia might be factors for diabetes, and their metabolic disorders may be closely related with insulin resistance in patients with type 2 diabetes. (authors)

  10. Acute inhibition of central c-Jun N-terminal kinase restores hypothalamic insulin signalling and alleviates glucose intolerance in diabetic mice.

    Science.gov (United States)

    Benzler, J; Ganjam, G K; Legler, K; Stöhr, S; Krüger, M; Steger, J; Tups, A

    2013-05-01

    The hypothalamus has been identified as a main insulin target tissue for regulating normal body weight and glucose metabolism. Recent observations suggest that c-Jun-N-terminal kinase (JNK)-signalling plays a crucial role in the development of obesity and insulin resistance because neuronal JNK-1 ablation in the mouse prevented high-fat diet-induced obesity (DIO) and increased energy expenditure, as well as insulin sensitivity. In the present study, we investigated whether central JNK inhibition is associated with sensitisation of hypothalamic insulin signalling in mice fed a high-fat diet for 3 weeks and in leptin-deficient mice. We determined whether i.c.v. injection of a pharmacological JNK-inhibitor (SP600125) improved impaired glucose homeostasis. By immunohistochemistry, we first observed that JNK activity was increased in the arcuate nucleus (ARC) and the ventromedial hypothalamus (VMH) in both mouse models, relative to normoglycaemic controls. This suggests that up-regulation of JNK in these regions is associated with glucose intolerance and obesity, independent of leptin levels. Acute i.c.v. injection of SP600125 ameliorated glucose tolerance within 30 min in both leptin-deficient and DIO mice. Given the acute nature of i.c.v. injections, these effects cannot be attributed to changes in food intake or energy balance. In a hypothalamic cell line, and in the ARC and VMH of leptin-deficient mice, JNK inhibition by SP600125 consistently improved impaired insulin signalling. This was determined by a reduction of phospho-insulin receptor substrate-1 [IRS-1(Ser612)] protein in a hypothalamic cell line and a decline in the number of pIRS-1(Ser612) immunoreactive cells in the ARC and VMH. Serine 612 phosphorylation of IRS-1 is assumed to negatively regulate insulin signalling. In leptin-deficient mice, in both nuclei, central inhibition of JNK increased the number of cells immunoreactive for phospho-Akt (Ser473) and phospho-GSK-3β (Ser9), which are important

  11. Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions.

    Science.gov (United States)

    Kaneko, Kentaro; Xu, Pingwen; Cordonier, Elizabeth L; Chen, Siyu S; Ng, Amy; Xu, Yong; Morozov, Alexei; Fukuda, Makoto

    2016-09-13

    The CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Turmeric Supplementation Improves Serum Glucose Indices and Leptin Levels in Patients with Nonalcoholic Fatty Liver Diseases.

    Science.gov (United States)

    Navekar, Roya; Rafraf, Maryam; Ghaffari, Aida; Asghari-Jafarabadi, Mohammad; Khoshbaten, Manouchehr

    2017-01-01

    Insulin and leptin resistance are important risk factors for non-alcoholic fatty liver disease (NAFLD). There is limited evidence regarding the effects of turmeric on NAFLD. The aim of this study was to investigate the effects of turmeric supplementation on glycemic status and serum leptin levels in patients with NAFLD. This double-blind randomized controlled clinical trial was conducted on 46 patients with NAFLD (21males and 25 females) aged 20-60 years old and body mass index (BMI) between 24.9 and 40 kg/m2. The turmeric group (n = 23) was given six turmeric capsules daily for 12 weeks. Each capsule contained 500 mg turmeric powder (6×500 mg). The placebo group (n = 23) was given six placebo capsules daily for the same period. Fasting blood samples, anthropometric measurements, and physical activity levels were collected at the baseline and at the end of the study. Daily dietary intakes also were obtained throughout the study. Data were analyzed by independent t test, paired t test and analysis of covariance. Turmeric consumption decreased serum levels of glucose, insulin, HOMA-IR and leptin (by 1.22, 17.69, 19.48 and 21.33% respectively, p Turmeric supplementation improved glucose indexes and serum leptin levels and may be useful in the control of NAFLD complications.

  13. Blood glucose lowering effect of ophiopogonis tuber extract and mechanism of anti-insulin-resistance

    Directory of Open Access Journals (Sweden)

    Meng NING

    2013-01-01

    Full Text Available Objective  To study the hypoglycemic effect and insulin sensitization mechanism of ophiopogonis tuber extracts on the 3T3-L1-induced adipocytes, and also in rats with reproduction of type 2 diabetes mellitus (T2DM. Methods  3T3-L1 cells were induced and differentiated into adipocytes. After the intervention with ophiopogonpolysaccharide (OPSR and ophiopogonin (OPG, glucose consuming rate was detected for screening the extracts which may have effective hypoglycemic effects. The insulin resistance (IR adipocyte model was established by dexamethasone induction, and then it was treated with OPSR. The protein expression levels of leptin, adiponectin and resistin were detected by Western blotting. The T2DM rat model was reproduced and then treated with OPSR for 4 weeks. Body weight (BW, triglyeride (TG, fasting blood glucose (FBG and fasting insulin (FINs of the rats were measured respectively. Results  OPSR in dosage of 0.5-50mg/L promoted glucose consumption of adipocytes in a dose-dependent manner, the glucose consumption ratios were 32.27%, 75.14% and 90.47% respectively. OPG of 50mg/L showed very weak activity with glucose consumption ratio of only 8.49%. OPSR could significantly promote the protein expression of leptin and adiponectin, and showed an inhibitory effect on the protein expression of resistin (P<0.05. After treatment with OPSR for 4 weeks, the BW of rats increased obviously, while TG, FBG and HOMA-IR decreased significantly (P<0.05 or P<0.01. Conclusions  OPSR may promote glucose transport and utilization of adipocytes, decrease the level of FBG and TG, and improve the condition of IR in T2DM rats. The mechanism of blood glucose lowering effect may be attributed to secretion of adipokines, such as leptin, adiponectin and resistin by IR adipocytes.

  14. LEPTIN RESISTANCE AND TYPE 2 DIABETES

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    O. M. Oleshchuk

    2017-07-01

    Full Text Available Leptin is one of adipocyte-secreted hormones. It signals to the brain and other tissues about the status of body energy reserves. Circulating leptin levels are directly proportional to the amount of the body fat. Leptin concentration increases when surfeit and decreases during fasting. Obese patients are hyperleptinemic compared with thin persons and they are tolerant to the central hypothalamic effects of leptin. The reduced sensitivity toward exogenous and endogenous leptin is commonly referred to as leptin resistance. Alterations in the signaling of the long isoform of the leptin receptor play the crucial role in leptin resistance. Surfeit may induce leptin resistance and other metabolic sequelae of obesity. Leptin insensitivity and insulin resistance play a major role in the development of type 2 diabetes. Metformin remains the preferred first-line pharmacologic agent for the treatment of type 2 diabetes. It reduces hepatic glucose production, increases glucose uptake in peripheral tissue and can lead to weight loss. Metformin decreases both insulin and leptin concentration, restores the sensitivity to these hormones. But some studies have shown poor relationship between metformin action and leptin level. And the mechanism of metformin action on leptin resistance remains unclear. Thus, these issues should be studied as well as polymorphisms in genes encoding metformin action.

  15. Metabolic syndrome and related variables, insulin resistance, leptin levels, and PPAR-γ2 and leptin gene polymorphisms in a pedigree of subjects with bipolar disorder

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    Trino Baptista

    2015-06-01

    Full Text Available Objective:Evidence points to a high prevalence of metabolic dysfunction in bipolar disorder (BD, but few studies have evaluated the relatives of subjects with BD. We conducted a cross-sectional study in an extended family of patients with BD type I.Methods:The available relatives of the same family were interviewed (DSM-IV-R and assessed in fasting conditions for body mass index, constituent variables of the metabolic syndrome (MS, leptin levels, insulin resistance index, and single nucleotide polymorphisms (SNPs for the leptin receptor and promoter and PPAR-γ2 genes. The frequency of MS was compared with that recorded in the local general population.Results:Ninety-three relatives of three adults with BD were evaluated (30 aged 18 years. The frequency of MS was similar to that of the general population. Significantly higher frequencies of abnormal glucose, total and low density cholesterol (LDL-c levels (all p < 0.05, waist circumference (p = 0.057, and leptin and insulin resistance values (in adults only were observed in the family. Adults with the QQ genotype of the leptin receptor displayed higher LDL-c levels than carriers of the R allele.Conclusions:The associations among BD consanguinity, familial hypercholesterolemia, and leptin receptor SNPs reported herein should be replicated and extended in other pedigrees.

  16. The Correlation of Plasma Levels of Apelin-13 with Insulin Resistance Index and Plasma Leptin of Diabetic Male Rats after 8-Week Aerobic Exercise

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    Fahimeh Kazemi

    2015-09-01

    Full Text Available Abstract Background: The physiological role of apelin, an adipokine secreted by adipose tissue, in insulin resistance and type 2 diabetes has been identified. The aim of this study was to determine the correlation of plasma levels of apelin-13 with insulin resistance index (HOMA-IR and plasma leptin of diabetic male rats after 8-week aerobic exercise. Materials and Methods: Peresent study was an experimental study with animal model. Twenty eight diabetic male Wistar rats were divided into 3 groups: Non-diabetic (n=9, control diabetic (n=9 and trained diabetic (n=10. Type 2 diabetes was induced by intraperitoneal injection of nicotinamide and streptozotocin. The trained diabetic rat ran 8-week on treadmill progressively. After the training period, plasma levels of glucose, insulin, leptin and apelin-13 were measured and HOMA-IR was calculated. One-way analysis of variance (ANOVA and Pearson’s correlation were used for analyzing data. p<0.05 was considered to be statistically significant. Results: A significant decrease in plasma levels of glucose, insulin and leptin and HOMA-IR in trained diabetic vs control diabetic rats, a significant increase in plasma levels of apelin in trained diabetic vs non-diabetic and control diabetic rats and a significant negative correlation of plasma levels of apelin with HOMA-IR and plasma leptin in trained diabetic rats was observed. Conclusion: In present study, 8-week aerobic training by improvement of insulin sensitivity (decrease of HOMA-IR and plasma leptin increased plasma levels of apelin-13 in diabetic male rats.

  17. Assessment of insulin sensitivity/resistance and their relations with leptin concentrations and anthropometric measures in a pregnant population with and without gestational diabetes mellitus.

    Science.gov (United States)

    Yilmaz, Ozgur; Kucuk, Mert; Ilgin, Aydin; Dagdelen, Muride

    2010-01-01

    Fifty-six pregnant women with gestational diabetes mellitus (GDM) and 42 normal glucose tolerant (NGT) pregnant women between 26 and 36 gestational weeks were included in the study prospectively. The body fat percentage (BFP) was calculated using the Siri formula from skinfold thickness (SFT) measurements. Both groups were comparable for gestational age, height, weight, and body mass index (P>.05). Insulin resistance assessed by homeostasis model assessment for insulin resistance (HOMA-IR) method was significantly higher in GDM patients compared to their NGT weight-matched control group. In contrast, the insulin sensitivity calculated from quantitative insulin sensitivity check index (QUICKI-IS) equation was significantly lower in GDM group. Calculated lean body mass was found to be similar in between both groups. Body fat percentage derived from SFT parameters was significantly higher in women with GDM. Women with GDM had significantly higher levels of serum insulin and leptin concentrations when compared with the NGT group. All SFT measurements were higher in GDM group when compared to those in NGT women. We did not find any correlation between leptin levels and insulin resistance; we found negative correlation between leptin levels and insulin sensitivity. Thus, we observed that leptin may contribute development of GDM by decreasing insulin sensitivity but not increasing insulin resistance. Also, we observed that the BFP estimated by the Siri formula from SFT measurements correlated significantly with HOMA-IR and QUICKI-IS and leptin concentrations in pregnant women. We suggest that by simply evaluating SFT, we may hold a view about BFP and leptin concentrations and insulin sensitivity in pregnant women.

  18. Pleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis

    DEFF Research Database (Denmark)

    Perry, Rachel J; Petersen, Kitt Falk; Shulman, Gerald I.

    2016-01-01

    In this review we discuss the mechanisms for the pleotropic effects of leptin replacement therapy to reverse liver and muscle insulin resistance in lipodystrophic individuals, as well as insulin-independent effects of leptin replacement therapy to suppress white adipose tissue lipolysis, hepatic...

  19. Leptin, insulin and body composition changes during adjuvant taxane based chemotherapy in patients with breast cancer, preliminary study.

    Science.gov (United States)

    Alacacioglu, A; Kebapcilar, L; Gokgoz, Z; Oztekin, O; Bozkaya, G; Tarhan, O; Somali, I; Yuksel, A; Sop, G; Sari, I

    2016-01-01

    The objectives of the present study were to compare the effect of adjuvant chemotherapy for breast cancer on serum insulin levels, serum leptin levels, and body composition in early stage breast cancer patients. 17 breast cancer patients underwent 6 cycles of docetaxel (75 mg), epirubicine (100 mg) and cyclophosphamide (500 mg) (TEC). Anthropometrical and foot-to-foot body fat analyzer BIA, serum glucose, insulin, lipids, HOMA-IR and leptin were compared pre- and post-treatment. There was no statistically significant weight gain after treatment; however, there was an overall trend toward weight gain (69.7 ± 9.8 kg vs 71.03 ± 9.8; P= 0.05). From baseline to the end of the study, percentage of body fat and body fat mass showed an upward trend at the end of chemotherapy (1%; 2 kg P> 0.05). Pre and post-treatment period, leptin was strongly correlated with insulin and HOMA-IR (Spearman's pre-T; r = 0.74; P cancer outcome, and insulin resistance may be increased in taxane based chemotherapy regimen. These data may have broad implications for diet and lifestyle strategies for the prevention and treatment of cancers.

  20. Alteration of brain insulin and leptin signaling promotes energy homeostasis impairment and neurodegenerative diseases

    Directory of Open Access Journals (Sweden)

    Taouis Mohammed

    2011-09-01

    Full Text Available The central nervous system (CNS controls vital functions, by efficiently coordinating peripheral and central cascades of signals and networks in a coordinated manner. Historically, the brain was considered to be an insulin-insensitive tissue. But, new findings demonstrating that insulin is present in different regions of themammalian brain, in particular the hypothalamus and the hippocampus. Insulin acts through specific receptors and dialogues with numerous peptides, neurotransmitters and adipokines such as leptin. The cross-talk between leptin and insulin signaling pathways at the hypothalamic level is clearly involved in the control of energy homeostasis. Both hormones are anorexigenic through their action on hypothalamic arcuate nucleus by inducing the expression of anorexigenic neuropetides such as POMC (pro-opiomelanocortin, the precursor of aMSH and reducing the expression of orexigenic neuropeptide such as NPY (Neuropeptide Y. Central defect of insulin and leptin signaling predispose to obesity (leptin-resistant state and type-2 diabetes (insulin resistant state. Obesity and type-2 diabetes are associated to deep alterations in energy homeostasis control but also to other alterations of CNS functions as the predisposition to neurodegenerative diseases such as Alzheimer’s disease (AD. AD is a neurodegenerative disorder characterized by distinct hallmarks within the brain. Postmortem observation of AD brains showed the presence of parenchymal plaques due to the accumulation of the amyloid beta (AB peptide and neurofibrillary tangles. These accumulations result from the hyperphosphorylation of tau (a mictrotubule-interacting protein. Both insulin and leptin have been described to modulate tau phosphorylation and therefore in leptin and insulin resistant states may contribute to AD. The concentrations of leptin and insulin cerebrospinal fluid are decreased type2 diabetes and obese patients. In addition, the concentration of insulin in the

  1. Changes of serum leptin, adiponection and insulin levels in females with simple obesity

    International Nuclear Information System (INIS)

    Wei Tao; Duan Wennuo; Ma Yongxiu; Chen Yanping

    2004-01-01

    Objective: To study the changes of serum leptin, insulin and adiponectin levels and their relationship with BMI in females with simple obesity. Methods: Serum leptin, adiponectin and insulin levels were measured with RIA in 48 pre-obese females (BMI=23-24.9 kg/m 2 ), 40 females with simple obesity, (BMI≥25 kg/m 2 ) and 42 female controls (BMI 18-22.9 kg/m 2 ). Correlations among these variables were studied. Results: Serum leptin, insulin levels were significantly higher and serum adiponectin levels were significantly lower in both the pre-obese and obese females than those in controls. Serum leptin, insulin levels were positively correlated to BMI; Serum adiponectin levels were negatively correlated to BMI. Conclusion: Within normal range of BMI, the leptin-insulin feedback mechanism provided satisfactory self-regulation. However, with excessive BMI, this dynamic equilibrium would be disrupted. The defective equilibrium, together with the abnormal low adiponectin level, would predispose to the development of diabetes mellitus. (authors)

  2. Endothelial function and its relationship to leptin, homocysteine, and insulin resistance in lean and overweight eumenorrheic women and PCOS patients: a pilot study.

    Science.gov (United States)

    Mancini, Fulvia; Cianciosi, Arianna; Reggiani, Giulio Marchesini; Facchinetti, Fabio; Battaglia, Cesare; de Aloysio, Domenico

    2009-06-01

    To verify if patients with polycystic ovarian syndrome (PCOS), have an increased cardiovascular risk compared with healthy controls. Prospective case-control study. University-based practice. Twenty eumenorrheic controls (ten lean [group A] and ten overweight [group B]) and 24 PCOS women (14 lean [group C] and ten overweight [group D]). Cardiovascular risk markers and hormonal parameters were assessed. Androgens, fasting glucose, insulin, leptin, fibrinogen, homocysteine, endothelin-1 and flow-mediated dilatation of the brachial artery were measured to investigate their relationship to weight and to PCOS. The brachial artery diameter and the pulsatility index, after the reactive hyperemia, showed in group A the most intense vasodilatation compared with the other groups. Homocysteine levels did not differ among the groups. Endothelin-1 was significantly higher in group A compared with groups B and D. Leptin was significantly lower in groups A and C compared with groups B and D. Insulin resistance was higher in groups B and D. Group A had significantly higher glucose-insulin ratio compared with all of the other groups; group C had significantly higher glucose-insulin ratio only compared with group D. Weight and PCOS are two independent variables affecting the endothelial function.

  3. A leptin-regulated circuit controls glucose mobilization during noxious stimuli.

    Science.gov (United States)

    Flak, Jonathan N; Arble, Deanna; Pan, Warren; Patterson, Christa; Lanigan, Thomas; Goforth, Paulette B; Sacksner, Jamie; Joosten, Maja; Morgan, Donald A; Allison, Margaret B; Hayes, John; Feldman, Eva; Seeley, Randy J; Olson, David P; Rahmouni, Kamal; Myers, Martin G

    2017-08-01

    Adipocytes secrete the hormone leptin to signal the sufficiency of energy stores. Reductions in circulating leptin concentrations reflect a negative energy balance, which augments sympathetic nervous system (SNS) activation in response to metabolically demanding emergencies. This process ensures adequate glucose mobilization despite low energy stores. We report that leptin receptor-expressing neurons (LepRb neurons) in the periaqueductal gray (PAG), the largest population of LepRb neurons in the brain stem, mediate this process. Application of noxious stimuli, which often signal the need to mobilize glucose to support an appropriate response, activated PAG LepRb neurons, which project to and activate parabrachial nucleus (PBN) neurons that control SNS activation and glucose mobilization. Furthermore, activating PAG LepRb neurons increased SNS activity and blood glucose concentrations, while ablating LepRb in PAG neurons augmented glucose mobilization in response to noxious stimuli. Thus, decreased leptin action on PAG LepRb neurons augments the autonomic response to noxious stimuli, ensuring sufficient glucose mobilization during periods of acute demand in the face of diminished energy stores.

  4. Leptin reverses hyperglycemia and hyperphagia in insulin deficient diabetic rats by pituitary-independent central nervous system actions.

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    Alexandre A da Silva

    Full Text Available The hypothalamic-pituitary-adrenal (HPA axis has been postulated to play a major role in mediating the antidiabetic effects of leptin. We tested if the pituitary is essential for the chronic central nervous system mediated actions of leptin on metabolic and cardiovascular function in insulin-dependent diabetic and non-diabetic rats. Male 12-week-old hypophysectomized Sprague-Dawley rats (Hypo, n = 5 were instrumented with telemetry probes for determination of mean arterial pressure (MAP and heart rate (HR 24-hrs/day and an intracerebroventricular (ICV cannula was placed into the brain lateral ventricle for continuous leptin infusion. In additional groups of Hypo and control rats (n = 5/group, diabetes was induced by single injection of streptozotocin (50 mg/kg, IP. Hypo rats were lighter, had lower MAP and HR (83±4 and 317±2 vs 105±4 mmHg and 339±4 bpm, with similar caloric intake per kilogram of body weight and fasting plasma glucose levels (84±4 vs 80±4 mg/dl compared to controls. Chronic ICV leptin infusion (7 days, 0.62 μg/hr in non-diabetic rats reduced caloric intake and body weight (-10% in Hypo and control rats and markedly increased HR in control rats (~25 bpm while causing only modest HR increases in Hypo rats (8 bpm. In diabetic Hypo and control rats, leptin infusion reduced caloric intake, body weight and glucose levels (323±74 to 99±20 and 374±27 to 108±10 mg/dl, respectively; however, the effects of leptin on HR were abolished in Hypo rats. These results indicate that hypophysectomy attenuates leptin's effect on HR regulation without altering leptin's ability to suppress appetite or normalize glucose levels in diabetes.

  5. Detection of leptin in serum from patients with polycystic ovary syndrome

    International Nuclear Information System (INIS)

    Chu Yongli; Sun Yongyu; Qiu Hongyu

    2002-01-01

    Objective: To investigate the relationship between leptin and insulin resistance in polycystic ovary syndrome (PCOS). Methods: Blood samples for leptin, LH/FSH, fasting insulin and glucose measurement from 17 patients with PCOS and 20 cases as control group were analyzed by radioimmunoassay or oxidase test. Results: It showed that leptin, LH/FSH levels of serum, insulin resistant index (IRI) and body mass index (BMI) in patients with PCOS were significantly higher than that in the control group (P<0.05). Leptin level was positively related with IRI and LH/FSH and BMI (P<0.01, P<0.05, P<0.01). Conclusion: It was suspected that leptin accelerate insulin resistance, the interaction of two factors aggravate the change of pathophysiology in PCOS

  6. Dietary fat and insulin resistance: a connection through leptin and PPARγ activation

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    Doaa Nader Al-Jada

    2016-06-01

    Full Text Available Insulin resistance refers to reduced insulin action in peripheral tissues and impaired suppression of endogenous glucose production, a state which is critical for maintaining normal glucose homeostasis. Insulin resistance is partly explained by genetic factors and is strongly influenced by the individual's habitual lifestyle. Investigating factors that may influence the development of insulin resistance and their mechanisms of action is highly significant; one of these factors include dietary fat. Both quantitative and qualitative terms of dietary fat have been known to play an important role in the development of insulin resistance, although the mechanism underlying this effect is not fully understood. In this regard, the classical view has been that dietary fat quality mainly affects cell membrane fatty acid composition and consequently the membrane function. Recently, the relationship between dietary fat and insulin resistance has entered an advanced level due to the discovery that different fatty acids can regulate gene expression, transcriptional activity and adipocytokines secretion. In essence, this provides new mechanisms by which fatty acids exert their cellular effects. The present review critically assesses the effect of dietary fat quality on the development of insulin resistance in relation to the adipocytokine, leptin and the activation of the transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ. It is evident that fat quality influences the development of insulin resistance and has a more important role than quantity. Leptin and PPARγ prove to be potential candidates linking dietary fat with insulin resistance. However, the exact role or mechanism of action of various types of dietary fat in the development of insulin resistance is still uncertain. Further well-controlled studies in humans are necessary to establish better evidence-based dietary fat recommendations for diabetes prevention and its

  7. Regulation of leptin synthesis in white adipose tissue of the female fruit bat, Cynopterus sphinx: role of melatonin with or without insulin.

    Science.gov (United States)

    Banerjee, A; Udin, S; Krishna, A

    2011-02-01

    Factors regulating leptin synthesis during adipogenesis in wild species are not well known. Studies in the female Cynopterus sphinx bat have shown that it undergoes seasonal changes in its fat deposition and serum leptin and melatonin levels. The aim of the present study was to investigate the hormonal regulation of leptin synthesis by the white adipose tissue during the period of fat deposition in female C. sphinx. This study showed a significant correlation between the seasonal changes in serum melatonin level with the circulating leptin level (r = 0.78; P sphinx. A significant correlation between circulating insulin and leptin levels (r = 0.65; P sphinx. The study showed MT(2) receptors in adipose tissue and a stimulatory effect of melatonin on leptin synthesis, which was blocked by treatment with an MT(2) receptor antagonist, suggesting that the effect of melatonin on leptin synthesis by adipose tissue is mediated through the MT(2) receptor in C. sphinx. The in vitro study showed that the synthesis of leptin is directly proportional to the amount of glucose uptake by the adipose tissue. It further showed that melatonin together with insulin synergistically enhanced the leptin synthesis by adipose tissue through phosphorylation of mitogen-activated protein kinase in C. sphinx.

  8. Correlation Between Insulin, Leptin and Polycystic Ovary Syndrome ...

    African Journals Online (AJOL)

    Background: Polycystic ovary syndrome (PCOS) is the most common endocrine disorder among women of fertile age. Insulin can stimulate ovarian androgen production in normal women and in women with PCOS. Leptin levels were reduced among women with PCOS treated with insulin sensitizers. Aim: This study aims to ...

  9. Clinical significance of changes of serum leptin and insulin levels in patients with polycystic ovary syndrome

    International Nuclear Information System (INIS)

    Chen Zhaojun; Zhang Lahong; Gao Ying; Ren Xiaohua

    2007-01-01

    Objective: To explore the relationship between the serum leptin, insulin levels and development of polycystic ovary syndrome (PCOS). Methods: Serum leptin and insulin levels (with RIA) were determined in 34 patients with PCOS and 30 controls. Results: The serum leptin and insulin levels in the 34 PCOS patients were significantly higher than those in controls (P<0. 01), and those in obese patients (n=22) were significantly higher than those in non-obese ones (n=12) too(P<0.01). Conclusion: Changes of serum leptin and insulin levels were closely related to the development of PCOS and leptin might be used as a diagnostic indicator for PCOS. (authors)

  10. Hypothalamic growth hormone receptor (GHR controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb expressing neurons

    Directory of Open Access Journals (Sweden)

    Gillian Cady

    2017-05-01

    Full Text Available Objective: The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR are active in the central nervous system (CNS and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. Methods: To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (LeprEYFPΔGHR. The mice were generated by crossing the Leprcre on the cre-inducible ROSA26-EYFP mice to GHRL/L mice. Parameters of body composition and glucose homeostasis were evaluated. Results: Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in LeprEYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in LeprEYFPΔGHR mice. Conclusion: These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding. Keywords: Growth hormone receptor, Hypothalamus, Leptin receptor, Glucose production, Liver

  11. The changes of serum leptin and insulin contents in elderly male patients with obesity-related hypertension

    International Nuclear Information System (INIS)

    Zhan Hao; Huang Daijuan; Yuan Bin; He Yong; Zhang Yongxue

    2004-01-01

    To study the contents of serum leptin and insulin in elderly male patients with obesity-related hypertension, the levels of serum leptin and insulin in 21 normotensive cases and 41 hypertensive cases of them were determined by RIA. The results showed that the levels of serum leptin and insulin between hypertensives and normotensives in the non-obese groups were not significantly different (P>0.05). Compared with normotensives, the levels of serum leptin and insulin of hypertensives in the obese groups remarkably increased 1.8μg/L and 2.7 mIU/L respectively (P<0.01). The levels of serum leptin and insulin in the patients with obesity - related hypertension were markedly higher than those in the patients with non-obesity-related hypertension and elevated 2.7μg/L and 4.7mIU/L (P<0.01) respectively. Insulin-sensitivity index (ISI) successively decreased in the groups of HBPOb, NBPOb, HBPNOb and NBPNOb (relative ISI 0.50, 0.68, 0.92, 1 respectively). It is concluded that leptin-resistance and insulin-resistance exist in male elderly patients with obesity-related hypertension

  12. [Relationship between leptin and body mass and metabolic syndrome in an adult population].

    Science.gov (United States)

    Martins, Maria do Carmo; Lima Faleiro, Luís; Fonseca, Aidil

    2012-11-01

    To analyze the relationship between leptin and obesity expressed as body mass index (BMI) and certain components of the metabolic syndrome (MS) in an adult population. The study included 103 subjects, 42 men and 61 women, aged over 30 years, clinically defined as non-diabetic but with personal or family history of cardiovascular disease. All subjects underwent fasting blood measurements of leptin, insulin, glucose, glucose after ingestion of 75g glucose, HDL cholesterol and triglycerides, and insulin resistance (IR) and BMI were calculated. BMI as an index of overall adiposity was strongly associated with serum leptin. BMI rose as serum leptin levels increased from the first to the third tertile; the correlation between leptin and BMI was strong, r=0.524 in men and r=0.603 in women, with high statistical significance (pcorrelations between leptin and IR, and leptin and insulinemia, were strong in both sexes. With regard to MS components, increased serum levels of the study variables were observed as leptin concentrations rose from the first to the third tertile (with the exception of HDL cholesterol, which decreased). Elevated serum leptin, particularly in obese individuals, should be taken as a warning sign of energy imbalance, poor diet, hyperinsulinemia, insulin resistance, or changes in other metabolic risk factors that are strongly associated with cardiovascular disease and type 2 diabetes. Copyright © 2011 Sociedade Portuguesa de Cardiologia. Published by Elsevier España. All rights reserved.

  13. [Contribution of leptin in the development of insulin resistance in pregnant women with obesity].

    Science.gov (United States)

    Tarasenko, K

    2014-03-01

    The aim of the present study was to investigate contribution of leptin in the development of insulin resistance in obese pregnant women depending on the obesity class as well as its effect on the progression of pregnancy. 36 pregnant women of I and II obesity classes and 21 pregnant women with normal body mass participated in the study. Concentrations of insulin, leptin and C-reactive protein in blood serum were measured with immunoenzymatic assays. Insulin resistance (IR) was determined with the Caro index. Contribution of leptin to development of IR was assessed with the ratio "leptin/Caro index". An increase of leptin concentration in blood serum was found in pregnant women with obesity compared to healthy controls. Moreover, the ratio "leptin/Caro index" increased with IR progression and reached maximum in the group with obesity class II, where it was 5.8 times higher than in the control group. An increased frequency of gestoses and placentary dysfunction were manifestations of weakening of adaptive mechanisms of the organism associated with the IR progression and increased role of leptin in its development. Therefore, activation of adipocyte function through the increased leptin secretion and increased ratio "leptin/Caro index" reflects the important role of leptin in pathogenesis of IR in pregnant women with obesity.

  14. Branched Chain Amino Acids Are Associated with Insulin Resistance Independent of Leptin and Adiponectin in Subjects with Varying Degrees of Glucose Tolerance

    NARCIS (Netherlands)

    Connelly, Margery A.; Wolak-Dinsmore, Justyna; Dullaart, Robin P. F.

    Background: Branched chain amino acids (BCAA) may be involved in the pathogenesis of insulin resistance and are associated with type 2 diabetes mellitus (T2DM) development. Adipokines such as leptin and adiponectin influence insulin resistance and reflect adipocyte dysfunction. We examined the

  15. Counterregulation of insulin by leptin as key component of autonomic regulation of body weight

    Science.gov (United States)

    Borer, Katarina T

    2014-01-01

    A re-examination of the mechanism controlling eating, locomotion, and metabolism prompts formulation of a new explanatory model containing five features: a coordinating joint role of the (1) autonomic nervous system (ANS); (2) the suprachiasmatic (SCN) master clock in counterbalancing parasympathetic digestive and absorptive functions and feeding with sympathetic locomotor and thermogenic energy expenditure within a circadian framework; (3) interaction of the ANS/SCN command with brain substrates of reward encompassing dopaminergic projections to ventral striatum and limbic and cortical forebrain. These drive the nonhomeostatic feeding and locomotor motivated behaviors in interaction with circulating ghrelin and lateral hypothalamic neurons signaling through melanin concentrating hormone and orexin-hypocretin peptides; (4) counterregulation of insulin by leptin of both gastric and adipose tissue origin through: potentiation by leptin of cholecystokinin-mediated satiation, inhibition of insulin secretion, suppression of insulin lipogenesis by leptin lipolysis, and modulation of peripheral tissue and brain sensitivity to insulin action. Thus weight-loss induced hypoleptimia raises insulin sensitivity and promotes its parasympathetic anabolic actions while obesity-induced hyperleptinemia supresses insulin lipogenic action; and (5) inhibition by leptin of bone mineral accrual suggesting that leptin may contribute to the maintenance of stability of skeletal, lean-body, as well as adipose tissue masses. PMID:25317239

  16. The Proton-Activated Receptor GPR4 Modulates Glucose Homeostasis by Increasing Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Luca Giudici

    2013-11-01

    Full Text Available Background: The proton-activated G protein-coupled receptor GPR4 is expressed in many tissues including white adipose tissue. GPR4 is activated by extracellular protons in the physiological pH range (i.e. pH 7.7 - 6.8 and is coupled to the production of cAMP. Methods: We examined mice lacking GPR4 and examined glucose tolerance and insulin sensitivity in young and aged mice as well as in mice fed with a high fat diet. Expression profiles of pro- and anti-inflammatory cytokines in white adipose tissue, liver and skeletal muscle was assessed. Results: Here we show that mice lacking GPR4 have an improved intraperitoneal glucose tolerance test and increased insulin sensitivity. Insulin levels were comparable but leptin levels were increased in GPR4 KO mice. Gpr4-/- showed altered expression of PPARα, IL-6, IL-10, TNFα, and TGF-1β in skeletal muscle, white adipose tissue, and liver. High fat diet abolished the differences in glucose tolerance and insulin sensitivity between Gpr4+/+ and Gpr4-/- mice. In contrast, in aged mice (12 months old, the positive effect of GPR4 deficiency on glucose tolerance and insulin sensitivity was maintained. Liver and adipose tissue showed no major differences in the mRNA expression of pro- and anti-inflammatory factors between aged mice of both genotypes. Conclusion: Thus, GPR4 deficiency improves glucose tolerance and insulin sensitivity. The effect may involve an altered balance between pro- and anti-inflammatory factors in insulin target tissues.

  17. The interaction of insulin, glucose, and insulin-glucose mixtures with a phospholipid monolayer.

    Science.gov (United States)

    Shigenobu, Hayato; McNamee, Cathy E

    2012-12-15

    We determined how glucose or insulin interacts with a phospholipid monolayer at the air/water interface and explained these mechanisms from a physico-chemical point of view. The 1,2-dipalmitoyl-2-sn-glycero-3-phosphatidylcholine (DPPC) monolayer at an air/water interface acted as a model membrane, which allowed the effect of the molecular packing density in the monolayer on the interactions to be determined. The interaction of glucose, insulin, and a mixture of glucose and insulin to the DPPC monolayer were investigated via surface pressure-area per molecule Langmuir isotherms and fluorescence microscopy. Glucose adsorbed to the underside of the DPPC monolayer, while insulin was able to penetrate through the monolayer when the phospholipid molecules were not densely packed. The presence of a mixture of insulin and glucose affected the molecular packing in the DPPC monolayer differently than the pure insulin or glucose solutions, and the glucose-insulin mixture was seen to be able to penetrate through the monolayer. These results indicated that glucose and insulin interact with one another, giving a material that may then transported through a pore in the monolayer or through the spaces between the molecules of the monolayer. Copyright © 2012 Elsevier Inc. All rights reserved.

  18. The Role of Leptin in Maintaining Plasma Glucose During Starvation.

    Science.gov (United States)

    Perry, Rachel J; Shulman, Gerald I

    2018-03-01

    For 20 years it has been known that concentrations of leptin, a hormone produced by the white adipose tissue (WAT) largely in proportion to body fat, drops precipitously with starvation, particularly in lean humans and animals. The role of leptin to suppress the thyroid and reproductive axes during a prolonged fast has been well defined; however, the impact of leptin on metabolic regulation has been incompletely understood. However emerging evidence suggests that, in starvation, hypoleptinemia increases activity of the hypothalamic-pituitary-adrenal axis, promoting WAT lipolysis, increasing hepatic acetyl-CoA concentrations, and maintaining euglycemia. In addition, leptin may be largely responsible for mediating a shift from a reliance upon glucose metabolism (absorption and glycogenolysis) to fat metabolism (lipolysis increasing gluconeogenesis) which preserves substrates for the brain, heart, and other critical organs. In this way a leptin-mediated glucose-fatty acid cycle appears to maintain glycemia and permit survival in starvation.

  19. Leptin and the central nervous system control of glucose metabolism.

    Science.gov (United States)

    Morton, Gregory J; Schwartz, Michael W

    2011-04-01

    The regulation of body fat stores and blood glucose levels is critical for survival. This review highlights growing evidence that leptin action in the central nervous system plays a key role in both processes. Investigation into underlying mechanisms has begun to clarify the physiological role of leptin in the control of glucose metabolism and raises interesting new possibilities for the treatment of diabetes and related disorders.

  20. Regulation of Blood Pressure, Appetite, and Glucose by Leptin After Inactivation of Insulin Receptor Substrate 2 Signaling in the Entire Brain or in Proopiomelanocortin Neurons.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Wang, Zhen; Freeman, Nathan J; Alsheik, Ammar J; Adi, Ahmad; Hall, John E

    2016-02-01

    Insulin receptor substrate 2 (IRS2) is one of the 3 major leptin receptor signaling pathways, but its role in mediating the chronic effects of leptin on blood pressure, food intake, and glucose regulation is unclear. We tested whether genetic inactivation of IRS2 in the entire brain (IRS2/Nestin-cre mice) or specifically in proopiomelanocortin (POMC) neurons (IRS2/POMC-cre mice) attenuates the chronic cardiovascular, metabolic, and antidiabetic effects of leptin. Mice were instrumented with telemetry probes for measurement of blood pressure and heart rate and with venous catheters for intravenous infusions. After a 5-day control period, mice received leptin infusion (2 μg/kg per minute) for 7 days. Compared with control IRS2(flox/flox) mice, IRS2/POMC-cre mice had similar body weight and food intake (33±1 versus 35±1 g and 3.6±0.5 versus 3.8±0.2 g per day) but higher mean arterial pressure (MAP) and heart rate (110±2 versus 102±2 mm Hg and 641±9 versus 616±5 bpm). IRS2/Nestin-cre mice were heavier (38±2 g), slightly hyperphagic (4.5±1.0 g per day), and had higher MAP and heart rate (108±2 mm Hg and 659±9 bpm) compared with control mice. Leptin infusion gradually increased MAP despite decreasing food intake by 31% in IRS2(flox/flox) and in Nestin-cre control mice. In contrast, leptin infusion did not change MAP in IRS2/Nestin-cre or IRS2/POMC-cre mice. The anorexic and antidiabetic effects of leptin, however, were similar in all 3 groups. These results indicate that IRS2 signaling in the central nervous system, and particularly in POMC neurons, is essential for the chronic actions of leptin to raise MAP but not for its anorexic or antidiabetic effects. © 2015 American Heart Association, Inc.

  1. Association between Follicular Fluid Leptin and Serum Insulin Levels in Nonoverweight Women with Polycystic Ovary Syndrome

    Directory of Open Access Journals (Sweden)

    G. Garruti

    2014-01-01

    Full Text Available Aims. We evaluated the links between leptin and visfatin levels and fertilization rates in nonoverweight (NOW women with PCOS (NOW-PCOS from Apulia undergoing in vitro fertilization/embryo transfer (IVF. Materials and Methodology. We recruited 16 NOW women with PCOS (NOW-PCOS and 10 normally ovulating NOW women (control-NOW. All women underwent IVF. Androgens, 17-β-estradiol (17β-E2, and insulin levels were measured in plasma and/or serum and leptin and visfatin levels were assayed in both serum and follicular fluid (FF-leptin, FF-visfatin. Results. In NOW-PCOS, both serum and FF-leptin were significantly lower than in control-NOW. In NOW-PCOS, significant correlations were found between BMI and serum leptin and insulinemia and FF-leptin. By contrast, in control-NOW, FF-leptin levels were not correlated with insulinemia. Serum visfatin levels were not significantly different in NOW-PCOS and control-NOW, but FF-visfatin levels were 1.6-fold higher, although not significantly, in NOW-PCOS than in control-NOW. Conclusions. Both serum leptin levels and FF-leptin are BMI- and insulin-related in Southern Italian NOW-PCOS from Apulia. In line with other reports showing that FF-leptin levels are predictive of fertilization rates, lower than normal FF-leptin levels in NOW-PCOS may explain their lower fertilization rate and this may be related to the level of insulin and/or insulin resistance.

  2. Insulin and leptin relations in obesity: a multimedia approach.

    Science.gov (United States)

    Yokaichiya, Daniela K; Galembeck, Eduardo; Torres, Bayardo B; Da Silva, José Antônio; de Araujo, Daniele R

    2008-09-01

    Obesity has been recognized as a worldwide public health problem. It significantly increases the chances of developing several diseases, including Type II diabetes. The roles of insulin and leptin in obesity involve reactions that can be better understood when they are presented step by step. The aim of this work was to design software with data from some of the most recent publications on obesity, especially those concerning the roles of insulin and leptin in this metabolic disturbance. The most notable characteristic of this software is the use of animations representing the cellular response together with the presentation of recently discovered mechanisms on the participation of insulin and leptin in processes leading to obesity. The software was field tested in the Biochemistry of Nutrition web-based course. After using the software and discussing its contents in chatrooms, students were asked to answer an evaluation survey about the whole activity and the usefulness of the software within the learning process. The teaching assistants (TA) evaluated the software as a tool to help in the teaching process. The students' and TAs' satisfaction was very evident and encouraged us to move forward with the software development and to improve the use of this kind of educational tool in biochemistry classes.

  3. Effects of prepartum fat supplementation on plasma concentrations of glucagon-like peptide-1, peptide YY, adropin, insulin, and leptin in periparturient dairy cows.

    Science.gov (United States)

    Zapata, Rizaldy C; Salehi, Reza; Ambrose, Divakar J; Chelikani, Prasanth K

    2015-10-01

    Dietary fat supplementation during the periparturient period is one strategy to increase energy intake and attenuate the degree of negative energy balance during early lactation; however, little is known of the underlying hormonal and metabolic adaptations. We evaluated the effects of prepartum fat supplementation on energy-balance parameters and plasma concentrations of glucagon-like peptide-1, peptide tyrosine-tyrosine (PYY), adropin, insulin, leptin, glucose, nonesterified fatty acid, and β-hydroxybutyric acid in dairy cows. Twenty-four pregnant dairy cows were randomized to diets containing either rolled canola or sunflower seed at 8% of dry matter, or no oilseed supplementation, during the last 5 wk of gestation and then assigned to a common lactation diet postpartum. Blood samples were collected at -2, +2, and +14 h relative to feeding, at 2 wk after the initiation of the diets, and at 2 wk postpartum. Dietary canola and sunflower supplementation alone did not affect energy balance, body weight, and plasma concentrations of glucagon-like peptide-1, PYY, adropin, insulin, leptin, nonesterified fatty acid, and β-hydroxybutyric acid; however, canola decreased and sunflower tended to decrease dry matter intake. We also observed that the physiological stage had a significant, but divergent, effect on circulating hormones and metabolite concentrations. Plasma glucagon-like peptide-1, PYY, adropin, nonesterified fatty acid, and β-hydroxybutyric acid concentrations were greater postpartum than prepartum, whereas glucose, insulin, leptin, body weight, and energy balance were greater prepartum than postpartum. Furthermore, the interaction of treatment and stage was significant for leptin and adropin, and tended toward significance for PYY and insulin; only insulin exhibited an apparent postprandial increase. Postpartum PYY concentrations exhibited a strong negative correlation with body weight, suggesting that PYY may be associated with body weight regulation during

  4. Serum leptin and its relationship with metabolic variables in Arabs with type 2 diabetes mellitus

    International Nuclear Information System (INIS)

    Al-Shoumer, Kamal A.; Doi, Suhail A.; Vasanthy, Bagavathy A.; Al-Asousi, Adnan A.

    2008-01-01

    Most studies on serum leptin in type 2 diabetes mellitus have focused on white populations. We studied serum leptin concentrations and parameters related to glycemic control and the association between leptin levels and anthropometric and metabolic factors in Arab patients with type 2 diabetes and in Arab control subjects. Ninety-two patients (65 females and 27 males) with type 2 diabetes and 69 matched normal and control subjects (48 females and 21 males) were included. Anthropometric measures (including body mass index (BMI) and waist: hip ratio) were assessed in all subjects. After an overnight fast, blood was collected for serum leptin assay. Other metabolic parameters include glucose, insulin, C-peptide, intact proinsulin, insulin resistance index (HOMA-IR), insulin-like growth factor 1 (IGF-1), lipids and hemoglobin A 1c (HbA) were determined. Fasting serum leptin levels, IGF-1 and high-density lipoprotein (HDL) cholesterol were similar in patients with type 2 diabetes and control subjects. When obese subjects (BMI>-30kg/m2) were analyzed separately, serum levels of leptin were significantly lower in patients compared to controls. In contrast, patients had higher fasting glucose, insulin, C-peptide, intact proinsulin, insulin resistance, total cholesterol, triglycerides, HbA, and a larger waist circumference and waist-to-hip ratio than controls. Serum leptin correlated positively with BM, negatively with waist-to-hip ratio, and demonstrated no relationship to other parameters. Patients with type 2 diabetes in an Arab ethnic population showed evidence of an unfavorable metabolic profile despite having leptin levels similar to controls. Obesity influences serum leptin levels more significantly in type 2 diabetes, in which leptin levels tends to be low. (author)

  5. [The role of alterations in the brain signaling systems regulated by insulin, IGF-1 and leptin in the transition of impaired glucose tolerance to overt type 2 diabetes mellitus].

    Science.gov (United States)

    Shpakov, A O

    2014-01-01

    One of the crucial factors leading to the development of pre-diabetes and type 2 diabetes mellitus (DM2) are the disturbances in the brain hormonal signaling systems regulated by insulin, insulin-like growth factor-1 (IGF-1) and leptin. The causes of these disturbances are the changes in the redox balance and lipid metabolism leading to lipotoxicity and endoplasmic reticulum stress in neuronal cells, as well as the dysfunctions in neurotransmitter systems of the brain that are functionally associated with insulin, IGF-1 and leptin signaling systems. The identification of molecular disturbances in insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 can be used for early diagnostics of these diseases, and to develop new strategies for preventive treatment of DM2 at the pre-diabetic stage. In the review, the literature data and the results of own investigations concerning the changes in the insulin, IGF-1 and leptin systems of the brain in pre-diabetes and DM2 and their role in the etiology and pathogenesis of DM2 are analyzed, and the approaches to restore the functional activity of these systems are discussed.

  6. LEPTIN AND OBESITY – NEUROENDOCRINE , METABOLIC AND ATHEROGENIC EFFECTS OF LEPTIN

    Directory of Open Access Journals (Sweden)

    Mišo Šabovič

    2003-01-01

    Full Text Available Background. Leptin is an adipocyte-derived hormone that was recently discovered. Leptin and leptin resistance play an important role in the pathogenesis of obesity. Leptin acts by binding to specific receptors in the hypothalamus to alter the expression of several neuropeptides that regulate food intake and energy expenditure. As commonly found, obese persons have leptin resistance and consequently attenuated effects of leptin. Mechanism underlying leptin resistance has not been explained yet: it might be the result of a receptor or post receptor defect, impaired transport of leptin through cerebrovascular barrier or inactivation of leptin by binding proteins. Phase I and II clinical trials proved that recombinant leptin administration to humans is safe. First results of the current phase III clinical trials demonstrated that leptin is moderately effective in the treatment of obesity.Conclusions. Beside anti-obesity effect, leptin can have important metabolic and neuroendocrine effects. It is involved in glucose metabolism and insulin secretion, pathogenesis of polymetabolic syndrome, diabetes and arterial hypertension. In addition it affects some processes of atherothrombosis. It interacts with and significantly influences hypothalamic-pituitaryadrenal, thyroid, sexual glands and growth hormone axes. Explaining the mechanism of leptin resistance could be important for understanding the pathogenesis of obesity and associated pathologic states as polymetabolic syndrom, diabetes, arterial hipertension and atherothrombosis.

  7. Endocrine and metabolic effects of consuming fructose- and glucose-sweetened beverages with meals in obese men and women: influence of insulin resistance on plasma triglyceride responses.

    Science.gov (United States)

    Teff, Karen L; Grudziak, Joanne; Townsend, Raymond R; Dunn, Tamara N; Grant, Ryan W; Adams, Sean H; Keim, Nancy L; Cummings, Bethany P; Stanhope, Kimber L; Havel, Peter J

    2009-05-01

    Compared with glucose-sweetened beverages, consumption of fructose-sweetened beverages with meals elevates postprandial plasma triglycerides and lowers 24-h insulin and leptin profiles in normal-weight women. The effects of fructose, compared with glucose, ingestion on metabolic profiles in obese subjects has not been studied. The objective of the study was to compare the effects of fructose- and glucose-sweetened beverages consumed with meals on hormones and metabolic substrates in obese subjects. The study had a within-subject design conducted in the clinical and translational research center. Participants included 17 obese men (n = 9) and women (n = 8), with a body mass index greater than 30 kg/m(2). Subjects were studied under two conditions involving ingestion of mixed nutrient meals with either glucose-sweetened beverages or fructose-sweetened beverages. The beverages provided 30% of total kilocalories. Blood samples were collected over 24 h. Area under the curve (24 h AUC) for glucose, lactate, insulin, leptin, ghrelin, uric acid, triglycerides (TGs), and free fatty acids was measured. Compared with glucose-sweetened beverages, fructose consumption was associated with lower AUCs for insulin (1052.6 +/- 135.1 vs. 549.2 +/- 79.7 muU/ml per 23 h, P glucose consumption. Increases of TGs were augmented in obese subjects with insulin resistance, suggesting that fructose consumption may exacerbate an already adverse metabolic profile present in many obese subjects.

  8. Body Fat Distribution, Serum Leptin, And Insulin Resistance In Obese Subjects With Obstructive Sleep Apnoea

    OpenAIRE

    Hassan ZA*,Attia MF**, Ahmed AH**;Hassan HA***,

    2006-01-01

    Obstructive sleep apnoea (OS A) is strongly associated with obesity and is characterized by endocrine and metabolic changes. The aim of the present study is to clarify whether there is interrelationship between body fat, serum leptin, glucose-insulin metabolism and OSA. Subjects and measurements: we studied 23 obese subjects with OSA (13 males,& 10 females; age mean 36 ± 4.4 years; BMI: 31.7 ± 3.6 kg/m2; WHR: 1.2 ± .25 in males and 0.81+.5 in females ;Apnoea Index "AI"( 9.2 ±6.1) event/hour o...

  9. The potential osteogenic effects of systemic lep tin and insulin administration in streptozotocin-induced diabetic female rats

    International Nuclear Information System (INIS)

    Gad, Hayam I.

    2007-01-01

    To evaluate the effect of leptin administration on some biochemical parameters of bone turnover in diabetic rats using either leptin alone or a combination of leptin and insulin. The study was carried out on 32 female Wistar rats supplied by Medical College animal house at King Khalid Hospital, Kingdom of Saudi Arabia during the period from March to December 2006. Rats were divided into 4 groups (8 rats each), controls, non-treated diabetic, leptin-treated diabetic and leptin plus insulin-treated diabetic rats. After induction of diabetes by 6 weeks, treatment with leptin either alone or combined with insulin was continued for 2 weeks more. At the end of treatment, serum samples were taken to measure levels of bone alkaline phosphate (BAP), alkaline phosphates, osteocalcin, insulin like growth factor-1 (IGF-1), parathyroid hormone (PTH), glucose, creatinine, calcium, calcium ions (Ca2+), and phosphorous using enzyme-linked immunoassay (ELISA) and spectrophotometric methods. Body weight and urinary calcium excretion were also measured. Combined leptin and insulin treatment produced a significant increase of serum BAP and a decrease of urinary calcium and serum glucose as compared to rats treated by leptin only, and a significant increase of BAP, alkaline phosphates, IGF-1, and glucose and a decrease in osteocalcin as compared to control rats. Positive correlations were detected between serum IGF-1 levels and each of BAP, alkaline phosphatase and osteocalcin in diabetic rats treated by leptin, and those with leptin plus insulin. Combined leptin plus insulin treatment can offer extra gain of bone formation over leptin treatment alone. Confirmation of these preliminary observations must await careful long-term studies of bone turnover experimental diabetes. (author)

  10. Transgenic neuronal expression of proopiomelanocortin attenuates hyperphagic response to fasting and reverses metabolic impairments in leptin-deficient obese mice.

    Science.gov (United States)

    Mizuno, Tooru M; Kelley, Kevin A; Pasinetti, Giulio M; Roberts, James L; Mobbs, Charles V

    2003-11-01

    Hypothalamic proopiomelanocortin (POMC) gene expression is reduced in many forms of obesity and diabetes, particularly in those attributable to deficiencies in leptin or its receptor. To assess the functional significance of POMC in mediating metabolic phenotypes associated with leptin deficiency, leptin-deficient mice bearing a transgene expressing the POMC gene under control of the neuron-specific enolase promoter were produced. The POMC transgene attenuated fasting-induced hyperphagia in wild-type mice. Furthermore, the POMC transgene partially reversed obesity, hyperphagia, and hypothermia and effectively normalized hyperglycemia, glucosuria, glucose intolerance, and insulin resistance in leptin-deficient mice. Effects of the POMC transgene on glucose homeostasis were independent of the partial correction of hyperphagia and obesity. Furthermore, the POMC transgene normalized the profile of hepatic and adipose gene expression associated with gluconeogenesis, glucose output, and insulin sensitivity. These results indicate that central POMC is a key modulator of glucose homeostasis and that agonists of POMC products may provide effective therapy in treating impairments in glucose homeostasis when hypothalamic POMC expression is reduced, as occurs with leptin deficiency, hypothalamic damage, and aging.

  11. Leptin regulates glutamate and glucose transporters in hypothalamic astrocytes

    Science.gov (United States)

    Fuente-Martín, Esther; García-Cáceres, Cristina; Granado, Miriam; de Ceballos, María L.; Sánchez-Garrido, Miguel Ángel; Sarman, Beatrix; Liu, Zhong-Wu; Dietrich, Marcelo O.; Tena-Sempere, Manuel; Argente-Arizón, Pilar; Díaz, Francisca; Argente, Jesús; Horvath, Tamas L.; Chowen, Julie A.

    2012-01-01

    Glial cells perform critical functions that alter the metabolism and activity of neurons, and there is increasing interest in their role in appetite and energy balance. Leptin, a key regulator of appetite and metabolism, has previously been reported to influence glial structural proteins and morphology. Here, we demonstrate that metabolic status and leptin also modify astrocyte-specific glutamate and glucose transporters, indicating that metabolic signals influence synaptic efficacy and glucose uptake and, ultimately, neuronal function. We found that basal and glucose-stimulated electrical activity of hypothalamic proopiomelanocortin (POMC) neurons in mice were altered in the offspring of mothers fed a high-fat diet. In adulthood, increased body weight and fasting also altered the expression of glucose and glutamate transporters. These results demonstrate that whole-organism metabolism alters hypothalamic glial cell activity and suggest that these cells play an important role in the pathology of obesity. PMID:23064363

  12. Glucose-induced insulin resistance of skeletal-muscle glucose transport and uptake

    DEFF Research Database (Denmark)

    Richter, Erik; Hansen, B F; Hansen, S A

    1988-01-01

    in the presence of glucose and insulin. The data indicate that exposure to a moderately increased glucose concentration (12 mM) leads to rapidly developing resistance of skeletal-muscle glucose transport and uptake to maximal insulin stimulation. The effect of glucose is enhanced by simultaneous insulin exposure......, whereas exposure for 5 h to insulin itself does not cause measurable resistance to maximal insulin stimulation.......The ability of glucose and insulin to modify insulin-stimulated glucose transport and uptake was investigated in perfused skeletal muscle. Here we report that perfusion of isolated rat hindlimbs for 5 h with 12 mM-glucose and 20,000 microunits of insulin/ml leads to marked, rapidly developing...

  13. Acute insulin-induced elevations of circulating leptin and feeding inhibition in lean but not obese rats.

    Science.gov (United States)

    Singh, Kimberly A; Boozer, Carol N; Vasselli, Joseph R

    2005-08-01

    Insulin has been shown to stimulate leptin mRNA expression acutely in rat adipose tissue, but its short-term effects on circulating leptin levels, and subsequent feeding behavior, have not been well described. We used 11-mo-old female selectively bred obesity-resistant (OR) and obesity-prone (OP) Sprague-Dawley rats maintained on laboratory chow to investigate this question. At testing, body weights and basal leptin levels of the OP rats were significantly elevated compared with the OR rats. In the 3-h fasted state, injection of 2.0 U insulin/kg ip resulted in significant elevations of plasma leptin at 4 h postinjection in both OP and OR groups (hour 4, +2.50 and +5.98 ng/ml, respectively). In separate feeding tests with the same groups, intake of laboratory chow pellets was significantly inhibited during hours 2-4 after 2.0 U/kg of insulin in the OR (-80.1%, P < 0.05), but not in the OP group, compared with intake after saline injections. In feeding tests with palatable moderately high-fat pellets after 2.0 and 3.0 U insulin/kg ip, significant decreases between hours 2 and 4 in intake were seen in the OR group only (-41.0 and -68.3%, respectively). Thus feeding inhibition coincides with insulin-induced elevations of plasma leptin in lean but not obese Sprague-Dawley rats. Our data suggest that elevations of leptin within the physiological range may contribute to short-term inhibition of food intake in rats and that this process may be stimulated by feeding-related insulin release.

  14. Hypothalamic growth hormone receptor (GHR) controls hepatic glucose production in nutrient-sensing leptin receptor (LepRb) expressing neurons.

    Science.gov (United States)

    Cady, Gillian; Landeryou, Taylor; Garratt, Michael; Kopchick, John J; Qi, Nathan; Garcia-Galiano, David; Elias, Carol F; Myers, Martin G; Miller, Richard A; Sandoval, Darleen A; Sadagurski, Marianna

    2017-05-01

    The GH/IGF-1 axis has important roles in growth and metabolism. GH and GH receptor (GHR) are active in the central nervous system (CNS) and are crucial in regulating several aspects of metabolism. In the hypothalamus, there is a high abundance of GH-responsive cells, but the role of GH signaling in hypothalamic neurons is unknown. Previous work has demonstrated that the Ghr gene is highly expressed in LepRb neurons. Given that leptin is a key regulator of energy balance by acting on leptin receptor (LepRb)-expressing neurons, we tested the hypothesis that LepRb neurons represent an important site for GHR signaling to control body homeostasis. To determine the importance of GHR signaling in LepRb neurons, we utilized Cre/loxP technology to ablate GHR expression in LepRb neurons (Lepr EYFPΔGHR ). The mice were generated by crossing the Lepr cre on the cre-inducible ROSA26-EYFP mice to GHR L/L mice. Parameters of body composition and glucose homeostasis were evaluated. Our results demonstrate that the sites with GHR and LepRb co-expression include ARH, DMH, and LHA neurons. Leptin action was not altered in Lepr EYFPΔGHR mice; however, GH-induced pStat5-IR in LepRb neurons was significantly reduced in these mice. Serum IGF-1 and GH levels were unaltered, and we found no evidence that GHR signaling regulates food intake and body weight in LepRb neurons. In contrast, diminished GHR signaling in LepRb neurons impaired hepatic insulin sensitivity and peripheral lipid metabolism. This was paralleled with a failure to suppress expression of the gluconeogenic genes and impaired hepatic insulin signaling in Lepr EYFPΔGHR mice. These findings suggest the existence of GHR-leptin neurocircuitry that plays an important role in the GHR-mediated regulation of glucose metabolism irrespective of feeding.

  15. Integrated model of insulin and glucose kinetics describing both hepatic glucose and pancreatic insulin regulation

    DEFF Research Database (Denmark)

    Erlandsen, Mogens; Martinussen, Christoffer; Gravholt, Claus Højbjerg

    2018-01-01

    AbstractBackground and objectives Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter-individual varia......AbstractBackground and objectives Modeling of glucose kinetics has to a large extent been based on models with plasma insulin as a known forcing function. Furthermore, population-based statistical methods for parameter estimation in these models have mainly addressed random inter......-individual variations and not intra-individual variations in the parameters. Here we present an integrated whole-body model of glucose and insulin kinetics which extends the well-known two-compartment glucose minimal model. The population-based estimation technique allow for quantification of both random inter......- and intra-individual variation in selected parameters using simultaneous data series on glucose and insulin. Methods We extend the two-compartment glucose model into a whole-body model for both glucose and insulin using a simple model for the pancreas compartment which includes feedback of glucose on both...

  16. Obese Neuronal PPARγ Knockout Mice Are Leptin Sensitive but Show Impaired Glucose Tolerance and Fertility.

    Science.gov (United States)

    Fernandez, Marina O; Sharma, Shweta; Kim, Sun; Rickert, Emily; Hsueh, Katherine; Hwang, Vicky; Olefsky, Jerrold M; Webster, Nicholas J G

    2017-01-01

    The peroxisome-proliferator activated receptor γ (PPARγ) is expressed in the hypothalamus in areas involved in energy homeostasis and glucose metabolism. In this study, we created a deletion of PPARγ brain-knockout (BKO) in mature neurons in female mice to investigate its involvement in metabolism and reproduction. We observed that there was no difference in age at puberty onset between female BKOs and littermate controls, but the BKOs gave smaller litters when mated and fewer oocytes when ovulated. The female BKO mice had regular cycles but showed an increase in the number of cycles with prolonged estrus. The mice also had increased luteinizing hormone (LH) levels during the LH surge and histological examination showed hemorrhagic corpora lutea. The mice were challenged with a 60% high-fat diet (HFD). Metabolically, the female BKO mice showed normal body weight, glucose and insulin tolerance, and leptin levels but were protected from obesity-induced leptin resistance. The neuronal knockout also prevented the reduction in estrous cycles due to the HFD. Examination of ovarian histology showed a decrease in the number of primary and secondary follicles in both genotypes due to the HFD, but the BKO ovaries showed an increase in the number of hemorrhagic follicles. In summary, our results show that neuronal PPARγ is required for optimal female fertility but is also involved in the adverse effects of diet-induced obesity by creating leptin resistance potentially through induction of the repressor Socs3. Copyright © 2017 by the Endocrine Society.

  17. Relationship and significance of serum leptin with blood insulin and lipid in 6-13 years old obese children

    International Nuclear Information System (INIS)

    Sheng Chunyong; Wang Chunlan; Zhang Linong

    2005-01-01

    To explore relationship and significance of Serum Leptin with BMI, Insulin, triglyceride (TG) and total cholesterol (TC) in obese children aged 6-13 years. Serum Leptin of school-age children 118 (64 male, 54 female; normal non-obese 56 and obese 62) were deter- mined and compared with BMI, Insulin, TG and TC. The results showed that: (1) Each index of obese children was remarkably higher than that of non-obese children (P 0.05). (3) Leptin was poritinely corelation with BMI, insulin, TG and TC(P=0.001). Leptin level in serum may varied according to sex, BMI or blood lipid level. It is of great significance in prevention and treatment of obesity to use drug which may improve Leptin receptor effect. (authors)

  18. Effects of Metformin on Serum Levels of Secreted Klotho and Leptin in PCOS Women

    Directory of Open Access Journals (Sweden)

    Savadali Saifi Novashnag

    2016-07-01

    Patients’ weights showed some decline. Fasting plasma glucose levels and insulin resistance decreased significantly (p<0.01. Hormonal assays indicated significant decrease in leptin and insulin levels and rise in Klotho levels. BMIs did not change meaningfully. Measurements of leptin and klotho levels showed a decrease in mean leptin levels from 34.74 to 28.41 ng/l and the level of klotho increased from 4.01 to 5.43 ng/l. Conclusion: This study showed that metformin treatment can cause a rise in klotho and a decrease in leptin levels without considerable effects on the weights of women with PCOS. Probably, leptin exerts its physiological effects in low concentrations while klotho in contrast acts physiologically in higher concentrations.

  19. Children with classic congenital adrenal hyperplasia have elevated serum leptin concentrations and insulin resistance: potential clinical implications.

    Science.gov (United States)

    Charmandari, Evangelia; Weise, Martina; Bornstein, Stefan R; Eisenhofer, Graeme; Keil, Margaret F; Chrousos, George P; Merke, Deborah P

    2002-05-01

    Leptin is secreted by the white adipose tissue and modulates energy homeostasis. Nutritional, neural, neuroendocrine, paracrine, and autocrine factors, including the sympathetic nervous system and the adrenal medulla, have been implicated in the regulation of leptin secretion. Classic congenital adrenal hyperplasia (CAH) is characterized by a defect in cortisol and aldosterone secretion, impaired development and function of the adrenal medulla, and adrenal hyperandrogenism. To examine leptin secretion in patients with classic CAH in relation to their adrenomedullary function and insulin and androgen secretion, we studied 18 children with classic CAH (12 boys and 6 girls; age range 2-12 yr) and 28 normal children (16 boys and 12 girls; age range 5-12 yr) matched for body mass index (BMI). Serum leptin concentrations were significantly higher in patients with CAH than in control subjects (8.1 +/- 2.0 vs. 2.5 +/- 0.6 ng/ml, P = 0.01), and this difference persisted when leptin values were corrected for BMI. When compared with their normal counterparts, children with CAH had significantly lower plasma epinephrine (7.1 +/- 1.3 vs. 50.0 +/- 4.2, P fasting serum insulin (10.6 +/- 1.4 vs. 3.2 +/- 0.2 microU/ml, P Insulin resistance determined by the homeostasis model assessment method was significantly greater in children with classic CAH than in normal children (2.2 +/- 0.3 vs. 0.7 +/- 0.04, P patients and controls. Gender predicted serum leptin concentrations in controls but not in patients with classic CAH. No association was found between the dose of hydrocortisone and serum leptin (r = -0.17, P = 0.5) or insulin (r = 0.24, P = 0.3) concentrations in children with CAH. Our findings indicate that children with classic CAH have elevated fasting serum leptin and insulin concentrations, and insulin resistance. These most likely reflect differences in long-term adrenomedullary hypofunction and glucocorticoid therapy. Elevated leptin and insulin concentrations in patients

  20. Serum level of orexin-A, leptin, adiponectin and insulin in north Indian obese women.

    Science.gov (United States)

    Mishra, Sameeksha; Gupta, Vani; Mishra, Supriya; Sachan, Rekha; Asthana, Akash

    2017-12-01

    Obesity is regulated by different metabolic factors like leptin, adiponectin insulin and neuropeptide orexin-A. The aim of this study is to assess the role of these hormones and their interrelationship with obesity in north Indian women. A total of 168 obese women with Body Mass Index (BMI)>30kg/m 2 and 150 lean women (BMIWomen with obesity were further subdivided into two groups according to their BMI, 71 overweight women with the BMI 25-29.9kg/m 2 (mean±S.D: 27.87±0.71) and the 97 obese women with BMI>30kg/m 2 (34.68±1.90). Orexin -A, leptin and adiponectin were estimated using quantitative sandwich enzyme linked immunoassay and insulin was estimated by using an immuno-radiometric assay. Orexin -A and adiponectin level were significantly lower however, leptin and inulin level were significantly higher in obese women as compared with control group. Further, the one- way group analysis showed that the orexin -A and adiponectin level were significantly lower but leptin and insulin level was significantly higher in obese women as compared to overweight and control group respectively. Result showed that the level of adiponectin, leptin, orexin-A and insulin play an important role in the regulation of energy expenditure. In obesity, the activity of these peptides is disturbed. Copyright © 2017 Diabetes India. Published by Elsevier Ltd. All rights reserved.

  1. Serum leptin concentrations in children with type 1 diabetes mellitus: relationship to body mass index, insulin dose, and glycemic control.

    Science.gov (United States)

    Soliman, Ashraf T; Omar, Magdi; Assem, Hala M; Nasr, Ibrahim S; Rizk, Mohamed M; El Matary, Wael; El Alaily, Rania K

    2002-03-01

    Although obesity is a frequent feature of type 2 diabetes mellitus (DM), many patients with type 1 DM are prone to high body mass index (BMI). We measured serum leptin concentrations in a cohort of children (n = 55) with type 1 diabetes mellitus (DM), as well as their anthropometric parameters including BMI, skin fold thickness at multiple sites, and midarm circumference. Glycemic control was assessed by blood glucose (BG) monitoring before meals, and measurement of glycated hemoglobin (HbA1c) and insulin dose/kg/d was recorded. Dietary evaluation and assessment of caloric intake (kg/d) was performed by an expert dietitian. In the newly diagnosed children (n = 10) before initiation of insulin therapy, circulating leptin concentration was significantly lower (1.1 +/- 0.8 ng/dL) versus 5 days after insulin therapy (1.45 +/- 0.7 ng/dL). The decreased leptin level appears to be related to insulinopenia in these patients. In 45 children with type 1 DM on conventional therapy (2 doses of insulin mixture (NPH and regular) subcutaneous (SC) before breakfast and dinner for more than 2 years), serum leptin concentration was significantly higher (2.15 +/- 1 ng/dL) compared with age-matched normal children (1.3 +/- 1 ng/dL). Diabetic children were further divided into 2 groups according to their HbA1c level: group 1 with HbA1C less than 7.5% (less than 2 SD above the mean for normal population) (n = 29) and group 2 with HbA1c greater than 7.5%. (greater than 2 SD above the mean for normal population) (n = 16). Patients with a higher HbA1c level (group 2) had a higher leptin concentration (2.3 +/- 0.8 ng/dL), higher BMI (17.8 +/- 1.7), and were receiving higher insulin dose/kg (0.92 +/- 0.2 U/kg/d) compared with group 1 (lower HbA1c) (1.78 +/- 0.8 ng/dL, 16.7 +/- 1.5, and 0.59 +/- 0.2 U/kg/d, respectively). Group 2 patients had a higher incidence of late morning hypoglycemia (9/29) versus group 1 patients (2/16). Analysis of dietary intake showed that patients with a higher Hb

  2. Leptin and variables of body adiposity, energy balance, and insulin resistance in a population-based study. The Hoorn Study

    NARCIS (Netherlands)

    Ruige, J B; Dekker, J M; Blum, W F; Stehouwer, C D; Nijpels, G; Mooy, J; Kostense, P J; Bouter, L M; Heine, R J

    OBJECTIVE: Leptin is thought to play a key role in the control of body weight. There is a complex interrelationship between leptin and insulin or insulin resistance, but it is unknown how leptin is regulated. We therefore explored, in a large population-based study of 2,484 Caucasian subjects aged

  3. Ingestion of carbohydrate-rich supplements during gestation programs insulin and leptin resistance but not body weight gain in adult rat offspring

    Directory of Open Access Journals (Sweden)

    Bernard eBeck

    2012-06-01

    Full Text Available Prenatal nutritional conditions can predispose to development of obesity and metabolic syndrome in adulthood. Gestation with its important hormonal status modification is a period of changes in usual feeding habits with pulses or avoidance for certain categories of food. We tried to mimic in an animal model some changes in food consumption patterns observed in pregnant women. For this purpose, Long-Evans female rats were fed during the dark period, their usual pre-gestational food quantity, and were allowed to complete their intake with either a control (Cr, high-fat (HF, or high-carbohydrate (HC diet available ad libitum during the light period. Dams fed a control diet ad libitum (Ca served as controls. Body weight and composition, food intake, and metabolic hormones (insulin, leptin were recorded in male offspring until 20 weeks after birth. Cr and HC females ate less than Ca females ( -16%; p<0.001 and their offspring presented a weight deficit from birth until 6 (HC group and 10 (Cr group weeks of age (p<0.05 or less. Plasma leptin corresponded to low body weight in Cr offspring, but was increased in HC offspring that in addition, had increased plasma insulin, blood glucose and subcutaneous adipose tissue mass. HF dams ate more than Ca dams (+13%;p<0.001, but plasma leptin and insulin were similar in their offspring. Hypothalamic Ob-Rb expression was increased in Cr, HC and HF offspring (+33-100% vs. Ca; p<0.05 or less. HC supplement ingestion during gestation leads therefore to insulin and leptin resistance in adult offspring independently of lower birth weight. These hormonal changes characterize obesity-prone animals. We therefore suggest to be heedful of the carbohydrate content in the diet during the last weeks (or months preceding delivery to limit development of later metabolic disorders in offspring.

  4. Gene expression of leptin, resistin, and adiponectin in the white adipose tissue of obese patients with non-alcoholic fatty liver disease and insulin resistance.

    Science.gov (United States)

    Baranova, Ancha; Gowder, Shobha J; Schlauch, Karen; Elariny, Hazem; Collantes, Rochelle; Afendy, Arian; Ong, Janus P; Goodman, Zachary; Chandhoke, Vikas; Younossi, Zobair M

    2006-09-01

    Adipose tissue is an active endocrine organ that secretes a variety of metabolically important substances including adipokines. These factors affect insulin sensitivity and may represent a link between obesity, insulin resistance, type 2 diabetes (DM), and nonalcoholic fatty liver disease (NAFLD). This study uses real-time polymerase chain reaction (PCR) quantification of mRNAs encoding adiponectin, leptin, and resistin on snap-frozen samples of intra-abdominal adipose tissue of morbidly obese patients undergoing bariatric surgery. Morbidly obese patients undergoing bariatric surgery were studied. Patients were classified into two groups: Group A (with insulin resistance) (N=11; glucose 149.84 +/- 40.56 mg/dL; serum insulin 8.28 +/- 3.52 microU/mL), and Group B (without insulin resistance) (N=10; glucose 102.2 +/- 8.43 mg/dL; serum insulin 3.431 +/- 1.162 microU/mL). Adiponectin mRNA in intra-abdominal adipose tissue and serum adiponectin levels were significantly lower in Group A compared to Group B patients (P<0.016 and P<0.03, respectively). Although serum resistin was higher in Group A than in Group B patients (P<0.005), resistin gene expression was not different between the two groups. Finally, for leptin, neither serum level nor gene expression was different between the two groups. Serum adiponectin level was the only predictor of nonalcoholic steatohepatitis (NASH) in this study (P=0.024). Obese patients with insulin resistance have decreased serum adiponectin and increased serum resistin. Additionally, adiponectin gene expression is also decreased in the adipose tissue of these patients. This low level of adiponectin expression may predispose patients to the progressive form of NAFLD or NASH.

  5. Decreases in fasting leptin and insulin concentrations after acute energy restriction and subsequent compensation in food intake.

    Science.gov (United States)

    Mars, Monica; de Graaf, Cees; de Groot, Lisette C P G M; Kok, Frans J

    2005-03-01

    The decrease in leptin after energy restriction is a starvation signal to the brain. Several studies have found an association between this decrease and subjective appetite; however, no solid data are available on the acute decrease in fasting leptin concentration and subsequent caloric compensation. The objective was to assess the effect of acute decreases in fasting leptin concentrations, induced by energy restriction, on subsequent energy intake compensation. We hypothesized that men with a large decrease in fasting leptin concentrations would have larger ad libitum energy intakes than would men with a small decrease in leptin. Thirty-four male unrestrained eaters [age: 23 +/- 3 y; body mass index (in kg/m(2)): 22.3 +/- 1.6] participated in a semicontrolled intervention study. Fasting serum leptin and insulin concentrations were measured before and 2 d after 62% energy restriction. Energy intake was measured on the 2 following days on which food was provided ad libitum. During energy restriction, fasting leptin and insulin concentrations decreased by 27.2% (95% CI: -34.4%, -19.9%) and 30.7% (95% CI: -41.0%, -20.4%), respectively. Subjects consumed 143 +/- 27% of their estimated energy requirements (18.3 +/- 2.9 MJ) on the first day and 124 +/- 20% (16.0 +/- 2.6 MJ) on the second day of ad libitum intake. No significant correlations were observed between decreases in fasting leptin or insulin concentrations and subsequent ad libitum energy intake; however, decreases in insulin were correlated with an increase in carbohydrate intake (r=-0.49, P < 0.01). Although fasting leptin concentrations decreased significantly during energy restriction and subjects showed compensatory behavior during subsequent ad libitum food intake, no association was observed between the decrease in fasting leptin concentrations and caloric compensation.

  6. Relation of Absolute or Relative Adiposity to Insulin Resistance, Retinol Binding Protein-4, Leptin, and Adiponectin in Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    You Lim Kim

    2012-12-01

    Full Text Available BackgroundCentral fat mass (CFM correlates with insulin resistance and increases the risk of type 2 diabetes and cardiovascular complications; however, peripheral fat mass (PFM is associated with insulin sensitivity. The aim of this study was to investigate the relation of absolute and relative regional adiposity to insulin resistance index and adipokines in type 2 diabetes.MethodsTotal of 83 overweighted-Korean women with type 2 diabetes were enrolled, and rate constants for plasma glucose disappearance (KITT and serum adipokines, such as retinol binding protein-4 (RBP4, leptin, and adiponectin, were measured. Using dual X-ray absorptiometry, trunk fat mass (in kilograms was defined as CFM, sum of fat mass on the lower extremities (in kilograms as PFM, and sum of CFM and PFM as total fat mass (TFM. PFM/TFM ratio, CFM/TFM ratio, and PFM/CFM ratio were defined as relative adiposity.ResultsMedian age was 55.9 years, mean body mass index 27.2 kg/m2, and mean HbA1c level 7.12±0.84%. KITT was positively associated with PMF/TFM ratio, PMF/CFM ratio, and negatively with CFM/TFM ratio, but was not associated with TFM, PFM, or CFM. RBP4 levels also had a significant relationship with PMF/TFM ratio and PMF/CFM ratio. Adiponectin, leptin, and apolipoprotein A levels were related to absolute adiposity, while only adiponectin to relative adiposity. In correlation analysis, KITT in type 2 diabetes was positively related with HbA1c, fasting glucose, RBP4, and free fatty acid.ConclusionThese results suggest that increased relative amount of peripheral fat mass may aggravate insulin resistance in type 2 diabetes.

  7. Chapter 10: Glucose control: insulin therapy*

    African Journals Online (AJOL)

    Insulin and its analogues lower blood glucose by stimulating peripheral glucose uptake, especially by skeletal muscle and fat, and by inhibiting hepatic glucose production. Insulin inhibits ... control on 2 or 3 oral glucose lowering drugs.

  8. Living without insulin: the role of leptin signaling in the hypothalamus

    OpenAIRE

    Fujikawa Teppei; Coppari Roberto

    2015-01-01

    Since its discovery in 1922, insulin has been thought to be required for normal metabolic homeostasis and survival. However, this view would need to be revised as recent results from different laboratories have convincingly indicated that life without insulin is possible in rodent models. These data indicate that particular neuronal circuitries, which include hypothalamic leptin-responsive neurons, are empowered with the capability of permitting life in complete absence of insulin. Here, we r...

  9. Interplay between glucose and leptin signalling determines the strength of GABAergic synapses at POMC neurons.

    Science.gov (United States)

    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-03-26

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin's action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signalling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signalling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons.

  10. Effect of exogenous leptin on serum levels of lipids, glucose, renal and hepatic variables in both genders of obese and streptozotocin-induced diabetic rats

    Directory of Open Access Journals (Sweden)

    Parichehr Hayatdavoudi

    2015-11-01

    Full Text Available Objective(s: Leptin exerts various effects on appetite and body weight. Disruption of the obesitygene is precedent to fatness. Insulin or glucose elevates leptin, but streptozotocin reduces it. However, controversial data exist for the effects of leptin on diabetes and leptin level in each gender. Leptin can damage the kidney function but little evidence exists for its hepatic effects. The aim of this study was to investigate the probable sex-dependent differences in blood sugar levels, lipid profile, and renal and hepatic biochemical factors in the obesity and streptozotocin-induced diabetic rats after leptin administration. Materials and Methods: Wistar rats of both sexes were randomly divided into two groups, namely obese and diabetic rats. Each group was further divided into male and female subgroups. Extra fat and carbohydrate was added to the diet to induce obesity. Furthermore, streptozotocin (55 mg/kg, IP was injected to induce diabetes. The treatment groups received leptin (0.1 mg/kg SC for 10 days, and then, blood samples were taken from the orbital sinus for laboratory evaluations. Results: Leptin resulted in a significant weight loss in both sexes (P

  11. Comparison of serum leptin, glucose, total cholesterol and total protein levels in fertile and repeat breeder cows

    Directory of Open Access Journals (Sweden)

    Saime Guzel

    2014-12-01

    Full Text Available In the present study we measured serum glucose, leptin, total cholesterol and total protein concentrations in repeat breeder cows and compared them with fertile cows. For this aim, 20 repeat breeder cows and 20 fertile cows were used as material. Repeat breeder cows were found to have lower levels of leptin and glucose as compared with fertile ones. No significant differences in total cholesterol and total protein levels were observed between the two groups. No significant correlation of leptin with glucose, total cholesterol and total protein was observed in fertile and repeat breeder cows. Low concentrations of glucose and leptin can have some effects on reproductive problems as repeat breeder and help to understand potential mechanisms impairing fertility in repeat breeder cows.

  12. Effects of Insulin on Brain Glucose Metabolism in Impaired Glucose Tolerance

    Science.gov (United States)

    Hirvonen, Jussi; Virtanen, Kirsi A.; Nummenmaa, Lauri; Hannukainen, Jarna C.; Honka, Miikka-Juhani; Bucci, Marco; Nesterov, Sergey V.; Parkkola, Riitta; Rinne, Juha; Iozzo, Patricia; Nuutila, Pirjo

    2011-01-01

    OBJECTIVE Insulin stimulates brain glucose metabolism, but this effect of insulin is already maximal at fasting concentrations in healthy subjects. It is not known whether insulin is able to stimulate glucose metabolism above fasting concentrations in patients with impaired glucose tolerance. RESEARCH DESIGN AND METHODS We studied the effects of insulin on brain glucose metabolism and cerebral blood flow in 13 patients with impaired glucose tolerance and nine healthy subjects using positron emission tomography (PET). All subjects underwent PET with both [18F]fluorodeoxyglucose (for brain glucose metabolism) and [15O]H2O (for cerebral blood flow) in two separate conditions (in the fasting state and during a euglycemic-hyperinsulinemic clamp). Arterial blood samples were acquired during the PET scans to allow fully quantitative modeling. RESULTS The hyperinsulinemic clamp increased brain glucose metabolism only in patients with impaired glucose tolerance (whole brain: +18%, P = 0.001) but not in healthy subjects (whole brain: +3.9%, P = 0.373). The hyperinsulinemic clamp did not alter cerebral blood flow in either group. CONCLUSIONS We found that insulin stimulates brain glucose metabolism at physiological postprandial levels in patients with impaired glucose tolerance but not in healthy subjects. These results suggest that insulin stimulation of brain glucose metabolism is maximal at fasting concentrations in healthy subjects but not in patients with impaired glucose tolerance. PMID:21270256

  13. Hormonal and adiposity state of women with polycystic ovary syndrome: implication of adiponectin and leptin

    Directory of Open Access Journals (Sweden)

    Aleksandra Atanasova Boshku

    2016-12-01

    Full Text Available Obesity and insulin resistance are frequently seen comorbidities in patients with polycystic ovary syndrome (PCOS, affecting the already disturbed metabolism of these patients. Disturbed secretion of adiponectin and leptin could be one of the contributing factors of obesity and insulin resistance in patients with PCOS. The aim of this study was to determine the levels of adiponectin and leptin in PCOS patients, as well as their association with other components of the syndrome. This cross-sectional study determined clinical, hormonal, and biochemical markers in 61 women with PCOS and 56 controls. There was a statistically significant difference in adiponectin and leptin between the groups (p>0.001. There was a significant negative correlation between adiponectin, body mass index (BMI, and waist circumference (r= -0.478; -0.452, p<0.001 and a negative correlation with testosterone, free androgen index (FAI, insulin, and the homeostasis model assessment for insulin resistance (HOMA-IR. A positive correlation between adiponectin, sex hormone binding globulin (SHGB, and fasting glucose levels was present. Correlation analysis of leptin with other metabolic parameters showed a positive correlation with BMI, waist circumference, insulin, and HOMA-IR. A significant inverse correlation was present between leptin and SHGB. In conclusion, adiponectin and leptin may serve as potential biomarkers of insulin resistance. Determining levels of adiponectin and leptin in the early course of this syndrome may enable earlier diagnosis of insulin resistance, or even early prevention in PCOS patients.

  14. Positive correlation of serum leptin with estradiol levels in patients with polycystic ovary syndrome

    Directory of Open Access Journals (Sweden)

    Mendonça H.C.

    2004-01-01

    Full Text Available Patients with polycystic ovary syndrome (PCOS usually are obese, insulin resistant and hyperinsulinemic. The known association between leptin, obesity andinsulin action suggests that leptin may have a role in PCOS but this has only been addressed peripherally. This study was designed to assess the relationship between serum leptin and the anthropometric, metabolic and endocrine variables of obese (body mass index, BMI ³30 kg/m² and non-obese (BMI <30 kg/m² PCOS patients. Twenty-eight PCOS patients and 24 control women subdivided into obese and non-obese groups were evaluated. Leptin, androgens, lipids, gonadotrophins and insulin-glucose response to the oral glucose tolerance test were measured by radioimmunoassay in all participants. The assays were done all in one time. The areas under the insulin curve (AUC-I and the glycemia curve were calculated to identify patients with insulin resistance. Mean leptin levels were not significantly higher in patients with PCOS compared to the control group (21.2 ± 10.2 vs 27.3 ± 12.4 ng/ml. Leptin levels were found to be significantly higher in the obese subgroups both in patients with PCOS (26.9 ± 9.3 vs 14.1 ± 7.0 ng/ml and in the control group (37.3 ± 15.5 vs 12.9 ± 5.8 ng/ml. The leptin of the PCOS group was correlated with BMI (r = 0.74; P < 0.0001 and estradiol (r = 0.48; P < 0.008 and tended to be correlated with the AUC-I (r = 0.36; P = 0.05. Of the parameters which showed a correlation with leptin in PCOS, only estradiol and probably insulinemia (AUC-I did not show a significant correlation with BMI, suggesting that the other parameters were correlated with leptin due to their correlation with BMI. Estradiol correlated with leptin in PCOS patients regardless of their weight.

  15. Insulin-stimulated glucose uptake in healthy and insulin-resistant skeletal muscle

    DEFF Research Database (Denmark)

    Deshmukh, Atul S

    2016-01-01

    transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type...... 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle....

  16. Effects of insulin and leptin in the ventral tegmental area and arcuate hypothalamic nucleus on food intake and brain reward function in female rats.

    Science.gov (United States)

    Bruijnzeel, Adrie W; Corrie, Lu W; Rogers, Jessica A; Yamada, Hidetaka

    2011-06-01

    There is evidence for a role of insulin and leptin in food intake, but the effects of these adiposity signals on the brain reward system are not well understood. Furthermore, the effects of insulin and leptin on food intake in females are underinvestigated. These studies investigated the role of insulin and leptin in the ventral tegmental area (VTA) and the arcuate hypothalamic nucleus (Arc) on food intake and brain reward function in female rats. The intracranial self-stimulation procedure was used to assess the effects of insulin and leptin on the reward system. Elevations in brain reward thresholds are indicative of a decrease in brain reward function. The bilateral administration of leptin into the VTA (15-500 ng/side) or Arc (15-150 ng/side) decreased food intake for 72 h. The infusion of leptin into the VTA or Arc resulted in weight loss during the first 48 (VTA) or 24 h (Arc) after the infusions. The administration of insulin (0.005-5 mU/side) into the VTA or Arc decreased food intake for 24 h but did not affect body weights. The bilateral administration of low, but not high, doses of leptin (15 ng/side) or insulin (0.005 mU/side) into the VTA elevated brain reward thresholds. Neither insulin nor leptin in the Arc affected brain reward thresholds. These studies suggest that a small increase in leptin or insulin levels in the VTA leads to a decrease in brain reward function. A relatively large increase in insulin or leptin levels in the VTA or Arc decreases food intake. Published by Elsevier B.V.

  17. Taurine ameliorates hyperglycemia and dyslipidemia by reducing insulin resistance and leptin level in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term diabetes

    Science.gov (United States)

    Oh, Da Hee; Kim, Jung Yeon; Lee, Bong Gn; You, Jeong Soon; Chang, Kyung Ja; Chung, Hyunju; Yoo, Myung Chul; Yang, Hyung-In; Kang, Ja-Heon; Hwang, Yoo Chul; Ahn, Kue Jeong; Chung, Ho-Yeon

    2012-01-01

    This study aimed to determine whether taurine supplementation improves metabolic disturbances and diabetic complications in an animal model for type 2 diabetes. We investigated whether taurine has therapeutic effects on glucose metabolism, lipid metabolism, and diabetic complications in Otsuka Long-Evans Tokushima fatty (OLETF) rats with long-term duration of diabetes. Fourteen 50-week-old OLETF rats with chronic diabetes were fed a diet supplemented with taurine (2%) or a non-supplemented control diet for 12 weeks. Taurine reduced blood glucose levels over 12 weeks, and improved OGTT outcomes at 6 weeks after taurine supplementation, in OLETF rats. Taurine significantly reduced insulin resistance but did not improve β-cell function or islet mass. After 12 weeks, taurine significantly decreased serum levels of lipids such as triglyceride, cholesterol, high density lipoprotein cholesterol, and low density lipoprotein cholesterol. Taurine significantly reduced serum leptin, but not adiponectin levels. However, taurine had no therapeutic effect on damaged tissues. Taurine ameliorated hyperglycemia and dyslipidemia, at least in part, by improving insulin sensitivity and leptin modulation in OLETF rats with long-term diabetes. Additional study is needed to investigate whether taurine has the same beneficial effects in human diabetic patients. PMID:23114424

  18. Diagnostic utility of leptin and insulin-like growth factor binding ...

    African Journals Online (AJOL)

    Serum levels of leptin, insulin growth factor binding protein-2 (IGFBP-2) and alpha fetoprotein (AFP) were measured. ... renewal in response to nutrients. IGF pathway is not only involved in cell growth in tissue culture, but it is also involved in ...

  19. Bilirubin Increases Insulin Sensitivity by Regulating Cholesterol Metabolism, Adipokines and PPARγ Levels

    Science.gov (United States)

    Liu, Jinfeng; Dong, Huansheng; Zhang, Yong; Cao, Mingjun; Song, Lili; Pan, Qingjie; Bulmer, Andrew; Adams, David B.; Dong, Xiao; Wang, Hongjun

    2015-01-01

    Obesity can cause insulin resistance and type 2 diabetes. Moderate elevations in bilirubin levels have anti-diabetic effects. This study is aimed at determining the mechanisms by which bilirubin treatment reduces obesity and insulin resistance in a diet-induced obesity (DIO) mouse model. DIO mice were treated with bilirubin or vehicle for 14 days. Body weights, plasma glucose, and insulin tolerance tests were performed prior to, immediately, and 7 weeks post-treatment. Serum lipid, leptin, adiponectin, insulin, total and direct bilirubin levels were measured. Expression of factors involved in adipose metabolism including sterol regulatory element-binding protein (SREBP-1), insulin receptor (IR), and PPARγ in liver were measured by RT-PCR and Western blot. Compared to controls, bilirubin-treated mice exhibited reductions in body weight, blood glucose levels, total cholesterol (TC), leptin, total and direct bilirubin, and increases in adiponectin and expression of SREBP-1, IR, and PPARγ mRNA. The improved metabolic control achieved by bilirubin-treated mice was persistent: at two months after treatment termination, bilirubin-treated DIO mice remained insulin sensitive with lower leptin and higher adiponectin levels, together with increased PPARγ expression. These results indicate that bilirubin regulates cholesterol metabolism, adipokines and PPARγ levels, which likely contribute to increased insulin sensitivity and glucose tolerance in DIO mice. PMID:26017184

  20. The effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women

    OpenAIRE

    Khoshdel, Abolfazl; Kheiri, Soleiman; Nasiri, Jafar; Tehran, Hoda Ahmari; Heidarian, Esfandiar

    2014-01-01

    Background: Many pregnant Muslim women choose to fast during Ramadan every year worldwide. This study aimed to examine the effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women and find whether fasting during pregnancy could have a negative effect on the health of mothers and fetuses. Methods: This cross-sectional study was conducted on 39 healthy volunteer fasting pregnant women. Serum leptin, neuropeptide Y, insulin levels, body mass index and weight were m...

  1. The effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women.

    Science.gov (United States)

    Khoshdel, Abolfazl; Kheiri, Soleiman; Nasiri, Jafar; Tehran, Hoda Ahmari; Heidarian, Esfandiar

    2014-01-01

    Many pregnant Muslim women choose to fast during Ramadan every year worldwide. This study aimed to examine the effect of Ramadan fasting on serum leptin, neuropeptide Y and insulin in pregnant women and find whether fasting during pregnancy could have a negative effect on the health of mothers and fetuses. This cross-sectional study was conducted on 39 healthy volunteer fasting pregnant women. Serum leptin, neuropeptide Y, insulin levels, body mass index and weight were measured five times on 0, 7th, 14th and 28th days of Ramadan and on the 14th day post-Ramadan. The data were analyzed by SPSS software (version 11.5) using repeated measures ANOVA to find whether any changes occurred in the variables of interest during the study, and Pearson correlation coefficient was used to examine the relations among the variables. A significant change in fasting blood sugar, neuropeptide Y and leptin was observed during the study (pRamadan and increased after Ramadan, with the lowest value at the end of Ramadan. Neuropeptide Y increased both during Ramadan and two weeks after Ramadan. Also, leptin decreased significantly two weeks after Ramadan compared to the end of Ramadan. No significant change was observed in insulin level during the study (p>0.05). The result of this study revealed the important role of leptin and neuropeptide Y in the long term regulation of energy balance in pregnant women with chronic diurnal fasting, and it further revealed that Ramadan fasting did not significantly change the serum insulin level.

  2. Glucose tolerance, insulin release, and insulin binding to monocytes in kidney transplant recipients

    International Nuclear Information System (INIS)

    Briggs, W.A.; Wielechowski, K.S.; Mahajan, S.K.; Migdal, S.D.; McDonald, F.D.

    1982-01-01

    In order to evaluate glucose tolerance following renal transplantation, intravenous glucose tolerance tests (IVGTT), with evaluation of hormonal responses to the intravenous glucose load and percent specific 125 I-insulin binding to peripheral blood monocytes, were studied in eight clinically stable kidney transplant recipients. For comparison purposes, identical studies were done in eight control subjects and seven clinically stable hemodialysis patients. One transplant recipient was glucose intolerant, with fasting hyperglycemia, elevated HbA1C, and abnormal glucose decay constant. Impaired pancreatic insulin release appeared to be the major factor accounting for his glucose intolerance. The seven glucose-tolerant transplant recipients had significantly increased insulin release during IVGTT compared to control subjects, and significant correlations were found among insulin release, glucose decay constant, and fasting blood sugar in those patients. Insulin binding to monocytes was significantly greater in transplant recipients than control subjects due to an increase in insulin binding capacity per cell. A significant correlation was found between percent specific 125 I-insulin binding and steroid dose, expressed as mg/kg body weight/day, in those patients. Thus, chronic steroid administration does not cause glucose intolerance in transplant recipients who manifest steroid-associated increases in pancreatic insulin release and cellular insulin binding capacity

  3. Resistant starch lowers postprandial glucose and leptin in overweight adults consuming a moderate-to-high-fat diet: a randomized-controlled trial.

    Science.gov (United States)

    Maziarz, Mindy Patterson; Preisendanz, Sara; Juma, Shanil; Imrhan, Victorine; Prasad, Chandan; Vijayagopal, Parakat

    2017-02-21

    High-amylose maize resistant starch type 2 (HAM-RS2) stimulates gut-derived satiety peptides and reduces adiposity in animals. Human studies have not supported these findings despite improvements in glucose homeostasis and insulin sensitivity after HAM-RS2 intake which can lower adiposity-related disease risk. The primary objective of this study was to evaluate the impact of HAM-RS2 consumption on blood glucose homeostasis in overweight, healthy adults. We also examined changes in biomarkers of satiety (glucagon-like peptide-1 [GLP-1], peptide YY [PYY], and leptin) and body composition determined by anthropometrics and dual-energy x-ray absorptiometry, dietary intake, and subjective satiety measured by a visual analogue scale following HAM-RS2 consumption. Using a randomized-controlled, parallel-arm, double-blind design, 18 overweight, healthy adults consumed either muffins enriched with 30 g HAM-RS2 (n = 11) or 0 g HAM-RS2 (control; n = 7) daily for 6 weeks. The HAM-RS2 and control muffins were similar in total calories and available carbohydrate. At baseline, total PYY concentrations were significantly higher 120 min following the consumption of study muffins in the HAM-RS2 group than control group (P = 0.043). Within the HAM-RS2 group, the area under the curve (AUC) glucose (P = 0.028), AUC leptin (P = 0.022), and postprandial 120-min leptin (P = 0.028) decreased independent of changes in body composition or overall energy intake at the end of 6 weeks. Fasting total PYY increased (P = 0.033) in the HAM-RS2 group, but changes in insulin or total GLP-1 were not observed. Mean overall change in subjective satiety score did not correlate with mean AUC biomarker changes suggesting the satiety peptides did not elicit a satiation response or change in overall total caloric intake. The metabolic response from HAM-RS2 occurred despite the habitual intake of a moderate-to-high-fat diet (mean range 34.5% to 39.4% of total calories). Consuming 30

  4. Leptin and insulin responses to a four-day energy-deficient diet in men with different weight history

    NARCIS (Netherlands)

    Mars, M.; de Graaf, C; Rossum, C.T.M; de Groot, C.P.G.M.; Seidell, J C; Kok, F. J.

    2003-01-01

    OBJECTIVE: To assess the leptin responses to a 4-day energy-restricted diet in men with different weight history; high retrospective weight gain was expected to be associated with a small decline in leptin. DESIGN: Changes in fasting leptin and insulin were measured during a 4-day controlled

  5. Adipocytokine Associations with Insulin Resistance in British South Asians

    Directory of Open Access Journals (Sweden)

    D. R. Webb

    2013-01-01

    Full Text Available Aims. Adipocytokines are implicated in the pathogenesis of type 2 diabetes and may represent identifiable precursors of metabolic disease within high-risk groups. We investigated adiponectin, leptin, and TNF-α and assessed the contribution of these molecules to insulin resistance in south Asians. Hypothesis. South Asians have adverse adipocytokine profiles which associate with an HOMA-derived insulin resistance phenotype. Methods. We measured adipocytokine concentrations in south Asians with newly diagnosed impaired glucose tolerance or Type 2 Diabetes Mellitus in a case-control study. 158 (48.5% males volunteers aged 25–75 years with risk factors for diabetes but no known vascular or metabolic disease provided serum samples for ELISA and bioplex assays. Results. Total adiponectin concentration progressively decreased across the glucose spectrum in both sexes. A reciprocal trend in leptin concentration was observed only in south Asian men. Adiponectin but not leptin independently associated with HOMA-derived insulin resistance after logistic multivariate regression. Conclusion. Diasporic south Asian populations have an adverse adipocytokine profile which deteriorates further with glucose dysregulation. Insulin resistance is inversely associated with adiponectin independent of BMI and waist circumference in south Asians, implying that adipocytokine interplay contributes to the pathogenesis of metabolic disease in this group.

  6. Association of adiponectin/leptin ratio with carbohydrate and lipid metabolism parameters in HIV-infected patients during antiretroviral therapy.

    Science.gov (United States)

    Tiliscan, Catalin; Arama, Victoria; Mihailescu, Raluca; Munteanu, Daniela; Iacob, Diana Gabriela; Popescu, Cristina; Catana, Remulus; Negru, Anca; Lobodan, Alina; Arama, Stefan Sorin

    2018-02-16

    Adiponectin and leptin are adipose tissue hormones that regulate important lipid and glucose metabolic pathways. Our objective was to evaluate the interplay of these hormones described by the adiponectin/leptin ratio (ALR) in correlation to lipid and carbohydrate metabolism parameters in nondiabetic HIV-infected patients during antiretroviral therapy (ART). We enrolled consecutive nondiabetic patients with confirmed HIV infection, undergoing stable ART regimens for at least six months. Blood samples were collected and tested for immunological and virological parameters, adiponectin and leptin, fasting insulin, fasting plasma glucose, fasting triglycerides, total cholesterol, LDL cholesterol, and HDL cholesterol. ALR was computed for each patient. Resistance to insulin was assessed by calculating the Quantitative Insulin Sensitivity Check Index (QUICKI). We enrolled 87 HIV-infected persons, with a mean age of 31.7 years (range: 18-65), including 47 men (mean age = 32.8 years) and 40 women (mean age = 30.5 years). The median value of ALR was 6.8 (interquartile range - IQR = 17.1). In male patients, ALR was inversely associated with the serum level of triglycerides (R = 0.285, p = 0.05), total cholesterol (R = 0.326, p = 0.02), and LDL cholesterol (R = 0.298, p = 0.04). Also for the male cohort, an increase in ALR seemed to improve insulin sensitivity (R = 0.323, p = 0.02) and serum HDL cholesterol (R = 0.597, p = 0.01). None of these correlations were observed in HIV-infected women. Adiponectin and leptin seem to play important but different gender-specific roles in the pathogenesis of lipid and glucose metabolism of HIV-infected patients undergoing antiretroviral therapy. ALR, adiponectin/leptin ratio; BMI, body mass index; LDL, low-density lipoprotein; HDL, high-density lipoprotein; QUICKI, Quantitative Insulin Sensitivity Check Index.

  7. Relationship between red cell membrane fatty acids and adipokines in individuals with varying insulin sensitivity.

    Science.gov (United States)

    Min, Y; Lowy, C; Islam, S; Khan, F S; Swaminathan, R

    2011-06-01

    Plasma leptin and adiponectin, and membrane phospholipid fatty acid composition are implicated into the mechanism of insulin resistance but no clear pattern has emerged. Hence, this study examined these variables in subjects presenting to the diabetic clinic for a diagnostic glucose tolerance test. Body composition, glucose, glycated hemoglobin, insulin, leptin, adiponectin, and red cell and plasma phospholipid fatty acids were assessed from 42 normal and 28 impaired glucose tolerant subjects. Insulin sensitivity was determined by homeostatic model assessment. The plasma phosphatidylcholine fatty acid composition of the impaired glucose tolerant subjects was similar to that of normal subjects. However, the impaired glucose tolerant subjects had significantly lower linoleic (Pphosphatidylcholine and phosphatidylethanolamine compared with the normal subjects. Moreover, red cell phosphatidylcholine docosahexaenoic acid correlated positively with adiponectin (r=0.290, Pinsulin (r=-0.335, Pinsulin resistance (r=-0.322, Pinsulin level whereas insulin was the only component that predicted the membrane fatty acids. We postulate that membrane phospholipids fatty acids have an indirect role in determining insulin concentration but insulin has a major role in determining membrane fatty acid composition.

  8. Changes in Glucose Homeostasis after Roux-en-Y Gastric Bypass Surgery for Obesity at Day Three, Two Months, and One Year after Surgery

    DEFF Research Database (Denmark)

    Falkén, Y; Hellström, P M; Holst, Jens Juul

    2011-01-01

    Context: Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood. Main Objective: The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose-dependent in......Context: Endocrine effects of gastric bypass (GBP) surgery for obesity on glucose homeostasis are not fully understood. Main Objective: The main objective of the study was to assess the changes in plasma glucose, insulin, glucagon-like peptide-1 (GLP-1), leptin, somatostatin, glucose......-dependent insulinotropic peptide, enteroglucagon, and glucagon early after GBP. Method: Twelve obese subjects (body mass index 45.3 ± 1.9 kg/m2) were subjected to a liquid meal without lipids before and 3 d, 2 months, and 1 yr after GBP. Plasma concentrations of glucose, insulin, leptin, and gut peptide hormones were...... index 30.3 ± 1.8 kg/m2 at 1 yr). Fasting glucose was significantly lower on d 3 (P

  9. Effects of intranasal insulin on endogenous glucose production in insulin-resistant men.

    Science.gov (United States)

    Xiao, Changting; Dash, Satya; Stahel, Priska; Lewis, Gary F

    2018-03-14

    The effects of intranasal insulin on the regulation of endogenous glucose production (EGP) in individuals with insulin resistance were assessed in a single-blind, crossover study. Overweight or obese insulin-resistant men (n = 7; body mass index 35.4 ± 4.4 kg/m 2 , homeostatic model assessment of insulin resistance 5.6 ± 1.6) received intranasal spray of either 40 IU insulin lispro or placebo in 2 randomized visits. Acute systemic spillover of intranasal insulin into the circulation was matched with a 30-minute intravenous infusion of insulin lispro in the nasal placebo arm. EGP was assessed under conditions of a pancreatic clamp with a primed, constant infusion of glucose tracer. Under these experimental conditions, compared with placebo, intranasal administration of insulin did not significantly affect plasma glucose concentrations, EGP or glucose disposal in overweight/obese, insulin-resistant men, in contrast to our previous study, in which an equivalent dose of intranasal insulin significantly suppressed EGP in lean, insulin-sensitive men. Insulin resistance is probably associated with impairment in centrally mediated insulin suppression of EGP. © 2018 John Wiley & Sons Ltd.

  10. Urinary tract infection during pregnancy affects the level of leptin, ghrelin and insulin in maternal and placental blood.

    Science.gov (United States)

    Piatek, Jacek; Gibas-Dorna, Magdalena; Budzynski, Wlodzimierz; Krauss, Hanna; Marzec, Ewa; Olszewski, Jan; Zukiewicz-Sobczak, Wioletta

    2014-03-01

    We examined ghrelin, leptin and insulin in maternal blood during normal pregnancy and pregnancy complicated by urinary tract infection (UTI), as well as in cord blood at labor. A total of 36 delivering women with history of UTI during the third trimester of pregnancy were enrolled in the study; 12 healthy pregnant women served as a control. Infection markers (CRP and procalcitonin) were determined in maternal blood during the course of UTI and at labor. Ghrelin, leptin and insulin were determined during labor in venous maternal and in umbilical cord blood. We found negative correlation between infection markers in maternal blood during UTI, and level of tested hormones in cord blood, indicating potential risk of placental impairment due to energetic imbalance. We noted lower level of leptin in mothers with UTI and no change in leptin from umbilical blood comparing subjects with and without UTI. Low level of ghrelin was observed in maternal and cord blood when pregnancy was complicated by UTI. Insulin concentrations were high in mothers with UTI and low in their newborn's cord blood. Increased maternal insulin level could indicate peripheral insulin resistance caused by the infection. UTI during pregnancy affects the concentration of hormones responsible for regulating energetic homeostasis within the placenta.

  11. Harnessing insulin- and leptin-induced oxidation of PTP1B for therapeutic development.

    Science.gov (United States)

    Krishnan, Navasona; Bonham, Christopher A; Rus, Ioana A; Shrestha, Om Kumar; Gauss, Carla M; Haque, Aftabul; Tocilj, Ante; Joshua-Tor, Leemor; Tonks, Nicholas K

    2018-01-18

    The protein tyrosine phosphatase PTP1B is a major regulator of glucose homeostasis and energy metabolism, and a validated target for therapeutic intervention in diabetes and obesity. Nevertheless, it is a challenging target for inhibitor development. Previously, we generated a recombinant antibody (scFv45) that recognizes selectively the oxidized, inactive conformation of PTP1B. Here, we provide a molecular basis for its interaction with reversibly oxidized PTP1B. Furthermore, we have identified a small molecule inhibitor that mimics the effects of scFv45. Our data provide proof-of-concept that stabilization of PTP1B in an inactive, oxidized conformation by small molecules can promote insulin and leptin signaling. This work illustrates a novel paradigm for inhibiting the signaling function of PTP1B that may be exploited for therapeutic intervention in diabetes and obesity.

  12. Interplay between glucose and leptin signaling determines the strength of GABAergic synapses at POMC neurons

    Science.gov (United States)

    Lee, Dong Kun; Jeong, Jae Hoon; Chun, Sung-Kun; Chua, Streamson; Jo, Young-Hwan

    2015-01-01

    Regulation of GABAergic inhibitory inputs and alterations in POMC neuron activity by nutrients and adiposity signals regulate energy and glucose homeostasis. Thus, understanding how POMC neurons integrate these two signal molecules at the synaptic level is important. Here we show that leptin’s action on GABA release to POMC neurons is influenced by glucose levels. Leptin stimulates the JAK2-PI3K pathway in both presynaptic GABAergic terminals and postsynaptic POMC neurons. Inhibition of AMPK activity in presynaptic terminals decreases GABA release at 10 mM glucose. However, postsynaptic TRPC channel opening by the PI3K-PLC signaling pathway in POMC neurons enhances spontaneous GABA release via activation of presynaptic MC3/4 and mGlu receptors at 2.5 mM glucose. High-fat feeding blunts AMPK-dependent presynaptic inhibition, whereas PLC-mediated GABAergic feedback inhibition remains responsive to leptin. Our data indicate that the interplay between glucose and leptin signaling in glutamatergic POMC neurons is critical for determining the strength of inhibitory tone towards POMC neurons. PMID:25808323

  13. Study of Blood Leptin Levels before and After Treatment with Metformin in Diabetes Type Ii Patients

    Directory of Open Access Journals (Sweden)

    R Didehdar

    2005-04-01

    Full Text Available Introduction: Leptin is a fat tissue hormone that has 176 amino acids with a molecular weight of 16 KD . Leptin has effects on the hypothalamus and peripheral tissues resulting in decreased food absorption and increased energy consumption that finally reduces the body weight and BMI. The aim of this research was to investigate the blood levels of leptin before and after treatment with Metformin in type II diabetic patients. Methods: 25 type II diabetic patients without any previous drug treatment history were investigated. This study was a clinical trail before and after treatment with Metformin. Results: There was no particular difference in BMI, average body weight, fat mass and free fat mass before and after treatment. Similarly, the difference in concentration levels of blood glucose, cholesterol, tri-glycerides and LDL-cholesterol before and after treatment was not statistically significant. Also, there was no difference in the average concentration of leptin and insulin before and after treatment Conclusion: This result showed that although metformin decreased glucose and lipid levels during the treatment period, (1 month it did not have an effect on leptin, Insulin and other related factors during treatment.;

  14. Glut2-dependent glucose-sensing controls thermoregulation by enhancing the leptin sensitivity of NPY and POMC neurons.

    Science.gov (United States)

    Mounien, Lourdes; Marty, Nell; Tarussio, David; Metref, Salima; Genoux, David; Preitner, Frédéric; Foretz, Marc; Thorens, Bernard

    2010-06-01

    The physiological contribution of glucose in thermoregulation is not completely established nor whether this control may involve a regulation of the melanocortin pathway. Here, we assessed thermoregulation and leptin sensitivity of hypothalamic arcuate neurons in mice with inactivation of glucose transporter type 2 (Glut2)-dependent glucose sensing. Mice with inactivation of Glut2-dependent glucose sensors are cold intolerant and show increased susceptibility to food deprivation-induced torpor and abnormal hypothermic response to intracerebroventricular administration of 2-deoxy-d-glucose compared to control mice. This is associated with a defect in regulated expression of brown adipose tissue uncoupling protein I and iodothyronine deiodinase II and with a decreased leptin sensitivity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons, as observed during the unfed-to-refed transition or following i.p. leptin injection. Sites of central Glut-2 expression were identified by a genetic tagging approach and revealed that glucose-sensitive neurons were present in the lateral hypothalamus, the dorsal vagal complex, and the basal medulla but not in the arcuate nucleus. NPY and POMC neurons were, however, connected to nerve terminals from Glut2-expressing neurons. Thus, our data suggest that glucose controls thermoregulation and the leptin sensitivity of NPY and POMC neurons through activation of Glut2-dependent glucose-sensing neurons located outside of the arcuate nucleus.

  15. Development of glucose-responsive 'smart' insulin systems.

    Science.gov (United States)

    Rege, Nischay K; Phillips, Nelson F B; Weiss, Michael A

    2017-08-01

    The complexity of modern insulin-based therapy for type I and type II diabetes mellitus and the risks associated with excursions in blood-glucose concentration (hyperglycemia and hypoglycemia) have motivated the development of 'smart insulin' technologies (glucose-responsive insulin, GRI). Such analogs or delivery systems are entities that provide insulin activity proportional to the glycemic state of the patient without external monitoring by the patient or healthcare provider. The present review describes the relevant historical background to modern GRI technologies and highlights three distinct approaches: coupling of continuous glucose monitoring (CGM) to deliver devices (algorithm-based 'closed-loop' systems), glucose-responsive polymer encapsulation of insulin, and molecular modification of insulin itself. Recent advances in GRI research utilizing each of the three approaches are illustrated; these include newly developed algorithms for CGM-based insulin delivery systems, glucose-sensitive modifications of existing clinical analogs, newly developed hypoxia-sensitive polymer matrices, and polymer-encapsulated, stem-cell-derived pancreatic β cells. Although GRI technologies have yet to be perfected, the recent advances across several scientific disciplines that are described in this review have provided a path towards their clinical implementation.

  16. Relationships between changes in leptin and insulin resistance levels in obese individuals following weight loss

    Directory of Open Access Journals (Sweden)

    Tsu-Nai Wang

    2013-08-01

    Full Text Available Obesity can augment insulin resistance (IR, leading to increased risk of diabetes and heart disease. Leptin, ghrelin, and various fatty acids present in the cell membrane may modulate IR. In this study, we aimed to investigate the impact of weight loss on IR, serum leptin/ghrelin levels, and erythrocyte fatty acids, and studied the associations between changes in these variables. A total of 35 obese (body mass index ≥ 27 adults participated in a weight loss program for 3 months. IR was assessed using homeostasis model assessment for insulin resistance (HOMA-IR. The obese participants had a mean weight loss of 5.6 ± 3.8 kg followed by a 16.7% and 23.3% reduction in HOMA-IR and leptin (p  0.05 levels. After adjusting for age, gender, changes in ghrelin, and body fat, we found a significant correlation between decreases in leptin and less risk of no improvement in HOMA-IR levels [odds ratio (OR = 0.69, p = 0.039]. In conclusion, a moderate weight reduction in obese participants over a short period significantly improved IR. This weight reduction concomitantly decreased serum leptin, increased ghrelin, and elevated some erythrocyte unsaturates. Only leptin correlated independently with IR improvement upon multivariable logistic regression analysis, which indicates that leptin may play a role in the modulation of IR following weight loss.

  17. Ghrelin, leptin and insulin in cirrhotic children and adolescents: relationship with cirrhosis severity and nutritional status.

    Science.gov (United States)

    Dornelles, Cristina T L; Goldani, Helena A S; Wilasco, Maria Inês A; Maurer, Rafael L; Kieling, Carlos O; Porowski, Marilene; Ferreira, Cristina T; Santos, Jorge L; Vieira, Sandra M G; Silveira, Themis R

    2013-01-10

    Ghrelin, leptin, and insulin concentrations are involved in the control of food intake and they seem to be associated with anorexia-cachexia in cirrhotic patients. The present study aimed to investigate the relationship between the nutritional status and fasting ghrelin, leptin and insulin concentrations in pediatric cirrhotic patients. Thirty-nine patients with cirrhosis and 39 healthy controls aged 0-15 years matched by sex and age were enrolled. Severity of liver disease was assessed by Child-Pugh classification, and Pediatric for End Stage Liver Disease (PELD) or Model for End-stage Liver Disease (MELD) scores. Blood samples were collected from patients and controls to assay total ghrelin, acyl ghrelin, leptin and insulin by using a commercial ELISA kit. Anthropometry parameters used were standard deviation score of height-for-age and triceps skinfold thickness-for-age ratio. A multiple linear regression analysis was used to determine the correlation between dependent and independent variables. Acyl ghrelin was significantly lower in cirrhotic patients than in controls [142 (93-278) pg/mL vs 275 (208-481) pg/mL, P=0.001]. After multiple linear regression analysis, total ghrelin and acyl ghrelin showed an inverse correlation with age; acyl ghrelin was associated with the severity of cirrhosis and des-acyl ghrelin with PELD or MELD scores ≥15. Leptin was positively correlated with gender and anthropometric parameters. Insulin was not associated with any variable. Low acyl ghrelin and high des-acyl ghrelin concentrations were associated with cirrhosis severity, whereas low leptin concentration was associated with undernourishment in children and adolescents with cirrhosis. Copyright © 2012 Elsevier B.V. All rights reserved.

  18. Serum Insulin, Glucose, Indices of Insulin Resistance, and Risk of Lung Cancer.

    Science.gov (United States)

    Argirion, Ilona; Weinstein, Stephanie J; Männistö, Satu; Albanes, Demetrius; Mondul, Alison M

    2017-10-01

    Background: Although insulin may increase the risk of some cancers, few studies have examined fasting serum insulin and lung cancer risk. Methods: We examined serum insulin, glucose, and indices of insulin resistance [insulin:glucose molar ratio and homeostasis model assessment of insulin resistance (HOMA-IR)] and lung cancer risk using a case-cohort study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish men. A total of 196 cases and 395 subcohort members were included. Insulin and glucose were measured in fasting serum collected 5 to 12 years before diagnosis. Cox proportional hazards models were utilized to estimate the relative risk of lung cancer. Results: The average time between blood collection and lung cancer was 9.6 years. Fasting serum insulin levels were 8.7% higher in subcohort members than cases. After multivariable adjustment, men in the fourth quartile of insulin had a significantly higher risk of lung cancer than those in the first quartile [HR = 2.10; 95% confidence interval (CI), 1.12-3.94]. A similar relationship was seen with HOMA-IR (HR = 1.83; 95% CI, 0.99-3.38). Risk was not strongly associated with glucose or the insulin:glucose molar ratio ( P trend = 0.55 and P trend = 0.27, respectively). Conclusions: Higher fasting serum insulin concentrations, as well as the presence of insulin resistance, appear to be associated with an elevated risk of lung cancer development. Impact: Although insulin is hypothesized to increase risk of some cancers, insulin and lung cancer remain understudied. Higher insulin levels and insulin resistance were associated with increased lung cancer risk. Although smoking cessation is the best method of lung cancer prevention, other lifestyle changes that affect insulin concentrations and sensitivity may reduce lung cancer risk. Cancer Epidemiol Biomarkers Prev; 26(10); 1519-24. ©2017 AACR . ©2017 American Association for Cancer Research.

  19. Assessment of insulin action in insulin-dependent diabetes mellitus using [6(14)C]glucose, [3(3)H]glucose, and [2(3)H]glucose. Differences in the apparent pattern of insulin resistance depending on the isotope used

    International Nuclear Information System (INIS)

    Bell, P.M.; Firth, R.G.; Rizza, R.A.

    1986-01-01

    To determine whether [2(3)H], [3(3)H], and [6(14)C]glucose provide an equivalent assessment of glucose turnover in insulin-dependent diabetes mellitus (IDDM) and nondiabetic man, glucose utilization rates were measured using a simultaneous infusion of these isotopes before and during hyperinsulinemic euglycemic clamps. In the nondiabetic subjects, glucose turnover rates determined with [6(14)C]glucose during insulin infusion were lower (P less than 0.02) than those determined with [2(3)H]glucose and higher (P less than 0.01) than those determined with [3(3)H]glucose. In IDDM, glucose turnover rates measured with [6(14)C]glucose during insulin infusion were lower (P less than 0.05) than those determined with [2(3)H]glucose, but were not different from those determined with [3(3)H]glucose. All three isotopes indicated the presence of insulin resistance. However, using [3(3)H]glucose led to the erroneous conclusion that glucose utilization was not significantly decreased at high insulin concentrations in the diabetic patients. [6(14)C] and [3(3)H]glucose but not [2(3)H]glucose indicated impairment in insulin-induced suppression of glucose production. These results indicate that tritiated isotopes do not necessarily equally reflect the pattern of glucose metabolism in diabetic and nondiabetic man

  20. Changes in Gastrointestinal Hormone Responses, Insulin Sensitivity, and Beta-Cell Function Within 2 Weeks After Gastric Bypass in Non-diabetic Subjects

    DEFF Research Database (Denmark)

    Jacobsen, Siv Hesse; Olesen, S C; Dirksen, C

    2012-01-01

    measured fasting and postprandial glucose, insulin, C-peptide, glucagon, total and intact glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-2 (GLP-2), peptide YY(3-36) (PYY), cholecystokinin (CCK), total and active ghrelin, gastrin, somatostatin......, pancreatic polypeptide (PP), amylin, leptin, free fatty acids (FFA), and registered postprandial dumping. Insulin sensitivity was measured by homeostasis model assessment of insulin resistance. RESULTS: Fasting glucose, insulin, ghrelin, and PYY were significantly decreased and FFA was elevated...... postoperatively. Insulin sensitivity increased after surgery. The postprandial response increased for C-peptide, GLP-1, GLP-2, PYY, CCK, and glucagon (in response to the mixed meal) and decreased for total and active ghrelin, leptin, and gastrin, but were unchanged for GIP, amylin, PP, and somatostatin after...

  1. Brain glucose sensing, counterregulation, and energy homeostasis.

    Science.gov (United States)

    Marty, Nell; Dallaporta, Michel; Thorens, Bernard

    2007-08-01

    Neuronal circuits in the central nervous system play a critical role in orchestrating the control of glucose and energy homeostasis. Glucose, beside being a nutrient, is also a signal detected by several glucose-sensing units that are located at different anatomical sites and converge to the hypothalamus to cooperate with leptin and insulin in controlling the melanocortin pathway.

  2. The relationship between maternal and fetal vitamin D, insulin resistance, and fetal growth.

    LENUS (Irish Health Repository)

    Walsh, Jennifer M

    2013-05-01

    Evidence for a role of vitamin D in maintaining normal glucose homeostasis is inconclusive. We sought to clarify the relationship between maternal and fetal insulin resistance and vitamin D status. This is a prospective cohort study of 60 caucasian pregnant women. Concentrations of 25-hydroxyvitamin D (25-OHD), glucose, insulin, and leptin were measured in early pregnancy and at 28 weeks. Ultrasound at 34 weeks assessed fetal anthropometry including abdominal wall width, a marker of fetal adiposity. At delivery birth weight was recorded and fetal 25-OHD, glucose, C-peptide, and leptin measured in cord blood. Insulin resistance was calculated using the Homeostasis Model Assessment (HOMA) equation. We found that those with lower 25-OHD in early pregnancy had higher HOMA indices at 28 weeks, (r = -.32, P = .02). No significant relationship existed between maternal or fetal leptin and 25-OHD, or between maternal or fetal 25-OHD and fetal anthropometry or birth weight. The incidence of vitamin D deficiency was high at each time point (15%-45%). These findings lend support to routine antenatal supplementation with vitamin D in at risk populations.

  3. Intermittent hypoxia increases insulin resistance in genetically obese mice.

    Science.gov (United States)

    Polotsky, Vsevolod Y; Li, Jianguo; Punjabi, Naresh M; Rubin, Arnon E; Smith, Philip L; Schwartz, Alan R; O'Donnell, Christopher P

    2003-10-01

    Obstructive sleep apnoea, a syndrome that leads to recurrent intermittent hypoxia, is associated with insulin resistance in obese individuals, but the mechanisms underlying this association remain unknown. We utilized a mouse model to examine the effects of intermittent hypoxia on insulin resistance in lean C57BL/6J mice and leptin-deficient obese (C57BL/6J-Lepob) mice. In lean mice, exposure to intermittent hypoxia for 5 days (short term) resulted in a decrease in fasting blood glucose levels (from 173 +/- 11 mg dl-1 on day 0 to 138 +/- 10 mg dl-1 on day 5, P obese mice, short-term intermittent hypoxia led to a decrease in blood glucose levels accompanied by a 607 +/- 136 % (P intermittent hypoxia was completely abolished by prior leptin infusion. Obese mice exposed to intermittent hypoxia for 12 weeks (long term) developed a time-dependent increase in fasting serum insulin levels (from 3.6 +/- 1.1 ng ml-1 at baseline to 9.8 +/- 1.8 ng ml-1 at week 12, P intermittent hypoxia is dependent on the disruption of leptin pathways.

  4. Association of leptin with cardiometabolic factors in schoolchildren and adolescents with congenital adrenal hyperplasia.

    Science.gov (United States)

    Zurita-Cruz, Jessie Nallely; Villasís-Keever, Miguel Ángel; Damasio-Santana, Leticia; Manuel-Apolinar, Leticia; Ferrusca-Ceja, Rosalba; Nishimura-Meguro, Elisa; Rivera-Hernández, Aleida de J; Garrido-Magaña, Eulalia

    2018-01-01

    In congenital adrenal hyperplasia (CAH), obesity, hyperinsulinemia and leptin levels are increased. To identify the frequency of cardiometabolic risk factors (CRF) in children and adolescents with CAH and to explore the relationship with leptin levels. Cross-sectional study of 40 patients who underwent anthropometric measurements and had fasting glucose, insulin, triglycerides, 17-hidroxyprogesterone, leptin, HDL and LDL-cholesterol assessed. The patients were classified according to the number of CRFs, and leptin levels were analyzed with the Kruskal-Wallis test. Pearson's correlation was applied between leptin, body mass index (BMI) z-score and body fat percentage. Fifty percent of the patients had obesity and overweight, 59% had hypertriglyceridemia, 40%, hypoalphalipoproteinemia, 27.5%, high LDL-cholesterol and 22.5% insulin resistance. There was positive correlation between leptin and body fat percentage (r = 0.64), BMI z-score (r = 0.55) and the number of CRFs (r = 0.65). In the obesity-adjusted multivariate analysis, leptin levels were associated with the number of CRFs. CAH had a high frequency of CRFs and leptin appeared to be associated with a more adverse cardiometabolic profile in subjects with obesity and overweight. Copyright: © 2018 SecretarÍa de Salud.

  5. Glucose-induced effects and joker function of glucose: endocrine or genotoxic prevalence?

    Science.gov (United States)

    Berstein, L M; Vasilyev, D A; Poroshina, T E; Kovalenko, I G

    2006-10-01

    The steady increase in chronic "glycemic load" is characteristic for modern times. Among myriad of glucose functions, two principals can be emphasized: first, endocrine (in particular, ability to induce insulin secretion) and second, DNA-damaging related to formation of reactive oxygen species (ROS). It was suggested by us earlier that a shift in the ratio of mentioned functions reflects a possible "joker" role of glucose as an important modifier of human pathology. Therefore, we embarked on a study to investigate an individual effect of peroral glucose challenge on serum insulin level and ROS generation by mononuclears (luminol-dependent/latex-induced chemiluminescence) in 20 healthy people aged between 28-75. Concentrations of glucose, blood lipids, carbonylated proteins, malondialdehyde, leptin and TNF-alpha were determined as well. On the basis of received data two separate groups could be distinguished: one (n=8), in which glucose stimulation of ROS generation by mononuclears was increased and relatively prevailed over induction of insulin secretion (state of the so called glucose-induced genotoxicity, GIGT), and another (n=12), in which signs of GIGT were not revealed. People who belonged to the first group were characterized with a tendency to lower body mass index, blood leptin and cholesterol and to higher TNF-alpha concentration. Thus, if joker function of glucose is realized in "genotoxic mode", the phenotype (and probably genotype) of subjects may be rather distinctive to the one discovered in glucose-induced "endocrine prevalence". Whether such changes may serve as a pro-mutagenic or pro-endocrine basis for the rise of different chronic diseases or, rather, different features/aggressiveness of the same disease warrants further study.

  6. What fans the fire: insights into mechanisms of leptin in metabolic syndrome-associated heart diseases.

    Science.gov (United States)

    Dong, Maolong; Ren, Jun

    2014-01-01

    Obesity and metabolic syndrome are one of the most devastating risk factors for cardiovascular diseases. The obesity gene product leptin plays a central role in the regulation of food intake and energy expenditure. The physiological and pathophysiological roles of leptin in cardiovascular system have been investigated extensively since its discovery in 1994. In addition to its well-established metabolic effects, more recent evidence have depicted a rather pivotal role of leptin in inflammation, oxidative stress, endoplasmic reticulum stress, apoptosis and tissue remodeling en route to the pathogenesis of type 2 diabetes mellitus, hypertension, atherosclerosis, and insulin resistance. Under physiological condition, leptin is known to reduce appetite, promote energy expenditure, increase sympathetic activity, facilitate glucose utilization and improve insulin sensitivity. In addition, leptin may regulate cardiac and vascular function through a nitric oxide-dependent mechanism. However, hyperleptinemia usually occurs with progressively increased body weight and metabolic syndrome development, leading to a state of global or selective leptin resistance. Both central and peripheral leptin resistance may be present under pathophysiological conditions such as inflammation, insulin resistance, hyperlipidemia and a cadre of other cardiovascular diseases including hypertension, atherosclerosis, obesity, ischemic heart disease and heart failure. In this review, we will discuss cardiovascular actions of leptin related to various components of metabolic syndrome. Particular emphasis will be given to insights derived from therapeutic interventions with lifestyle modification, cardiovascular drugs, anti-diabetic and anti-obesity drugs.

  7. Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients.

    Science.gov (United States)

    Janukonyté, Jurgita; Parkner, Tina; Bruun, Niels Henrik; Lauritzen, Torsten; Christiansen, Jens Sandahl; Laursen, Torben

    2015-05-01

    Little is known about the influence of exogenous insulin and actual glucose levels on the release of endogenous insulin in insulin-treated type 2 diabetes mellitus (T2DM) patients. This study investigated the interaction among serum endogenous insulin (s-EI), serum exogenous insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m(2)) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU/h) as a continuous subcutaneous insulin infusion (CSII) during a 10-h period on two occasions with different duration of hyperglycemia: (1) transient hyperglycemia for 2 h (visit TH) and (2) continuous hyperglycemia for 12 h (visit CH). During steady state the variances of plasma glucose (p-glucose), s-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first 100 min of both visits when s-IAsp was undetectable (adjusted R(2)=0.9). A complex but statistically significant interaction among s-IAsp, s-EI, p-glucose, and patients was observed during measurable s-IAsp levels (adjusted R(2)=0.70). Endogenous and exogenous insulin showed higher variation during continuous hyperglycemia. Significantly lower levels of exogenous insulin were observed following CSII during continuous hyperglycemia compared with transient hyperglycemia. Endogenous insulin levels could in a complex way be explained by an individual interaction among p-glucose and serum exogenous insulin, if present.

  8. DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.

    Science.gov (United States)

    Santoro, Anna; Campolo, Michela; Liu, Chen; Sesaki, Hiromi; Meli, Rosaria; Liu, Zhong-Wu; Kim, Jung Dae; Diano, Sabrina

    2017-03-07

    Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1 fl/fl -POMC-cre:ER T2 ) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1 fl/fl -POMC-cre:ER T2 mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons. Copyright © 2017 Elsevier Inc. All rights reserved.

  9. Leptin, insulin like growth factor-1 and thyroid profile in a studied ...

    African Journals Online (AJOL)

    Howida Hosny El Gebali

    2014-02-26

    Feb 26, 2014 ... roid stimulating hormone (TSH) and free thyroxin (FT4) in a prepubertal Egyptian sample of chil- dren with DS ... serum levels of leptin, IGF-I (insulin like growth factor-I), ..... a deficit in receptor synthesis in DS. They also ...

  10. Adipokines and their relation to maternal energy substrate production, insulin resistance and fetal size.

    Science.gov (United States)

    Ahlsson, Fredrik; Diderholm, Barbro; Ewald, Uwe; Jonsson, Björn; Forslund, Anders; Stridsberg, Mats; Gustafsson, Jan

    2013-05-01

    The role of adipokines in the regulation of energy substrate production in non-diabetic pregnant women has not been elucidated. We hypothesize that serum concentrations of adiponectin are related to fetal growth via maternal fat mass, insulin resistance and glucose production, and further, that serum levels of leptin are associated with lipolysis and that this also influences fetal growth. Hence, we investigated the relationship between adipokines, energy substrate production, insulin resistance, body composition and fetal weight in non-diabetic pregnant women in late gestation. Twenty pregnant women with normal glucose tolerance were investigated at 36 weeks of gestation at Uppsala University Hospital. Levels of adipokines were related to rates of glucose production and lipolysis, maternal body composition, insulin resistance, resting energy expenditure and estimated fetal weights. Rates of glucose production and lipolysis were estimated by stable isotope dilution technique. Median (range) rate of glucose production was 805 (653-1337) μmol/min and that of glycerol production, reflecting lipolysis, was 214 (110-576) μmol/min. HOMA insulin resistance averaged 1.5 ± 0.75 and estimated fetal weights ranged between 2670 and 4175 g (-0.2 to 2.7 SDS). Mean concentration of adiponectin was 7.2 ± 2.5mg/L and median level of leptin was 47.1 (9.9-58.0) μg/L. Adiponectin concentrations (7.2 ± 2.5mg/L) correlated inversely with maternal fat mass, insulin resistance, glucose production and fetal weight, r=-0.50, pinsulin resistance, r=0.76, pinsulin resistance as well as endogenous glucose production rates indicate that low levels of adiponectin in obese pregnant women may represent one mechanism behind increased fetal size. Maternal levels of leptin are linked to maternal fat mass and its metabolic consequences, but the data indicate that leptin lacks a regulatory role with regard to maternal lipolysis in late pregnancy. Copyright © 2012 Elsevier Ireland Ltd. All rights

  11. Leptin and insulin up-regulate miR-4443 to suppress NCOA1 and TRAF4, and decrease the invasiveness of human colon cancer cells

    International Nuclear Information System (INIS)

    Meerson, Ari; Yehuda, Hila

    2016-01-01

    Obesity is a risk factor for colorectal cancer (CRC). Normal and tumor cells respond to metabolic hormones, such as leptin and insulin. Thus, obesity-associated resistance to these hormones likely leads to changes in gene expression and behavior of tumor cells. However, the mechanisms affected by leptin and insulin signaling in CRC cells remain mostly unknown. We hypothesized that microRNAs (miRNAs) are involved in the regulation of tumorigenesis-related gene expression in CRC cells by leptin and insulin. To test this hypothesis, miRNA levels in the CRC-derived cell lines HCT-116, HT-29 and DLD-1 were profiled, following leptin and insulin treatment. Candidate miRNAs were validated by RT-qPCR. Predicted miRNA targets with known roles in cancer, were validated by immunoblots and reporter assays in HCT-116 cells. Transfection of HCT-116 cells with candidate miRNA mimic was used to test in vitro effects on proliferation and invasion. Of ~800 miRNAs profiled, miR-4443 was consistently up-regulated by leptin and insulin in HCT-116 and HT-29, but not in DLD-1, which lacked normal leptin receptor expression. Dose response experiments showed that leptin at 100 ng/ml consistently up-regulated miR-4443 in HCT-116 cells, concomitantly with a significant decrease in cell invasion ability. Transfection with miR-4443 mimic decreased invasion and proliferation of HCT-116 cells. Moreover, leptin and miR-4443 transfection significantly down-regulated endogenous NCOA1 and TRAF4, both predicted targets of miR-4443 with known roles in cancer metastasis. miR-4443 was found to directly regulate TRAF4 and NCOA1, as validated by a reporter assay. The up-regulation of miR-4443 by leptin or insulin was attenuated by the inhibition of MEK1/2. Our findings suggest that miR-4443 acts in a tumor-suppressive manner by down-regulating TRAF4 and NCOA1 downstream of MEK-C/EBP-mediated leptin and insulin signaling, and that insulin and/or leptin resistance (e.g. in obesity) may suppress this pathway

  12. Alterations in human milk leptin and insulin are associated with early changes in the infant intestinal microbiome.

    Science.gov (United States)

    Lemas, Dominick J; Young, Bridget E; Baker, Peter R; Tomczik, Angela C; Soderborg, Taylor K; Hernandez, Teri L; de la Houssaye, Becky A; Robertson, Charles E; Rudolph, Michael C; Ir, Diana; Patinkin, Zachary W; Krebs, Nancy F; Santorico, Stephanie A; Weir, Tiffany; Barbour, Linda A; Frank, Daniel N; Friedman, Jacob E

    2016-05-01

    Increased maternal body mass index (BMI) is a robust risk factor for later pediatric obesity. Accumulating evidence suggests that human milk (HM) may attenuate the transfer of obesity from mother to offspring, potentially through its effects on early development of the infant microbiome. Our objective was to identify early differences in intestinal microbiota in a cohort of breastfeeding infants born to obese compared with normal-weight (NW) mothers. We also investigated relations between HM hormones (leptin and insulin) and both the taxonomic and functional potentials of the infant microbiome. Clinical data and infant stool and fasting HM samples were collected from 18 NW [prepregnancy BMI (in kg/m(2)) obese (prepregnancy BMI >30.0) mothers and their exclusively breastfed infants at 2 wk postpartum. Infant body composition at 2 wk was determined by air-displacement plethysmography. Infant gastrointestinal microbes were estimated by using 16S amplicon and whole-genome sequencing. HM insulin and leptin were determined by ELISA; short-chain fatty acids (SCFAs) were measured in stool samples by using gas chromatography. Power was set at 80%. Infants born to obese mothers were exposed to 2-fold higher HM insulin and leptin concentrations (P obesity may adversely affect the early infant intestinal microbiome, HM insulin and leptin are independently associated with beneficial microbial metabolic pathways predicted to increase intestinal barrier function and reduce intestinal inflammation. This trial was registered at clinicaltrials.gov as NCT01693406. © 2016 American Society for Nutrition.

  13. Serum leptin levels in female patients with niddm

    International Nuclear Information System (INIS)

    Haque, Z.; Rahman, M.A.

    2003-01-01

    Objective: To compare serum leptin levels of diabetic and non-diabetic female subjects and also assess the relationship of hyperglycemia with serum insulin, C-peptide and leptin levels. Results: Serum leptin levels of obese diabetic and non-diabetic subjects were significantly higher as compared with lean diabetic patients and non-diabetic subjects (P<0.05). Leptin levels were positively correlated with serum insulin and C-peptide levels. Serum leptin increased with increase in body mass index and waist hip ratio was strongly related with insulin resistance in NIDDM. Conclusion: Leptin levels are increased in obesity and may play a role in development of insulin resistance and NIDDM. (author)

  14. Relationship of Neonatal Leptin and Insulin to Birth Weight and Gender Difference as well as Their Relationship to Maternal Levels

    International Nuclear Information System (INIS)

    Ashry, Kh.M.

    2005-01-01

    Normal intrauterine growth and development is dependent on many factors of which hormonal factors have been implicated. The aim of the present work was to study the relationship of neonatal leptin and insulin to birth weight and gender difference as well as their relationship to maternal levels. Serum leptin level was assessed by competitive enzyme immunoassay and insulin level by radioimmunoassay in the cord blood of sixty neonates and the venous blood of their mothers. The neonates were classified according to their birth weight into: 23 appropriate for gestational age (AGA) (12 females and 11 males); 20 large for gestational age (LGA) (11 females and 9 males) and 17 small for gestational age (SGA) (9 femals and 8 males). Our results revealed a highly significant increase in maternal serum levels of leptin and insulin (24.1±11.8 ng/ml and 22.3±5.8 μ U/ml, respectively) when compared to neonatal levels (10.0 ± 7.4ng/ml and 7.4±4.3 μ U/ml, p<0.001, respectively). Cord blood leptin and insulin levels showed statistically significant differences between all weight classes with the highest levels in LGA neonates

  15. The fluctuation of blood glucose, insulin and glucagon concentrations before and after insulin therapy in type 1 diabetes

    Science.gov (United States)

    Arif, Idam; Nasir, Zulfa

    2015-09-01

    A dynamical-systems model of plasma glucose, insulin and glucagon concentrations has been developed to investigate the effects of insulin therapy on blood glucose, insulin and glucagon regulations in type 1 diabetic patients. Simulation results show that the normal regulation of blood glucose concentration depends on insulin and glucagon concentrations. On type 1 diabetic case, the role of insulin on regulating blood glucose is not optimal because of the destruction of β cells in pancreas. These β cells destructions cause hyperglycemic episode affecting the whole body metabolism. To get over this, type 1 diabetic patients need insulin therapy to control the blood glucose level. This research has been done by using rapid acting insulin (lispro), long-acting insulin (glargine) and the combination between them to know the effects of insulin therapy on blood glucose, insulin and glucagon concentrations. Simulation results show that these different types of insulin have different effects on blood glucose concentration. Insulin therapy using lispro shows better blood glucose control after consumption of meals. Glargin gives better blood glucose control between meals and during sleep. Combination between lispro and glargine shows better glycemic control for whole day blood glucose level.

  16. Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation.

    Science.gov (United States)

    Frank, N; Hermida, P; Sanchez-Londoño, A; Singh, R; Gradil, C M; Uricchio, C K

    2017-07-01

    Octreotide is a somatostatin analog that suppresses insulin secretion. We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Twelve horses, N = 5, ID = 7. Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1.0 μg/kg IV) was then administered, and blood was collected at 0, 5, 10, 15, 20, 25, 30, 45, 60, 75, and 90 minute, and 2, 3, 4, 6, 8, 12, and 24 hour for measurement of glucose and insulin concentrations. Area under the curve (AUC) values were calculated. Mean AUC values for glucose and insulin did not differ between normal (n = 5) and ID (n = 7) groups after octreotide injection. Significant time (P glucose and insulin concentrations. A group × time interaction (P = .091) was detected for insulin concentrations after administration of octreotide, but the group (P = .33) effect was not significant. Octreotide suppresses insulin secretion, resulting in hyperglycemia, and then concentrations increase above baseline as glycemic control is restored. Our hypothesis that octreotide causes insulin concentrations to decrease in horses was supported, but differences between N and ID groups did not reach statistical significance when blood glucose and insulin responses were compared. The utility of an octreotide response test remains to be determined. Copyright © 2017 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of the American College of Veterinary Internal Medicine.

  17. Insulin secretion and incretin hormones after oral glucose in non-obese subjects with impaired glucose tolerance

    DEFF Research Database (Denmark)

    Rask, E; Olsson, T; Söderberg, S

    2004-01-01

    of glucose, insulin, C-peptide, GLP-1, and GIP. Insulin secretion (TIS) and insulin sensitivity (OGIS) were assessed using models describing the relationship between glucose, insulin and C-peptide data. These models allowed estimation also of the hepatic extraction of insulin. The age (54.2 +/- 9.7 [mean......Subjects with impaired glucose tolerance (IGT) are usually overweight and exhibit insulin resistance with a defective compensation of insulin secretion. In this study, we sought to establish the interrelation between insulin secretion and insulin sensitivity after oral glucose in non-obese subjects...... over the whole 180-minute period was higher in IGT (26.2 +/- 2.4 v 20.0 +/- 2.0 nmol/L; P =.035). Hepatic insulin extraction correlated linearly with OGIS (r = 0.71; P

  18. Continuous glucose monitoring, oral glucose tolerance, and insulin - glucose parameters in adolescents with simple obesity.

    Science.gov (United States)

    El Awwa, A; Soliman, A; Al-Ali, M; Yassin, M; De Sanctis, V

    2012-09-01

    In obese adolescents pancreatic beta-cells may not be able to cope with insulin resistance leading to hyperglycemia and type2 diabetes (T2DM To assess oral glucose tolerance, 72-h continuous blood glucose concentrations (CGM) and calculate homeostatic model assessment (HOMA), and the quantitative insulin sensitivity check index (QUICKI) in 13 adolescents with simple obesity (BMI SDS=4 ± 1.06). OGTT performed in 13 obese adolescents (13.47 ± 3 years) revealed 3 cases (23%) with impaired fasting glucose (IFG: fasting glucose >5.6 mmol/L), 4 cases (30%) with impaired glucose tolerance (IGT: 2h blood glucose >7.8 continuous glucose monitoring system ( CGMS), IFG was detected in 4 cases, the maximum serum blood glucose (BG : 2h or more after meal) was >7.8 and 11.1 mmol/L (diabetes) in one case (7.6%). Five cases had a minimum BG recorded of 2.6 and QUICKI values obese adolescents, CGMS is superior to OGTT and HbA1C in detecting glycemic abnormalities, which appears to be secondary to insulin resistance.

  19. Adipocyte-specific protein tyrosine phosphatase 1B deletion increases lipogenesis, adipocyte cell size and is a minor regulator of glucose homeostasis.

    Directory of Open Access Journals (Sweden)

    Carl Owen

    Full Text Available Protein tyrosine phosphatase 1B (PTP1B, a key negative regulator of leptin and insulin signaling, is positively correlated with adiposity and contributes to insulin resistance. Global PTP1B deletion improves diet-induced obesity and glucose homeostasis via enhanced leptin signaling in the brain and increased insulin signaling in liver and muscle. However, the role of PTP1B in adipocytes is unclear, with studies demonstrating beneficial, detrimental or no effect(s of adipose-PTP1B-deficiency on body mass and insulin resistance. To definitively establish the role of adipocyte-PTP1B in body mass regulation and glucose homeostasis, adipocyte-specific-PTP1B knockout mice (adip-crePTP1B(-/- were generated using the adiponectin-promoter to drive Cre-recombinase expression. Chow-fed adip-crePTP1B(-/- mice display enlarged adipocytes, despite having similar body weight/adiposity and glucose homeostasis compared to controls. High-fat diet (HFD-fed adip-crePTP1B(-/- mice display no differences in body weight/adiposity but exhibit larger adipocytes, increased circulating glucose and leptin levels, reduced leptin sensitivity and increased basal lipogenesis compared to controls. This is associated with decreased insulin receptor (IR and Akt/PKB phosphorylation, increased lipogenic gene expression and increased hypoxia-induced factor-1-alpha (Hif-1α expression. Adipocyte-specific PTP1B deletion does not beneficially manipulate signaling pathways regulating glucose homeostasis, lipid metabolism or adipokine secretion in adipocytes. Moreover, PTP1B does not appear to be the major negative regulator of the IR in adipocytes.

  20. Epac2a-null mice exhibit obesity-prone nature more susceptible to leptin resistance.

    Science.gov (United States)

    Hwang, M; Go, Y; Park, J-H; Shin, S-K; Song, S E; Oh, B-C; Im, S-S; Hwang, I; Jeon, Y H; Lee, I-K; Seino, S; Song, D-K

    2017-02-01

    The exchange protein directly activated by cAMP (Epac), which is primarily involved in cAMP signaling, has been known to be essential for controlling body energy metabolism. Epac has two isoforms: Epac1 and Epac2. The function of Epac1 on obesity was unveiled using Epac1 knockout (KO) mice. However, the role of Epac2 in obesity remains unclear. To evaluate the role of Epac2 in obesity, we used Epac2a KO mice, which is dominantly expressed in neurons and endocrine tissues. Physiological factors related to obesity were analyzed: body weight, fat mass, food intake, plasma leptin and adiponectin levels, energy expenditure, glucose tolerance, and insulin and leptin resistance. To determine the mechanism of Epac2a, mice received exogenous leptin and then hypothalamic leptin signaling was analyzed. Epac2a KO mice appeared to have normal glucose tolerance and insulin sensitivity until 12 weeks of age, but an early onset increase of plasma leptin levels and decrease of plasma adiponectin levels compared with wild-type mice. Acute leptin injection revealed impaired hypothalamic leptin signaling in KO mice. Consistently, KO mice fed a high-fat diet (HFD) were significantly obese, presenting greater food intake and lower energy expenditure. HFD-fed KO mice were also characterized by greater impairment of hypothalamic leptin signaling and by weaker leptin-induced decrease in food consumption compared with HFD-fed wild-type mice. In wild-type mice, acute exogenous leptin injection or chronic HFD feeding tended to induce hypothalamic Epac2a expression. Considering that HFD is an inducer of hypothalamic leptin resistance and that Epac2a functions in pancreatic beta cells during demands of greater work load, hypothalamic Epac2a may have a role in facilitating leptin signaling, at least in response to higher metabolic demands. Thus, our data indicate that Epac2a is critical for preventing obesity and thus Epac2a activators may be used to manage obesity and obesity-mediated metabolic

  1. [Plasma levels of insulin and leptin in patients with morbid obesity and anorexia nervosa after weight loss or gain, respectively].

    Science.gov (United States)

    Escobar, L; Freire, J M; Girón, J A; Vázquez, J M; Pajares, M; Ortego, J; Gavilán, I; Chover, A J; Carrasco, M; Epinosa, R; Marín, F; Aguilar, M

    2000-06-01

    The present study was conducted in order to analyze the relationship existing between leptin and insulin levels in massive weight loss and weight recovery. Thirteen patients with severe obesity, 14 patients with anorexia nervosa and 13 healthy control subjects were studied. The patients with severe obesity underwent a vertical banded gastroplasty followed by an 800 kcal/day diet for 12 weeks. They were evaluated prior to (body mass index [BMI] 51.2 +/- 8.8 Kg/m2) and after drastic weight loss (BMI 40.6 +/- 6.7 Kg/m2). Patients with anorexia nervosa were treated exclusively with nutritional therapy during 12 weeks, and they were evaluated at their lowest weight status (BMI 16.2 +/- 2.2 Kg/m2) and after weight recovery (BMI 17.9 +/- 2.3 Kg/m2). The BMI of the normal subjects was in the normal range of 20 to 27 Kg/m2 (average 22.8 +/- 2.6 Kg/m2). BMI, percentage of body fat, waist circumference, and serum levels of leptin, insulin, and C-peptide were determined in each patient and normal subject. In severely obese patients, serum leptin and insulin decreased significantly after drastic weight reduction (leptin: from 51.8 +/- 22.3 to 23.7 +/- 10.2 ng/ml; insulin: from 27.1 +/- 13.3 to 17.2 +/- 7.2 mU/ml). In patients with anorexia nervosa, the mean serum leptin levels were significantly higher after weight recovery (5.5 +/- 3.2 vs 7.6 +/- 6 ng/ml). Serum leptin in the severe obesity group correlated positively with BMI, percentage body fat and waist circumference before and after weight loss. In those patients suffering from anorexia nervosa, serum leptin correlated positively with the BMI, percentage of body fat, and waist circumference in the low weight state and after weight recovery. In addition, their serum insulin correlated with BMI and waist circumference after weight recovery. These data reveal that serum leptin concentration correlates significantly with the BMI and body fat content 1) in subjects with a range of weight and caloric intake, 2) in obese

  2. Acute up-regulation of the rat brain somatostatin receptor-effector system by leptin is related to activation of insulin signaling and may counteract central leptin actions.

    Science.gov (United States)

    Perianes-Cachero, A; Burgos-Ramos, E; Puebla-Jiménez, L; Canelles, S; Frago, L M; Hervás-Aguilar, A; de Frutos, S; Toledo-Lobo, M V; Mela, V; Viveros, M P; Argente, J; Chowen, J A; Arilla-Ferreiro, E; Barrios, V

    2013-11-12

    Leptin and somatostatin (SRIF) have opposite effects on food seeking and ingestive behaviors, functions partially regulated by the frontoparietal cortex and hippocampus. Although it is known that the acute suppression of food intake mediated by leptin decreases with time, the counter-regulatory mechanisms remain unclear. Our aims were to analyze the effect of acute central leptin infusion on the SRIF receptor-effector system in these areas and the implication of related intracellular signaling mechanisms in this response. We studied 20 adult male Wister rats including controls and those treated intracerebroventricularly with a single dose of 5 μg of leptin and sacrificed 1 or 6h later. Density of SRIF receptors was unchanged at 1h, whereas leptin increased the density of SRIF receptors at 6h, which was correlated with an elevated capacity of SRIF to inhibit forskolin-stimulated adenylyl cyclase activity in both areas. The functional capacity of SRIF receptors was unaltered as cell membrane levels of αi1 and αi2 subunits of G inhibitory proteins were unaffected in both brain areas. The increased density of SRIF receptors was due to enhanced SRIF receptor subtype 2 (sst2) protein levels that correlated with higher mRNA levels for this receptor. These changes in sst2 mRNA levels were concomitant with increased activation of the insulin signaling, c-Jun and cyclic AMP response element-binding protein (CREB); however, activation of signal transducer and activator of transcription 3 was reduced in the cortex and unchanged in the hippocampus and suppressor of cytokine signaling 3 remained unchanged in these areas. In addition, the leptin antagonist L39A/D40A/F41A blocked the leptin-induced changes in SRIF receptors, leptin signaling and CREB activation. In conclusion, increased activation of insulin signaling after leptin infusion is related to acute up-regulation of the SRIF receptor-effector system that may antagonize short-term leptin actions in the rat brain

  3. Leptin in humans: lessons from translational research.

    Science.gov (United States)

    Blüher, Susann; Mantzoros, Christos S

    2009-03-01

    Leptin has emerged over the past decade as a key hormone in not only the regulation of food intake and energy expenditure but also in the regulation of neuroendocrine and immune function as well as the modulation of glucose and fat metabolism as shown by numerous observational and interventional studies in humans with (complete) congenital or relative leptin deficiency. These results have led to proof-of-concept studies that have investigated the effect of leptin administration in subjects with complete (congenital) leptin deficiency caused by mutations in the leptin gene as well as in humans with relative leptin deficiency, including states of lipoatrophy or negative energy balance and neuroendocrine dysfunction, as for instance seen with hypothalamic amenorrhea in states of exercise-induced weight loss. In those conditions, most neuroendocrine, metabolic, or immune disturbances can be restored by leptin administration. Leptin replacement therapy is thus a promising approach in several disease states, including congenital complete leptin deficiency, states of energy deprivation, including anorexia nervosa or milder forms of hypothalamic amenorrhea, as well as syndromes of insulin resistance seen in conditions such as congenital or acquired lipodystrophy. In contrast, states of energy excess such as garden-variety obesity are associated with hyperleptinemia that reflects either leptin tolerance or leptin resistance. For those conditions, development of leptin sensitizers is currently a focus of pharmaceutical research. This article summarizes our current understanding of leptin's role in human physiology and its potential role as a novel therapeutic option in human disease states associated with a new hormone deficiency, ie, leptin deficiency.

  4. ROLE OF LEPTIN ON CYTOCHROME P-450 AND SOME LIVER MICROSOMAL ENZYMES ACTIVITIES IN THE OBESE AND LEAN MICE

    International Nuclear Information System (INIS)

    HEBEISHY, M.I.A.; MAZEN, G.M.A.; SHAHIN, M.I

    2008-01-01

    Leptin is a hormone that is secreted by adipocytes and regulates body weight through its effect on satiety and energy metabolism. The obese mouse is deficient in this protein and is characterized by obesity and other metabolic disorders. This study investigated the alterations of several hepatic cytochrome P 4 -5 0 (CYP), conjugation and antioxidant enzymes in lean and obese mice and the role of leptin in the modulation of these enzymes. Lean and obese male mice were injected with leptin (100 μg / rat) for 15 days. The obtained results revealed that administration of leptin to lean mice caused a significant elevation in the level of blood glucose, serum insulin, 6α, 6β, 16α- hydroxylation of testosterone, the activity of CYP 1 A 1 , CYP 4 A and GSH reductase in liver microsomes while serum corticosterone and the activity of total GSH were significantly decreased when compared to lean control mice. Moreover, obese mice treated with leptin recorded significant reduction in body weight, blood glucose concentration, serum levels of insulin and corticosterone, 7α and 16α- hydroxylation of testosterone, the activity of CYP 1A 1, CYP 2 B 1 and CYP 4 A and GST in liver microsomes. On the other hand, 6α, 6β-hydroxylation of testosterone, the activity of CYP 2 E 1 and GSH reductase in liver microsome were significantly increased when compared to obese control mice. The mechanism for the observed alterations may be due to direct leptin effects or via indirect alterations in insulin, corticosterone and/or growth hormone

  5. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice.

    Science.gov (United States)

    Coomans, Claudia P; Biermasz, Nienke R; Geerling, Janine J; Guigas, Bruno; Rensen, Patrick C N; Havekes, Louis M; Romijn, Johannes A

    2011-12-01

    Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated tissue-specific glucose uptake. Tolbutamide, an inhibitor of ATP-sensitive K(+) channels (K(ATP) channels), or vehicle was infused into the lateral ventricle in the basal state and during hyperinsulinemic-euglycemic conditions in postabsorptive, chow-fed C57Bl/6J mice and in postabsorptive C57Bl/6J mice with diet-induced obesity. Whole-body glucose uptake was measured by d-[(14)C]glucose kinetics and tissue-specific glucose uptake by 2-deoxy-d-[(3)H]glucose uptake. During clamp conditions, intracerebroventricular administration of tolbutamide impaired the ability of insulin to inhibit EGP by ∼20%. In addition, intracerebroventricular tolbutamide diminished insulin-stimulated glucose uptake in muscle (by ∼59%) but not in heart or adipose tissue. In contrast, in insulin-resistant mice with diet-induced obesity, intracerebroventricular tolbutamide did not alter the effects of insulin during clamp conditions on EGP or glucose uptake by muscle. Insulin stimulates glucose uptake in muscle in part through effects via K(ATP) channels in the central nervous system, in analogy with the inhibitory effects of insulin on EGP. High-fat diet-induced obesity abolished the central effects of insulin on liver and muscle. These observations stress the role of central insulin resistance in the pathophysiology of diet-induced insulin resistance.

  6. Shp2 signaling in POMC neurons is important for leptin's actions on blood pressure, energy balance, and glucose regulation.

    Science.gov (United States)

    do Carmo, Jussara M; da Silva, Alexandre A; Ebaady, Sabira E; Sessums, Price O; Abraham, Ralph S; Elmquist, Joel K; Lowell, Bradford B; Hall, John E

    2014-12-15

    Previous studies showed that Src homology-2 tyrosine phosphatase (Shp2) is an important regulator of body weight. In this study, we examined the impact of Shp2 deficiency specifically in proopiomelanocortin (POMC) neurons on metabolic and cardiovascular function and on chronic blood pressure (BP) and metabolic responses to leptin. Mice with Shp2 deleted in POMC neurons (Shp2/Pomc-cre) and control mice (Shp2(flox/flox)) were implanted with telemetry probes and venous catheters for measurement of mean arterial pressure (MAP) and leptin infusion. After at least 5 days of stable control measurements, mice received leptin infusion (2 μg·kg(-1)·day(-1) iv) for 7 days. Compared with Shp2(flox/flox) controls, Shp2/Pomc-cre mice at 22 wk of age were slightly heavier (34 ± 1 vs. 31 ± 1 g) but consumed a similar amount of food (3.9 ± 0.3 vs. 3.8 ± 0.2 g/day). Leptin infusion reduced food intake in Shp2(flox/flox) mice (2.6 ± 0.5 g) and Shp2/Pomc-cre mice (3.2 ± 0.3 g). Despite decreasing food intake, leptin infusion increased MAP in control mice, whereas no significant change in MAP was observed in Shp2/Pomc-cre mice. Leptin infusion also decreased plasma glucose and insulin levels in controls (12 ± 1 to 6 ± 1 μU/ml and 142 ± 12 to 81 ± 8 mg/100 ml) but not in Shp2/Pomc-cre mice. Leptin increased V̇o2 by 16 ± 2% in controls and 7 ± 1% in Shp2/Pomc-cre mice. These results indicate that Shp2 signaling in POMC neurons contributes to the long-term BP and antidiabetic actions of leptin and may play a modest role in normal regulation of body weight. Copyright © 2014 the American Physiological Society.

  7. Characterization of the intravenous glucose tolerance test and the combined glucose-insulin test in donkeys.

    Science.gov (United States)

    Mendoza, F J; Aguilera-Aguilera, R; Gonzalez-De Cara, C A; Toribio, R E; Estepa, J C; Perez-Ecija, A

    2015-12-01

    Glucose-insulin dynamic challenges such as the intravenous glucose tolerance test (IVGTT) and combined glucose-insulin test (CGIT) have not been described in donkeys. The objectives of this study were (1) to characterize the IVGTT and CGIT in healthy adult donkeys, and (2) to establish normal glucose-insulin proxies. Sixteen donkeys were used and body morphometric variables obtained each. For the IVGTT, glucose (300 mg/kg) was given IV. For the CGIT, glucose (150 mg/kg) followed by recombinant insulin (0.1 IU/kg) were administered IV. Blood samples for glucose and insulin determinations were collected over 300 min. In the IVGTT the positive phase lasted 160.9 ± 13.3 min, glucose concentration peaked at 323.1 ± 9.2 mg/dL and declined at a rate of 1.28 ± 0.15 mg/dL/min. The glucose area under the curve (AUC) was 21.4 ± 1.9 × 10(3) mg/dL/min and the insulin AUC was 7.2 ± 0.9 × 10(3) µIU/mL/min. The positive phase of the CGIT curve lasted 44 ± 3 min, with a glucose clearance rate of 2.01 ± 0.18 mg/dL/min. The negative phase lasted 255.9 ± 3 min, decreasing glucose concentration at rate of -0.63 ± 0.06 mg/dL/min, and reaching a nadir (33.1 ± 3.6 mg/dL) at 118.3 ± 6.3 min. The glucose and insulin AUC values were 15.2 ± 0.9 × 10(3) mg/dL/min and 13.2 ± 0.9 × 10(3) µIU/mL/min. This is the first study characterizing CGIT and IVGTT, and glucose-insulin proxies in healthy adult donkeys. Distinct glucose dynamics, when compared with horses, support the use of species-specific protocols to assess endocrine function. Copyright © 2015 Elsevier Ltd. All rights reserved.

  8. The integrative role of leptin, oestrogen and the insulin family in obesity-associated breast cancer: potential effects of exercise.

    Science.gov (United States)

    Schmidt, S; Monk, J M; Robinson, L E; Mourtzakis, M

    2015-06-01

    Obesity is an established risk factor for postmenopausal breast cancer. The mechanisms through which obesity influences the development and progression of breast cancer are not fully elucidated; however, several factors such as increased oestrogen, concentrations of various members of the insulin family and inflammation that are associated with adiposity are purported to be important factors in this relationship. Emerging research has also begun to focus on the role of adipokines, (i.e. adipocyte secreted factors), in breast cancer. Leptin secretion is directly related to adiposity and is believed to promote breast cancer directly and independently, as well as through involvement with the oestrogen and insulin signalling pathways. As leptin is secreted from white adipose tissue, any intervention that reduces adiposity may be favourable. However, it is also important to consider that energy expenditure through exercise, independent of fat loss, may improve leptin regulation. The purpose of this narrative review was to explore the role of leptin in breast cancer development and progression, identify key interactions with oestrogen and the insulin family, and distinguish the potential effects of exercise on these interactions. © 2015 The Authors. Obesity Reviews published by John Wiley & Sons Ltd on behalf of World Obesity.

  9. Leptin, insulin like growth factor-1 and thyroid profile in a studied ...

    African Journals Online (AJOL)

    Background: Several mechanisms have been suggested for obesity in Down syndrome. Aim of the study: Assessment of serum levels of leptin, insulin like growth factor-I (IGF-I), thyroid stimulating hormone (TSH) and free thyroxin (FT4) in a prepubertal Egyptian sample of children with DS compared to their age and sex ...

  10. Antidiabetic Effect of Hydroalcholic Urtica dioica Leaf Extract in Male Rats with Fructose-Induced Insulin Resistance

    Science.gov (United States)

    Ahangarpour, Akram; Mohammadian, Maryam; Dianat, Mahin

    2012-01-01

    Background: Urtica dioica has been used as antihypertensive, antihyperlipidemic and antidiabetic herbal medicine. The purpose of this study was to study the effect of hydroalcoholic extract of Urtica dioica on fructose-induced insulin resistance rats. Methods: Forty male Wistar rats were randomly divided into five groups including control, fructose, extract 50, extract 100 and extract 200. The control rat received vehicle, the fructose and extract groups received fructose 10% for eight weeks. The extract groups received single daily injection of vehicle, 50, 100 or 200 mg/kg/day for the two weeks. Blood glucose, insulin, last fasting insulin resistance index (FIRI), serum triglyceride (TG), low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), high-density lipoprotein (HDL), alanin trasaminase (AST) and alkaline phosphatase (ALP), leptin and LDL/HDL ratio were determined. Results: Compared to control group, daily administration of fructose was associated with significant increase in FIRI, blood glucose and insulin, significant decrease in lepin, and no significant change in TG, HDL, LDL, LDL/HDL ratio, VLDL, ALT, and ALP. The extract significantly decreased serum glucose, insulin, LDL and leptin, and LDL/HDL ratio and FIRI. It also significantly increased serum TG, VLDL, and AST, but did not change serum ALP. Conclusion: We suggest that Urtica dioica extract, by decreasing serum glucose, and FIRI, may be useful to improve type 2 diabetes mellitus. Also, by positive effect on lipid profile and by decreasing effect on leptin, it may improve metabolic syndrome. PMID:23115450

  11. Antidiabetic Effect of Hydroalcholic Urtica dioica Leaf Extract in Male Rats with Fructose-Induced Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Akram Ahangarpour

    2012-09-01

    Full Text Available Background: Urtica dioica has been used as antihypertensive, antihyperlipidemic and antidiabetic herbal medicine. The purpose of this study was to study the effect of hydroalcoholic extract of Urtica dioica on fructose-induced insulin resistance rats. Methods: Forty male Wistar rats were randomly divided into five groups including control, fructose, extract 50, extract 100 and extract 200. The control rat received vehicle, the fructose and extract groups received fructose 10% for eight weeks. The extract groups received single daily injection of vehicle, 50, 100 or 200 mg/kg/day for the two weeks. Blood glucose, insulin, last fasting insulin resistance index (FIRI, serum triglyceride (TG, low-density lipoprotein (LDL, very low-density lipoprotein (VLDL, high-density lipoprotein (HDL, alanin trasaminase (AST and alkaline phosphatase (ALP, leptin and LDL/HDL ratio were determined.Results: Compared to control group, daily administration of fructose was associated with significant increase in FIRI, blood glucose and insulin, significant decrease in lepin, and no significant change in TG, HDL, LDL, LDL/HDL ratio, VLDL, ALT, and ALP. The extract significantly decreased serum glucose, insulin, LDL and leptin, and LDL/HDL ratio and FIRI. It also significantly increased serum TG, VLDL, and AST, but did not change serum ALP.Conclusion: We suggest that Urtica dioica extract, by decreasing serum glucose, and FIRI, may be useful to improve type 2 diabetes mellitus. Also, by positive effect on lipid profile and by decreasing effect on leptin, it may improve metabolic syndrome.

  12. Effects of turtle oil on insulin sensitivity and glucose metabolism in insulin resistant cell model

    International Nuclear Information System (INIS)

    Bai Jing; Tian Yaping; Guo Duo

    2007-01-01

    To evaluate the effects of turtle oil on insulin sensitivity and glucose metabolism in an insulin-resistant (IR) cell model which was established by the way of high concentration of insulin induction with HepG 2 cell in vitro culture. The IR cells were treated by turtle oil, the glucose consumption and 3 H-D-glucose incorporation rate in IR cells were detected by the way of glucose oxidase and 3 H-D-glucose incorporation assay respectively. The state of cell proliferation was tested by MTT method. The results showed that the incorporation rate of 3 H-D-glucose in IR cells was significantly lower than that in the control cells(P 3 H-D-glucose incorporation rate in either IR cells or control cells was increased with the increase of insulin concentration. Moreover, the 3 H-D-glucose incorporation rate of IR cells increased slower than that of control cells. The MTT assay showed that turtle oil can promote the proliferation of IR cell and control cell. The glucose uptake and glucose consumption in IR cell which treated with turtle oil was significantly increase than that in the control cells (P<0.05). Turtle oil can improve the insulin sensitivity and glucose metabolism in the IR cell model. (authors)

  13. Leptin and insulin responses to a four-day energy-deficient diet in men with different weight history.

    Science.gov (United States)

    Mars, M; de Graaf, C; van Rossum, C T M; de Groot, C P G M; Seidell, J C; Kok, F J

    2003-05-01

    To assess the leptin responses to a 4-day energy-restricted diet in men with different weight history; high retrospective weight gain was expected to be associated with a small decline in leptin. Changes in fasting leptin and insulin were measured during a 4-day controlled intervention, in which men with high retrospective weight gain and men who had stable weight consumed 35% of their estimated energy needs. A total of 44 healthy men (age: 31-52 y, BMI: 22.7-39.8 kg/m(2)) were recruited from a cohort study: 22 men who had gained weight (weight change >1 kg/y) and 22 men whose weight had remained stable (weight change +/-0.3 kg/y) between the first (1987-1991) and the second measurement (1993-1997) of the cohort study. The intervention study was carried out in 2001. After intervention, changes in fasting leptin levels were similar for both groups of retrospective weight gain: -2.2 microlU/ml (95% CI: -2.8; -1.7) and -2.4 microlU/ml (95% CI: -3.2; -1.7) respectively (P=0.69). Proportional changes in fasting leptin levels were different: -43.3% (95% CI: -47.8; -38.4) in the participants whose weight had remained stable (n=22) and -35.2% (95% CI: -42.4; -27.1) in those who had gained weight (n=22)(Pmen (n=18), in which the contrast in weight history was more pronounced than in the total group, did not show this difference. A higher proportional decrease in insulin levels was seen in men whose weight remained stable than in those who had gained weight: -35.4% (95% CI: -46.9; -21.3) and -12.8% (95% CI: -28.1; 5.7), respectively. The proportional decrease in leptin was positively associated with the proportional decrease in insulin (r=0.52; Pmen with retrospective weight gain, our study does not show convincing evidence that men who gained weight are less leptin responsive to changes in energy balance than those who were weight stable.

  14. TrpC5 Mediates Acute Leptin and Serotonin Effects via Pomc Neurons

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    Yong Gao

    2017-01-01

    Full Text Available The molecular mechanisms underlying acute leptin and serotonin 2C receptor-induced hypophagia remain unclear. Here, we show that neuronal and pro-opiomelanocortin (Pomc-specific loss of transient receptor potential cation 5 (TrpC5 subunits is sufficient to decrease energy expenditure and increase food intake resulting in elevated body weight. Deficiency of Trpc5 subunits in Pomc neurons is also sufficient to block the anorexigenic effects of leptin and serotonin 2C receptor (Ht2Cr agonists. The loss of acute anorexigenic effects of these receptors is concomitant with a blunted electrophysiological response to both leptin and Ht2Cr agonists in arcuate Pomc neurons. We also demonstrate that the Ht2Cr agonist lorcaserin-induced improvements in glucose and insulin tolerance are blocked by TrpC5 deficiency in Pomc neurons. Together, our results link TrpC5 subunits in the brain with leptin- and serotonin 2C receptor-dependent changes in neuronal activity, as well as energy balance, feeding behavior, and glucose metabolism.

  15. Gender Specific Association of Serum Leptin and Insulinemic Indices with Nonalcoholic Fatty Liver Disease in Prediabetic Subjects.

    Science.gov (United States)

    Hossain, Israt Ara; Akter, Salima; Rahman, Mohammad Khalilur; Ali, Liaquat

    2015-01-01

    Adipose tissue-derived hormone leptin plays a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity which also represent the risk factors for nonalcoholic fatty liver disease (NAFLD). The present study explored the gender specific association of serum leptin and insulinemic indices with NAFLD in Bangladeshi prediabetic subjects. Under a cross-sectional analytical design a total of 110 ultrasound examined prediabetic subjects, aged 25-68 years consisting of 57.3% male (55.6% non NAFLD and 44.4% NAFLD) and 42.7% female (57.4% non NAFLD and 42.6% NAFLD), were investigated. Insulin secretory function (HOMA%B) and insulin sensitivity (HOMA%S) were calculated from homeostasis model assessment (HOMA). Serum leptin showed significant positive correlation with fasting insulin (r = 0.530, P = 0.004), postprandial insulin (r = 0.384, P = 0.042) and HOMA-IR (r = 0.541, P = 0.003) as well as significant negative correlation with HOMA%S (r = -0.388, P = 0.046) and HOMA%B (r = -0.356, P = 0.039) in male prediabetic subjects with NAFLD. In multiple linear regression analysis, log transformed leptin showed significant positive association with HOMA-IR (β = 0.706, P binary logistic regression analysis, only log leptin [OR 1.29 95% (C.I) (1.11-1.51), P = 0.001] in male subjects as well as HOMA%B [OR 0.94 95% (C.I) (0.89-0.98), P = 0.012], HOMA-IR [OR 3.30 95% (C.I) (0.99-10.95), P = 0.049] and log leptin [OR 1.10 95% (C.I) (1.01-1.20), P = 0.026] in female subjects were found to be independent determinants of NAFLD after adjusting the BMI and TG. Serum leptin seems to have an association with NAFLD both in male and female prediabetic subjects and this association in turn, is mediated by insulin secretory dysfunction and insulin resistance among these subjects.

  16. Gender Specific Association of Serum Leptin and Insulinemic Indices with Nonalcoholic Fatty Liver Disease in Prediabetic Subjects.

    Directory of Open Access Journals (Sweden)

    Israt Ara Hossain

    Full Text Available Adipose tissue-derived hormone leptin plays a functional role in glucose tolerance through its effects on insulin secretion and insulin sensitivity which also represent the risk factors for nonalcoholic fatty liver disease (NAFLD. The present study explored the gender specific association of serum leptin and insulinemic indices with NAFLD in Bangladeshi prediabetic subjects. Under a cross-sectional analytical design a total of 110 ultrasound examined prediabetic subjects, aged 25-68 years consisting of 57.3% male (55.6% non NAFLD and 44.4% NAFLD and 42.7% female (57.4% non NAFLD and 42.6% NAFLD, were investigated. Insulin secretory function (HOMA%B and insulin sensitivity (HOMA%S were calculated from homeostasis model assessment (HOMA. Serum leptin showed significant positive correlation with fasting insulin (r = 0.530, P = 0.004, postprandial insulin (r = 0.384, P = 0.042 and HOMA-IR (r = 0.541, P = 0.003 as well as significant negative correlation with HOMA%S (r = -0.388, P = 0.046 and HOMA%B (r = -0.356, P = 0.039 in male prediabetic subjects with NAFLD. In multiple linear regression analysis, log transformed leptin showed significant positive association with HOMA-IR (β = 0.706, P <0.001 after adjusting the effects of body mass index (BMI, triglyceride (TG and HOMA%B in male subjects with NAFLD. In binary logistic regression analysis, only log leptin [OR 1.29 95% (C.I (1.11-1.51, P = 0.001] in male subjects as well as HOMA%B [OR 0.94 95% (C.I (0.89-0.98, P = 0.012], HOMA-IR [OR 3.30 95% (C.I (0.99-10.95, P = 0.049] and log leptin [OR 1.10 95% (C.I (1.01-1.20, P = 0.026] in female subjects were found to be independent determinants of NAFLD after adjusting the BMI and TG. Serum leptin seems to have an association with NAFLD both in male and female prediabetic subjects and this association in turn, is mediated by insulin secretory dysfunction and insulin resistance among these subjects.

  17. Neurotrophin Signaling Is Required for Glucose-Induced Insulin Secretion.

    Science.gov (United States)

    Houtz, Jessica; Borden, Philip; Ceasrine, Alexis; Minichiello, Liliana; Kuruvilla, Rejji

    2016-11-07

    Insulin secretion by pancreatic islet β cells is critical for glucose homeostasis, and a blunted β cell secretory response is an early deficit in type 2 diabetes. Here, we uncover a regulatory mechanism by which glucose recruits vascular-derived neurotrophins to control insulin secretion. Nerve growth factor (NGF), a classical trophic factor for nerve cells, is expressed in pancreatic vasculature while its TrkA receptor is localized to islet β cells. High glucose rapidly enhances NGF secretion and increases TrkA phosphorylation in mouse and human islets. Tissue-specific deletion of NGF or TrkA, or acute disruption of TrkA signaling, impairs glucose tolerance and insulin secretion in mice. We show that internalized TrkA receptors promote insulin granule exocytosis via F-actin reorganization. Furthermore, NGF treatment augments glucose-induced insulin secretion in human islets. These findings reveal a non-neuronal role for neurotrophins and identify a new regulatory pathway in insulin secretion that can be targeted to ameliorate β cell dysfunction. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Insulin secretion and insulin resistance in Korean women with gestational diabetes mellitus and impaired glucose tolerance.

    Science.gov (United States)

    Yang, Sae Jeong; Kim, Tae Nyun; Baik, Sei Hyun; Kim, Tae Sun; Lee, Kwan Woo; Nam, Moonsuk; Park, Yong Soo; Woo, Jeong-Teak; Kim, Young Seol; Kim, Sung-Hoon

    2013-05-01

    The aim was to compare the insulin sensitivity and secretion index of pregnant Korean women with normal glucose tolerance (NGT), gestational impaired glucose tolerance (GIGT; only one abnormal value according to the Carpenter and Coustan criteria), and gestational diabetes mellitus (GDM). A cross-sectional study was performed with 1,163 pregnant women with positive (1-hour plasma glucose ≥ 7.2 mmol/L) in a 50-g oral glucose challenge test (OGCT). The 100-g oral glucose tolerance test (OGTT) was used to stratify the participants into three groups: NGT (n = 588), GIGT (n = 294), and GDM (n = 281). The GDM group had higher homeostasis model assessment of insulin resistance and lower insulin sensitivity index (ISOGTT), quantitative insulin sensitivity check index, homeostasis model assessment for estimation of index β-cell secretion (HOMA-B), first and second phase insulin secretion, and insulin secretion-sensitivity index (ISSI) than the NGT group (p ≤ 0.001 for all). Moreover, the GIGT group had lower ISOGTT, HOMA-B, first and second phase insulin secretion, and ISSI than the NGT group (p insulin secretion status than the 3-hour abnormal levels group. Korean women with GDM show impairments of both insulin secretion and insulin sensitivity. In addition, GIGT is associated with both β-cell dysfunction and insulin resistance.

  19. Effects of Oral Glucose Load on Endothelial Function and on Insulin and Glucose Fluctuations in Healthy Individuals

    Directory of Open Access Journals (Sweden)

    A. Major-Pedersen

    2008-01-01

    Full Text Available Background/aims. Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order to better understand and cope with the postprandial state in insulin resistant individuals. Methods. We assessed post-oral glucose load endothelial function (flow mediated dilation, plasma insulin, and blood glucose in 9 healthy subjects. Results. The largest increases in delta FMD values (fasting FMD value subtracted from postprandial FMD value occurred at 3 hours after both glucose or placebo load, respectively: 4.80±1.41 (P = .009 and 2.34±1.47 (P = .15. Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. Conclusion. Oral glucose load does not induce endothelial dysfunction in healthy individuals with mean insulin and glucose values of 5.6 mmol/L and 27.2 mmol/L, respectively, 2 hours after glucose load.

  20. Dynamic Metabolomics Reveals that Insulin Primes the Adipocyte for Glucose Metabolism

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    James R. Krycer

    2017-12-01

    Full Text Available Insulin triggers an extensive signaling cascade to coordinate adipocyte glucose metabolism. It is considered that the major role of insulin is to provide anabolic substrates by activating GLUT4-dependent glucose uptake. However, insulin stimulates phosphorylation of many metabolic proteins. To examine the implications of this on glucose metabolism, we performed dynamic tracer metabolomics in cultured adipocytes treated with insulin. Temporal analysis of metabolite concentrations and tracer labeling revealed rapid and distinct changes in glucose metabolism, favoring specific glycolytic branch points and pyruvate anaplerosis. Integrating dynamic metabolomics and phosphoproteomics data revealed that insulin-dependent phosphorylation of anabolic enzymes occurred prior to substrate accumulation. Indeed, glycogen synthesis was activated independently of glucose supply. We refer to this phenomenon as metabolic priming, whereby insulin signaling creates a demand-driven system to “pull” glucose into specific anabolic pathways. This complements the supply-driven regulation of anabolism by substrate accumulation and highlights an additional role for insulin action in adipocyte glucose metabolism.

  1. Bilirubin Increases Insulin Sensitivity in Leptin-Receptor Deficient and Diet-Induced Obese Mice Through Suppression of ER Stress and Chronic Inflammation

    Science.gov (United States)

    Dong, Huansheng; Huang, Hu; Yun, Xinxu; Kim, Do-sung; Yue, Yinan; Wu, Hongju; Sutter, Alton; Chavin, Kenneth D.; Otterbein, Leo E.; Adams, David B.; Kim, Young-Bum

    2014-01-01

    Obesity-induced endoplasmic reticulum (ER) stress causes chronic inflammation in adipose tissue and steatosis in the liver, and eventually leads to insulin resistance and type 2 diabetes (T2D). The goal of this study was to understand the mechanisms by which administration of bilirubin, a powerful antioxidant, reduces hyperglycemia and ameliorates obesity in leptin-receptor-deficient (db/db) and diet-induced obese (DIO) mouse models. db/db or DIO mice were injected with bilirubin or vehicle ip. Blood glucose and body weight were measured. Activation of insulin-signaling pathways, expression of inflammatory cytokines, and ER stress markers were measured in skeletal muscle, adipose tissue, and liver of mice. Bilirubin administration significantly reduced hyperglycemia and increased insulin sensitivity in db/db mice. Bilirubin treatment increased protein kinase B (PKB/Akt) phosphorylation in skeletal muscle and suppressed expression of ER stress markers, including the 78-kDa glucose-regulated protein (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein, X box binding protein (XBP-1), and activating transcription factor 4 in db/db mice. In DIO mice, bilirubin treatment significantly reduced body weight and increased insulin sensitivity. Moreover, bilirubin suppressed macrophage infiltration and proinflammatory cytokine expression, including TNF-α, IL-1β, and monocyte chemoattractant protein-1, in adipose tissue. In liver and adipose tissue of DIO mice, bilirubin ameliorated hepatic steatosis and reduced expression of GRP78 and C/EBP homologous protein. These results demonstrate that bilirubin administration improves hyperglycemia and obesity by increasing insulin sensitivity in both genetically engineered and DIO mice models. Bilirubin or bilirubin-increasing drugs might be useful as an insulin sensitizer for the treatment of obesity-induced insulin resistance and type 2 diabetes based on its profound anti-ER stress and antiinflammatory properties. PMID

  2. Obese mice on a high-fat alternate-day fasting regimen lose weight and improve glucose tolerance.

    Science.gov (United States)

    Joslin, P M N; Bell, R K; Swoap, S J

    2017-10-01

    Alternate-day fasting (ADF) causes body weight (BW) loss in humans and rodents. However, it is not clear that ADF while maintaining a high-fat (HF) diet results in weight loss and the accompanying improvement in control of circulating glucose. We tested the hypotheses that a high-fat ADF protocol in obese mice would result in (i) BW loss, (ii) improved glucose control, (iii) fluctuating phenotypes on 'fasted' days when compared to 'fed' days and (iv) induction of torpor on 'fasted days'. We evaluated the physiological effects of ADF in diet-induced obese mice for BW, heart rate (HR), body temperature (T b ), glucose tolerance, insulin responsiveness, blood parameters (leptin, insulin, free fatty acids) and hepatic gene expression. Diet-induced obese male C57BL/6J mice lost one-third of their pre-diet BW while on an ADF diet for 10 weeks consisting of HF food. The ADF protocol improved glucose tolerance and insulin sensitivity, although mice on a fast day were less glucose tolerant than the same mice on a fed day. ADF mice on a fast day had low circulating insulin, but had an enhanced response to an insulin-assisted glucose tolerance test, suggesting the impaired glucose tolerance may be a result of insufficient insulin production. On fed days, ADF mice were the warmest, had a high HR and displayed hepatic gene expression and circulating leptin that closely mimicked that of mice fed an ad lib HF diet. ADF mice never entered torpor as assessed by HR and T b . However, on fast days, they were the coolest, had the slowest HR, and displayed hepatic gene expression and circulating leptin that closely mimicked that of Chow-Fed mice. Collectively, the ADF regimen with a HF diet in obese mice results in weight loss, improved blood glucose control, and daily fluctuations in selected physiological and biochemical parameters in the mouse. Journal of Animal Physiology and Animal Nutrition © 2016 Blackwell Verlag GmbH.

  3. Polysomnographic sleep, growth hormone insulin-like growth factor-I axis, leptin, and weight loss

    DEFF Research Database (Denmark)

    Rasmussen, Michael; Wildschiødtz, Gordon; Juul, Anders

    2008-01-01

    compared with nonobese subjects After diet-induced weight loss the differences in GH, free IGF-I, and leptin were no longer present between previously obese and nonobese subjects, whereas a significant difference in sleep duration and total IGF-I levels persisted. Rapid eye movement (REM) sleep, non-REM......Short sleep appears to be strongly associated with obesity and altered metabolic function, and sleep and growth hormone (GH) secretion seems interlinked. In obesity, both the GH-insulin-like-growth-factor-I (GH-IGF-I) axis and sleep have been reported to be abnormal, however, no studies have...... investigated sleep in relation to the GH-IGF-I axis and weight loss in obese subjects. In this study polygraphic sleep recordings, 24-h GH release, 24-h leptin levels, free-IGF-I, total-IGF-I, IGF-binding protein-3 (IGFBP-3), acid-labile subunit (ALS), cortisol and insulin sensitivity were determined in six...

  4. Study on the inter-relationship among the changes of serum levels of leptin, insulin and glucagon in patients with DM2 complicated with hypertension

    International Nuclear Information System (INIS)

    Zeng Zhiwei; Yan Songqin; Tan Wei

    2006-01-01

    Objective: To investigate the inter-relationship among the changes of serum leptin, insulin and glucagon levels in patients with type 2 diabetes mellitus (DM2) complicated with hypertension. Methods: Serum leptin, insulin and glucagon levels were, measured with RIA in 30 DM2 patients complicated with hypertension, 30 DM2 patients without hypertension and 30 controls. Results: Serum levels of leptin, insulin and glucagon in all the DM2 patients were significantly higher than those in controls (P<0.01). In addition, the serum levels in DM2 patients with hypertension were significantly higher than those in DM2 patients without hypertension (P<0.05). These levels were positively correlated with the severity of hypertension. Conclusion: The role played by leptin and glucagon in the pathogenesis of type 2 diabetes mellitns should be furthur studied. (authors)

  5. Limited impact on glucose homeostasis of leptin receptor deletion from insulin- or proglucagon-expressing cells

    Directory of Open Access Journals (Sweden)

    Helen Soedling

    2015-09-01

    Conclusions/interpretation: The use here of a highly selective Cre recombinase indicates that leptin signalling plays a relatively minor, age- and sex-dependent role in the control of β cell function in the mouse. No in vivo role for leptin receptors on α cells, nor in other proglucagon-expressing cells, was detected in this study.

  6. Insulin resistance in human subjects having impaired glucose regulation

    International Nuclear Information System (INIS)

    Khan, S.H.; Khan, F.A.; Ijaz, A.

    2007-01-01

    To determine insulin resistance in human subjects having impaired glucose regulation (IGR) by Homeostasis Model Assessment for Insulin Resistance (HOMA-IR). A total of 100 subjects with impaired glucose regulation were selected for evaluation of metabolic syndrome as per the criteria of National Cholesterol Education Program, Adult Treatment Panel III (NCEP, ATP III), along with 47 healthy age and gender-matched controls. Physical examination to determine blood pressure and waist circumference was carried out and so was sampling for plasma glucose, serum triglycerides, HDL-cholesterol and insulin. Insulin resistance was calculated by the HOMA-IR. Finally, subjects with and without metabolic syndrome were compared with controls (n=47), using one-way ANOVA for studying insulin resistance between groups, with Tukey's post-hoc comparison. The frequency of finding metabolic syndrome in cases of IGR remained 47%. The insulin resistance demonstrated stepwise worsening from control population (mean=1.54, 95 % CI: 1.77 - 2.37) to subjects suffering from only IGR (mean=2.07, 95 % CI: 1.77- 2.37) to metabolic syndrome (mean=2.67, 95 %, CI: 2.34 - 3.00) (p < 0.001). Patients with impaired glucose regulation may have significant insulin resistance. It is, thus, recommended that a vigorous search be made to measure insulin resistance in all cases diagnosed to have impaired glucose regulation. (author)

  7. Jejunal gluconeogenesis associated with insulin resistance level and its evolution after Roux-en-Y gastric bypass.

    Science.gov (United States)

    Gutierrez-Repiso, Carolina; Garcia-Serrano, Sara; Moreno-Ruiz, Francisco J; Alcain-Martinez, Guillermo; Rodriguez-Pacheco, Francisca; Garcia-Fuentes, Eduardo

    2017-04-01

    Intestinal gluconeogenesis (GNG) may play an important role in glucose homeostasis, but there is little information about the condition in humans. To study the relationship between intestinal GNG and insulin resistance, its association with the evolution of morbidly obese patients after bariatric surgery, and the effect of insulin and or leptin. Regional university hospital, Malaga (Spain). Jejunal mRNA expression of genes involved in GNG was analyzed in 3 groups of morbidly obese patients who underwent Roux-en-Y gastric bypass: with low insulin resistance (MO-low-IR), with high insulin resistance (MO-high-IR), and with type 2 diabetes treated with metformin (MO-metf-T2D). Also, intestinal epithelial cells (IEC) from MO-low-IR were incubated with different doses of insulin and or leptin. In MO-high-IR, glutaminase, phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6 Pase), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1 α), and sterol regulatory element-binding proteins 1 c (SREBP-1 c) expressions were significantly higher than in MO-low-IR. In MO-metf-T2 D, only PEPCK was significantly lower than in MO-high-IR. In IEC, an incubation with a high glucose and insulin dose produced an increase of PEPCK and SREBP-1 c, and a decrease of glutaminase, fructose 1,6-bisphosphatase (FBPase), and PGC-1 α expression. At high doses of leptin, G6 Pase and FBPase were significantly increased. The improvement of insulin resistance 3 months after bariatric surgery was positively associated with high G6 Pase and FBPase expression. mRNA expression of genes involved in GNG is increased in the jejunum of MO-high-IR, and regulated by insulin and or leptin. High mRNA expression of genes involved in GNG is associated with a better evolution of insulin resistance after bariatric surgery. Copyright © 2016 American Society for Bariatric Surgery. Published by Elsevier Inc. All rights reserved.

  8. Simulation and qualitative analysis of glucose variability, mean glucose, and hypoglycemia after subcutaneous insulin therapy for stress hyperglycemia.

    Science.gov (United States)

    Strilka, Richard J; Stull, Mamie C; Clemens, Michael S; McCaver, Stewart C; Armen, Scott B

    2016-01-27

    The critically ill can have persistent dysglycemia during the "subacute" recovery phase of their illness because of altered gene expression; it is also not uncommon for these patients to receive continuous enteral nutrition during this time. The optimal short-acting subcutaneous insulin therapy that should be used in this clinical scenario, however, is unknown. Our aim was to conduct a qualitative numerical study of the glucose-insulin dynamics within this patient population to answer the above question. This analysis may help clinicians design a relevant clinical trial. Eight virtual patients with stress hyperglycemia were simulated by means of a mathematical model. Each virtual patient had a different combination of insulin resistance and insulin deficiency that defined their unique stress hyperglycemia state; the rate of gluconeogenesis was also doubled. The patients received 25 injections of subcutaneous regular or Lispro insulin (0-6 U) with 3 rates of continuous nutrition. The main outcome measurements were the change in mean glucose concentration, the change in glucose variability, and hypoglycemic episodes. These end points were interpreted by how the ultradian oscillations of glucose concentration were affected by each insulin preparation. Subcutaneous regular insulin lowered both mean glucose concentrations and glucose variability in a linear fashion. No hypoglycemic episodes were noted. Although subcutaneous Lispro insulin lowered mean glucose concentrations, glucose variability increased in a nonlinear fashion. In patients with high insulin resistance and nutrition at goal, "rebound hyperglycemia" was noted after the insulin analog was rapidly metabolized. When the nutritional source was removed, hypoglycemia tended to occur at higher Lispro insulin doses. Finally, patients with severe insulin resistance seemed the most sensitive to insulin concentration changes. Subcutaneous regular insulin consistently lowered mean glucose concentrations and glucose

  9. Endocrine determinants of changes in insulin sensitivity and insulin secretion during a weight cycle in healthy men.

    Directory of Open Access Journals (Sweden)

    Judith Karschin

    Full Text Available Changes in insulin sensitivity (IS and insulin secretion occur with perturbations in energy balance and glycemic load (GL of the diet that may precede the development of insulin resistance and hyperinsulinemia. Determinants of changes in IS and insulin secretion with weight cycling in non-obese healthy subjects remain unclear.In a 6wk controlled 2-stage randomized dietary intervention 32 healthy men (26±4y, BMI: 24±2kg/m2 followed 1wk of overfeeding (OF, 3wks of caloric restriction (CR containing either 50% or 65% carbohydrate (CHO and 2wks of refeeding (RF with the same amount of CHO but either low or high glycaemic index at ±50% energy requirement. Measures of IS (basal: HOMA-index, postprandial: Matsuda-ISI, insulin secretion (early: Stumvoll-index, total: tAUC-insulin/tAUC-glucose and potential endocrine determinants (ghrelin, leptin, adiponectin, thyroid hormone levels, 24h-urinary catecholamine excretion were assessed.IS improved and insulin secretion decreased due to CR and normalized upon RF. Weight loss-induced improvements in basal and postprandial IS were associated with decreases in leptin and increases in ghrelin levels, respectively (r = 0.36 and r = 0.62, p<0.05. Weight regain-induced decrease in postprandial IS correlated with increases in adiponectin, fT3, TSH, GL of the diet and a decrease in ghrelin levels (r-values between -0.40 and 0.83, p<0.05 whereas increases in early and total insulin secretion were associated with a decrease in leptin/adiponectin-ratio (r = -0.52 and r = -0.46, p<0.05 and a decrease in fT4 (r = -0.38, p<0.05 for total insulin secretion only. After controlling for GL associations between RF-induced decrease in postprandial IS and increases in fT3 and TSH levels were no longer significant.Weight cycling induced changes in IS and insulin secretion were associated with changes in all measured hormones, except for catecholamine excretion. While leptin, adiponectin and ghrelin seem to be the major

  10. Effects of oral glucose load on endothelial function and on insulin and glucose fluctuations in healthy individuals

    DEFF Research Database (Denmark)

    Major-Pedersen, A; Ihlemann, N; Hermann, T S

    2008-01-01

    to better understand and cope with the postprandial state in insulin resistant individuals. METHODS: We assessed post-oral glucose load endothelial function (flow mediated dilation), plasma insulin, and blood glucose in 9 healthy subjects. RESULTS: The largest increases in delta FMD values (fasting FMD......BACKGROUND/AIMS: Postprandial hyperglycemia, an independent risk factor for cardiovascular disease, is accompanied by endothelial dysfunction. We studied the effect of oral glucose load on insulin and glucose fluctuations, and on postprandial endothelial function in healthy individuals in order...... value subtracted from postprandial FMD value) occurred at 3 hours after both glucose or placebo load, respectively: 4.80 +/- 1.41 (P = .009) and 2.34 +/- 1.47 (P = .15). Glucose and insulin concentrations achieved maximum peaks at one hour post-glucose load. CONCLUSION: Oral glucose load does not induce...

  11. Peripheral insulin resistance and impaired insulin signaling contribute to abnormal glucose metabolism in preterm baboons.

    Science.gov (United States)

    Blanco, Cynthia L; McGill-Vargas, Lisa L; Gastaldelli, Amalia; Seidner, Steven R; McCurnin, Donald C; Leland, Michelle M; Anzueto, Diana G; Johnson, Marney C; Liang, Hanyu; DeFronzo, Ralph A; Musi, Nicolas

    2015-03-01

    Premature infants develop hyperglycemia shortly after birth, increasing their morbidity and death. Surviving infants have increased incidence of diabetes as young adults. Our understanding of the biological basis for the insulin resistance of prematurity and developmental regulation of glucose production remains fragmentary. The objective of this study was to examine maturational differences in insulin sensitivity and the insulin-signaling pathway in skeletal muscle and adipose tissue of 30 neonatal baboons using the euglycemic hyperinsulinemic clamp. Preterm baboons (67% gestation) had reduced peripheral insulin sensitivity shortly after birth (M value 12.5 ± 1.5 vs 21.8 ± 4.4 mg/kg · min in term baboons) and at 2 weeks of age (M value 12.8 ± 2.6 vs 16.3 ± 4.2, respectively). Insulin increased Akt phosphorylation, but these responses were significantly lower in preterm baboons during the first week of life (3.2-fold vs 9.8-fold). Preterm baboons had lower glucose transporter-1 protein content throughout the first 2 weeks of life (8%-12% of term). In preterm baboons, serum free fatty acids (FFAs) did not decrease in response to insulin, whereas FFAs decreased by greater than 80% in term baboons; the impaired suppression of FFAs in the preterm animals was paired with a decreased glucose transporter-4 protein content in adipose tissue. In conclusion, peripheral insulin resistance and impaired non-insulin-dependent glucose uptake play an important role in hyperglycemia of prematurity. Impaired insulin signaling (reduced Akt) contributes to the defect in insulin-stimulated glucose disposal. Counterregulatory hormones are not major contributors.

  12. Glucose-Responsive Implantable Polymeric Microdevices for "Smart" Insulin Therapy of Diabetes

    Science.gov (United States)

    Chu, Michael Kok Loon

    Diabetes mellitus is a chronic illness manifested by improper blood glucose management, affecting over 350 million worldwide. As a result, all type 1 patients and roughly 20% of type 2 patients require exogenous insulin therapy to survive. Typically, daily multiple injections are taken to maintain normal glucose levels in response glucose spikes from meals. However, patient compliance and dosing accuracy can fluctuate with variation in meals, exercise, glucose metabolism or stress, leading to poor clinical outcomes. A 'smart', closed-loop insulin delivery system providing on-demand release kinetics responding to circulating glucose levels would be a boon for diabetes patients, replacing constant self monitoring and insulin. This thesis focuses on the development of a novel, 'smart' insulin microdevice that can provide on-demand insulin release in response to blood glucose levels. In the early stage, the feasibility of integrating a composite membrane with pH-responsive nanoparticles embedded in ethylcellulose membrane to provide pH-responsive in vitro release was examined and confirmed using a model drug, vitamin B12. In the second microdevice, glucose oxidase for generating pH signals from glucose oxidation, catalase and manganese dioxide nanoparticles, as peroxide scavengers, were used in a bioinorganic, albumin-based membrane cross-linked with a polydimethylsiloxane (PDMS) grid-microdevice system. This prototype device demonstrated insulin release in response to glucose levels in vitro and regulating plasma glucose in type 1 diabetic rats when implanted intraperitoneally. Advancement allowing for subcutaneous implantation and improved biocompatibility was achieved with surface modification of PDMS microdevices grafted with activated 20 kDa polyethylene glycol (PEG) chains, dramatically reducing immune response and local inflammation. When implanted subcutaneously in diabetic rats, glucose-responsive insulin delivery microdevices showed short and long

  13. Thylakoids promote release of the satiety hormone cholecystokinin while reducing insulin in healthy humans

    DEFF Research Database (Denmark)

    Köhnke, Rickard; Lindbo, Agnes; Larsson, Therese

    2009-01-01

    (CCK, leptin and ghrelin), insulin and blood metabolites (glucose and free fatty acids). RESULTS: The CCK level increased, in particular between the 120 min time-point and onwards, the ghrelin level was reduced at 120 min and leptin level increased at 360 min after intake of the thylakoid-enriched meal....... The insulin level was reduced, whereas glucose concentrations were unchanged. Free fatty acids were reduced between time-point 120 min and onwards after the thylakoid meal. CONCLUSIONS: The addition of thylakoids to energy-dense food promotes satiety signals and reduces insulin response during a single meal......OBJECTIVE: The effects of a promising new appetite suppressor named "thylakoids" (membrane proteins derived from spinach leaves) were examined in a single meal in man. Thylakoids inhibit the lipase/colipase hydrolysis of triacylglycerols in vitro and suppress food intake, decrease body-weight gain...

  14. Conjoint regulation of glucagon concentrations via plasma insulin and glucose in dairy cows.

    Science.gov (United States)

    Zarrin, M; Wellnitz, O; Bruckmaier, R M

    2015-04-01

    Insulin and glucagon are glucoregulatory hormones that contribute to glucose homeostasis. Plasma insulin is elevated during normoglycemia or hyperglycemia and acts as a suppressor of glucagon secretion. We have investigated if and how insulin and glucose contribute to the regulation of glucagon secretion through long term (48 h) elevated insulin concentrations during simultaneous hypoglycemia or euglycemia in mid-lactating dairy cows. Nineteen Holstein dairy cows were randomly assigned to 3 treatment groups: an intravenous insulin infusion (HypoG, n = 5) to decrease plasma glucose concentrations (2.5 mmol/L), a hyperinsulinemic-euglycemic clamp to study effects of insulin at simultaneously normal glucose concentrations (EuG, n = 6) and a 0.9% saline infusion (NaCl, n = 8). Plasma glucose was measured at 5-min intervals, and insulin and glucose infusion rates were adjusted accordingly. Area under the curve of hourly glucose, insulin, and glucagon concentrations on day 2 of infusion was evaluated by analysis of variance with treatments as fixed effect. Insulin infusion caused an increase of plasma insulin area under the curve (AUC)/h in HypoG (41.9 ± 8.1 mU/L) and EuG (57.8 ± 7.8 mU/L) compared with NaCl (13.9 ± 1.1 mU/L; P insulin infusion induces elevated glucagon concentrations during hypoglycemia, although the same insulin infusion reduces glucagon concentrations at simultaneously normal glucose concentrations. Thus, insulin does not generally have an inhibitory effect on glucagon concentrations. If simultaneously glucose is low and insulin is high, glucagon is upregulated to increase glucose availability. Therefore, insulin and glucose are conjoint regulatory factors of glucagon concentrations in dairy cows, and the plasma glucose status is the key factor to decide if its concentrations are increased or decreased. This regulatory effect can be important for the maintenance of glucose homeostasis if insulin secretion is upregulated by other factors than high

  15. Sweet taste receptor serves to activate glucose- and leptin-responsive neurons in the hypothalamic arcuate nucleus and participates in glucose responsiveness.

    Directory of Open Access Journals (Sweden)

    Daisuke Kohno

    2016-11-01

    Full Text Available The hypothalamic feeding center plays an important role in energy homeostasis. In the feeding center, whole-body energy signals including hormones and nutrients are sensed, processed, and integrated. As a result, food intake and energy expenditure are regulated. Two types of glucose-sensing neurons exist in the hypothalamic arcuate nucleus (ARC: glucose-excited neurons and glucose-inhibited neurons. While some molecules are known to be related to glucose sensing in the hypothalamus, the mechanism underlying glucose sensing in the hypothalamus are not fully understood. The sweet taste receptor is a heterodimer of taste type 1 receptor 2 (T1R2 and taste type 1 receptor 3 (T1R3 and senses sweet tastes. T1R2 and T1R3 receptors are distributed in multiple organs including the tongue, pancreas, adipose tissue, and hypothalamus. However, the role of sweet taste receptors in the ARC remains to be clarified. To examine the role of sweet taste receptors in the ARC, cytosolic Ca2+ concentration ([Ca2+]i in isolated single ARC neurons were measured using Fura-2 fluorescent imaging. An artificial sweetener, sucralose at 10-5 M-10-2 M dose dependently increased [Ca2+]i in 12-16% of ARC neurons. The sucralose-induced [Ca2+]i increase was suppressed by a sweet taste receptor inhibitor, gurmarin. The sucralose-induced [Ca2+]i increase was inhibited under an extracellular Ca2+-free condition and in the presence of an L-type Ca2+ channel blocker, nitrendipine. Sucralose-responding neurons were activated by high-concentration of glucose. This response to glucose was markedly suppressed by gurmarin. More than half of sucralose-responding neurons were activated by leptin but not ghrelin. Percentage of proopiomelanocortin (POMC neurons among sucralose-responding neurons and sweet taste receptor expressing neurons were low, suggesting that majority of sucralose-responding neurons are non-POMC neurons. These data suggest that sweet taste receptor-mediated cellular

  16. Sweet Taste Receptor Serves to Activate Glucose- and Leptin-Responsive Neurons in the Hypothalamic Arcuate Nucleus and Participates in Glucose Responsiveness.

    Science.gov (United States)

    Kohno, Daisuke; Koike, Miho; Ninomiya, Yuzo; Kojima, Itaru; Kitamura, Tadahiro; Yada, Toshihiko

    2016-01-01

    The hypothalamic feeding center plays an important role in energy homeostasis. In the feeding center, whole-body energy signals including hormones and nutrients are sensed, processed, and integrated. As a result, food intake and energy expenditure are regulated. Two types of glucose-sensing neurons exist in the hypothalamic arcuate nucleus (ARC): glucose-excited neurons and glucose-inhibited neurons. While some molecules are known to be related to glucose sensing in the hypothalamus, the mechanisms underlying glucose sensing in the hypothalamus are not fully understood. The sweet taste receptor is a heterodimer of taste type 1 receptor 2 (T1R2) and taste type 1 receptor 3 (T1R3) and senses sweet tastes. T1R2 and T1R3 are distributed in multiple organs including the tongue, pancreas, adipose tissue, and hypothalamus. However, the role of sweet taste receptors in the ARC remains to be clarified. To examine the role of sweet taste receptors in the ARC, cytosolic Ca 2+ concentration ([Ca 2+ ] i ) in isolated single ARC neurons were measured using Fura-2 fluorescent imaging. An artificial sweetener, sucralose at 10 -5 -10 -2 M dose dependently increased [Ca 2+ ] i in 12-16% of ARC neurons. The sucralose-induced [Ca 2+ ] i increase was suppressed by a sweet taste receptor inhibitor, gurmarin. The sucralose-induced [Ca 2+ ] i increase was inhibited under an extracellular Ca 2+ -free condition and in the presence of an L-type Ca 2+ channel blocker, nitrendipine. Sucralose-responding neurons were activated by high-concentration of glucose. This response to glucose was markedly suppressed by gurmarin. More than half of sucralose-responding neurons were activated by leptin but not ghrelin. Percentages of proopiomelanocortin (POMC) neurons among sucralose-responding neurons and sweet taste receptor expressing neurons were low, suggesting that majority of sucralose-responding neurons are non-POMC neurons. These data suggest that sweet taste receptor-mediated cellular activation

  17. Efficacy of 2-hour post glucose insulin levels in predicting insulin resistance in polycystic ovarian syndrome with infertility

    Directory of Open Access Journals (Sweden)

    Pikee Saxena

    2011-01-01

    Full Text Available Background : Insulin resistance (IR is central to the pathogenesis of polycystic ovarian syndrome (PCOS, but tests for determining IR are elaborate, tedious and expensive. Aims : To evaluate if "2-hour post-glucose insulin level" is an effective indicator of IR and can aid in diagnosing IR in infertile PCOS women. Settings and Design : Observational study at infertility clinic of a tertiary care center. Materials and Methods : 50 infertile women with PCOS and 20 females with tubal/male factor infertility were evaluated for the presence of IR, as defined by the fasting/2-hour post-glucose insulin levels cutoffs of >25/>41 μU/mL, respectively. The clinical, metabolic and endocrinologic profile was determined in both the groups. Statistical Analysis : Statistical analysis was performed using SPSS (Chicago, IL, USA. Results : Body mass index, post load glucose, insulin, glucose/insulin ratio, area under curve (AUC of glucose and insulin and insulinogenic index were significantly lower in the controls as compared to the PCOS group. "2-hour post-glucose insulin levels" were elevated in 88% of PCOS individuals but were normal in all females not suffering from PCOS. These levels significantly correlated with AUC of glucose and insulin, and insulinogenic index and inversely correlated with 2-hour glucose to insulin ratio (r=0.827, 0.749 and −0.732, respectively. Conclusions : "2-hour post-glucose insulin levels" appears to be a good indicator of IR. It can be a useful tool, especially in low resource setting where a single sample can confirm the diagnosis, thus reducing cost and repeat visits.

  18. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice

    NARCIS (Netherlands)

    Coomans, Claudia P.; Biermasz, Nienke R.; Geerling, Janine J.; Guigas, Bruno; Rensen, Patrick C. N.; Havekes, Louis M.; Romijn, Johannes A.

    2011-01-01

    Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated

  19. Studies on leptin utilizing to obesity

    International Nuclear Information System (INIS)

    Zhao Minghui

    2001-01-01

    Leptin is a hormone synthesized and secreted by lipid cells. It is a product encoded and expressed by the obese gene. Administration of recombinant leptin decreases food intake, increases energy expenditure and promotes weight loss. Most studies indicate that leptin is a main regulating factor of catabolism and anabolism of adipose tissue. The circulating leptin level is a sensitive index which indicates the confusion of the rate of lipid metabolism such as hyperlipemia, lipo-liver and so on. The human leptin radioimmunoassay has been developed to quantitate human leptin in plasma or serum, and to further investigate the relationship between serum leptin concentration and body fat, gender, age, sexual hormones, endocrine of insulin, etc. Especially, serum leptin concentrations are correlated with body-mass-index (BMI), suggesting that most obese persons are resistant to leptin; Those who are relatively deficient of leptin may become the good candidates of leptin treatment in the future. The discovery and application of leptin make the study of obesity, non-insulin dependent diabetes and other correlation diseases enter a new stage

  20. Leptin as well as Free Leptin Receptor Is Associated with Polycystic Ovary Syndrome in Young Women

    Science.gov (United States)

    Rizk, Nasser M.; Sharif, Elham

    2015-01-01

    Background and Aim. Leptin has two forms in the circulation: free and bound forms. The soluble leptin receptor (sOB-R) circulates in the blood and can bind to leptin. The aim of this study is to assess the concentrations of the leptin and the sOB-R in PCOS and its relation to adiposity, insulin resistance, and androgens. Methods. A cross-sectional study included 78 female students aged 17–25 years. Fasting serum leptin and sOB-R concentrations were measured. The anthropometric variables and the hormonal profile such as insulin, female and male sex hormones, and prolactin were assessed. Results. In PCOS, leptin level (ng/ml) and free leptin index (FLI) increased significantly while sOB-R (ng/ml) significantly decreased compared to control subjects. In age-matched subjects, obese PCOS had increased leptin level in ng/ml (median level with interquartile levels) of 45.67 (41.98–48.04) and decreased sOB-R in ng/ml 11.47 (7.59–16.44) compared to lean PCOS 16.97 (10.60–45.55) for leptin and 16.62 (11.61–17.96) for sOB-R with p values 0.013 and 0.042, respectively. However, body mass index (BMI) is significantly correlated with leptin and s-OBR, while no significant correlations with parameters of insulin resistance were detected. Conclusion. PCOS is associated with hyperleptinemia and increased free leptin index. Decreased sOB-R could be a compensatory mechanism for the defective action of leptin. PMID:26180527

  1. Leptin as well as Free Leptin Receptor Is Associated with Polycystic Ovary Syndrome in Young Women

    Directory of Open Access Journals (Sweden)

    Nasser M. Rizk

    2015-01-01

    Full Text Available Background and Aim. Leptin has two forms in the circulation: free and bound forms. The soluble leptin receptor (sOB-R circulates in the blood and can bind to leptin. The aim of this study is to assess the concentrations of the leptin and the sOB-R in PCOS and its relation to adiposity, insulin resistance, and androgens. Methods. A cross-sectional study included 78 female students aged 17–25 years. Fasting serum leptin and sOB-R concentrations were measured. The anthropometric variables and the hormonal profile such as insulin, female and male sex hormones, and prolactin were assessed. Results. In PCOS, leptin level (ng/ml and free leptin index (FLI increased significantly while sOB-R (ng/ml significantly decreased compared to control subjects. In age-matched subjects, obese PCOS had increased leptin level in ng/ml (median level with interquartile levels of 45.67 (41.98–48.04 and decreased sOB-R in ng/ml 11.47 (7.59–16.44 compared to lean PCOS 16.97 (10.60–45.55 for leptin and 16.62 (11.61–17.96 for sOB-R with p values 0.013 and 0.042, respectively. However, body mass index (BMI is significantly correlated with leptin and s-OBR, while no significant correlations with parameters of insulin resistance were detected. Conclusion. PCOS is associated with hyperleptinemia and increased free leptin index. Decreased sOB-R could be a compensatory mechanism for the defective action of leptin.

  2. Stimulatory effect of insulin on glucose uptake by muscle involves the central nervous system in insulin-sensitive mice

    NARCIS (Netherlands)

    Coomans, C.P.; Biermasz, N.R.; Geerling, J.J.; Guigas, B.; Rensen, P.C.N.; Havekes, L.M.; Romijn, J.A.

    2011-01-01

    OBJECTIVE - Insulin inhibits endogenous glucose production (EGP) and stimulates glucose uptake in peripheral tissues. Hypothalamic insulin signaling is required for the inhibitory effects of insulin on EGP. We examined the contribution of central insulin signaling on circulating insulin-stimulated

  3. Effect of fat supplementation on leptin, insulin-like growth factor I, growth hormone, and insulin in cattle.

    Science.gov (United States)

    Becú-Villalobos, Damasia; García-Tornadú, Isabel; Shroeder, Guillermo; Salado, Eloy E; Gagliostro, Gerardo; Delavaud, Carole; Chilliard, Yves; Lacau-Mengido, Isabel M

    2007-07-01

    We investigated the effect of fat supplementation on plasma levels of hormones related to metabolism, with special attention to leptin, in cows in early lactation and in feedlot steers. In experiment 1, 34 lactating cows received no fat or else 0.5 or 1.0 kg of partially hydrogenated oil per day in addition to their basal diet from day 20 before the expected calving date to day 70 postpartum. In experiment 2, part of the corn in the basal concentrate was replaced with 0.7 kg of the same oil such that the diets were isocaloric; 18 cows received the fat-substituted diet and 18 a control diet from day 20 before the expected calving date to day 75 postpartum. In experiment 3, calcium salts of fatty acids were added to the basal diet of 14 feedlot steers for 80 d; another 14 steers received a control diet. The basal plasma levels of leptin were higher in the cows than in the steers. Dietary fat supplementation did not affect the leptin levels in the lactating cows but lowered the levels in the feedlot steers despite greater energy intake and body fatness (body weight) in the steers receiving the supplement than in those receiving the control diet. The levels of insulin-like growth factor I and insulin were decreased with dietary fat supplementation in the lactating cows but were unaffected in the steers, suggesting that responses to fat ingestion depend on the physiological state of the animal, including age and sex. Finally, no effects of supplementary fat on the level of growth hormone were demonstrated in any of the models.

  4. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays

    Science.gov (United States)

    Kalra, Satya P.

    2009-01-01

    Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin -hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs - liver, skeletal muscle and brown adipose tissue - to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae-hyperinsulinemia, insulin resistance and hyperglycemia - in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans. PMID:19647774

  5. Osteocalcin as a negative regulator of serum leptin concentration in humans: insight from triathlon competitions.

    Science.gov (United States)

    Guadalupe-Grau, Amelia; Ara, Ignacio; Dorado, Cecilia; Vicente-Rodríguez, German; Perez-Gomez, Jorge; Cabrero, Javier Chavarren; Serrano-Sanchez, José A; Santana, Alfredo; Calbet, Jose A L

    2010-10-01

    Osteocalcin is a hormone produced by osteoblasts which acts as a negative regulator of fat mass, protecting against diet induced obesity and insulin resistance in rodents. To determine if an acute increase in osteocalcin concentration is associated with opposed changes in circulating leptin levels and insulin resistance we studied 15 middle and long distance male triathletes, (age 32.1 ± 6.9 years), before and 48 h after an Olympic (OT) or an Ironman (IT) triathlon competition. Muscle power, anaerobic capacity, body composition (dual-energy X-ray absorptiometry), and serum concentrations of testosterone, dihydrotestosterone, osteocalcin, leptin, glucose, insulin and insulin resistance (HOMA) were determined pre- and post-race. Pre- and 48 h post-race total and regional lean body mass was not altered, but fat mass was similarly increased (~250 g) 48 h after the competitions. This elicited an increase in plasma leptin of 33% after the IT while it remained unchanged after the OT, likely due to a 25% increase in plasma osteocalcin which occurred only after the OT (all p < 0.05). Post-race HOMA remained unchanged in OT and IT. Performance was normalized 48 h after the competitions, with the exception of a slightly lower jumping capacity after the IT. Serum testosterone concentration tended to decrease by 10% after the IT whilst dihydrotestosterone was reduced by 24% after the IT. In conclusion, an acute increase in serum osteocalcin concentration blunts the expected increase of serum leptin concentration that should occur with fat mass gain. This study provides evidence for osteocalcin as a negative regulator of serum leptin in humans.

  6. Effects of exercise training on glucose control, lipid metabolism, and insulin sensitivity in hypertriglyceridemia and non-insulin dependent diabetes mellitus.

    Science.gov (United States)

    Lampman, R M; Schteingart, D E

    1991-06-01

    Exercise training has potential benefits for patients with hyperlipidemia and/or non-insulin dependent diabetes mellitus. In nondiabetic, nonobese subjects with hypertriglyceridemia, exercise training alone increased insulin sensitivity, improved glucose tolerance, and lowered serum triglyceride and cholesterol levels. These improvements did not occur when exercise training alone was given to similar patients with impaired glucose tolerance. In severely obese (X = 125 kg) subjects without diabetes melitus, a 600 calorie diet alone decreased glucose and insulin concentrations and improved glucose tolerance but did not increase insulin sensitivity. The addition of exercise training improved insulin sensitivity. Obese, non-insulin dependent diabetes mellitus subjects on sulfonylurea therapy alone increased insulin levels but failed to improve insulin sensitivity or glucose levels. In contrast, the addition of exercise training to this medication resulted in improved insulin sensitivity and lowered glucose levels. We conclude that exercise training has major effects on lowering triglyceride levels in hyperlipidemic subjects and can potentiate the effect of diet or drug therapy on glucose metabolism in patients with non-insulin dependent diabetes mellitus.

  7. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity

    DEFF Research Database (Denmark)

    Beck Jørgensen, Sebastian; O'Neill, Hayley M; Sylow, Lykke

    2013-01-01

    Obesity is associated with chronic low-grade inflammation that contributes to defects in energy metabolism and insulin resistance. Suppressor of cytokine signaling (SOCS)-3 expression is increased in skeletal muscle of obese humans. SOCS3 inhibits leptin signaling in the hypothalamus and insulin...... of hyperinsulinemia and insulin resistance because of enhanced skeletal muscle insulin receptor substrate 1 (IRS1) and Akt phosphorylation that resulted in increased skeletal muscle glucose uptake. These data indicate that skeletal muscle SOCS3 does not play a critical role in regulating muscle development or energy...... expenditure, but it is an important contributing factor for inhibiting insulin sensitivity in obesity. Therapies aimed at inhibiting SOCS3 in skeletal muscle may be effective in reversing obesity-related glucose intolerance and insulin resistance....

  8. Activation of SF1 Neurons in the Ventromedial Hypothalamus by DREADD Technology Increases Insulin Sensitivity in Peripheral Tissues.

    Science.gov (United States)

    Coutinho, Eulalia A; Okamoto, Shiki; Ishikawa, Ayako Wendy; Yokota, Shigefumi; Wada, Nobuhiro; Hirabayashi, Takahiro; Saito, Kumiko; Sato, Tatsuya; Takagi, Kazuyo; Wang, Chen-Chi; Kobayashi, Kenta; Ogawa, Yoshihiro; Shioda, Seiji; Yoshimura, Yumiko; Minokoshi, Yasuhiko

    2017-09-01

    The ventromedial hypothalamus (VMH) regulates glucose and energy metabolism in mammals. Optogenetic stimulation of VMH neurons that express steroidogenic factor 1 (SF1) induces hyperglycemia. However, leptin acting via the VMH stimulates whole-body glucose utilization and insulin sensitivity in some peripheral tissues, and this effect of leptin appears to be mediated by SF1 neurons. We examined the effects of activation of SF1 neurons with DREADD (designer receptors exclusively activated by designer drugs) technology. Activation of SF1 neurons by an intraperitoneal injection of clozapine- N -oxide (CNO), a specific hM3Dq ligand, reduced food intake and increased energy expenditure in mice expressing hM3Dq in SF1 neurons. It also increased whole-body glucose utilization and glucose uptake in red-type skeletal muscle, heart, and interscapular brown adipose tissue, as well as glucose production and glycogen phosphorylase a activity in the liver, thereby maintaining blood glucose levels. During hyperinsulinemic-euglycemic clamp, such activation of SF1 neurons increased insulin-induced glucose uptake in the same peripheral tissues and tended to enhance insulin-induced suppression of glucose production by suppressing gluconeogenic gene expression and glycogen phosphorylase a activity in the liver. DREADD technology is thus an important tool for studies of the role of the brain in the regulation of insulin sensitivity in peripheral tissues. © 2017 by the American Diabetes Association.

  9. Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index

    DEFF Research Database (Denmark)

    Kiess, W; Anil, M; Blum, W F

    1998-01-01

    . It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin...... concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were...... compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0...

  10. Serum leptin levels in children and adolescents with insulin-dependent diabetes mellitus in relation to metabolic control and body mass index

    DEFF Research Database (Denmark)

    Kiess, W; Anil, M; Blum, W F

    1998-01-01

    . It is unclear at present whether this insulin action is a direct or an indirect effect. To investigate whether leptin concentrations in children and adolescents with type 1 diabetes (IDDM) were related to metabolic status, body weight, body mass index and insulin treatment, we have measured leptin...... compared with normative data that were derived from a large cohort of healthy children and adolescents. Serum from children with newly diagnosed diabetes had significantly lower levels of leptin (mean 1.28+/-1.60 ng/ml, range 0.14-6.13 ng/ml) compared with healthy children (n=710) (mean 2.2 ng/ml, range 0...... concentrations in serum from 13 newly diagnosed IDDM patients before the beginning of insulin treatment (8 girls, 5 boys, aged 4.7-17.5 years) and in 134 patients with IDDM during treatment (64 girls, 70 boys, aged 2.6-20.1 years) using a specific radioimmunoassay. The data from patients with diabetes were...

  11. Phosphatidyl inositol 3-kinase signaling in hypothalamic proopiomelanocortin neurons contributes to the regulation of glucose homeostasis.

    Science.gov (United States)

    Hill, Jennifer W; Xu, Yong; Preitner, Frederic; Fukuda, Makota; Cho, You-Ree; Luo, Ji; Balthasar, Nina; Coppari, Roberto; Cantley, Lewis C; Kahn, Barbara B; Zhao, Jean J; Elmquist, Joel K

    2009-11-01

    Recent studies demonstrated a role for hypothalamic insulin and leptin action in the regulation of glucose homeostasis. This regulation involves proopiomelanocortin (POMC) neurons because suppression of phosphatidyl inositol 3-kinase (PI3K) signaling in these neurons blunts the acute effects of insulin and leptin on POMC neuronal activity. In the current study, we investigated whether disruption of PI3K signaling in POMC neurons alters normal glucose homeostasis using mouse models designed to both increase and decrease PI3K-mediated signaling in these neurons. We found that deleting p85alpha alone induced resistance to diet-induced obesity. In contrast, deletion of the p110alpha catalytic subunit of PI3K led to increased weight gain and adipose tissue along with reduced energy expenditure. Independent of these effects, increased PI3K activity in POMC neurons improved insulin sensitivity, whereas decreased PI3K signaling resulted in impaired glucose regulation. These studies show that activity of the PI3K pathway in POMC neurons is involved in not only normal energy regulation but also glucose homeostasis.

  12. Effect of insulin and glucocorticoids on glucose transporters in rat adipocytes

    International Nuclear Information System (INIS)

    Carter-Su, C.; Okamoto, K.

    1987-01-01

    The ability of glucocorticoids to modify the effect of insulin on glucose (L-1- 3 H(N)]glucose and D-[ 14 C-U]glucose) transport was investigated in both intact isolated rat adipocytes and in membranes isolated from hormone-treated adipocytes. In intact adipocytes, dexamethasone, a potent synthetic glucocorticoid, inhibited insulin-stimulated 3-O-methylglucose transport at all concentrations of insulin tested. Insulin sensitivity, as well as the maximal response to insulin, was decreased by dexamethasone in the absence of a change in 125 I insulin binding. The inhibition was observed regardless of which hormone acted first, was blocked by actinomycin D, and resulted from a decrease in V/sub max/ rather than an increase in K/sub t/ of transport. In plasma membranes isolated from insulin-treated adipocytes, glucose transport activity and the amount of glucose transporter covalently labeled with [ 3 H]cytochalasin B were increased in parallel in a dose-dependent fashion. The amount of labeled transporter in a low-density microsomal fraction (LDMF) was decreased in a reciprocal fashion. In contrast, addition of dexamethasone to insulin-stimulated cells caused decreases in both transport activity and amount of labeled transporter in the plasma membranes. This was accompanied by a small increase in the amount of [ 3 H]cytochalasin B incorporated into the glucose transporter in the LDMF. These results are consistent with both insulin and glucocorticoids altering the distribution of glucose transporters between the plasma membrane and LDMF, in opposite directions

  13. Insulin modulates hippocampally-mediated spatial working memory via glucose transporter-4.

    Science.gov (United States)

    Pearson-Leary, J; Jahagirdar, V; Sage, J; McNay, E C

    2018-02-15

    The insulin-regulated glucose transporter, GluT4, is a key molecule in peripheral insulin signaling. Although GluT4 is abundantly expressed in neurons of specific brain regions such as the hippocampus, the functional role of neuronal GluT4 is unclear. Here, we used pharmacological inhibition of GluT4-mediated glucose uptake to determine whether GluT4 mediates insulin-mediated glucose uptake in the hippocampus. Consistent with previous reports, we found that glucose utilization increased in the dorsal hippocampus of male rats during spontaneous alternation (SA), a hippocampally-mediated spatial working memory task. We previously showed that insulin signaling within the hippocampus is required for processing this task, and that administration of exogenous insulin enhances performance. At baseline levels of hippocampal insulin, inhibition of GluT4-mediated glucose uptake did not affect SA performance. However, inhibition of an upstream regulator of GluT4, Akt, did impair SA performance. Conversely, when a memory-enhancing dose of insulin was delivered to the hippocampus prior to SA-testing, inhibition of GluT4-mediated glucose transport prevented cognitive enhancement. These data suggest that baseline hippocampal cognitive processing does not require functional hippocampal GluT4, but that cognitive enhancement by supra-baseline insulin does. Consistent with these findings, we found that in neuronal cell culture, insulin increases glucose utilization in a GluT4-dependent manner. Collectively, these data demonstrate a key role for GluT4 in transducing the procognitive effects of elevated hippocampal insulin. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Closed-loop controlled noninvasive ultrasonic glucose sensing and insulin delivery

    Science.gov (United States)

    Park, Eun-Joo; Werner, Jacob; Jaiswal, Devina; Smith, Nadine Barrie

    2010-03-01

    To prevent complications in diabetes, the proper management of blood glucose levels is essential. Previously, ultrasonic transdermal methods using a light-weight cymbal transducer array has been studied for noninvasive methods of insulin delivery for Type-1 diabetes and glucose level monitoring. In this study, the ultrasound systems of insulin delivery and glucose sensing have been combined by a feedback controller. This study was designed to show the feasibility of the feedback controlled ultrasound system for the noninvasive glucose control. For perspective human application, in vivo experiments were performed on large animals that have a similar size to humans. Four in vivo experiments were performed using about 200 lbs pigs. The cymbal array of 3×3 pattern has been used for insulin delivery at 30 kHz with the spatial-peak temporal-peak intensity (Isptp) of 100 mW/cm2. For glucose sensing, a 2×2 array was operated at 20 kHz with Isptp = 100 mW/cm2. Based on the glucose level determined by biosensors after the ultrasound exposure, the ultrasound system for the insulin delivery was automatically operated. The glucose level of 115 mg/dl was set as a reference value for operating the insulin delivery system. For comparison, the glucose levels of blood samples collected from the ear vein were measured by a commercial glucose meter. Using the ultrasound system operated by the close-loop, feed-back controller, the glucose levels of four pigs were determined every 20 minutes and continuously controlled for 120 minutes. In comparison to the commercial glucose meter, the glucose levels determined by the biosensor were slightly higher. The results of in vivo experiments indicate the feasibility of the feedback controlled ultrasound system using the cymbal array for noninvasive glucose sensing and insulin delivery. Further studies on the extension of the glucose control will be continued for the effective method of glucose control.

  15. The Glucose-Insulin Control System

    DEFF Research Database (Denmark)

    Hallgreen, Christine Erikstrup; Korsgaard, Thomas Vagn; Hansen, RenéNormann N.

    2008-01-01

    This chapter reviews the glucose-insulin control system. First, classic control theory is described briefly and compared with biological control. The following analysis of the control system falls into two parts: a glucose-sensing part and a glucose-controlling part. The complex metabolic pathways...... are divided into smaller pieces and analyzed via several small biosimulation models that describe events in beta cells, liver, muscle and adipose tissue etc. In the glucose-sensing part, the beta cell are shown to have some characteristics of a classic PID controller, but with nonlinear properties...... control, the analysis shows that the system has many more facets than just keeping the glucose concentration within narrow limits. After glucose enters the cell and is phosphorylated to glucose-6-phosphate, the handling of glucose-6-phosphate is critical for glucose regulation. Also, this handling...

  16. Proximity to Delivery Alters Insulin Sensitivity and Glucose Metabolism in Pregnant Mice.

    Science.gov (United States)

    Musial, Barbara; Fernandez-Twinn, Denise S; Vaughan, Owen R; Ozanne, Susan E; Voshol, Peter; Sferruzzi-Perri, Amanda N; Fowden, Abigail L

    2016-04-01

    In late pregnancy, maternal insulin resistance occurs to support fetal growth, but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy at day 16 (D16) and near term at D19. Nonpregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by DEXA, tissue insulin signaling protein abundance by Western blotting, glucose tolerance and utilization, and insulin sensitivity using acute insulin administration and hyperinsulinemic-euglycemic clamps with [(3)H]glucose infusion. Whole-body insulin resistance occurred in D16 pregnant dams in association with basal hyperinsulinemia, insulin-resistant endogenous glucose production, and downregulation of several proteins in hepatic and skeletal muscle insulin signaling pathways relative to NP and D19 values. Insulin resistance was less pronounced at D19, with restoration of NP insulin concentrations, improved hepatic insulin sensitivity, and increased abundance of hepatic insulin signaling proteins. At D16, insulin resistance at whole-body, tissue, and molecular levels will favor fetal glucose acquisition, while improved D19 hepatic insulin sensitivity will conserve glucose for maternal use in anticipation of lactation. Tissue sensitivity to insulin, therefore, alters differentially with proximity to delivery in pregnant mice, with implications for human and other species. © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity.

    Science.gov (United States)

    Kelly, Karen R; Brooks, Latina M; Solomon, Thomas P J; Kashyap, Sangeeta R; O'Leary, Valerie B; Kirwan, John P

    2009-06-01

    Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response to glucose in older (66.8 +/- 1.5 yr), obese (34.4 +/- 1.7 kg/m(2)) adults with impaired glucose tolerance. In addition to GIP, plasma PYY(3-36), insulin, and glucose responses were measured during a 3-h, 75-g oral glucose tolerance test. Both interventions led to a significant improvement in Vo(2 max) (P HYPO (-8.3 +/- 1.1 vs. -2.8 +/- 0.5, P = 0.002). The glucose-stimulated insulin response was reduced after EX-HYPO (P = 0.02), as was the glucose-stimulated GIP response (P caloric restriction and exercise reduces the GIP response to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults.

  18. Human milk insulin is related to maternal plasma insulin and BMI: but other components of human milk do not differ by BMI.

    Science.gov (United States)

    Young, B E; Patinkin, Z; Palmer, C; de la Houssaye, B; Barbour, L A; Hernandez, T; Friedman, J E; Krebs, N F

    2017-09-01

    The impact of maternal BMI and insulin sensitivity on bioactive components of human milk (HM) is not well understood. As the prevalence of obesity and diabetes rises, it is increasingly critical that we understand how maternal BMI and hormones associated with metabolic disease relate to concentrations of bioactive components in HM. This longitudinal cohort design followed 48 breastfeeding mothers through the first four months of lactation, collecting fasting morning HM samples at 2-weeks and 1, 2, 3 and 4-months, and fasting maternal blood at 2-weeks and 4-months. Insulin, glucose, adipokines leptin and adiponectin, appetite regulating hormone ghrelin, marker of oxidative stress 8OHdG and inflammatory cytokines (IL-6, IL-8, and TNF-a) were measured in HM and maternal plasma. A total of 26 normal weight (NW) (BMI=21.4±2.0 kg/m 2 ) and 22 overweight/obese (OW/Ob) (BMI=30.4±4.2 kg/m 2 ) were followed. Of all HM analytes measured, only insulin and leptin were different between groups - consistently higher in the OW/Ob group (leptin: P<0.001; insulin: P<0.03). HM insulin was 98% higher than maternal plasma insulin at 2-weeks and 32% higher at 4-months (P<0.001). Maternal fasting plasma insulin and HOMA-IR were positively related to HM insulin at 2-weeks (P<0.001, R 2 ⩾0.38, n=31), and 4-months (P⩽0.005, R 2 ⩾0.20, n=38). The concentrations of insulin in HM are higher than in maternal plasma and are related to maternal BMI and insulin sensitivity. With the exception of leptin, there were minimal other differences observed in HM composition across a wide range in maternal BMI.

  19. Impaired insulin secretion and glucose intolerance in synaptotagmin-7 null mutant mice

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Lao, Ye; Maximov, Anton

    2008-01-01

    and insulin release. Here, we show that synaptotagmin-7 is required for the maintenance of systemic glucose tolerance and glucose-stimulated insulin secretion. Mutant mice have normal insulin sensitivity, insulin production, islet architecture and ultrastructural organization, and metabolic and calcium...... secretion in pancreatic beta-cells. Of these other synaptotagmins, synaptotagmin-7 is one of the most abundant and is present in pancreatic beta-cells. To determine whether synaptotagmin-7 regulates Ca(2+)-dependent insulin secretion, we analyzed synaptotagmin-7 null mutant mice for glucose tolerance...... responses but exhibit impaired glucose-induced insulin secretion, indicating a calcium-sensing defect during insulin-containing secretory granule exocytosis. Taken together, our findings show that synaptotagmin-7 functions as a positive regulator of insulin secretion and may serve as a calcium sensor...

  20. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians12

    Science.gov (United States)

    Fretts, Amanda M; Follis, Jack L; Nettleton, Jennifer A; Lemaitre, Rozenn N; Ngwa, Julius S; Wojczynski, Mary K; Kalafati, Ioanna Panagiota; Varga, Tibor V; Frazier-Wood, Alexis C; Houston, Denise K; Lahti, Jari; Ericson, Ulrika; van den Hooven, Edith H; Mikkilä, Vera; Kiefte-de Jong, Jessica C; Mozaffarian, Dariush; Rice, Kenneth; Renström, Frida; North, Kari E; McKeown, Nicola M; Feitosa, Mary F; Kanoni, Stavroula; Smith, Caren E; Garcia, Melissa E; Tiainen, Anna-Maija; Sonestedt, Emily; Manichaikul, Ani; van Rooij, Frank JA; Dimitriou, Maria; Raitakari, Olli; Pankow, James S; Djoussé, Luc; Province, Michael A; Hu, Frank B; Lai, Chao-Qiang; Keller, Margaux F; Perälä, Mia-Maria; Rotter, Jerome I; Hofman, Albert; Graff, Misa; Kähönen, Mika; Mukamal, Kenneth; Johansson, Ingegerd; Ordovas, Jose M; Liu, Yongmei; Männistö, Satu; Uitterlinden, André G; Deloukas, Panos; Seppälä, Ilkka; Psaty, Bruce M; Cupples, L Adrienne; Borecki, Ingrid B; Franks, Paul W; Arnett, Donna K; Nalls, Mike A; Eriksson, Johan G; Orho-Melander, Marju; Franco, Oscar H; Lehtimäki, Terho; Dedoussis, George V; Meigs, James B; Siscovick, David S

    2015-01-01

    Background: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the associations of meat intake and the interaction of meat with genotype on fasting glucose and insulin concentrations in Caucasians free of diabetes mellitus. Design: Fourteen studies that are part of the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium participated in the analysis. Data were provided for up to 50,345 participants. Using linear regression within studies and a fixed-effects meta-analysis across studies, we examined 1) the associations of processed meat and unprocessed red meat intake with fasting glucose and insulin concentrations; and 2) the interactions of processed meat and unprocessed red meat with genetic risk score related to fasting glucose or insulin resistance on fasting glucose and insulin concentrations. Results: Processed meat was associated with higher fasting glucose, and unprocessed red meat was associated with both higher fasting glucose and fasting insulin concentrations after adjustment for potential confounders [not including body mass index (BMI)]. For every additional 50-g serving of processed meat per day, fasting glucose was 0.021 mmol/L (95% CI: 0.011, 0.030 mmol/L) higher. Every additional 100-g serving of unprocessed red meat per day was associated with a 0.037-mmol/L (95% CI: 0.023, 0.051-mmol/L) higher fasting glucose concentration and a 0.049–ln-pmol/L (95% CI: 0.035, 0.063–ln-pmol/L) higher fasting insulin concentration. After additional adjustment for BMI, observed associations were attenuated and no longer statistically significant. The association of processed meat and fasting insulin did not reach statistical significance after correction for multiple comparisons. Observed associations were not modified by genetic

  1. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability.

    Science.gov (United States)

    García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W; Pfluger, Paul T; Fernandez, Ana M; Luquet, Serge; Woods, Stephen C; Torres-Alemán, Ignacio; Kahn, C Ronald; Götz, Magdalena; Horvath, Tamas L; Tschöp, Matthias H

    2016-08-11

    We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and circuit connectivity. Accordingly, astrocytic IR ablation reduces glucose-induced activation of hypothalamic pro-opio-melanocortin (POMC) neurons and impairs physiological responses to changes in glucose availability. Hypothalamus-specific knockout of astrocytic IRs, as well as postnatal ablation by targeting glutamate aspartate transporter (GLAST)-expressing cells, replicates such alterations. A normal response to altering directly CNS glucose levels in mice lacking astrocytic IRs indicates a role in glucose transport across the blood-brain barrier (BBB). This was confirmed in vivo in GFAP-IR KO mice by using positron emission tomography and glucose monitoring in cerebral spinal fluid. We conclude that insulin signaling in hypothalamic astrocytes co-controls CNS glucose sensing and systemic glucose metabolism via regulation of glucose uptake across the BBB. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Relationship of leptin and insulin-like growth factor I to nutritional status in hemodialyzed children.

    Science.gov (United States)

    Besbas, Nesrin; Ozaltin, Fatih; Coşkun, Turgay; Ozalp, Sila; Saatçi, Umit; Bakkaloğlu, Aysin; El Nahas, A Meguid

    2003-12-01

    Malnutrition is prevalent in patients with end-stage renal disease (ESRD). Elevated serum leptin levels were thought to contribute to the anorexia and poor nutrition in renal failure. However, studies of the relationship between nutritional status and leptin concentration in chronic renal failure have yielded conflicting results. Plasma insulin-like growth factor I (IGF-I) level has been used as an indicator of nutritional status in patients with renal failure. The relationship between leptin and IGF-I is controversial. The present study was conducted with the aim of assessing the relationship between nutritional status, hyperleptinemia, and serum IGF-I. Seventeen ESRD patients (8 male, 9 female), aged 8-18 years (mean 15.3+/-3.3 years) and undergoing standard hemodialysis for 58.8+/-23.1 months were enrolled. Nine age-matched healthy children served as controls. In all patients, energy and protein intakes were 40-70 kcal/kg per day and 1-1.54 g/kg per day, respectively. Predialysis serum leptin and IGF-I levels were measured by radioimmunoassay. Body mass index was decreased in 13 (76%) patients. Triceps skinfold thickness (TST) was reduced (below the 5th percentile) in 7 (41%), whereas mid arm circumference and mid arm muscle circumference were reduced in 14 (82.5%) and 13 (76.5%), respectively. The median serum leptin level was significantly higher in patients than in controls [13.7 interquartile range (IQR) 30.50 pg/ml vs. 6.50 IQR 8.65 pg/ml, P=0.01]. The median serum IGF-I level was lower in the patients (205.1 ng/ml IQR 194.4 ng/l) than controls (418.0 ng/l IQR 310.5 ng/ml) ( P=0.01). IGF-I levels were more decreased in patients with severe malnutrition, defined according to TST (145.0 ng/ml IQR 125.5 ng/l) than patients without malnutrition (301.2 ng/l IQR 218.8 ng/ml) ( P=0.03) and healthy children ( P=0.002). Although statistically not significant, IGF-I levels tended to be decreased, while leptin levels were increased. The median plasma insulin

  3. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Science.gov (United States)

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR), and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1). In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown) with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  4. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling.

    Directory of Open Access Journals (Sweden)

    Ha-Na Na

    Full Text Available Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a retrovirus plasmid expressing E4orf1, or a null vector. E4orf1 significantly improved insulin sensitivity in response to a glucose load. Yet, their proximal insulin signaling in fat depots was impaired, as indicated by reduced tyrosine phosphorylation of insulin receptor (IR, and significantly increased abundance of ectonucleotide pyrophosphatase/phosphodiesterase-1 (ENPP1. In 3T3-L1 pre-adipocytes E4orf1 expression impaired proximal insulin signaling. Whereas, treatment with rosiglitazone reduced ENPP1 abundance. Unaffected by IR-KD (insulin receptor knockdown with siRNA, E4orf1 significantly up-regulated distal insulin signaling pathway and enhanced cellular glucose uptake. In vivo, E4orf1 impairs proximal insulin signaling in fat depots yet improves glycemic control. This is probably explained by the ability of E4orf1 to promote cellular glucose uptake independent of proximal insulin signaling. E4orf1 may provide a therapeutic template to enhance glucose disposal in the presence of impaired proximal insulin signaling.

  5. Observation of the imbalance among insulin, true insulin and leptin in type 2 diabetes mellitus patients

    International Nuclear Information System (INIS)

    Wang Susu; Zhang Zhaofu; Peng Chaosheng; Cao Ruian; Ma Xiaobing; Zang Guiming; Xia Qing; Long Nanzhan; Zhang Baohe; Wang Hongying

    2005-01-01

    To observe the imbalance among immunoreactive insulin (IRI), true insulin (TI) and leptin (LEP) in type 2 diabetes mellitus (DM)patients, 39 subjects with type 2 DM patients and 31 normal control subjects were studied. IRI was measured with RIA, while TI and LEP were determined by BA-ELISA. In type 2 DM patients the IRI concentration (16.87±1.22 mIU/L) was higher than that of normal subjects(12.33±l.31 mIU/L), and the ratio of IRI/TI(11.10±1.98) was significantly increased, but the insulin sensitivity index was obviously reduced. There was good positive correlation between IRI, TI and LEP in control individuals(r value for IRI and TI was 0.553, for IRI and LEP was 0.631 and for LEP and TI was 0.483; P<0.001 for all), where as similar correlation was not observed in the cases of type 2 DM. The results suggest that there is a good modulation among IRI, TI and LEP in normal individuals, but there exist insulin resistance, relative lack of TI and imbalance of IRI-TI-LEP axis in type 2 DM patients. (authors)

  6. The associations between serum adiponectin, leptin, C-reactive protein, insulin, and serum long-chain omega-3 fatty acids in Labrador Retrievers

    Directory of Open Access Journals (Sweden)

    Streeter RM

    2015-04-01

    Full Text Available Renee M Streeter,1 Angela M Struble,1 Sabine Mann,2 Daryl V Nydam,2 John E Bauer,3 Marta G Castelhano,1 Rory J Todhunter,1 Bethany P Cummings,4 Joseph J Wakshlag11Department of Clinical Sciences, 2Department of Population Medicine, College of Veterinary Medicine, Cornell University, Ithaca, NY, USA; 3Department of Clinical Sciences, Texas A&M University, College Station, TX, USA; 4Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY, USAAbstract: Obesity has been associated with an increased inflammatory response and insulin resistance due to adipose tissue–derived adipokines and increases in C-reactive protein (CRP. Dogs appear to be similar to other species with the exception of adiponectin, which might not be affected by obesity status. Serum long-chain polyunsaturated fatty acid concentrations have been positively and negatively associated with serum adipokines. The aim of the study was to examine the relationship between leptin, CRP, adiponectin, and insulin to body condition score (BCS and to the long-chain omega-3 fatty acids in serum lipoproteins, including alpha-linolenic acid, eicosapentaenoic acid (EPA, docosapentanenoic acid (DPA, and docosahexaenoic acid (DHA as a reflection of dietary omega-3 status in the Labrador Retriever. Seventy-seven Labrador Retrievers were evaluated for BCS, percent fasting serum lipoprotein fatty acid concentrations, as well as serum leptin, adiponectin, insulin, and CRP. A multivariable general linear regression model was constructed to examine the association between the dependent variables leptin, CRP, adiponectin, and insulin and the predictor variables of BCS, age, and sex, as well as concentrations of alpha-linolenic acid, EPA, DHA, and DPA. Adiponectin concentration was positively associated with age (P<0.0008, EPA (P=0.027 and negatively associated with DHA (P=0.008. Leptin concentration was positively associated with an increased DHA (P=0.009, BCS (P

  7. Insulin resistance in brain and possible therapeutic approaches.

    Science.gov (United States)

    Cetinkalp, Sevki; Simsir, Ilgin Y; Ertek, Sibel

    2014-01-01

    Although the brain has long been considered an insulin-independent organ, recent research has shown that insulin has significant effects on the brain, where it plays a role in maintaining glucose and energy homeostasis. To avoid peripheral insulin resistance, the brain may act via hypoinsulinemic responses, maintaining glucose metabolism and insulin sensitivity within its own confines; however, brain insulin resistance may develop due to environmental factors. Insulin has two important functions in the brain: controlling food intake and regulating cognitive functions, particularly memory. Notably, defects in insulin signaling in the brain may contribute to neurodegenerative disorders. Insulin resistance may damage the cognitive system and lead to dementia states. Furthermore, inflammatory processes in the hypothalamus, where insulin receptors are expressed at high density, impair local signaling systems and cause glucose and energy metabolism disorders. Excessive caloric intake and high-fat diets initiate insulin and leptin resistance by inducing mitochondrial dysfunction and endoplasmic reticulum stress in the hypothalamus. This may lead to obesity and diabetes mellitus (DM). Exercise can enhance brain and hypothalamic insulin sensitivity, but it is the option least preferred and/or continuously practiced by the general population. Pharmacological treatments that increase brain and hypothalamic insulin sensitivity may provide new insights into the prevention of dementia disorders, obesity, and type 2 DM in the future.

  8. Response of osteocalcin and insulin resistance after a hypocaloric diet in obese patients.

    Science.gov (United States)

    de Luis, D A; Perez Castrillon, J L; Aller, R; Izaola, O; Bachiller, C

    2015-06-01

    Osteocalcin is a hormone with a complex cross-talk between adipose tissue and the skeleton. The aim of the present study was to explore the change of osteocalcin, insulin resistance, and adipocytokines after hypocaloric diet in obese patients. A population of 178 obese patients was analyzed. At basal time and 2 months after the dietary intervention, weight, fat mass, body mass index, basal glucose, insulin, insulin resistance (HOMA), total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, leptin, adiponectin, IL-6, TNF alpha and osteocalcin levels were measured. After dietary treatment, BMI, weight, fat mass, waist circumference, waist to hip ratio, systolic pressure, glucose, HOMA, triglycerides, total cholesterol, leptin and LDL cholesterol decreased significantly. Osteocalcin levels have a significant decrease after weight loss (Osteocalcin (ng/ml); 9.76 ± 5.3 vs 9.31 ± 4.1: p < 0.05). In correlation analysis, a negative association was detected among osteocalcin and age, BMI, fat mass, glucose, C reactive protein, interleukin-6. In the linear regression with age-, sex-, BMI, fat mass- and insulin- adjusted, only C reactive protein concentrations are related with osteocalcin levels -0.21 (CI 95%: -0.40 -0.009). Osteocalcin decreased after a weight loss treatment. Moreover, osteocalcin levels, before and after treatment, were related in a negative way with CRP fat mass, body mass index, age and glucose levels.

  9. Does overnight normalization of plasma glucose by insulin infusion affect assessment of glucose metabolism in Type 2 diabetes?

    DEFF Research Database (Denmark)

    Staehr, P; Højlund, Kurt; Hother-Nielsen, O

    2003-01-01

    AIMS: In order to perform euglycaemic clamp studies in Type 2 diabetic patients, plasma glucose must be reduced to normal levels. This can be done either (i) acutely during the clamp study using high-dose insulin infusion, or (ii) slowly overnight preceding the clamp study using a low-dose insulin...... infusion. We assessed whether the choice of either of these methods to obtain euglycaemia biases subsequent assessment of glucose metabolism and insulin action. METHODS: We studied seven obese Type 2 diabetic patients twice: once with (+ ON) and once without (- ON) prior overnight insulin infusion. Glucose...... turnover rates were quantified by adjusted primed-constant 3-3H-glucose infusions, and insulin action was assessed in 4-h euglycaemic, hyperinsulinaemic (40 mU m-2 min-1) clamp studies using labelled glucose infusates (Hot-GINF). RESULTS: Basal plasma glucose levels (mean +/- sd) were 5.5 +/- 0.5 and 10...

  10. Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects

    Science.gov (United States)

    Onishi, Airin; Fujiwara, Yoshinori; Ishiwata, Kiichi; Ishii, Kenji

    2017-01-01

    Background Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG) in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD)-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images. Methods Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years) underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR) was calculated. Results Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05), and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4–5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002), and no correlation with plasma insulin levels (r = 0.156, p = 0.12) or HOMA-IR (r = 0.096, p = 0.24). Conclusion This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images. PMID:28715453

  11. Effects of glucose, insulin, and insulin resistance on cerebral 18F-FDG distribution in cognitively normal older subjects.

    Directory of Open Access Journals (Sweden)

    Kenji Ishibashi

    Full Text Available Increasing plasma glucose levels and insulin resistance can alter the distribution pattern of fluorine-18-labeled fluorodeoxyglucose (18F-FDG in the brain and relatively reduce 18F-FDG uptake in Alzheimer's disease (AD-related hypometabolic regions, leading to the appearance of an AD-like pattern. However, its relationship with plasma insulin levels is unclear. We aimed to compare the effects of plasma glucose levels, plasma insulin levels and insulin resistance on the appearance of the AD-like pattern in 18F-FDG images.Fifty-nine cognitively normal older subjects (age = 75.7 ± 6.4 years underwent 18F-FDG positron emission tomography along with measurement of plasma glucose and insulin levels. As an index of insulin resistance, the Homeostasis model assessment of Insulin Resistance (HOMA-IR was calculated.Plasma glucose levels, plasma insulin levels, and HOMA-IR were 102.2 ± 8.1 mg/dL, 4.1 ± 1.9 μU/mL, and 1.0 ± 0.5, respectively. Whole-brain voxelwise analysis showed a negative correlation of 18F-FDG uptake with plasma glucose levels in the precuneus and lateral parietotemporal regions (cluster-corrected p < 0.05, and no correlation with plasma insulin levels or HOMA-IR. In the significant cluster, 18F-FDG uptake decreased by approximately 4-5% when plasma glucose levels increased by 20 mg/dL. In the precuneus region, volume-of-interest analysis confirmed a negative correlation of 18F-FDG uptake with plasma glucose levels (r = -0.376, p = 0.002, and no correlation with plasma insulin levels (r = 0.156, p = 0.12 or HOMA-IR (r = 0.096, p = 0.24.This study suggests that, of the three parameters, plasma glucose levels have the greatest effect on the appearance of the AD-like pattern in 18F-FDG images.

  12. Effect of High Fat and High Sugar Diet on Glucose Tolerance, Insulin Response to Glucose Load and Insulin Sensitivity in Rats

    OpenAIRE

    岡﨑, 悟

    1987-01-01

    To investigate the precipitating effects of the westernized diet on diabetes mellitus, glucose tolerance and insulin response to oral glucose load (1.5g/kg body weight) and insulin sensitivity to exogenous insulin (0.2U/kg) were studied in rats fed an experimental diet for 8 weeks. Four experimental diets were used : low fat-no sugar diet (energy ratio of 10% fat, 70% starch, a model of the traditional Japanese diet), high fat-high sugar diet (40% fat, 20% starch, 20% sugar, a model of the we...

  13. A role for polyamines in glucose-stimulated insulin-gene expression.

    Science.gov (United States)

    Welsh, N

    1990-01-01

    The aim of the present study was to evaluate the possible role for polyamines in the glucose regulation of the metabolism of insulin mRNA of pancreatic islet cells. For this purpose islets were prepared from adult mice and cultured for 2 days in culture medium RPMI 1640 containing 3.3 mM- or 16.7 mM-glucose with or without the addition of the inhibitors of polyamine biosynthesis difluoromethylornithine (DFMO) and ethylglyoxal bis(guanylhydrazone) (EGBG). Culture at the high glucose concentration increased the islet contents of both insulin mRNA and polyamines. The synthesis of total RNA, total islet polyamines and polyamines associated with islet nuclei was also increased. When the combination of DFMO and EGBG was added in the presence of 16.7 mM-glucose, low contents of insulin mRNA, spermine and spermidine were observed. Total islet polyamine synthesis was also depressed by DFMO + EGBG, unlike islet biosynthesis of polyamines associated with nuclei, which was not equally decreased by the polyamine-synthesis inhibitors. Total RNA synthesis and turnover was not affected by DFMO + EGBG. Finally, actinomycin D attenuated the glucose-induced enhancement of insulin mRNA, and cycloheximide counteracted the insulin-mRNA attenuation induced by inhibition of polyamine synthesis. It is concluded that the glucose-induced increase in insulin mRNA is paralleled by increased contents and rates of polyamine biosynthesis and that an attenuation of the increase in polyamines prevents the increase in insulin mRNA. In addition, the results are compatible with the view that polyamines exert their effects on insulin mRNA mainly by increasing the stability of this messenger. PMID:2241922

  14. Effect of adrenomedullin gene delivery on insulin resistance in type 2 diabetic rats

    Directory of Open Access Journals (Sweden)

    Hoda Y. Henein

    2011-01-01

    Full Text Available Type 2 diabetes mellitus is one of the common metabolic disorders that ultimately afflicts large number of individuals. Adrenomedullin (AM is a potent vasodilator peptide; previous studies reported development of insulin resistance in aged AM deficient mice. In this study, we employed a gene delivery approach to explore its potential role in insulin resistance. Four groups were included: control, diabetic, non-diabetic injected with the AM gene and diabetic injected with the AM gene. One week following gene delivery, serum glucose, insulin, triglycerides, leptin, adiponectin and corticosterone were measured as well as the insulin resistance index (HOMA-IR. Soleus muscle glucose uptake and RT-PCR of both AM and glucose transporter-4 (GLUT 4 gene expressions were assessed. A single tail vein injection of adrenomedullin gene in type 2 diabetic rats improved skeletal muscle insulin responsiveness with significant improvement of soleus muscle glucose uptake, HOMA-IR, serum glucose, insulin and triglycerides and significant increase in muscle GLUT 4 gene expression (P < 0.05 compared with the non-injected diabetic rats. The beneficial effects of AM gene delivery were accompanied by a significant increase in the serum level of adiponectin (2.95 ± 0.09 versus 2.33 ± 0.17 μg/ml in the non-injected diabetic group as well as a significant decrease in leptin and corticosterone levels (7.51 ± 0.51 and 262.88 ± 10.34 versus 10.63 ± 1.4 and 275.86 ± 11.19 ng/ml respectively in the non-injected diabetic group. The conclusion of the study is that AM gene delivery can improve insulin resistance and may have significant therapeutic applications in type 2 diabetes mellitus.

  15. [Serum leptin levels and soluble leptin receptors in female patients with anorexia nervosa].

    Science.gov (United States)

    Jiskra, J; Haluzík, M; Svobodová, J; Haluzíková, D; Nedvídková, J; Parízková, J; Kotrlíková, E

    2000-10-25

    Leptin action in peripheral tissues is enabled by an interaction with specific transmembrane receptors. Several of leptin receptor isoforms were identified, including soluble leptin receptor isoform structurally identical to extracellular domain of the the long leptin receptor isoform. The soluble receptor isoform is released to the circulation and acts probably as leptin-binding factor. The aim of our study was to measure serum concentrations of the soluble leptin receptor in patients with anorexia nervosa and in the control group of healthy women. Relationships of soluble leptin receptor levels to body mass index (BMI), body fat content, serum leptin, TNF-alpha and insulin levels were also studied. 16 patients with anorexia nervosa and 16 age-matched lean healthy women were included into the study. All of the subjects were measured and weighed, the body fat content was estimated from the skinfold thickness measurement. The blood for the determination of leptin, soluble leptin receptor and other hormonal parameters was obtained from all subjects after the overnight fasting. BMI, body fat content, serum leptin and insulin levels in patients with anorexia nervosa were significantly lower than in the control group (BMI: 14.98 +/- 2.32 vs. 22.21 +/- 2.48, p anorexia nervosa were significantly higher compared the to control group (24.67 +/- 8.3 U.ml-1 vs. 15.71 +/- 2.79 U.ml-1, p anorexia nervosa were significantly higher in comparison with the healthy subjects. Except of the negative correlation between serum soluble leptin receptor levels and BMI no statistically significant relationships between serum soluble leptin receptor and the rest of parameters studied were found.

  16. Hypothalamic and Striatal Insulin Action Suppresses Endogenous Glucose Production and May Stimulate Glucose Uptake During Hyperinsulinemia in Lean but Not in Overweight Men.

    Science.gov (United States)

    Heni, Martin; Wagner, Robert; Kullmann, Stephanie; Gancheva, Sofiya; Roden, Michael; Peter, Andreas; Stefan, Norbert; Preissl, Hubert; Häring, Hans-Ulrich; Fritsche, Andreas

    2017-07-01

    Intranasal spray application facilitates insulin delivery to the human brain. Although brain insulin modulates peripheral metabolism, the mechanisms involved remain elusive. Twenty-one men underwent two hyperinsulinemic-euglycemic clamps with d-[6,6- 2 H 2 ]glucose infusion to measure endogenous glucose production and glucose disappearance. On two separate days, participants received intranasal insulin or placebo. Insulin spillover into circulation after intranasal insulin application was mimicked by an intravenous insulin bolus on placebo day. On a different day, brain insulin sensitivity was assessed by functional MRI. Glucose infusion rates (GIRs) had to be increased more after nasal insulin than after placebo to maintain euglycemia in lean but not in overweight people. The increase in GIRs was associated with regional brain insulin action in hypothalamus and striatum. Suppression of endogenous glucose production by circulating insulin was more pronounced after administration of nasal insulin than after placebo. Furthermore, glucose uptake into tissue tended to be higher after nasal insulin application. No such effects were detected in overweight participants. By increasing insulin-mediated suppression of endogenous glucose production and stimulating peripheral glucose uptake, brain insulin may improve glucose metabolism during systemic hyperinsulinemia. Obese people appear to lack these mechanisms. Therefore, brain insulin resistance in obesity may have unfavorable consequences for whole-body glucose homeostasis. © 2017 by the American Diabetes Association.

  17. Insulin Regulates Astrocytic Glucose Handling Through Cooperation With IGF-I.

    Science.gov (United States)

    Fernandez, Ana M; Hernandez-Garzón, Edwin; Perez-Domper, Paloma; Perez-Alvarez, Alberto; Mederos, Sara; Matsui, Takashi; Santi, Andrea; Trueba-Saiz, Angel; García-Guerra, Lucía; Pose-Utrilla, Julia; Fielitz, Jens; Olson, Eric N; Fernandez de la Rosa, Ruben; Garcia Garcia, Luis; Pozo, Miguel Angel; Iglesias, Teresa; Araque, Alfonso; Soya, Hideaki; Perea, Gertrudis; Martin, Eduardo D; Torres Aleman, Ignacio

    2017-01-01

    Brain activity requires a flux of glucose to active regions to sustain increased metabolic demands. Insulin, the main regulator of glucose handling in the body, has been traditionally considered not to intervene in this process. However, we now report that insulin modulates brain glucose metabolism by acting on astrocytes in concert with IGF-I. The cooperation of insulin and IGF-I is needed to recover neuronal activity after hypoglycemia. Analysis of underlying mechanisms show that the combined action of IGF-I and insulin synergistically stimulates a mitogen-activated protein kinase/protein kinase D pathway resulting in translocation of GLUT1 to the cell membrane through multiple protein-protein interactions involving the scaffolding protein GAIP-interacting protein C terminus and the GTPase RAC1. Our observations identify insulin-like peptides as physiological modulators of brain glucose handling, providing further support to consider the brain as a target organ in diabetes. © 2017 by the American Diabetes Association.

  18. Serum bile acids and leptin interact with glucose metabolism in patients with liver cirrhosis

    NARCIS (Netherlands)

    Valentini, Luzia; Glaeser, Silja; Schuetz, Tatjana; Omar, Ajmal; Kasim, Esmatollah; Kroencke, Thomas; Tietge, Uwe J. F.; Lochs, Herbert; Schulzke, Joerg-Dieter; Brabant, Georg; Ockenga, Johann

    Background & aims: We investigated possible involvements of bile acids (BA) and leptin in hepatogenous insulin resistance being present in up to 90% of cirrhotic patients. Methods: Blood was analysed in 10 cirrhotic patients (8m/2f, 48 +/- 10.4 yrs) and 10 controls (8m/2f, 43 +/- 9.3 yrs) after oral

  19. Astrocytic Insulin Signaling Couples Brain Glucose Uptake with Nutrient Availability

    NARCIS (Netherlands)

    García-Cáceres, Cristina; Quarta, Carmelo; Varela, Luis; Gao, Yuanqing; Gruber, Tim; Legutko, Beata; Jastroch, Martin; Johansson, Pia; Ninkovic, Jovica; Yi, Chun-Xia; Le Thuc, Ophelia; Szigeti-Buck, Klara; Cai, Weikang; Meyer, Carola W.; Pfluger, Paul T.; Fernandez, Ana M.; Luquet, Serge; Woods, Stephen C.; Torres-Alemán, Ignacio; Kahn, C. Ronald; Götz, Magdalena; Horvath, Tamas L.; Tschöp, Matthias H.

    2016-01-01

    We report that astrocytic insulin signaling co-regulates hypothalamic glucose sensing and systemic glucose metabolism. Postnatal ablation of insulin receptors (IRs) in glial fibrillary acidic protein (GFAP)-expressing cells affects hypothalamic astrocyte morphology, mitochondrial function, and

  20. A comparison between the minimal model and the glucose clamp in the assessment of insulin sensitivity across the spectrum of glucose tolerance. Insulin Resistance Atherosclerosis Study.

    Science.gov (United States)

    Saad, M F; Anderson, R L; Laws, A; Watanabe, R M; Kades, W W; Chen, Y D; Sands, R E; Pei, D; Savage, P J; Bergman, R N

    1994-09-01

    An insulin-modified frequently sampled intravenous glucose tolerance test (FSIGTT) with minimal model analysis was compared with the glucose clamp in 11 subjects with normal glucose tolerance (NGT), 20 with impaired glucose tolerance (IGT), and 24 with non-insulin-dependent diabetes mellitus (NIDDM). The insulin sensitivity index (SI) was calculated from FSIGTT using 22- and 12-sample protocols (SI(22) and SI(12), respectively). Insulin sensitivity from the clamp was expressed as SI(clamp) and SIP(clamp). Minimal model parameters were similar when calculated with SI(22) and SI(12). SI could not be distinguished from 0 in approximately 50% of diabetic patients with either protocol. SI(22) correlated significantly with SI(clamp) in the whole group (r = 0.62), and in the NGT (r = 0.53), IGT (r = 0.48), and NIDDM (r = 0.41) groups (P SIP(clamp) were expressed in the same units, SI(22) was 66 +/- 5% (mean +/- SE) and 50 +/- 8% lower than SI(clamp) and SIP(clamp), respectively. Thus, minimal model analysis of the insulin-modified FSIGTT provides estimates of insulin sensitivity that correlate significantly with those from the glucose clamp. The correlation was weaker, however, in NIDDM. The insulin-modified FSIGTT can be used as a simple test for assessment of insulin sensitivity in population studies involving nondiabetic subjects. Additional studies are needed before using this test routinely in patients with NIDDM.

  1. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

    Directory of Open Access Journals (Sweden)

    Kyle S. McCommis

    2016-08-01

    Full Text Available Objective: Transport of pyruvate into the mitochondrial matrix by the Mitochondrial Pyruvate Carrier (MPC is an important and rate-limiting step in its metabolism. In pancreatic β-cells, mitochondrial pyruvate metabolism is thought to be important for glucose sensing and glucose-stimulated insulin secretion. Methods: To evaluate the role that the MPC plays in maintaining systemic glucose homeostasis, we used genetically-engineered Drosophila and mice with loss of MPC activity in insulin-producing cells. Results: In both species, MPC deficiency results in elevated blood sugar concentrations and glucose intolerance accompanied by impaired glucose-stimulated insulin secretion. In mouse islets, β-cell MPC-deficiency resulted in decreased respiration with glucose, ATP-sensitive potassium (KATP channel hyperactivity, and impaired insulin release. Moreover, treatment of pancreas-specific MPC knockout mice with glibenclamide, a sulfonylurea KATP channel inhibitor, improved defects in islet insulin secretion and abnormalities in glucose homeostasis in vivo. Finally, using a recently-developed biosensor for MPC activity, we show that the MPC is rapidly stimulated by glucose treatment in INS-1 insulinoma cells suggesting that glucose sensing is coupled to mitochondrial pyruvate carrier activity. Conclusions: Altogether, these studies suggest that the MPC plays an important and ancestral role in insulin-secreting cells in mediating glucose sensing, regulating insulin secretion, and controlling systemic glycemia. Keywords: Stimulus-coupled secretion, Insulin, β-Cell, Diabetes, Pyruvate, Mitochondria, Drosophila

  2. Glucose uptake and pulsatile insulin infusion: euglycaemic clamp and [3-3H]glucose studies in healthy subjects

    International Nuclear Information System (INIS)

    Schmitz, O.; Arnfred, J.; Hother Nielsen, O.; Beck-Nielsen, H.; Oerskov, H.

    1986-01-01

    To test the hypothesis that insulin has a greater effect on glucose metabolism when given as pulsatile than as continuous infusion, a 354-min euglycaemic clamp study was carried out in 8 healthy subjects. At random order soluble insulin was given intravenously either at a constant rate of 0.45mU/kg · min or in identical amounts in pulses of 1 1 / 2 to 2 1 / 4 min followed by intervals of 10 1 / 2 to 9 3 / 4 min. Average serum insulin levels were similar during the two infusion protocols, but pulsatile administration induced oscillations ranging between 15 and 62 μU/ml. Glucose uptake expressed as metabolic clearance rate (MCR) for glucose was significantly increased during pulsatile insulin delivery as compared with continuous administration (270-294 min: 8.7±0.7 vs 6.8±0.9 ml/kg · min, P 3 H]glucose infusion technique was suppressed to insignificant values. Finally, the effect of insulin on endogenous insulin secretion and lipolysis as assessed by changes in serum C-peptide and serum FFA was uninfluenced by the infusion mode. In conclusion, insulin infusion resulting in physiological serum insulin levels enhances glucose uptake in peripheral tissues in healthy subjects to a higher degree when given in a pulsed pattern mimicking that of the normal endocrine pancreas than when given as a continuous infusion. (author)

  3. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens J

    2003-01-01

    We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp...... Intralipid infusion. At LI, glucose oxidation decreased by 10%, whereas glucose disposal, glycolytic flux, glucose storage, and glucose production were not significantly altered. At HI, glucose disposal, and glucose oxidation decreased by 12% and 24%, respectively, during Intralipid infusion. Glycolytic flux......, glucose storage, and glucose production were unchanged. Insulin secretion rates increased in response to Intralipid infusion, but disposition indices (DI = insulin action.insulin secretion) were unchanged. In conclusion, a 24-h low-grade Intralipid infusion caused insulin resistance in the oxidative (but...

  4. A novel insulin resistance index to monitor changes in insulin sensitivity and glucose tolerance: the ACT NOW study.

    Science.gov (United States)

    Tripathy, Devjit; Cobb, Jeff E; Gall, Walter; Adam, Klaus-Peter; George, Tabitha; Schwenke, Dawn C; Banerji, MaryAnn; Bray, George A; Buchanan, Thomas A; Clement, Stephen C; Henry, Robert R; Kitabchi, Abbas E; Mudaliar, Sunder; Ratner, Robert E; Stentz, Frankie B; Reaven, Peter D; Musi, Nicolas; Ferrannini, Ele; DeFronzo, Ralph A

    2015-05-01

    The objective was to test the clinical utility of Quantose M(Q) to monitor changes in insulin sensitivity after pioglitazone therapy in prediabetic subjects. Quantose M(Q) is derived from fasting measurements of insulin, α-hydroxybutyrate, linoleoyl-glycerophosphocholine, and oleate, three nonglucose metabolites shown to correlate with insulin-stimulated glucose disposal. Participants were 428 of the total of 602 ACT NOW impaired glucose tolerance (IGT) subjects randomized to pioglitazone (45 mg/d) or placebo and followed for 2.4 years. At baseline and study end, fasting plasma metabolites required for determination of Quantose, glycated hemoglobin, and oral glucose tolerance test with frequent plasma insulin and glucose measurements to calculate the Matsuda index of insulin sensitivity were obtained. Pioglitazone treatment lowered IGT conversion to diabetes (hazard ratio = 0.25; 95% confidence interval = 0.13-0.50; P < .0001). Although glycated hemoglobin did not track with insulin sensitivity, Quantose M(Q) increased in pioglitazone-treated subjects (by 1.45 [3.45] mg·min(-1)·kgwbm(-1)) (median [interquartile range]) (P < .001 vs placebo), as did the Matsuda index (by 3.05 [4.77] units; P < .0001). Quantose M(Q) correlated with the Matsuda index at baseline and change in the Matsuda index from baseline (rho, 0.85 and 0.79, respectively; P < .0001) and was progressively higher across closeout glucose tolerance status (diabetes, IGT, normal glucose tolerance). In logistic models including only anthropometric and fasting measurements, Quantose M(Q) outperformed both Matsuda and fasting insulin in predicting incident diabetes. In IGT subjects, Quantose M(Q) parallels changes in insulin sensitivity and glucose tolerance with pioglitazone therapy. Due to its strong correlation with improved insulin sensitivity and its ease of use, Quantose M(Q) may serve as a useful clinical test to identify and monitor therapy in insulin-resistant patients.

  5. Blueberries’ Impact on Insulin Resistance and Glucose Intolerance

    Directory of Open Access Journals (Sweden)

    April J. Stull

    2016-11-01

    Full Text Available Blueberries are a rich source of polyphenols, which include anthocyanin bioactive compounds. Epidemiological evidence indicates that incorporating blueberries into the diet may lower the risk of developing type 2 diabetes (T2DM. These findings are supported by pre-clinical and clinical studies that have shown improvements in insulin resistance (i.e., increased insulin sensitivity after obese and insulin-resistant rodents or humans consumed blueberries. Insulin resistance was assessed by homeostatic model assessment-estimated insulin resistance (HOMA-IR, insulin tolerance tests, and hyperinsulinemic-euglycemic clamps. Additionally, the improvements in glucose tolerance after blueberry consumption were assessed by glucose tolerance tests. However, firm conclusions regarding the anti-diabetic effect of blueberries cannot be drawn due to the small number of existing clinical studies. Although the current evidence is promising, more long-term, randomized, and placebo-controlled trials are needed to establish the role of blueberries in preventing or delaying T2DM.

  6. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis.

    Science.gov (United States)

    Williams, Kevin W; Liu, Tiemin; Kong, Xingxing; Fukuda, Makoto; Deng, Yingfeng; Berglund, Eric D; Deng, Zhuo; Gao, Yong; Liu, Tianya; Sohn, Jong-Woo; Jia, Lin; Fujikawa, Teppei; Kohno, Daisuke; Scott, Michael M; Lee, Syann; Lee, Charlotte E; Sun, Kai; Chang, Yongsheng; Scherer, Philipp E; Elmquist, Joel K

    2014-09-02

    The molecular mechanisms underlying neuronal leptin and insulin resistance in obesity and diabetes remain unclear. Here we show that induction of the unfolded protein response transcription factor spliced X-box binding protein 1 (Xbp1s) in pro-opiomelanocortin (Pomc) neurons alone is sufficient to protect against diet-induced obesity as well as improve leptin and insulin sensitivity, even in the presence of strong activators of ER stress. We also demonstrate that constitutive expression of Xbp1s in Pomc neurons contributes to improved hepatic insulin sensitivity and suppression of endogenous glucose production. Notably, elevated Xbp1s levels in Pomc neurons also resulted in activation of the Xbp1s axis in the liver via a cell-nonautonomous mechanism. Together our results identify critical molecular mechanisms linking ER stress in arcuate Pomc neurons to acute leptin and insulin resistance as well as liver metabolism in diet-induced obesity and diabetes. Copyright © 2014 Elsevier Inc. All rights reserved.

  7. Geniposide regulates glucose-stimulated insulin secretion possibly through controlling glucose metabolism in INS-1 cells.

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    Full Text Available Glucose-stimulated insulin secretion (GSIS is essential to the control of metabolic fuel homeostasis. The impairment of GSIS is a key element of β-cell failure and one of causes of type 2 diabetes mellitus (T2DM. Although the KATP channel-dependent mechanism of GSIS has been broadly accepted for several decades, it does not fully describe the effects of glucose on insulin secretion. Emerging evidence has suggested that other mechanisms are involved. The present study demonstrated that geniposide enhanced GSIS in response to the stimulation of low or moderately high concentrations of glucose, and promoted glucose uptake and intracellular ATP levels in INS-1 cells. However, in the presence of a high concentration of glucose, geniposide exerted a contrary role on both GSIS and glucose uptake and metabolism. Furthermore, geniposide improved the impairment of GSIS in INS-1 cells challenged with a high concentration of glucose. Further experiments showed that geniposide modulated pyruvate carboxylase expression and the production of intermediates of glucose metabolism. The data collectively suggest that geniposide has potential to prevent or improve the impairment of insulin secretion in β-cells challenged with high concentrations of glucose, likely through pyruvate carboxylase mediated glucose metabolism in β-cells.

  8. Adipose tissue insulin receptor and glucose transporter 4 expression, and blood glucose and insulin responses during glucose tolerance tests in transition Holstein cows with different body condition.

    Science.gov (United States)

    Jaakson, H; Karis, P; Ling, K; Ilves-Luht, A; Samarütel, J; Henno, M; Jõudu, I; Waldmann, A; Reimann, E; Pärn, P; Bruckmaier, R M; Gross, J J; Kaart, T; Kass, M; Ots, M

    2018-01-01

    Glucose uptake in tissues is mediated by insulin receptor (INSR) and glucose transporter 4 (GLUT4). The aim of this study was to examine the effect of body condition during the dry period on adipose tissue mRNA and protein expression of INSR and GLUT4, and on the dynamics of glucose and insulin following the i.v. glucose tolerance test in Holstein cows 21 d before (d -21) and after (d 21) calving. Cows were grouped as body condition score (BCS) ≤3.0 (thin, T; n = 14), BCS = 3.25 to 3.5 (optimal, O; n = 14), and BCS ≥3.75 (overconditioned, OC; n = 14). Blood was analyzed for glucose, insulin, fatty acids, and β-hydroxybutyrate concentrations. Adipose tissue was analyzed for INSR and GLUT4 mRNA and protein concentrations. During the glucose tolerance test 0.15 g/kg of body weight glucose was infused; blood was collected at -5, 5, 10, 20, 30, 40, 50, and 60 min, and analyzed for glucose and insulin. On d -21 the area under the curve (AUC) of glucose was smallest in group T (1,512 ± 33.9 mg/dL × min) and largest in group OC (1,783 ± 33.9 mg/dL × min), and different between all groups. Basal insulin on d -21 was lowest in group T (13.9 ± 2.32 µU/mL), which was different from group OC (24.9 ± 2.32 µU/mL. On d -21 the smallest AUC 5-60 of insulin in group T (5,308 ± 1,214 µU/mL × min) differed from the largest AUC in group OC (10,867 ± 1,215 µU/mL × min). Time to reach basal concentration of insulin in group OC (113 ± 14.1 min) was longer compared with group T (45 ± 14.1). The INSR mRNA abundance on d 21 was higher compared with d -21 in groups T (d -21: 3.3 ± 0.44; d 21: 5.9 ± 0.44) and O (d -21: 3.7 ± 0.45; d 21: 4.7 ± 0.45). The extent of INSR protein expression on d -21 was highest in group T (7.3 ± 0.74 ng/mL), differing from group O (4.6 ± 0.73 ng/mL), which had the lowest expression. The amount of GLUT4 protein on d -21 was lowest in group OC (1.2 ± 0.14 ng/mL), different from group O (1.8 ± 0.14 ng/mL), which had the highest amount

  9. The regulatory system for diabetes mellitus: Modeling rates of glucose infusions and insulin injections

    Science.gov (United States)

    Yang, Jin; Tang, Sanyi; Cheke, Robert A.

    2016-08-01

    Novel mathematical models with open and closed-loop control for type 1 or type 2 diabetes mellitus were developed to improve understanding of the glucose-insulin regulatory system. A hybrid impulsive glucose-insulin model with different frequencies of glucose infusions and insulin injections was analyzed, and the existence and uniqueness of the positive periodic solution for type 1 diabetes, which is globally asymptotically stable, was studied analytically. Moreover, permanence of the system for type 2 diabetes was demonstrated which showed that the glucose concentration level is uniformly bounded above and below. To investigate how to prevent hyperinsulinemia and hyperglycemia being caused by this system, we developed a model involving periodic intakes of glucose with insulin injections applied only when the blood glucose level reached a given critical glucose threshold. In addition, our numerical analysis revealed that the period, the frequency and the dose of glucose infusions and insulin injections are crucial for insulin therapies, and the results provide clinical strategies for insulin-administration practices.

  10. Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

    OpenAIRE

    Smith, G D; Amos, T A; Mahler, R; Peters, T J

    1987-01-01

    Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes melli...

  11. Correlation between the Plasma Insulin and Glucose Concentration in Normal Korean Adults

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Jang Kyu; Sung, Ho Kyung; Kim, Jin Eui [Radiological Research Institute, Seoul (Korea, Republic of)

    1971-09-15

    The correlation between the plasma insulin, and glucose concentration was studied in healthy Korean adults consisting of 20 males and 22 females of 16 to 38 years of age. The blood samples of above subjects were obtained through cubital vein at arbitrary times during their usual working hours. Plasma insulin was assayed by means of double antibody system of radioimmunoassay technics, and blood glucose was determined by means of Van Slyke-Folch method. Results were as follows : 1. There were no differences in the blood sugar levels in relation to the plasma insulin concentration either by sex or age. 2. In the case, when the plasma insulin concentration was within 50 mmuU/ml, the correlation between the insulin, and glucose concentration existed, the ratio of which was expressed as; Plasma glucose concentration (mg/dl)=91.9 + 0.08 X Insulin concentration r=0.62. 3. Insulinogenic index was 12.4%, which was somewhat higher than other reports. 4. It is suggested that the correlation between plasma insulin and glucose concentration could be determined at arbitrary times instead of fasting times.

  12. Significance of insulin for glucose metabolism in skeletal muscle during contractions

    DEFF Research Database (Denmark)

    Hespel, P; Vergauwen, Lieven; Vandenberghe, K

    1996-01-01

    is essentially effected via increased blood flow, significantly contributes to stimulate glucose uptake. Again, however, increased glucose delivery appears to be a more potent stimulus of muscle glucose uptake as the circulating insulin level is increased. Furthermore, contractions and elevated flow prove...... is effected primarily via mechanisms exerted within the muscle cell related to the contractile activity per se. Yet contractions become a more potent stimulus of muscle glucose uptake as the plasma insulin level is increased. In addition, enhanced glucose delivery to muscle, which during exercise...... to be additive stimuli of muscle glucose uptake at any plasma insulin level. In conclusion, the extent to which muscle glucose uptake is stimulated during exercise depends on various factors, including 1) the intensity of the contractile activity, 2) the magnitude of the exercise-associated increase in muscle...

  13. THE EFFECTS OF EXERCISE ON FOOD INTAKE AND HUNGER: RELATIONSHIP WITH ACYLATED GHRELIN AND LEPTIN

    Directory of Open Access Journals (Sweden)

    Serife Vatansever-Ozen

    2011-06-01

    Full Text Available This study investigated the effects of a long bout of aerobic exercise on hunger and energy intake and circulating levels of leptin and acylated ghrelin. Ten healthy male subjects undertook two, 4 h trials in a randomized crossover design. In the exercise trial subjects ran for 105 min at 50% of maximal oxygen uptake and the last 15 min at 70% of maximal oxygen uptake followed by a 120 min rest period. In the control trial, subjects rested for 4 h. Subjects consumed a buffet test meal at 180 min during each trial. Hunger ratings, acylated ghrelin, leptin, glucose and insulin concentrations were measured at 0, 1, 2, 3 and 4 h. No differences were found at baseline values for hunger, acylated ghrelin, leptin, insulin and glucose for both trials (p > 0.05. The estimated energy expenditure of the exercise trial was 1550 ± 136 kcal. Exercise did not change subsequent absolute energy intake, but produced a significant decrease (p < 0.05 in relative energy intake. A two-way ANOVA revealed a significant (p < 0. 05 interaction effect for hunger and acylated ghrelin. In conclusion, this exercise regimen had a positive effect on reducing appetite which is related to reduced acylated ghrelin responses over time. This finding lends support for a role of exercise in weight management

  14. Study on the relationship between serum leptin level and ischemic cerebrovascular disease (ICVD)

    International Nuclear Information System (INIS)

    Luo Nanping; Hu Chengjing; Wang Ruishan; Yin Qiuxia; Niu Aijun; Xue Lian; Xue Shenwu; Chen Qing

    2004-01-01

    Objective: To investigate the inter-relationship among serum leptin insulin resistance and blood lipids, and to explore the role of leptin in the pathogenesis of ischemic cerebrovascular diseases (ICVD). Methods: Levels of serum leptin, insulin and blood lipids were determined with RIA in 131 patients with different types of ICVD and 36 controls. Results: The levels of serum leptin in ICVD patients were significantly higher than those in the controls (P<0.01). Changes of blood lipids and insulin paralleled those of leptin (cxcept with HDL-C). The serum leptin were positively correlated to cholesterol, TG and insulin levels (r=0.45, P<0.05; r=0.31, P<0.05, r=0.55, P<0.01), but negatively correlated to HDL-C (r=-0.88, P<0.05). Conclusion: The high expression of leptin in ICVD patients is associated with high lipid and insulin levels. The close relationship among them indicates that high leptin levels play an important role in the pathogenesis of metabolic syndrome as well as atheromatous cerebrovascular diseases. (authors)

  15. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity.

    Science.gov (United States)

    Shi, Xuemei; Chacko, Shaji; Li, Feng; Li, Depei; Burrin, Douglas; Chan, Lawrence; Guan, Xinfu

    2017-11-01

    Glucagon-like peptides are co-released from enteroendocrine L cells in the gut and preproglucagon (PPG) neurons in the brainstem. PPG-derived GLP-1/2 are probably key neuroendocrine signals for the control of energy balance and glucose homeostasis. The objective of this study was to determine whether activation of PPG neurons per se modulates glucose homeostasis and insulin sensitivity in vivo. We generated glucagon (Gcg) promoter-driven Cre transgenic mice and injected excitatory hM3Dq-mCherry AAV into their brainstem NTS. We characterized the metabolic impact of PPG neuron activation on glucose homeostasis and insulin sensitivity using stable isotopic tracers coupled with hyperinsulinemic euglycemic clamp. We showed that after ip injection of clozapine N-oxide, Gcg-Cre lean mice transduced with hM3Dq in the brainstem NTS downregulated basal endogenous glucose production and enhanced glucose tolerance following ip glucose tolerance test. Moreover, acute activation of PPG neurons NTS enhanced whole-body insulin sensitivity as indicated by increased glucose infusion rate as well as augmented insulin-suppression of endogenous glucose production and gluconeogenesis. In contrast, insulin-stimulation of glucose disposal was not altered significantly. We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity. Copyright © 2017 The Authors. Published by Elsevier GmbH.. All rights reserved.

  16. Decreased insulin clearance in individuals with elevated 1-h post-load plasma glucose levels.

    Directory of Open Access Journals (Sweden)

    Maria Adelaide Marini

    Full Text Available Reduced insulin clearance has been shown to predict the development of type 2 diabetes. Recently, it has been suggested that plasma glucose concentrations ≥ 8.6 mmol/l (155 mg/dl at 1 h during an oral glucose tolerance test (OGTT can identify individuals at high risk for type 2 diabetes among those who have normal glucose tolerance (NGT 1 h-high. The aim of this study was to examine whether NGT 1 h-high have a decrease in insulin clearance, as compared with NGT individuals with 1-h post-load glucose <8.6 mmol/l (l (155 mg/dl, NGT 1 h-low. To this end, 438 non-diabetic White individuals were subjected to OGTT and euglycemic-hyperinsulinemic clamp to evaluate insulin clearance and insulin sensitivity. As compared with NGT 1 h-low individuals, NGT 1 h-high had significantly higher 1-h and 2-h post-load plasma glucose and 2-h insulin levels as well as higher fasting glucose and insulin levels. NGT 1 h-high exhibited also a significant decrease in both insulin sensitivity (P<0.0001 and insulin clearance (P = 0.006 after adjusting for age, gender, adiposity measures, and insulin sensitivity. The differences in insulin clearance remained significant after adjustment for fasting glucose (P = 0.02 in addition to gender, age, and BMI. In univariate analyses adjusted for gender and age, insulin clearance was inversely correlated with body weight, body mass index, waist, fat mass, 1-h and 2-h post-load glucose levels, fasting, 1-h and 2-h post-load insulin levels, and insulin-stimulated glucose disposal. In conclusion, our data show that NGT 1 h-high have a reduction in insulin clearance as compared with NGT 1 h-low individuals; this suggests that impaired insulin clearance may contribute to sustained fasting and post-meal hyperinsulinemia.

  17. CNC-bZIP protein Nrf1-dependent regulation of glucose-stimulated insulin secretion.

    Science.gov (United States)

    Zheng, Hongzhi; Fu, Jingqi; Xue, Peng; Zhao, Rui; Dong, Jian; Liu, Dianxin; Yamamoto, Masayuki; Tong, Qingchun; Teng, Weiping; Qu, Weidong; Zhang, Qiang; Andersen, Melvin E; Pi, Jingbo

    2015-04-01

    The inability of pancreatic β-cells to secrete sufficient insulin in response to glucose stimulation is a major contributing factor to the development of type 2 diabetes (T2D). We investigated both the in vitro and in vivo effects of deficiency of nuclear factor-erythroid 2-related factor 1 (Nrf1) in β-cells on β-cell function and glucose homeostasis. Silencing of Nrf1 in β-cells leads to a pre-T2D phenotype with disrupted glucose metabolism and impaired insulin secretion. Specifically, MIN6 β-cells with stable knockdown of Nrf1 (Nrf1-KD) and isolated islets from β-cell-specific Nrf1-knockout [Nrf1(b)-KO] mice displayed impaired glucose responsiveness, including elevated basal insulin release and decreased glucose-stimulated insulin secretion (GSIS). Nrf1(b)-KO mice exhibited severe fasting hyperinsulinemia, reduced GSIS, and glucose intolerance. Silencing of Nrf1 in MIN6 cells resulted in oxidative stress and altered glucose metabolism, with increases in both glucose uptake and aerobic glycolysis, which is associated with the elevated basal insulin release and reduced glucose responsiveness. The elevated glycolysis and reduced glucose responsiveness due to Nrf1 silencing likely result from altered expression of glucose metabolic enzymes, with induction of high-affinity hexokinase 1 and suppression of low-affinity glucokinase. Our study demonstrated a novel role of Nrf1 in regulating glucose metabolism and insulin secretion in β-cells and characterized Nrf1 as a key transcription factor that regulates the coupling of glycolysis and mitochondrial metabolism and GSIS. Nrf1 plays critical roles in regulating glucose metabolism, mitochondrial function, and insulin secretion, suggesting that Nrf1 may be a novel target to improve the function of insulin-secreting β-cells.

  18. Insulin secretion and glucose uptake by isolated islets of the hamster. Effect of insulin, proinsulin and C-peptide

    Energy Technology Data Exchange (ETDEWEB)

    Dunbar, J C; McLaughlin, W J; Walsh, M F.J.; Foa, P P [Sinai Hospital of Detroit, Mich. (USA). Dept. of Research

    1976-01-01

    Isolated pancreatic islets of normal hamsters were perfused either in a closed or in a open system. When the buffer was recirculated and the endogenous insulin was allowed to accumulate, the islets secreted significantly less insulin than when the system was open and the endogenous insulin was washed away. The addition of monocomponent insulin or of proinsulin to the perfusion buffer significantly decreased insulin secretion. The inhibitory action of proinsulin was significantly greater than that of monocomponent insulin. C peptide had no effect. When pancreatic islets were incubated in a fixed volume of stationary buffer containing unlabeled glucose (1.0 mg or 3.0 mg/ml) and glucose-U-/sup 14/C (1.0 ..mu..C/ml), the amount of insulin secreted and the /sup 14/CO/sub 2/ produced by each islet decreased progressively as the number of islets in the sample increased. Under these conditions, the concentration of insulin required to inhibit insulin secretion increased with the concentration of glucose in the medium. Proinsulin did not alter the incorporation of leucine-4.5-/sup 3/H into total extractable insulin (insulin + proinsulin). Thus, insulin and proinsulin appear to inhibit insulin release, but not insulin synthesis.

  19. Fenugreek, A Potent Hypoglycaemic Herb Can Cause Central Hypothyroidism Via Leptin - A Threat To Diabetes Phytotherapy.

    Science.gov (United States)

    Majumdar, Jayjeet; Chakraborty, Pratip; Mitra, Analava; Sarkar, Nirmal Kumar; Sarkar, Supriti

    2017-07-01

    Fenugreek ( Trigonella foenum graecum) , a medicinal herb with potent antihyperglycaemic and hypoglycaemic effects, is used to treat diabetes. This study is aimed to explore the interaction of fenugreek seed extract (FSE) and HPT (hypothalamic-pituitary-thyroid) axis in context of leptin secretion which have important role in normal and type-1 diabetic subjects. FSE (confirmed to contain trigonelline, diosgenin, 4 hydroxyisoleucine) was gavaged (0.25 gm/kg body weight/day) to normal and alloxan-induced type-1 diabetic rats for 4 weeks. Expression of hypothalamic prepro-TRH (Thyrotropin releasing hormone) mRNA, serum levels of TRH, TSH (Thyroid stimulating hormone), fT 3 , fT 4 , insulin, leptin, glucose; thyroperoxidase activity and growth of thyroid gland, food intake, adiposity index were also studied FSE significantly down regulated prepro-TRH mRNA expression; decreased serum TRH, TSH, fT 3 , fT 4 levels, and regressed thyroid gland in FSE-fed normal and diabetic rats than those observed in normal diet-fed control and diabetic rats. FSE decreased (psecretion, increased food intake and body weight in all FSE-fed rats. FSE improved insulin secretion, decreased glucose level but impaired HPT axis in diabetic rats, indicating insulin-independent central hypothyroidism. Results suggested that the dominant signal to hypothalamus suppressing HPT axis is the fall in leptin level which i resulted from decreased adiposity index following FSE feeding. Fenugreek simultaneously having hypoglycaemic and hypothyroidal actions raises questions whether it can be safely used to treat diabetes and/or hyperthyroidism as was suggested by many workers. © Georg Thieme Verlag KG Stuttgart · New York.

  20. Prevalence of impaired glucose tolerance and insulin resistance among obese children and adolescents

    Directory of Open Access Journals (Sweden)

    Robabeh Ghergherechi

    2010-07-01

    Full Text Available Robabeh Ghergherechi1, Ali Tabrizi21Department of Pediatrics Endocrinology, Tabriz University of Medical Sciences, Tabriz, Iran; 2Students’ Research Committee, Tabriz University of Medical Sciences, Tabriz, IranPurpose: Obesity is one of the most important nutritional disorders in the world which has an obvious relationship with the incidence of metabolic diseases. Obesity prevalence has increased among children and adolescents during recent decades, leading to a rise in Type 2 diabetes mellitus (DM II prevalence in these two age brackets. Hence, the aim of this study was to assess impaired glucose tolerance and insulin resistance, and gather metabolic findings in obese children and adolescents.Methods and materials: We studied 110 obese children and adolescents (body mass index > 95th percentile for age and gender 4–18 years of age referred to the endocrine clinic of the Children’s Hospital at Tabriz University in a descriptive cross-sectional study. ­Fasting glucose, insulin, and lipid profile in all subjects were determined. Oral glucose tolerance test after eating 75 g/kg glucose was performed. Homeostatic model assessment was used to ­estimate insulin resistance.Results: Impaired glucose tolerance and insulin resistance prevalence in 68 obese adolescents was 14.7% and 31.8%, respectively. Impaired glucose tolerance and insulin resistance was not seen in 23.8% of 42 obese children. No case of DM II was seen. There was a significant statistical difference in glucose (P = 0.003 and insulin (P < 0.001 level at minute 120 in individuals with impaired glucose tolerance compared to obese children and adolescents without impaired glucose tolerance. Rate of insulin resistance in patients with impaired glucose tolerance was greater and had a significant statistical difference (P = 0.03.Conclusion: Obesity has a close relationship with increased risk of impaired glucose tolerance and insulin resistance in children and adolescents. Oral glucose

  1. Effect of chloroquine on insulin and glucose homoeostasis in normal subjects and patients with non-insulin-dependent diabetes mellitus.

    Science.gov (United States)

    Smith, G D; Amos, T A; Mahler, R; Peters, T J

    1987-01-01

    Plasma glucose, insulin, and C peptide concentrations were determined after an oral glucose load in normal subjects and in a group of patients with non-insulin-dependent diabetes mellitus before and during a short course of treatment with chloroquine. In the control group there was a small but significant reduction in fasting blood glucose concentration but overall glucose tolerance and hormone concentrations were unaffected. In contrast, the patients with non-insulin-dependent diabetes mellitus showed a significant improvement in their glucose tolerance, which paralleled the severity of their diabetes. This response seems to reflect decreased degradation of insulin rather than increased pancreatic output. These observations suggest that treatment with chloroquine or suitable analogues may be a new approach to the management of diabetes. PMID:3103729

  2. Metabolic syndrome, leptin-insulin resistance and uric acid: a trinomial foe for Algerian city-dweller adolescents' health.

    Science.gov (United States)

    Bouhenni, Hamida; Daoudi, Hadjer; Djemai, Haidar; Rouabah, Abdelkader; Vitiello, Damien; Rouabah, Leila

    2018-03-28

    Background Adolescence is one of the critical periods where increased risk for long-term obesity-related complications is an important health concern. This highlights the need to perform early diagnostics based on precise biomarkers to decrease the risk of complications in adolescents with obesity. Objective To determine the relationships between serum levels of uric acid (UA), leptin and insulin with metabolic syndrome (MS) components in Algerian adolescents. Subjects Nondiabetic adolescents (n = 204). Methods Blood pressure (BP) and anthropometric measurements were performed using standardized techniques. Blood samples were taken for determination of glycemia, triglyceridemia, uricemia, cholesterolemia, leptinemia and insulinemia. Results The rate of MS among an excess weight group was 17.4% [95% confidence interval (CI)]. Serum levels of UA, leptin and insulin were significantly higher in the excess weight group compared to a normal weight group (279.4 ± 86.05 vs. 204.9 ± 50.34 μmol/L and 25.65 ± 14.01 vs. 4.09 ± 2.60 μg/L, p < 0.001; 24.58 ± 13.85 vs. 13.34 ± 6.41 μIU/L, p < 0.05). Serum levels of UA, leptin and insulin were significantly higher in adolescents with MS compared to those without MS (304.86 ± 111.41 vs. 224.72 ± 77.81 μmol/L, 30.26 ± 12.46 vs. 16.93 ± 14.97 μg/L and 30.91 ± 17.30 vs. 18.71 ± 10.14 μIU/L, p < 0.05, respectively). Significant correlations were found between UA and leptin with waist circumference (r = 0.50 and 0.76), diastolic blood pressure (r = 0.58 and 0.43), triglycerides (r = 0.42 and 0.35) and high-density lipoprotein-cholesterol (r = -0.36 and -0.35). Conclusion Serum levels of UA and leptin may be useful biomarkers for early diagnosis of the risk of MS in our Algerian adolescent population.

  3. Detection of transketolase in bone marrow-derived insulin-producing cells: benfotiamine enhances insulin synthesis and glucose metabolism.

    Science.gov (United States)

    Oh, Seh-Hoon; Witek, Rafal P; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E

    2009-01-01

    Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus.

  4. Detection of Transketolase in Bone Marrow—Derived Insulin-Producing Cells: Benfotiamine Enhances Insulin Synthesis and Glucose Metabolism

    Science.gov (United States)

    Witek, Rafal P.; Bae, Si-Hyun; Darwiche, Houda; Jung, Youngmi; Pi, Liya; Brown, Alicia; Petersen, Bryon E.

    2009-01-01

    Adult bone marrow (BM)-derived insulin-producing cells (IPCs) are capable of regulating blood glucose levels in chemically induced hyperglycemic mice. Using cell transplantation therapy, fully functional BM-derived IPCs help to mediate treatment of diabetes mellitus. Here, we demonstrate the detection of the pentose phosphate pathway enzyme, transketolase (TK), in BM-derived IPCs cultured under high-glucose conditions. Benfotiamine, a known activator of TK, was not shown to affect the proliferation of insulinoma cell line, INS-1; however, when INS-1 cells were cultured with oxythiamine, an inhibitor of TK, cell proliferation was suppressed. Treatment with benfotiamine activated glucose metabolism in INS-1 cells in high-glucose culture conditions, and appeared to maximize the BM-derived IPCs ability to synthesize insulin. Benfotiamine was not shown to induce the glucose receptor Glut-2, however it was shown to activate glucokinase, the enzyme responsible for conversion of glucose to glucose-6-phosphate. Furthermore, benfotiamine-treated groups showed upregulation of the downstream glycolytic enzyme, glyceraldehyde phosphate dehydrogenase (GAPDH). However, in cells where the pentose phosphate pathway was blocked by oxythiamine treatment, there was a clear downregulation of Glut-2, glucokinase, insulin, and GAPDH. When benfotiamine was used to treat mice transplanted with BM-derived IPCs transplanted, their glucose level was brought to a normal range. The glucose challenge of normal mice treated with benfotiamine lead to rapidly normalized blood glucose levels. These results indicate that benfotiamine activates glucose metabolism and insulin synthesis to prevent glucose toxicity caused by high concentrations of blood glucose in diabetes mellitus. PMID:18393672

  5. Prediction of clamp-derived insulin sensitivity from the oral glucose insulin sensitivity index

    DEFF Research Database (Denmark)

    Tura, Andrea; Chemello, Gaetano; Szendroedi, Julia

    2018-01-01

    that underwent both a clamp and an OGTT or meal test, thereby allowing calculation of both the M value and OGIS. The population was divided into a training and a validation cohort (n = 359 and n = 154, respectively). After a stepwise selection approach, the best model for M value prediction was applied......AIMS/HYPOTHESIS: The euglycaemic-hyperinsulinaemic clamp is the gold-standard method for measuring insulin sensitivity, but is less suitable for large clinical trials. Thus, several indices have been developed for evaluating insulin sensitivity from the oral glucose tolerance test (OGTT). However......, most of them yield values different from those obtained by the clamp method. The aim of this study was to develop a new index to predict clamp-derived insulin sensitivity (M value) from the OGTT-derived oral glucose insulin sensitivity index (OGIS). METHODS: We analysed datasets of people...

  6. DEFECTS IN INSULIN-SECRETION IN NIDDM - B-CELL GLUCOSE INSENSITIVITY OR GLUCOSE TOXICITY

    NARCIS (Netherlands)

    VANHAEFTEN, TW

    In NIDDM, first-phase insulin release to glucose is (almost) absent. However, in contrast to older studies which suggested that in NIDDM the B-cell is ''blind'' for glucose, recent evidence indicates that the B-cell is not insensitive for glucose as far as second phase release is concerned. This

  7. Neuronal LRP1 regulates glucose metabolism and insulin signaling in the brain.

    Science.gov (United States)

    Liu, Chia-Chen; Hu, Jin; Tsai, Chih-Wei; Yue, Mei; Melrose, Heather L; Kanekiyo, Takahisa; Bu, Guojun

    2015-04-08

    Alzheimer's disease (AD) is a neurological disorder characterized by profound memory loss and progressive dementia. Accumulating evidence suggests that Type 2 diabetes mellitus, a metabolic disorder characterized by insulin resistance and glucose intolerance, significantly increases the risk for developing AD. Whereas amyloid-β (Aβ) deposition and neurofibrillary tangles are major histological hallmarks of AD, impairment of cerebral glucose metabolism precedes these pathological changes during the early stage of AD and likely triggers or exacerbates AD pathology. However, the mechanisms linking disturbed insulin signaling/glucose metabolism and AD pathogenesis remain unclear. The low-density lipoprotein receptor-related protein 1 (LRP1), a major apolipoprotein E receptor, plays critical roles in lipoprotein metabolism, synaptic maintenance, and clearance of Aβ in the brain. Here, we demonstrate that LRP1 interacts with the insulin receptor β in the brain and regulates insulin signaling and glucose uptake. LRP1 deficiency in neurons leads to impaired insulin signaling as well as reduced levels of glucose transporters GLUT3 and GLUT4. Consequently, glucose uptake is reduced. By using an in vivo microdialysis technique sampling brain glucose concentration in freely moving mice, we further show that LRP1 deficiency in conditional knock-out mice resulted in glucose intolerance in the brain. We also found that hyperglycemia suppresses LRP1 expression, which further exacerbates insulin resistance, glucose intolerance, and AD pathology. As loss of LRP1 expression is seen in AD brains, our study provides novel insights into insulin resistance in AD. Our work also establishes new targets that can be explored for AD prevention or therapy. Copyright © 2015 the authors 0270-6474/15/355851-09$15.00/0.

  8. Leptin, soluble leptin receptor, and free leptin index in patients with metabolic syndrome

    Directory of Open Access Journals (Sweden)

    Elena N. Smirnova

    2017-06-01

    Full Text Available Aim. To assess the levels of leptin, its soluble receptor, and index of the formation of free leptin in metabolic syndrome (MS. Materials and methods. The study included 110 individuals with obesity and overweight. The group 1 consisted of 70 patients with MS (IDF, 2005, the average body mass index (BMI 38.4 ± 4.4 kg/m2, aged 48.2 ± 2.4 years, with arterial hypertension (AH 1–2 degree, without regular antihypertensive therapy. Group 2 – "healthy" obesity accounted for 40 patients aged 38.4 ± 6.2 years, BMI 36.0 ± 5.5 kg/m2 without hypertension and metabolic disorders. Group 3 consisted of 30 healthy persons, BMI 27.1 ± 1.3 kg/m2. All patients were evaluated for insulin, HOMA index, leptin, leptin receptor, leptin free index (calculated as the ratio of leptin (ng/ml to the leptin receptor (ng/ml, multiplied by 100. Results: In patients with MS as compared to other two groups there were higher levels of HOMA IR index, leptin and free leptin index. Values of leptin receptor in groups 1 and 2 did not differ significantly and were lower than in healthy persons. The free leptin index was significantly higher in MS group relative to the group 2 and 15 times higher than in the healthy individuals. Free leptin index correlated with values of BMI (R = 0.32; p = 0.02, blood pressure (R = 0.3; p = 0.04, uric acid (R = 0.27; p = 0.04, triglycerides (R = 0.42; p = 0.02, index HOMA-IR (R = 0.45; p = 0.02. Conclusions: Reduction of soluble leptin receptor, depending on the degree of abdominal obesity, may cause progression of leptin resistance in patients with MS. The levels of leptin and soluble leptin receptor appears to have dramatical gender differences. Calculation of free leptin index should be used for the objective evaluation of leptin resistance, regardless of gender, degree of obesity, and other metabolic parameters.

  9. Neuronal SH2B1 is essential for controlling energy and glucose homeostasis.

    Science.gov (United States)

    Ren, Decheng; Zhou, Yingjiang; Morris, David; Li, Minghua; Li, Zhiqin; Rui, Liangyou

    2007-02-01

    SH2B1 (previously named SH2-B), a cytoplasmic adaptor protein, binds via its Src homology 2 (SH2) domain to a variety of protein tyrosine kinases, including JAK2 and the insulin receptor. SH2B1-deficient mice are obese and diabetic. Here we demonstrated that multiple isoforms of SH2B1 (alpha, beta, gamma, and/or delta) were expressed in numerous tissues, including the brain, hypothalamus, liver, muscle, adipose tissue, heart, and pancreas. Rat SH2B1beta was specifically expressed in neural tissue in SH2B1-transgenic (SH2B1(Tg)) mice. SH2B1(Tg) mice were crossed with SH2B1-knockout (SH2B1(KO)) mice to generate SH2B1(TgKO) mice expressing SH2B1 only in neural tissue but not in other tissues. Systemic deletion of the SH2B1 gene resulted in metabolic disorders in SH2B1(KO) mice, including hyperlipidemia, leptin resistance, hyperphagia, obesity, hyperglycemia, insulin resistance, and glucose intolerance. Neuron-specific restoration of SH2B1beta not only corrected the metabolic disorders in SH2B1(TgKO) mice, but also improved JAK2-mediated leptin signaling and leptin regulation of orexigenic neuropeptide expression in the hypothalamus. Moreover, neuron-specific overexpression of SH2B1 dose-dependently protected against high-fat diet-induced leptin resistance and obesity. These observations suggest that neuronal SH2B1 regulates energy balance, body weight, peripheral insulin sensitivity, and glucose homeostasis at least in part by enhancing hypothalamic leptin sensitivity.

  10. Blood Glucose and Insulin Concentrations after Octreotide Administration in Horses With Insulin Dysregulation

    OpenAIRE

    Frank, N.; Hermida, P.; Sanchez?Londo?o, A.; Singh, R.; Gradil, C.M.; Uricchio, C.K.

    2017-01-01

    Background Octreotide is a somatostatin analog that suppresses insulin secretion. Hypothesis We hypothesized that octreotide would suppress insulin concentrations in horses and that normal (N) horses and those with insulin dysregulation (ID) would differ significantly in their plasma glucose and insulin responses to administration of octreotide. Animals Twelve horses, N = 5, ID = 7. Methods Prospective study. An oral sugar test was performed to assign horses to N and ID groups. Octreotide (1....

  11. Is Insulin Action in the Brain Relevant in Regulating Blood Glucose in Humans?

    Science.gov (United States)

    Dash, Satya; Xiao, Changting; Morgantini, Cecilia; Koulajian, Khajag; Lewis, Gary F

    2015-07-01

    In addition to its direct action on the liver to lower hepatic glucose production, insulin action in the central nervous system (CNS) also lowers hepatic glucose production in rodents after 4 hours. Although CNS insulin action (CNSIA) modulates hepatic glycogen synthesis in dogs, it has no net effect on hepatic glucose output over a 4-hour period. The role of CNSIA in regulating plasma glucose has recently been examined in humans and is the focus of this review. Intransal insulin (INI) administration increases CNS insulin concentration. Hence, INI can address whether CNSIA regulates plasma glucose concentration in humans. We and three other groups have sought to answer this question, with differing conclusions. Here we will review the critical aspects of each study, including its design, which may explain these discordant conclusions. The early glucose-lowering effect of INI is likely due to spillover of insulin into the systemic circulation. In the presence of simultaneous portal and CNS hyperinsulinemia, portal insulin action is dominant. INI administration does lower plasma glucose independent of peripheral insulin concentration (between ∼3 and 6 h after administration), suggesting that CNSIA may play a role in glucose homeostasis in the late postprandial period when its action is likely greatest and portal insulin concentration is at baseline. The potential physiological role and purpose of this pathway are discussed in this review. Because the effects of INI are attenuated in patients with type 2 diabetes and obesity, this is unlikely to be of therapeutic utility.

  12. Higher glucose, insulin and insulin resistance (HOMA-IR) in childhood predict adverse cardiovascular risk in early adulthood: the Pune Children's Study.

    Science.gov (United States)

    Yajnik, Chittaranjan S; Katre, Prachi A; Joshi, Suyog M; Kumaran, Kalyanaraman; Bhat, Dattatray S; Lubree, Himangi G; Memane, Nilam; Kinare, Arun S; Pandit, Anand N; Bhave, Sheila A; Bavdekar, Ashish; Fall, Caroline H D

    2015-07-01

    The Pune Children's Study aimed to test whether glucose and insulin measurements in childhood predict cardiovascular risk factors in young adulthood. We followed up 357 participants (75% follow-up) at 21 years of age who had undergone detailed measurements at 8 years of age (glucose, insulin, HOMA-IR and other indices). Oral glucose tolerance, anthropometry, plasma lipids, BP, carotid intima-media thickness (IMT) and arterial pulse wave velocity (PWV) were measured at 21 years. Higher fasting glucose, insulin and HOMA-IR at 8 years predicted higher glucose, insulin, HOMA-IR, BP, lipids and IMT at 21 years. A 1 SD change in 8 year variables was associated with a 0.10-0.27 SD change at 21 years independently of obesity/adiposity at 8 years of age. A greater rise in glucose-insulin variables between 8 and 21 years was associated with higher cardiovascular risk factors, including PWV. Participants whose HOMA-IR measurement remained in the highest quartile (n = 31) had a more adverse cardiovascular risk profile compared with those whose HOMA-IR measurement remained in the lowest quartile (n = 28). Prepubertal glucose-insulin metabolism is associated with adult cardiovascular risk and markers of atherosclerosis. Our results support interventions to improve glucose-insulin metabolism in childhood to reduce cardiovascular risk in later life.

  13. Effect of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome.

    Science.gov (United States)

    Belli, Susana H; Graffigna, Mabel N; Oneto, Adriana; Otero, Patricia; Schurman, Leon; Levalle, Oscar A

    2004-03-01

    To evaluate the effects of rosiglitazone on insulin resistance, growth factors, and reproductive disturbances in women with polycystic ovary syndrome (PCOS). Prospective study. Women with PCOS attending as outpatients of the Endocrine Division, Hospital Durand, Buenos Aires. Twenty-four insulin-resistant women with PCOS. Hormonal evaluations and a standardized oral glucose tolerance test before and after a 3-month trial of 4 mg of rosiglitazone daily. Serum LH, FSH, T, IGF-1, IGFBP-1, IGFBP-3, leptin, 17alpha-hydroxyprogesterone, insulin, and glucose concentrations. The area under insulin curve (AUC-insulin), the HOMA index (insulin resistance), the QUICKI index (insulin sensitivity), and the beta-cell function were calculated. Body mass index (BMI) and the waist/hip ratio were evaluated. A significant decrease was observed in serum fasting insulin, AUC insulin, HOMA index, beta-cell function, IGF-1, LH, and waist/hip ratio. The QUICKI index and IGFBP-1 increased significantly. Serum sex hormone-binding globulin, androgens, leptin, IGFBP-3, and BMI remained unchanged. Twenty-two of 23 females had their menses restored, and three patients became pregnant. One patient was excluded because she became pregnant at the second month. Associated with the decrease in LH, rosiglitazone improved insulin-resistance parameters and normalized the menstrual cycle, which suggests that this drug could improve the endocrine-reproductive condition in insulin-resistant women with PCOS.

  14. Psidium guajava Linn. leaf extract affects hepatic glucose transporter-2 to attenuate early onset of insulin resistance consequent to high fructose intake: An experimental study

    Science.gov (United States)

    Mathur, R.; Dutta, Shagun; Velpandian, T.; Mathur, S.R.

    2015-01-01

    Background: Insulin resistance (IR) is amalgam of pathologies like altered glucos metabolism, dyslipidemia, impaired glucose tolerance, non-alcoholic fatty liver disease, and associated with type-II diabetes and cardiometabolic diseases. One of the reasons leading to its increased and early incidence is understood to be a high intake of processed fructose containing foods and beverages by individuals, especially, during critical developmental years. Objective: To investigate the preventive potential of aqueous extract of Psidium guajava leaves (PG) against metabolic pathologies, vis-à-vis, IR, dyslipidemia, hyperleptinemia and hypertension, due to excess fructose intake initiated during developmental years. Materials and Methods: Post-weaning (4 weeks old) male rats were provided fructose (15%) as drinking solution, ad libitum, for 8 weeks and assessed for food and water/fructose intake, body weight, fasting blood sugar, mean arterial pressure, lipid biochemistry, endocrinal (insulin, leptin), histopathological (fatty liver) and immunohistochemical (hepatic glucose transporter [GLUT2]) parameters. Parallel treatment groups were administered PG in doses of 250 and 500 mg/kg/d, po × 8 weeks and assessed for same parameters. Using extensive liquid chromatography-mass spectrometry protocols, PG was analyzed for the presence of phytoconstituents like Myrecetin, Luteolin, Kaempferol and Guavanoic acid and validated to contain Quercetin up to 9.9%w/w. Results: High fructose intake raised circulating levels of insulin and leptin and hepatic GLUT2 expression to promote IR, dyslipidemia, and hypertension that were favorably re-set with PG. Although PG is known for its beneficial role in diabetes mellitus, for the first time we report its potential in the management of lifelong pathologies arising from high fructose intake initiated during developmental years. PMID:25829790

  15. Insulin Stimulates S100B Secretion and These Proteins Antagonistically Modulate Brain Glucose Metabolism.

    Science.gov (United States)

    Wartchow, Krista Minéia; Tramontina, Ana Carolina; de Souza, Daniela F; Biasibetti, Regina; Bobermin, Larissa D; Gonçalves, Carlos-Alberto

    2016-06-01

    Brain metabolism is highly dependent on glucose, which is derived from the blood circulation and metabolized by the astrocytes and other neural cells via several pathways. Glucose uptake in the brain does not involve insulin-dependent glucose transporters; however, this hormone affects the glucose influx to the brain. Changes in cerebrospinal fluid levels of S100B (an astrocyte-derived protein) have been associated with alterations in glucose metabolism; however, there is no evidence whether insulin modulates glucose metabolism and S100B secretion. Herein, we investigated the effect of S100B on glucose metabolism, measuring D-(3)H-glucose incorporation in two preparations, C6 glioma cells and acute hippocampal slices, and we also investigated the effect of insulin on S100B secretion. Our results showed that: (a) S100B at physiological levels decreases glucose uptake, through the multiligand receptor RAGE and mitogen-activated protein kinase/ERK signaling, and (b) insulin stimulated S100B secretion via PI3K signaling. Our findings indicate the existence of insulin-S100B modulation of glucose utilization in the brain tissue, and may improve our understanding of glucose metabolism in several conditions such as ketosis, streptozotocin-induced dementia and pharmacological exposure to antipsychotics, situations that lead to changes in insulin signaling and extracellular levels of S100B.

  16. Role of adiponectin and leptin on body development in infants during the first year of life

    Directory of Open Access Journals (Sweden)

    Gasparoni Antonella

    2010-03-01

    Full Text Available Abstract Background The control of growth and nutritional status in the foetus and neonate is a complex mechanism, in which also hormones produced by adipose tissue, such as adiponectin and leptin are involved. The aim of this study was to evaluate levels of adiponectin, leptin and insulin in appropriate (AGA and small for gestational age (SGA children during the 1st year of life and to correlate these with auxological parameters. Methods In 33 AGA and 29 SGA infants, weight, length, head circumference, glucose, insulin, adiponectin and leptin levels were evaluated at the second day of life, and at one, six and twelve months, during which a portion of SGA could show catch-up growth (rapid growth in infants born small for their gestational age. Results Both total and isoform adiponectin levels were comparable between AGA and SGA infants at birth and until age one year. These levels significantly increased from birth to the first month of life and then decreased to lower values at 1 year of age in all subjects. Circulating leptin concentrations were higher in AGA (2.1 ± 4.1 ng/ml than in SGA neonates (0.88 ± 1.03 ng/ml, p st and the 6th month of age, but they increased in SGA from six months to one year, when they showed catch-up growth. Circulating insulin levels were not statistically different in AGA and SGA neonates at any study time point. Insulin levels in both AGA and SGA infants increased over the study period, and were significantly lower at birth compared to one, six and 12 months of age. Conclusions During the first year of life, in both AGA and SGA infants a progressive decrease in adiponectin levels was observed, while a difference in leptin values was correlated with the nutritional status.

  17. Partial ablation of adult Drosophila insulin-producing neurons modulates glucose homeostasis and extends life span without insulin resistance.

    Science.gov (United States)

    Haselton, Aaron; Sharmin, Effat; Schrader, Janel; Sah, Megha; Poon, Peter; Fridell, Yih-Woei C

    2010-08-01

    In Drosophila melanogaster (D. melanogaster), neurosecretory insulin-like peptide-producing cells (IPCs), analogous to mammalian pancreatic beta cells are involved in glucose homeostasis. Extending those findings, we have developed in the adult fly an oral glucose tolerance test and demonstrated that IPCs indeed are responsible for executing an acute glucose clearance response. To further develop D. melanogaster as a relevant system for studying age-associated metabolic disorders, we set out to determine the impact of adult-specific partial ablation of IPCs (IPC knockdown) on insulin-like peptide (ILP) action, metabolic outcomes and longevity. Interestingly, while IPC knockdown flies are hyperglycemic and glucose intolerant, these flies remain insulin sensitive as measured by peripheral glucose disposal upon insulin injection and serine phosphorylation of a key insulin-signaling molecule, Akt. Significant increases in stored glycogen and triglyceride levels as well as an elevated level of circulating lipid measured in adult IPC knockdown flies suggest profound modulation in energy metabolism. Additional physiological outcomes measured in those flies include increased resistance to starvation and impaired female fecundity. Finally, increased life span and decreased mortality rates measured in IPC knockdown flies demonstrate that it is possible to modulate ILP action in adult flies to achieve life span extension without insulin resistance. Taken together, we have established and validated an invertebrate genetic system to further investigate insulin action, metabolic homeostasis and regulation of aging regulated by adult IPCs.

  18. Assessment of insulin, lectin and vitamin C in chronic renal failure patients before and after haemodialysis

    International Nuclear Information System (INIS)

    Ahmed, A.M.; El-Yamani, N.A.; Youssif, Z.A.; Abdel-Razik, D.E.

    2006-01-01

    The present study was carried out to investigate the relative interaction between insulin, leptin and vitamin C in male patients with chronic renal failure and undergo regular haemodialysis (3 times/week). The study was carried out on 20 healthy volunteers as control (group I) and 20 with chronic renal failure (group II) which were studied before dialysis (A) and after dialysis (B). The serum results showed significant increases in creatinine, insulin and leptin levels in patient groups as compared to the control. On the other hand, significant decreases in the levels of glucose and vitamin C were recorded

  19. Effect of feeding glucose, fructose, and inulin on blood glucose and insulin concentrations in normal ponies and those predisposed to laminitis.

    Science.gov (United States)

    Borer, K E; Bailey, S R; Menzies-Gow, N J; Harris, P A; Elliott, J

    2012-09-01

    Identification of ponies (Equus caballus) at increased risk of pasture-associated laminitis would aid in the prevention of the disease. Insulin resistance has been associated with laminitis and could be used to identify susceptible individuals. Insulin resistance may be diagnosed by feeding supplementary water-soluble carbohydrate (WSC) and measuring blood glucose and insulin concentrations. The aim of this study was to assess the glycemic and insulinemic responses of 7 normal (NP) and 5 previously laminitic (PLP), mixed breed, native UK ponies fed glucose, fructose, and inulin [1 g/(kg·d) for 3 d] or no supplementary WSC (control) in spring and fall after a 7-d adaptation to a pasture or hay diet. Blood samples were taken for 12 h after feeding on each day, and baseline and peak concentrations and area under the curve (AUC) for glucose and insulin were recorded. Linear mixed models were used for statistical analysis. Differences between PLP and NP groups were most marked after glucose feeding with differences in peak glucose (P = 0.02) and peak insulin (P = 0.016) concentrations. Season and diet adaptation also affected results. Peak concentrations of glucose and insulin occurred 2 to 4 h after WSC feeding. Peak insulin concentration was greater and more variable in fall, particularly in PLP adapted to fall pasture. Baseline glucose and insulin concentrations varied between individuals and with season and diet adaptation but were not greater in PLP than NP. Insulin AUC was greater in PLP than NP after feeding both glucose and fructose (P = 0.017), but there were no differences between PLP and NP in glucose AUC. Glycemic and insulinemic changes were less (P ≤ 0.05) after feeding fructose than glucose, although differences between PLP and NP were still evident. Minimal changes in glucose and insulin concentrations occurred after inulin feeding. Measurement of peak insulin 2 h after feeding of a single dose of glucose (1 g/kg) may be a simple and practical way to

  20. Trajectories of BMI change impact glucose and insulin metabolism.

    Science.gov (United States)

    Walsh, E I; Shaw, J; Cherbuin, N

    2018-03-01

    The aim of this study was to examine, in a community setting, whether trajectory of weight change over twelve years is associated with glucose and insulin metabolism at twelve years. Participants were 532 community-living middle-aged and elderly adults from the Personality and Total Health (PATH) Through Life study. They spanned the full weight range (underweight/normal/overweight/obese). Latent class analysis and multivariate generalised linear models were used to investigate the association of Body Mass Index (BMI, kg/m 2 ) trajectory over twelve years with plasma insulin (μlU/ml), plasma glucose (mmol/L), and HOMA2 insulin resistance and beta cell function at follow-up. All models were adjusted for age, gender, hypertension, pre-clinical diabetes status (normal fasting glucose or impaired fasting glucose) and physical activity. Four weight trajectories were extracted; constant normal (mean baseline BMI = 25; follow-up BMI = 25), constant high (mean baseline BMI = 36; follow-up BMI = 37), increase (mean baseline BMI = 26; follow-up BMI = 32) and decrease (mean baseline BMI = 34; follow-up BMI = 28). At any given current BMI, individuals in the constant high and increase trajectories had significantly higher plasma insulin, greater insulin resistance, and higher beta cell function than those in the constant normal trajectory. Individuals in the decrease trajectory did not differ from the constant normal trajectory. Current BMI significantly interacted with preceding BMI trajectory in its association with plasma insulin, insulin resistance, and beta cell function. The trajectory of preceding weight has an independent effect on blood glucose metabolism beyond body weight measured at any given point in time. Copyright © 2017 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier

  1. Long-term correction of obesity and diabetes in genetically obese mice by a single intramuscular injection of recombinant adeno-associated virus encoding mouse leptin

    Science.gov (United States)

    Murphy, John E.; Zhou, Shangzhen; Giese, Klaus; Williams, Lewis T.; Escobedo, Jaime A.; Dwarki, Varavani J.

    1997-01-01

    The ob/ob mouse is genetically deficient in leptin and exhibits a phenotype that includes obesity and non-insulin-dependent diabetes melitus. This phenotype closely resembles the morbid obesity seen in humans. In this study, we demonstrate that a single intramuscular injection of a recombinant adeno-associated virus (AAV) vector encoding mouse leptin (rAAV-leptin) in ob/ob mice leads to prevention of obesity and diabetes. The treated animals show normalization of metabolic abnormalities including hyperglycemia, insulin resistance, impaired glucose tolerance, and lethargy. The effects of a single injection have lasted through the 6-month course of the study. At all time points measured the circulating levels of leptin in the serum were similar to age-matched control C57 mice. These results demonstrate that maintenance of normal levels of leptin (2–5 ng/ml) in the circulation can prevent both the onset of obesity and associated non-insulin-dependent diabetes. Thus a single injection of a rAAV vector expressing a therapeutic gene can lead to complete and long-term correction of a genetic disorder. Our study demonstrates the long-term correction of a disease caused by a genetic defect and proves the feasibility of using rAAV-based vectors for the treatment of chronic disorders like obesity. PMID:9391128

  2. Effect of diet on insulin binding and glucose transport in rat sarcolemmal vesicles

    International Nuclear Information System (INIS)

    Grimditch, G.K.; Barnard, R.J.; Sternlicht, E.; Whitson, R.H.; Kaplan, S.A.

    1987-01-01

    The purpose of this study was to compare the effects of a high-fat, high-sucrose diet (HFS) and a low-fat, high-complex carbohydrate diet (LFC) on glucose tolerance, insulin binding, and glucose transport in rat skeletal muscle. During the intravenous glucose tolerance test, peak glucose values at 5 min were significantly higher in the HFS group; 0-, 20-, and 60-min values were similar. Insulin values were significantly higher in the HFS group at all time points (except 60 min), indicating whole-body insulin resistance. Skeletal muscle was responsible, in part, for this insulin resistance, because specific D-glucose transport in isolated sarcolemmal (SL) vesicles under basal conditions was similar between LFC and HFS rats, despite the higher plasma insulin levels. Scatchard analyses of insulin binding curves to sarcolemmal vesicles revealed that the K/sub a/ of the high-affinity binding sites was significantly reduced by the HFS diet; no other binding changes were noted. Specific D-glucose transport in SL vesicles after maximum insulin stimulation (1 U/kg) was significantly depressed in the HFS group, indicating that HFS feeding also caused a postbinding defect. These results indicate that the insulin resistance in skeletal muscle associated with a HFS diet is due to both a decrease in the K/sub a/ of the high-affinity insulin receptors and a postbinding defect

  3. The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity

    DEFF Research Database (Denmark)

    Kelly, Karen R; Brooks, Latina M; Solomon, Thomas

    2009-01-01

    the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% Vo(2 max)) combined with a eucaloric (EX, n = 10) or hypocaloric (EX-HYPO, pre: 1,945 +/- 190, post: 1,269 +/- 70, kcal/day; n = 9) diet on the GIP response......Aging and obesity are characterized by decreased beta-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through...... to ingested glucose, 2) GIP may mediate the attenuated glucose-stimulated insulin response after exercise/diet interventions, and 3) the increased PYY(3-36) response represents an improved capacity to regulate satiety and potentially body weight in older, obese, insulin-resistant adults....

  4. Exogenous thyroxine improves glucose intolerance in insulin-resistant rats.

    Science.gov (United States)

    Vazquez-Anaya, Guillermo; Martinez, Bridget; Soñanez-Organis, José G; Nakano, Daisuke; Nishiyama, Akira; Ortiz, Rudy M

    2017-03-01

    Both hypothyroidism and hyperthyroidism are associated with glucose intolerance, calling into question the contribution of thyroid hormones (TH) on glucose regulation. TH analogues and derivatives may be effective treatment options for glucose intolerance and insulin resistance (IR), but their potential glucoregulatory effects during conditions of impaired metabolism are not well described. To assess the effects of thyroxine (T 4 ) on glucose intolerance in a model of insulin resistance, an oral glucose tolerance test (oGTT) was performed on three groups of rats (n = 8): (1) lean, Long Evans Tokushima Otsuka (LETO), (2) obese, Otsuka Long Evans Tokushima Fatty (OLETF) and (3) OLETF + T 4 (8.0 µg/100 g BM/day × 5 weeks). T 4 attenuated glucose intolerance by 15% and decreased IR index (IRI) by 34% in T 4 -treated OLETF compared to untreated OLETF despite a 31% decrease in muscle Glut4 mRNA expression. T 4 increased the mRNA expressions of muscle monocarboxylate transporter 10 (Mct10), deiodinase type 2 (Di2), sirtuin 1 (Sirt1) and uncoupling protein 2 (Ucp2) by 1.8-, 2.2-, 2.7- and 1.4-fold, respectively, compared to OLETF. Activation of AMP-activated protein kinase (AMPK) and insulin receptor were not significantly altered suggesting that the improvements in glucose intolerance and IR were independent of enhanced insulin-mediated signaling. The results suggest that T 4 treatment increased the influx of T 4 in skeletal muscle and, with an increase of DI2, increased the availability of the biologically active T 3 to upregulate key factors such SIRT1 and UCP2 involved in cellular metabolism and glucose homeostasis. © 2017 Society for Endocrinology.

  5. Circulating glucagon to ghrelin ratio as a determinant of insulin resistance in hyperthyroidism.

    Science.gov (United States)

    Ağbaht, Kemal; Erdogan, Murat Faik; Emral, Rifat; Baskal, Nilgun; Güllü, Sevim

    2014-02-01

    Due to stimulated overall metabolism, a state of nutritional inadequacy often ensues, during thyrotoxicosis. We aimed to investigate circulating levels of some major components of the system that regulates energy stores, glucose, and fat metabolism, during thyrotoxicosis compared to euthyroidism. Fasting serum ghrelin, leptin, adiponectin, insulin, glucagon, glucose, as well as body fat composition were analyzed during thyrotoxicosis in 40 hyperthyroid patients (50.5 ± 15.2 years old, 22 females, 31 with Graves disease, and 9 with toxic nodular goiter). The same measurements were repeated an average 3 months later, when all patients achieved euthyroidism. Compared to euthyroidism, in thyrotoxicosis, patients had lower ghrelin and fat mass; had comparable insulin, HOMA-IR, glucagon, and leptin levels; higher levels of circulating adiponectin. Fasting serum glucose tended to be higher during thyrotoxicosis. The unique correlation of HOMA-IR was with the-glucagon to ghrelin ratio-(r = 0.801, p hyperthyroidism. The fasting HOMA-IR tends to be higher, despite the decreased adiposity in hyperthyroidism. The-glucagon to ghrelin ratio-strongly correlates with fasting HOMA-IR in hyperthyroidism.

  6. Bayesian model discrimination for glucose-insulin homeostasis

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Brooks, Stephen P.; Højbjerre, Malene

    In this paper we analyse a set of experimental data on a number of healthy and diabetic patients and discuss a variety of models for describing the physiological processes involved in glucose absorption and insulin secretion within the human body. We adopt a Bayesian approach which facilitates...... as parameter uncertainty. Markov chain Monte Carlo methods are used, combining Metropolis Hastings, reversible jump and simulated tempering updates to provide rapidly mixing chains so as to provide robust inference. We demonstrate the methodology for both healthy and type II diabetic populations concluding...... that whilst both populations are well modelled by a common insulin model, their glucose dynamics differ considerably....

  7. E4orf1 Enhances Glucose Uptake Independent of Proximal Insulin Signaling

    OpenAIRE

    Na, Ha-Na; Hegde, Vijay; Dubuisson, Olga; Dhurandhar, Nikhil V.

    2016-01-01

    Impaired proximal insulin signaling is often present in diabetes. Hence, approaches to enhance glucose disposal independent of proximal insulin signaling are desirable. Evidence indicates that Adenovirus-derived E4orf1 protein may offer such an approach. This study determined if E4orf1 improves insulin sensitivity and downregulates proximal insulin signaling in vivo and enhances cellular glucose uptake independent of proximal insulin signaling in vitro. High fat fed mice were injected with a ...

  8. Differential Role of Insulin/IGF-1 Receptor Signaling in Muscle Growth and Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Brian T. O’Neill

    2015-05-01

    Full Text Available Insulin and insulin-like growth factor 1 (IGF-1 are major regulators of muscle protein and glucose homeostasis. To determine how these pathways interact, we generated mice with muscle-specific knockout of IGF-1 receptor (IGF1R and insulin receptor (IR. These MIGIRKO mice showed >60% decrease in muscle mass. Despite a complete lack of insulin/IGF-1 signaling in muscle, MIGIRKO mice displayed normal glucose and insulin tolerance. Indeed, MIGIRKO mice showed fasting hypoglycemia and increased basal glucose uptake. This was secondary to decreased TBC1D1 resulting in increased Glut4 and Glut1 membrane localization. Interestingly, overexpression of a dominant-negative IGF1R in muscle induced glucose intolerance in MIGIRKO animals. Thus, loss of insulin/IGF-1 signaling impairs muscle growth, but not whole-body glucose tolerance due to increased membrane localization of glucose transporters. Nonetheless, presence of a dominant-negative receptor, even in the absence of functional IR/IGF1R, induces glucose intolerance, indicating that interactions between these receptors and other proteins in muscle can impair glucose homeostasis.

  9. Insulin resistance in type 1 (insulin-dependent) diabetes: dissimilarities for glucose and intermediary metabolites

    NARCIS (Netherlands)

    Nijs, H. G.; Radder, J. K.; Poorthuis, B. J.; Krans, H. M.

    1990-01-01

    To study insulin action on intermediary metabolism in relation to glucose disposal in Type 1 (insulin-dependent) diabetes, 29 patients and 15 control subjects underwent sequential euglycemic clamps (insulin infusion rates 0.5, 1.0, 2.0 and 5.0 mU.kg-1.min-1 in 2 hour periods). Dose-response curves

  10. Sympathetic overactivity precedes metabolic dysfunction in a fructose model of glucose intolerance in mice

    Science.gov (United States)

    Angelis, Katia De; Senador, Danielle D.; Mostarda, Cristiano; Irigoyen, Maria C.

    2012-01-01

    Consumption of high levels of fructose in humans and animals leads to metabolic and cardiovascular dysfunction. There are questions as to the role of the autonomic changes in the time course of fructose-induced dysfunction. C57/BL male mice were given tap water or fructose water (100 g/l) to drink for up to 2 mo. Groups were control (C), 15-day fructose (F15), and 60-day fructose (F60). Light-dark patterns of arterial pressure (AP) and heart rate (HR), and their respective variabilities were measured. Plasma glucose, lipids, insulin, leptin, resistin, adiponectin, and glucose tolerance were quantified. Fructose increased systolic AP (SAP) at 15 and 60 days during both light (F15: 123 ± 2 and F60: 118 ± 2 mmHg) and dark periods (F15: 136 ± 4 and F60: 136 ± 5 mmHg) compared with controls (light: 111 ± 2 and dark: 117 ± 2 mmHg). SAP variance (VAR) and the low-frequency component (LF) were increased in F15 (>60% and >80%) and F60 (>170% and >140%) compared with C. Cardiac sympatho-vagal balance was enhanced, while baroreflex function was attenuated in fructose groups. Metabolic parameters were unchanged in F15. However, F60 showed significant increases in plasma glucose (26%), cholesterol (44%), triglycerides (22%), insulin (95%), and leptin (63%), as well as glucose intolerance. LF of SAP was positively correlated with SAP. Plasma leptin was correlated with triglycerides, insulin, and glucose tolerance. Results show that increased sympathetic modulation of vessels and heart preceded metabolic dysfunction in fructose-consuming mice. Data suggest that changes in autonomic modulation may be an initiating mechanism underlying the cluster of symptoms associated with cardiometabolic disease. PMID:22319048

  11. Leptin as a Potential Regulator of FGF21

    Directory of Open Access Journals (Sweden)

    Mohamed Asrih

    2016-03-01

    Full Text Available Background/Aims: Fibroblast growth factor 21 (FGF21, a potent metabolic regulator, has been shown to improve insulin sensitivity in animal models of insulin resistance. Several studies have focused on identifying mediators of FGF21 effects. However, the identification of factors involved in FGF21 regulation is far from complete. As leptin is a potent metabolic modulator as well, we aimed at characterizing whether leptin may regulate FGF21. Methods: We investigated a potential regulation of FGF21 by leptin in vivo in Wistar rats and in vitro using human derived hepatocarcinoma HepG2 cells. This model was chosen as the liver is considered the main FGF21 expression site. Results: We found that leptin injections increased plasma FGF21 levels in adult Wistar rats. This was confirmed in vitro, as leptin increased FGF21 expression in HepG2 cells. We also showed that the leptin effect on FGF21 expression was mediated by STAT3 activation in HepG2 cells. Conclusion: New findings regarding a leptin-STAT3-FGF21 axis were provided in this study, although investigating the exact mechanisms linking leptin and FGF21 are still needed. These results are of great interest in the context of identifying potential new clinical approaches to treat metabolic diseases associated with insulin resistance, such as obesity and type 2 diabetes.

  12. Fasting leptin and glucose in normal weight, over weight and obese men and women diabetes patients with and without clinical depression.

    Science.gov (United States)

    Haleem, Darakhshan Jabeen; Sheikh, Shehnaz; Fawad, Asher; Haleem, Muhammad A

    2017-06-01

    A large number of diabetes patients suffer from major depression and are at high risk of mortality. In view of a role of leptin in diabetes, depression and energy homeostasis, the present study concerns circulating levels of leptin in different BMI groups of un-depressed and depressed diabetes patients. Six hundred thirty male and female patients with a primary diagnosis of diabetes were grouped according to BMI and with or without clinical symptoms of depression. Age matched healthy, normal weight male and female volunteers without clinical symptoms of depression or diabetes were taken as controls. Blood samples were obtained after an overnight fast of 12 h. Serum was stored for the determination of leptin and glucose. We found that there were more female than male diabetes patients with comorbid depression. Fasting leptin was higher in normal weight non-diabetes women than men; but comparable in normal weight men and women diabetes patients. Fasting glucose levels were higher in diabetes than non diabetes groups; values were comparable in men and women. Depression was associated with a decrease and increase in leptin respectively in normal-overweight and obese men and women diabetes patients. Glucose levels were also higher in obese depressed than un-depressed diabetes patients. The results suggested that the female gender is at greater risk to comorbid diabetes with depression. Adipo-insular axis plays an important role in diabetes, associated depression and in the greater risk of the female gender to comorbid diabetes with depression.

  13. Circulating Glucagon 1-61 Regulates Blood Glucose by Increasing Insulin Secretion and Hepatic Glucose Production

    Directory of Open Access Journals (Sweden)

    Nicolai J. Wewer Albrechtsen

    2017-11-01

    Full Text Available Glucagon is secreted from pancreatic α cells, and hypersecretion (hyperglucagonemia contributes to diabetic hyperglycemia. Molecular heterogeneity in hyperglucagonemia is poorly investigated. By screening human plasma using high-resolution-proteomics, we identified several glucagon variants, among which proglucagon 1-61 (PG 1-61 appears to be the most abundant form. PG 1-61 is secreted in subjects with obesity, both before and after gastric bypass surgery, with protein and fat as the main drivers for secretion before surgery, but glucose after. Studies in hepatocytes and in β cells demonstrated that PG 1-61 dose-dependently increases levels of cAMP, through the glucagon receptor, and increases insulin secretion and protein levels of enzymes regulating glycogenolysis and gluconeogenesis. In rats, PG 1-61 increases blood glucose and plasma insulin and decreases plasma levels of amino acids in vivo. We conclude that glucagon variants, such as PG 1-61, may contribute to glucose regulation by stimulating hepatic glucose production and insulin secretion.

  14. Evaluation of the role of leptin, interleukin-8 (Il-8) and nitric oxide (No) in children with insulin dependent diabetes mellitus (type 1)

    International Nuclear Information System (INIS)

    Ll-Nashar, N.A.; Abdel-Latif, A.; Mostafa, A.M.E.; Ahmed, S.M.

    2005-01-01

    The autoimmune nature of insulin dependent diabetes mellitus (IDDM), type 1, is well established. The documentation of altered Th 1/Th 2 balance and the finding of antibodies in the circulation directed against the b-cells can indicate the role of the immune system. The stimulating effect of insulin on leptin expression is well identified. The aim of this study is to investigate the profile and the relationships between leptin, interleukin-8 (IL-8) and nitric oxide (NO) and to reveal their possible role in the development and progression of IDDM. Serum leptin was evaluated using radioimmunoassay (RIA), serum concentration of IL-8 was assayed by enzyme linked immunosorbent assay (ELISA), while serum nitrite level (end product of NO) was determined by Griess reaction. The study was carried out on twenty IDDM children who compared with other twenty healthy non-diabetic ones with the same age and sex. The data revealed that children with IDDM established high weight-for-age (W/A)Z (P < 0.001) , high weight-for-height (W/H)Z (P < 0.05) and high glycated hemoglobin (HbA1c% ) (P < 0.0001). Both diabetic boys and girls showed higher serum leptin levels (7.48 ± 1.86 ng/ml) than the control group (5.92 ± 1.39 ng/ml). Leptin levels were higher in diabetic girls (8.46 ± 2.29 ng/ml) than diabetic boys (6.68 ± 0.91 ng/ml). Significant high level of serum IL-8 concentration (23 ± 11.92 pg/ml) was detected in IDDM children versus the control group (5.69 ± 1.67 pg/ml). On the other hand, serum nitrite values showed significant reduction in the IDDM children (430.78 ± 155.14 Μmol/l) compared to the control group (610.08 ± 192.82 Μmol/l). Correlation analysis showed positive correlation between leptin with age, (W/H)Z and fasting glucose level, furthermore, a positive correlation was established between IL-8 with (W/H)Z, hinting the adipose tissue as a site of its production and no association between NO and other relevant variables was detected. It could be concluded that

  15. Insulin resistance, β-cell dysfunction and differences in curves of plasma glucose and insulin in the intermediate points of the standard glucose tolerance test in adults with cystic fibrosis.

    Science.gov (United States)

    Cano Megías, Marta; González Albarrán, Olga; Guisado Vasco, Pablo; Lamas Ferreiro, Adelaida; Máiz Carro, Luis

    2015-02-01

    diabetes has become a co-morbidity with a negative impact on nutritional status, lung function and survival in cystic fibrosis. To identify any changes in intermediate points after a 2-hour oral glucose tolerance test (OGTT), pancreatic β-cell dysfunction, and insulin resistance in cystic fibrosis-related diabetes. It was carried out a retrospective analysis in a cohort of 64 patients affected of cystic fibrosis, older than 14 years, using the first pathological OGTT. Peripheral insulin resistance was measured using the homeostasis model assessment for insulin resistance (HOMA- IR), and pancreatic β-cell function was calculated according to Wareham. Time to maximum plasma insulin and glucose levels and area under the curve (AUC0-120) were also measured. Twenty-eight women and 36 men with a mean age of 26.8 years were enrolled, of whom 26.7% had normal glucose tolerance (NGT), 18.3% cystic fibrosis-related diabetes without fasting hyperglycemia (CFRD w/o FPG), 10% indeterminate (INDET), and 45% impaired glucose tolerance (IGT). HOMA-IR values were not significantly different between the diagnostic categories. Patients with any pathological change had worse β cell function, with a significant delay in insulin secretion, although there were no differences in total insulin production (AUC0-120). Time to maximum glucose levels was significantly shorter in NGT patients as compared to other categories, with glucose AUC0-120 being higher in the different diagnostic categories as compared to NGT. In over half the cases, peak blood glucose levels during a standard OGTT are reached in the intermediate time points, rather than at the usual time of 120minutes. Patients with cystic fibrosis and impaired glucose metabolism have a delayed insulin secretion during the standard OGTT due to loss of first-phase insulin secretion, with no differences in total insulin production. Absence of significant changes in HOMA-IR suggests that β-cell dysfunction is the main pathogenetic

  16. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: A meta-analysis of 50,345 Caucasians

    NARCIS (Netherlands)

    A.M. Fretts (Amanda M.); J.L. Follis (Jack ); J.A. Nettleton (Jennifer ); R.N. Lemaitre (Rozenn ); J.S. Ngwa; M.K. Wojczynski (Mary ); I.-P. Kalafati (Ioanna-Panagiota); T.V. Varga (Tibor V.); A.C. Frazier-Wood (Alexis C.); D.K. Houston (Denise); J. Lahti (Jari); U. Ericson (Ulrika); E.H. van den Hooven (Edith); V. Mikkilä (Vera); J.C. Kiefte-de Jong (Jessica); D. Mozaffarian (Dariush); K.M. Rice (Kenneth); F. Renström (Frida); K.E. North (Kari); N.M. McKeown (Nicola ); M.F. Feitosa (Mary Furlan); S. Kanoni (Stavroula); C.E. Smith (Caren); M. Garcia (Melissa); A.-M. Tiainen (Anna-Maija); E. Sonestedt (Emily); A. Manichaikul (Ani); F.J.A. van Rooij (Frank); M. Dimitriou (Maria); O. Raitakari (Olli); J.S. Pankow (James); L. Djoussé (Luc); M.A. Province (Mike); F.B. Hu (Frank); C.-Q. Lai (Chao-Qiang); M.F. Keller (Margaux); M.-M. Perälä (Mia-Maria); J.I. Rotter (Jerome I.); A. Hofman (Albert); M.J. Graff (Maud J.L.); M. Kähönen (Mika); K. Mukamal (Kenneth); I. Johansson (Ingegerd); J.M. Ordovas (Jose); Y. Liu (YongMei); S. Männistö (Satu); A.G. Uitterlinden (André); P. Deloukas (Panagiotis); I. Seppälä (Ilkka); B.M. Psaty (Bruce); L.A. Cupples (Adrienne); I.B. Borecki (Ingrid); P.W. Franks (Paul W.); D.K. Arnett (Donna); M.A. Nalls (Michael); K. Hagen (Knut); M. Orho-Melander (Marju); O.H. Franco (Oscar); T. Lehtimäki (Terho); G.V. Dedoussis (George); J.B. Meigs (James); D.S. Siscovick (David)

    2015-01-01

    textabstractBackground: Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. Objective: We investigated the

  17. A Study on the Glucose and Immunoreactive Insulin Response during Oral Glucose Tolerance Test in Patients with Chronic Liver Diseases

    International Nuclear Information System (INIS)

    Choe, Kang Won; Lee, Hong Kyu; Koh, Chang Soon; Lee, Mu Ho

    1973-01-01

    The blood glucose and plasma immunoreactive insulin (IRI) levels were measured during aral glucose tolerance test in 7 healthy subjects and 6 patients with chronic liver diseases. The glucose tolerance was impaired in 5 of the 6 patients and normal in I. Plasma IRI responses were markedly increased and delayed in all patients, suggesting endogenous insulin resistance. Patients with more glucose intolerance showed less increase in plasma IRI than the group with less intolerance. lt is suggested that some insulin antagonists may decrease the peripheral insulin sensitivity and stimulate compensatory hyperactivity of pancreatic islets. If the compensatory hyperactivity is inadequate due to gemetic predisposition to diabetes mellitus or exhaustion of β-cells of pancreatic islets, the glucose intolerance and overt diabetes mellitus may ensue.

  18. A Study on the Glucose and Immunoreactive Insulin Response during Oral Glucose Tolerance Test in Patients with Chronic Liver Diseases

    Energy Technology Data Exchange (ETDEWEB)

    Choe, Kang Won; Lee, Hong Kyu; Koh, Chang Soon; Lee, Mu Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1973-03-15

    The blood glucose and plasma immunoreactive insulin (IRI) levels were measured during aral glucose tolerance test in 7 healthy subjects and 6 patients with chronic liver diseases. The glucose tolerance was impaired in 5 of the 6 patients and normal in I. Plasma IRI responses were markedly increased and delayed in all patients, suggesting endogenous insulin resistance. Patients with more glucose intolerance showed less increase in plasma IRI than the group with less intolerance. lt is suggested that some insulin antagonists may decrease the peripheral insulin sensitivity and stimulate compensatory hyperactivity of pancreatic islets. If the compensatory hyperactivity is inadequate due to gemetic predisposition to diabetes mellitus or exhaustion of beta-cells of pancreatic islets, the glucose intolerance and overt diabetes mellitus may ensue.

  19. Glucose-responsive insulin delivery for type 1 diabetes: The artificial pancreas story.

    Science.gov (United States)

    Bally, Lia; Thabit, Hood; Hovorka, Roman

    2018-06-15

    Insulin replacement therapy is integral to the management of type 1 diabetes, which is characterised by absolute insulin deficiency. Optimal glycaemic control, as assessed by glycated haemoglobin, and avoidance of hyper- and hypoglycaemic excursions have been shown to prevent diabetes-related complications. Insulin pump use has increased considerably over the past decade with beneficial effects on glycaemic control, quality of life and treatment satisfaction. The advent and progress of ambulatory glucose sensor technology has enabled continuous glucose monitoring based on real-time glucose levels to be integrated with insulin therapy. Low glucose and predictive low glucose suspend systems are currently used in clinical practice to mitigate against hypoglycaemia, and provide the first step towards feedback glucose control. The more advanced technology approach, an artificial pancreas or a closed-loop system, gradually increases and decreases insulin delivery in a glucose-responsive fashion to mitigate against hyper- and hypoglycaemia. Randomised outpatient clinical trials over the past 5 years have demonstrated the feasibility, safety and efficacy of the approach, and the recent FDA approval of the first single hormone closed-loop system establishes a new standard of care for people with type 1 diabetes. Copyright © 2017 Elsevier B.V. All rights reserved.

  20. Leptin and insulin growth factor 1: diagnostic markers of the refeeding syndrome and mortality.

    Science.gov (United States)

    Elnenaei, Manal O; Alaghband-Zadeh, Jamshid; Sherwood, Roy; Awara, Mahmoud A; Moniz, Caje; le Roux, Carel W

    2011-09-01

    Refeeding syndrome is difficult to diagnose since the guidelines for identifying those at risk are largely based on subjective clinical parameters and there are no predictive biochemical markers. We examined the suitability of insulin-like growth factor 1 (IGF1) and leptin as markers to identify patients at risk of the refeeding syndrome before initiation of parenteral nutrition (PN). A total of thirty-five consecutive patients referred for commencement of PN were included. Serum leptin and IGF1 were measured before starting PN. Electrolytes, liver and renal function tests were conducted before and daily for 1 week after initiating PN. The primary outcome was a decrease in phosphate 12-36 h after initiating PN. 'Refeeding index' (RI) was defined as leptin × IGF1 divided by 2800 to produce a ratio of 1·0 in patients who are well nourished. RI had better sensitivity (78 %; 95 % CI 40, 97 %) and specificity (78 %; 95 % CI 40, 97 %) with a likelihood ratio of 3·4, at a cut-off value of 0·19 for predicting a ≥ 30 % decrease in phosphate concentration within 12-36 h after starting PN, compared with IGF1 or leptin alone. However, IGF1 was a better predictor of mortality than either leptin or the RI. The present study is the first to derive and test the 'RI', and find that it is a sensitive and specific predictor of the refeeding syndrome in hospitalised patients before starting PN.

  1. Cold exposure potentiates the effect of insulin on in vivo glucose uptake

    International Nuclear Information System (INIS)

    Vallerand, A.L.; Perusse, F.; Bukowiecki, L.J.

    1987-01-01

    The effects of cold exposure and insulin injection on the rates of net 2-[ 3 H]deoxyglucose uptake (K i ) in peripheral tissues were investigated in warm-acclimated rats. Cold exposure and insulin treatment independently increased K i values in skeletal muscles, heart, white adipose tissue, and brown adipose tissue. The effects of cold exposure were particularly evident in brown adipose tissue where the K i increased >100 times. When the two treatments were combined, it was found that cold exposure synergistically enhanced the maximal insulin responses for glucose uptake in brown adipose tissue, all white adipose tissue depots, and skeletal muscles investigated. The results indicate that cold exposure induces an insulin-like effect on K i that does not appear to be specifically associated with shivering thermogenesis in skeletal muscles, because that effect was observed in all insulin-sensitive tissues. The data also demonstrate that cold exposure significantly potentiates the maximal insulin responses for glucose uptake in the same tissues. This potentialization may result from (1) an enhanced responsiveness of peripheral tissues to insulin, possibly occurring at metabolic steps lying beyond the insulin receptor and (2) an increased tissue blood flow augmenting glucose and insulin availability and thereby amplifying glucose uptake

  2. Coexistence of insulin resistance and increased glucose tolerance in pregnant rats: a physiological mechanism for glucose maintenance.

    Science.gov (United States)

    Carrara, Marcia Aparecida; Batista, Márcia Regina; Saruhashi, Tiago Ribeiro; Felisberto, Antonio Machado; Guilhermetti, Marcio; Bazotte, Roberto Barbosa

    2012-06-06

    The contribution of insulin resistance (IR) and glucose tolerance to the maintenance of blood glucose levels in non diabetic pregnant Wistar rats (PWR) was investigated. PWR were submitted to conventional insulin tolerance test (ITT) and glucose tolerance test (GTT) using blood sample collected 0, 10 and 60 min after intraperitoneal insulin (1 U/kg) or oral (gavage) glucose (1g/kg) administration. Moreover, ITT, GTT and the kinetics of glucose concentration changes in the fed and fasted states were evaluated with a real-time continuous glucose monitoring system (RT-CGMS) technique. Furthermore, the contribution of the liver glucose production was investigated. Conventional ITT and GTT at 0, 7, 14 and 20 days of pregnancy revealed increased IR and glucose tolerance after 20 days of pregnancy. Thus, this period of pregnancy was used to investigate the kinetics of glucose changes with the RT-CGMS technique. PWR (day 20) exhibited a lower (pinsulin sensitivity and/or glucose tolerance during late pregnancy. In contrast to the general view that IR is a pathological process associated with gestational diabetes, a certain degree of IR may represent an important physiological mechanism for blood glucose maintenance during fasting. Copyright © 2012 Elsevier Inc. All rights reserved.

  3. Long-term correction of type 1 and 2 diabetes by central leptin gene therapy independent of effects on appetite and energy expenditure

    Directory of Open Access Journals (Sweden)

    Masako Nakano

    2012-01-01

    Full Text Available Adipocyte-derived leptin is a hormone associated with the regulation of energy homeostasis, including glucose metabolism. Hyperleptinemia, induced by the consumption of energy-enriched diets, inhibits leptin transport across the blood-brain barrier, and thereby produces leptin insufficiency in the hypothalamus. As a result of sustained leptin insufficiency, the hypothalamic restraint on pancreatic insulin secretion is lost. Additionally, both glucose metabolism and energy expenditure are also diminished, and both type 1 and type 2 diabetes are induced. A replication-deficient recombinant adeno-associated virus vector engineered to encode the leptin gene (rAVV-LEP has been used in models of diabetes as a novel therapeutic approach. After rAVV-LEP injection in ob/ob mice, hypothalamic leptin expression was increased, body weight was suppressed, and hyperinsulinemia was ameliorated. Additionally injection of rAVV-LEP into the hypothalamus suppressed the expression of orexigenic neuropeptide Y (NPY and enhanced anorexigenic pro-opiomelanocortin (POMC in the arcuate nucleus (ARC in rats. It is proposed that central leptin gene therapy should be tested clinically to reduce the worldwide epidemic of obesity, diabetes, and shortened life span. In this article, the information has been assembled from published review articles on this topic.

  4. Glucose but not insulin or insulin resistance is associated with memory performance in middle-aged non-diabetic women: a cross sectional study.

    Science.gov (United States)

    Backeström, Anna; Eriksson, Sture; Nilsson, Lars-Göran; Olsson, Tommy; Rolandsson, Olov

    2015-01-01

    Elevated concentrations of plasma glucose appear to play a role in memory impairment, and it has been suggested that insulin might also have a negative effect on cognitive function. Our aim was to study whether glucose, insulin or insulin resistance are associated with episodic or semantic memory in a non-diabetic and non-demented population. We linked and matched two population-based data sets identifying 291 participants (127 men and 164 women, mean age of 50.7 ± 8.0 years). Episodic and semantic memory functions were tested, and fasting plasma insulin, fasting plasma glucose, and 2-hour glucose were analysed along with other potential influencing factors on memory function. Since men and women display different results on memory functions they were analysed separately. Insulin resistance was calculated using the HOMA-IR method. A higher fasting plasma glucose concentration was associated with lower episodic memory in women (r = -0.08, 95% CI -0.14; -0.01), but not in men. Plasma insulin levels and insulin resistance were not associated with episodic or semantic memory in women or in men after adjustments for age, fasting glucose, 2-hour glucose, BMI, education, smoking, cardiovascular disease, hypertension, cholesterol, and physical activity. This indicates that fasting glucose but not insulin, might have impact on episodic memory in middle-aged women.

  5. Glucose-lowering effect and glycaemic variability of insulin glargine, insulin detemir and insulin lispro protamine in people with type 1 diabetes.

    Science.gov (United States)

    Derosa, G; Franzetti, I; Querci, F; Romano, D; D'Angelo, A; Maffioli, P

    2015-06-01

    To compare, using a continuous glucose monitoring (CGM) system, the effect on glycaemic variability of insulin glargine, detemir and lispro protamine. A total of 49 white people with type 1 diabetes, not well controlled by three times daily insulin lispro, taken for at least 2 months before study and on a stable dose, were enrolled. The study participants were randomized to add insulin glargine, detemir or lispro protamine, once daily, in the evening. We used a CGM system, the iPro Digital Recorder (Medtronic MiniMed, Northridge, CA, USA) for 1 week. Glycaemic control was assessed according to mean blood glucose values, the area under the glucose curve above 3.9 mmol/l (AUC(>3.9)) or above 10.0 mmol/l (AUC(>10.0)), and the percentage of time spent with glucose values >3.9 or >10.0 mmol/l. Intraday glycaemic variability was assessed using standard deviation (s.d.) values, the mean amplitude of glycaemic excursions and continuous overlapping of net glycaemic action. Day-to-day glycaemic variability was assessed using the mean of daily differences. The s.d. was found to be significantly lower with insulin lispro protamine and glargine compared with insulin detemir. AUC(>3.9) was higher and AUC(>10.0) was lower with insulin lispro protamine and glargine compared with detemir. The mean amplitude of glycaemic excursions and continuous overlapping net glycaemic action values were lower with insulin lispro protamine and glargine compared with detemir. In addition, the mean of daily differences was significantly lower with insulin lispro protamine and glargine compared with detemir. Fewer hypoglycaemic events were recorded during the night-time with insulin lispro protamine compared with glargine and detemir. The results suggest that insulin lispro protamine and glargine are more effective than detemir in reducing glycaemic variability and improving glycaemic control in people with type 1 diabetes. Insulin lispro protamine seems to lead to fewer hypoglycaemic

  6. Clinical assessment of blood glucose homeostasis in horses: comparison of a continuous glucose monitoring system with a combined intravenous glucose and insulin test protocol.

    Science.gov (United States)

    Johnson, P J; Wiedmeyer, C E; LaCarrubba, A; Messer, N T; Dingfelder, H A; Cogswell, A M; Amorim, J R R; Ganjam, V K

    2011-01-01

    The combined glucose-insulin test (CGIT) is helpful for evaluating insulin sensitivity. A continuous glucose monitoring system (CGMS) reports changes in interstitial glucose concentrations as they occur in the blood. Use of the CGMS minimizes animal contact and may be useful when performing a CGIT. Results obtained using a CGMS are useful for the evaluation of glucose responses during the evaluation of insulin sensitivity in equids. Seven mature, obese ponies. Ponies were equipped with CGMS for determination of interstitial glucose concentrations. Glucose (150 mg/kg, i.v.) and insulin (0.1 U/kg, i.v.) were administered and blood glucose concentrations determined at (minutes after time zero) 1, 5, 15, 25, 35, 45, 60, 75, 90, 105, and 120 with a hand-held glucometer. Blood chemistry results were compared with simultaneously obtained results using CGMS. Concordance coefficients determined for comparison of blood glucose concentrations determined by a hand-held glucometer and those determined by CGMS after the zero time point were 0.623, 0.764, 0.834, 0.854, and 0.818 (for delays of 0, 5, 10, 15, and 20 minutes, respectively). Interstitial glucose concentrations obtained by the CGMS compared favorably to blood glucose concentrations. CGMS may be useful for assessment of glucose dynamics in the CGIT. Copyright © 2010 by the American College of Veterinary Internal Medicine.

  7. Adiponectin, in contrast to leptin, is not associated with body mass index, waist circumference and HOMA-IR in subjects of a west-African population.

    Science.gov (United States)

    Awede, Bonaventure; Adovoekpe, Diane; Adehan, Grace; MacFarlane, Niall G; Azonbakin, Simon; Dossou, Emmanuel; Amoussou-Guenou, Marcellin; Djrolo, François

    2018-06-01

    Factors associated with plasma levels of adiponectin and leptin were studied in adult subjects without diabetes from Cotonou in Benin (West-Africa). Seventy (70) men and 45 women were included in the study. Anthropometric variables were measured and a venous blood sample was drawn from each subject, after an overnight fasting period, for measurement of plasma glucose, insulin, leptin, and adiponectin levels. HOMA-IR was determined to assess insulin resistance. Adiponectin and leptin levels were higher in women than in men (with adiponectin 18.48 ± 12.77 vs.7.8 ± 10.39 μg/mL, P HOMA-IR were also higher in the females. Hyperleptinemia was observed in 66,96% of subjects and hypoadiponectinemia was present in 44.35% of subjects. In both men and women, leptin correlated with age (r = 0.2; P = 0.02), BMI (r = 0.572; P HOMA-IR (r = 0.430; P < 0.0001). No significant correlation was observed for adiponectin levels with these variables. Only in women, adiponectin was inversely correlated with fasting glucose (r = -0.423; P < 0.004). These data confirm previous descriptions of leptin but suggest that variations in factors determining serum adiponectin levels observed between ethnicities could also been seen between populations from the same ethnicity. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  8. Trichosanthes cucumerina extracts enhance glucose uptake and regulate adiponectin and leptin concentrations in 3T3-L1 adipocytes model

    Directory of Open Access Journals (Sweden)

    Sassi, A.,

    2017-10-01

    Full Text Available Trichosanthes cucumerina (Cucurbitaceae commonly known as Snake gourd or Labu Ular is considered the largest genre in the Cucurbitaceae family and is mainly found in the southeast areas of Asia. It has been used in Ayurvedic medicine as a treatment for certain diseases such as Diabetes mellitus, but these acclaims lack scientific-based evidence. In this study, water and ethanol extracts of three parts of Trichosanthes cucumerina namely; whole vegetable, peels, and seeds, were assessed for toxicity through a cell viability assay using 3T3-L1 pre-adipocytes model which revealed a maximum toleration concentration of 0.063 mg/mL. The extracts were further tested on adipocytes’ differentiation and positively showed a stimulation of lipid droplets formation during adipogenesis and significantly (p<0.001 increased glycerol release levels (75.34±3.69 μg/ml during adipolysis. The extracts also significantly (p<0.001 promoted the uptake of glucose into the cells (2636.22±91.33 Bq in an action similar to that of insulin. Similar results were observed during ELISA assay with a significant increase (p<0.001 in adiponectin concentrations (3593.1±225.25 ng/mL and a decrease in leptin concentrations (23870±5066.07 pg/mL. The present study results indicate a beneficial effect of Trichosanthes cucumerina extracts on adipogenesis, adipolysis and glucose uptake, in addition to a regulation of adiponectin and leptin concentrations in 3T3-L1 adipocytes which can be of clinical importance in energy regulation which is a key factor in treating diabetes, obesity, and metabolic syndrome.

  9. Circulating Irisin Levels Are Not Regulated by Nutritional Status, Obesity, or Leptin Levels in Rodents.

    Science.gov (United States)

    Quiñones, Mar; Folgueira, Cintia; Sánchez-Rebordelo, Estrella; Al-Massadi, Omar

    2015-01-01

    Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5) that is mainly released by skeletal muscle and was proposed to mediate the beneficial effects of exercise on metabolism. In the present study we aim to investigate the regulation of the circulating levels of irisin in obese animal models (diet-induced obese (DIO) rats and leptin-deficient (ob/ob) mice), as well as the influence of nutritional status and leptin. Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA) and Radioimmunoassay (RIA). Serum irisin levels remained unaltered in DIO rats and ob/ob mice. Moreover, its circulating levels were also unaffected by fasting, leptin deficiency, and exogenous leptin administration in rodents. In spite of these negative results we find a negative correlation between irisin and insulin in DIO animals and a positive correlation between irisin and glucose under short-term changes in nutritional status. Our findings indicate that serum irisin levels are not modulated by different physiological settings associated to alterations in energy homeostasis. These results suggest that in rodents circulating levels of irisin are not involved in the pathophysiology of obesity and could be unrelated to metabolic status; however, further studies should clarify its precise role in states of glucose homeostasis imbalance.

  10. Circulating Irisin Levels Are Not Regulated by Nutritional Status, Obesity, or Leptin Levels in Rodents

    Directory of Open Access Journals (Sweden)

    Mar Quiñones

    2015-01-01

    Full Text Available Irisin is a cleaved and secreted fragment of fibronectin type III domain containing 5 (FNDC5 that is mainly released by skeletal muscle and was proposed to mediate the beneficial effects of exercise on metabolism. In the present study we aim to investigate the regulation of the circulating levels of irisin in obese animal models (diet-induced obese (DIO rats and leptin-deficient (ob/ob mice, as well as the influence of nutritional status and leptin. Irisin levels were measured by Enzyme-Linked Immunosorbent Assay (ELISA and Radioimmunoassay (RIA. Serum irisin levels remained unaltered in DIO rats and ob/ob mice. Moreover, its circulating levels were also unaffected by fasting, leptin deficiency, and exogenous leptin administration in rodents. In spite of these negative results we find a negative correlation between irisin and insulin in DIO animals and a positive correlation between irisin and glucose under short-term changes in nutritional status. Our findings indicate that serum irisin levels are not modulated by different physiological settings associated to alterations in energy homeostasis. These results suggest that in rodents circulating levels of irisin are not involved in the pathophysiology of obesity and could be unrelated to metabolic status; however, further studies should clarify its precise role in states of glucose homeostasis imbalance.

  11. Bariatric surgery in morbidly obese insulin resistant humans normalises insulin signalling but not insulin-stimulated glucose disposal.

    Directory of Open Access Journals (Sweden)

    Mimi Z Chen

    Full Text Available Weight-loss after bariatric surgery improves insulin sensitivity, but the underlying molecular mechanism is not clear. To ascertain the effect of bariatric surgery on insulin signalling, we examined glucose disposal and Akt activation in morbidly obese volunteers before and after Roux-en-Y gastric bypass surgery (RYGB, and compared this to lean volunteers.The hyperinsulinaemic euglycaemic clamp, at five infusion rates, was used to determine glucose disposal rates (GDR in eight morbidly obese (body mass index, BMI=47.3 ± 2.2 kg/m(2 patients, before and after RYGB, and in eight lean volunteers (BMI=20.7 ± 0.7 kg/m2. Biopsies of brachioradialis muscle, taken at fasting and insulin concentrations that induced half-maximal (GDR50 and maximal (GDR100 GDR in each subject, were used to examine the phosphorylation of Akt-Thr308, Akt-473, and pras40, in vivo biomarkers for Akt activity.Pre-operatively, insulin-stimulated GDR was lower in the obese compared to the lean individuals (P<0.001. Weight-loss of 29.9 ± 4 kg after surgery significantly improved GDR50 (P=0.004 but not GDR100 (P=0.3. These subjects still remained significantly more insulin resistant than the lean individuals (p<0.001. Weight loss increased insulin-stimulated skeletal muscle Akt-Thr308 and Akt-Ser473 phosphorylation, P=0.02 and P=0.03 respectively (MANCOVA, and Akt activity towards the substrate PRAS40 (P=0.003, MANCOVA, and in contrast to GDR, were fully normalised after the surgery (obese vs lean, P=0.6, P=0.35, P=0.46, respectively.Our data show that although Akt activity substantially improved after surgery, it did not lead to a full restoration of insulin-stimulated glucose disposal. This suggests that a major defect downstream of, or parallel to, Akt signalling remains after significant weight-loss.

  12. Combining insulins for optimal blood glucose control in type 1 and 2 diabetes: focus on insulin glulisine

    Directory of Open Access Journals (Sweden)

    Heather Ulrich

    2007-07-01

    Full Text Available Heather Ulrich1,4, Benjamin Snyder1,Satish K Garg1,2,31Barbara Davis Center for Childhood Diabetes; 2Department of Medicine; 3Pediatrics; 4Department of Clinical Pharmacy, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, Denver, CO, USAAbstract: Normalization of blood glucose is essential for the prevention of diabetes mellitus (DM-related microvascular and macrovascular complications. Despite substantial literature to support the benefits of glucose lowering and clear treatment targets, glycemic control remains suboptimal for most people with DM in the United States. Pharmacokinetic limitations of conventional insulins have been a barrier to achieving treatment targets secondary to adverse effects such as hypoglycemia and weight gain. Recombinant DNA technology has allowed modification of the insulin molecule to produce insulin analogues that overcome these pharmacokinetic limitations. With time action profiles that more closely mimic physiologic insulin secretion, rapid acting insulin analogues (RAAs reduce post-prandial glucose excursions and hypoglycemia when compared to regular human insulin (RHI. Insulin glulisine (Apidra® is a rapid-acting insulin analogue created by substituting lysine for asparagine at position B3 and glutamic acid for lysine at position B29 on the B chain of human insulin. The quick absorption of insulin glulisine more closely reproduces physiologic first-phase insulin secretion and its rapid acting profile is maintained across patient subtypes. Clinical trials have demonstrated comparable or greater efficacy of insulin glulisine versus insulin lispro or RHI, respectively. Efficacy is maintained even when insulin glulisine is administered post-meal. In addition, glulisine appears to have a more rapid time action profile compared with insulin lispro across various body mass indexes (BMIs. The safety and tolerability profile of insulin glulisine is also comparable to that of insulin

  13. Changes in serum leptin level in patients with diabetic retinopathy

    International Nuclear Information System (INIS)

    Yu Jing; Cao Huiling

    2003-01-01

    Objective: To explore the regulation of changes in serum leptin level in patients with diabetic retinopathy. Methods: The 120 participating subjects were of four groups: healthy controls, diabetic patients without retinopathy, patients with NPDR and patients with PDR, each group consisted of 18 males and 12 females with comparable BMI. The levels of serum leptin, IVC, insulin and blood glucose of these patients were measured and the correlation between serum leptin level and other parameters was analysed. Results: The level of serum leptin in controls, diabetic patients without retinopathy, patients with NPDR and patients with PDR were 6.91 ± 1.87 μg/L, 7,83 ±2.11 μg/L, 9.56 ± 2.43 μg/L and 11.69 ± 2.57 μg/L respectively. The patients with PDR had higher serum leptin levels than patients with NPDR (t=2.15, p < 0.05), diabetic patients without retinopathy (t = 2.71, p < 0.01), and controls (t = 3.50, p < 0.001), the patients with NPDR had higher serum leptin levels than diabetic patients without retinopathy (t = 2.23, p < 0.05) and controls (t = 2.75, p < 0.01), while the difference in serum leptin was not significant between diabetic patients without retinopathy and controls. The serum level was positively correlated to BMI (r = 0.22, p < 0.05) and FINS (r = 0.28, p < 0.01). Conclusion: Serum leptin level is elevated in patients with diabetic retinopathy and is positively correlated to the severity of the disease

  14. Insulin sensitivity, insulin release and glucagon-like peptide-1 levels in persons with impaired fasting glucose and/or impaired glucose tolerance in the EUGENE2 study

    DEFF Research Database (Denmark)

    Laakso, M; Zilinskaite, J; Hansen, T

    2008-01-01

    AIMS/HYPOTHESIS: We examined the phenotype of individuals with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) with regard to insulin release and insulin resistance. METHODS: Non-diabetic offspring (n=874; mean age 40+/-10.4 years; BMI 26.6+/-4.9 kg/m(2)) of type 2 diabetic...

  15. Consumption of meat is associated with higher fasting glucose and insulin concentrations regardless of glucose and insulin genetic risk scores: a meta-analysis of 50,345 Caucasians

    Science.gov (United States)

    Recent studies suggest that meat intake is associated with diabetes-related phenotypes. However, whether the associations of meat intake and glucose and insulin homeostasis are modified by genes related to glucose and insulin is unknown. We investigated the associations of meat intake and the intera...

  16. Insulin-resistant glucose metabolism in patients with microvascular angina--syndrome X

    DEFF Research Database (Denmark)

    Vestergaard, H; Skøtt, P; Steffensen, R

    1995-01-01

    Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study was to exa......Studies in patients with microvascular angina (MA) or the cardiologic syndrome X have shown a hyperinsulinemic response to an oral glucose challenge, suggesting insulin resistance and a role for increased serum insulin in coronary microvascular dysfunction. The aim of the present study...... was to examine whether patients with MA are insulin-resistant. Nine patients with MA and seven control subjects were studied. All were sedentary and glucose-tolerant. Coronary arteriography was normal in all participants, and exercise-induced coronary ischemia was demonstrated in all MA patients. A euglycemic...... metabolism (8.4 +/- 0.9 v 12.5 +/- 1.3 mg.kg FFM-1.min-1, P

  17. Insulin dynamics and biochemical markers for predicting impaired glucose tolerance in obese Thai youth.

    Science.gov (United States)

    Tirabanchasak, Sirapassorn; Siripunthana, Sukumarn; Supornsilchai, Vichit; Wacharasindhu, Suttipong; Sahakitrungruang, Taninee

    2015-09-01

    Subjects with impaired glucose tolerance (IGT) are at risk for type 2 diabetes mellitus (T2DM) and cardiovascular disease. The predictors of IGT in obese youth are not well described. We studied 115 obese Thai children who underwent an oral glucose tolerance test (OGTT). Plasma glucose and insulin levels were calculated for assessment of β-cell function. Hemoglobin A1c (HbA1c), lipid profile, and clinical parameters were also used to determine predictors of IGT. We found that three patients had T2DM and 30 subjects had IGT. IGT patients had significantly higher fasting glucose (FG), 1-h postload glucose, 2-h postload insulin, and lower whole-body insulin sensitivity indices than in normal glucose tolerance subjects whereas other indices were comparable. By ROC curve analyses, 1-h postload glucose was the best predictor of IGT, but FG or HbA1c represented a poor diagnostic tool for prediabetes screening. Subjects with 1-h OGTT glucose > 155 mg/dL had significantly lower high-density lipoprotein levels, lower insulin sensitivity, and more insulin resistance than those with 1-h postload glucose of ≤ 155 mg/dL. Abnormal glucose tolerance is highly prevalent in obese Thai youth. Several fasting indices and HbA1c fail to predict IGT. An 1-h OGTT glucose of > 155 mg/dL appears to be more associated with adverse insulin dynamics and metabolic profile than 2-h postload glucose.

  18. Central leptin gene therapy ameliorates diabetes type 1 and 2 through two independent hypothalamic relays; a benefit beyond weight and appetite regulation.

    Science.gov (United States)

    Kalra, Satya P

    2009-10-01

    Although its role in energy homeostasis is firmly established, the evidence accumulated over a decade linking the adipocyte leptin-hypothalamus axis in the pathogenesis of diabetes mellitus has received little attention in the contemporary thinking. In this context various lines of evidence are collated here to show that (1) under the direction of leptin two independent relays emanating from the hypothalamus restrain insulin secretion from the pancreas and mobilize peripheral organs--liver, skeletal muscle and brown adipose tissue--to upregulate glucose disposal, and (2), leptin insufficiency in the hypothalamus produced by either leptinopenia or restriction of leptin transport across the blood brain barrier due to hyperleptinemia of obesity and aging, initiate antecedent pathophysiological sequalae of diabetes type 1 and 2. Further, we document here the efficacy of leptin replenishment in vivo, especially by supplying it to the hypothalamus with the aid of gene therapy, in preventing the antecedent pathophysiological sequalae--hyperinsulinemia, insulin resistance and hyperglycemia--in various animal models and clinical paradigms of diabetes type 1 and 2 with or without attendant obesity. Overall, the new insights on the long-lasting antidiabetic potential of two independent hypothalamic relays engendered by central leptin gene therapy and the preclinical safety indicators in rodents warrant further validation in subhuman primates and humans.

  19. The Unscented Kalman Filter estimates the plasma insulin from glucose measurement.

    Science.gov (United States)

    Eberle, Claudia; Ament, Christoph

    2011-01-01

    Understanding the simultaneous interaction within the glucose and insulin homeostasis in real-time is very important for clinical treatment as well as for research issues. Until now only plasma glucose concentrations can be measured in real-time. To support a secure, effective and rapid treatment e.g. of diabetes a real-time estimation of plasma insulin would be of great value. A novel approach using an Unscented Kalman Filter that provides an estimate of the current plasma insulin concentration is presented, which operates on the measurement of the plasma glucose and Bergman's Minimal Model of the glucose insulin homeostasis. We can prove that process observability is obtained in this case. Hence, a successful estimator design is possible. Since the process is nonlinear we have to consider estimates that are not normally distributed. The symmetric Unscented Kalman Filter (UKF) will perform best compared to other estimator approaches as the Extended Kalman Filter (EKF), the simplex Unscented Kalman Filter (UKF), and the Particle Filter (PF). The symmetric UKF algorithm is applied to the plasma insulin estimation. It shows better results compared to the direct (open loop) estimation that uses a model of the insulin subsystem. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  20. Mathematical model of glucose-insulin homeostasis in healthy rats.

    Science.gov (United States)

    Lombarte, Mercedes; Lupo, Maela; Campetelli, German; Basualdo, Marta; Rigalli, Alfredo

    2013-10-01

    According to the World Health Organization there are over 220 million people in the world with diabetes and 3.4 million people died in 2004 as a consequence of this pathology. Development of an artificial pancreas would allow to restore control of blood glucose by coupling an infusion pump to a continuous glucose sensor in the blood. The design of such a device requires the development and application of mathematical models which represent the gluco-regulatory system. Models developed by other research groups describe very well the gluco-regulatory system but have a large number of mathematical equations and require complex methodologies for the estimation of its parameters. In this work we propose a mathematical model to study the homeostasis of glucose and insulin in healthy rats. The proposed model consists of three differential equations and 8 parameters that describe the variation of: blood glucose concentration, blood insulin concentration and amount of glucose in the intestine. All parameters were obtained by setting functions to the values of glucose and insulin in blood obtained after oral glucose administration. In vivo and in silico validations were performed. Additionally, a qualitative analysis has been done to verify the aforementioned model. We have shown that this model has a single, biologically consistent equilibrium point. This model is a first step in the development of a mathematical model for the type I diabetic rat. Copyright © 2013 Elsevier Inc. All rights reserved.

  1. A palatable hyperlipidic diet causes obesity and affects brain glucose metabolism in rats

    Directory of Open Access Journals (Sweden)

    Motoyama Caio SM

    2011-09-01

    Full Text Available Abstract Background We have previously shown that either the continuous intake of a palatable hyperlipidic diet (H or the alternation of chow (C and an H diet (CH regimen induced obesity in rats. Here, we investigated whether the time of the start and duration of these feeding regimens are relevant and whether they affect brain glucose metabolism. Methods Male Wistar rats received C, H, or CH diets during various periods of their life spans: days 30-60, days 30-90, or days 60-90. Experiments were performed the 60th or the 90th day of life. Rats were killed by decapitation. The glucose, insulin, leptin plasma concentration, and lipid content of the carcasses were determined. The brain was sliced and incubated with or without insulin for the analysis of glucose uptake, oxidation, and the conversion of [1-14C]-glucose to lipids. Results The relative carcass lipid content increased in all of the H and CH groups, and the H30-60 and H30-90 groups had the highest levels. Groups H30-60, H30-90, CH30-60, and CH30-90 exhibited a higher serum glucose level. Serum leptin increased in all H groups and in the CH60-90 and CH30-90 groups. Serum insulin was elevated in the H30-60, H60-90, CH60-90, CH30-90 groups. Basal brain glucose consumption and hypothalamic insulin receptor density were lower only in the CH30-60 group. The rate of brain lipogenesis was increased in the H30-90 and CH30-90 groups. Conclusion These findings indicate that both H and CH diet regimens increased body adiposity independent treatment and the age at which treatment was started, whereas these diets caused hyperglycemia and affected brain metabolism when started at an early age.

  2. Inhaled insulin for controlling blood glucose in patients with diabetes

    Directory of Open Access Journals (Sweden)

    Bernard L Silverman

    2008-01-01

    Full Text Available Bernard L Silverman1, Christopher J Barnes2, Barbara N Campaigne3, Douglas B Muchmore31Alkermes, Inc, Cambridge, MA, USA; 2i3 Statprobe, Ann Arbor, MI; 3Eli Lilly and Company, Indianapolis, IN, USAAbstract: Diabetes mellitus is a significant worldwide health problem, with the incidence of type 2 diabetes increasing at alarming rates. Insulin resistance and dysregulated blood glucose control are established risk factors for microvascular complications and cardiovascular disease. Despite the recognition of diabetes as a major health issue and the availability of a growing number of medications designed to counteract its detrimental effects, real and perceived barriers remain that prevent patients from achieving optimal blood glucose control. The development and utilization of inhaled insulin as a novel insulin delivery system may positively influence patient treatment adherence and optimal glycemic control, potentially leading to a reduction in cardiovascular complications in patients with diabetes.Keywords: diabetes, inhaled insulin, cardiovascular disease, blood glucose

  3. Metabolic Risk Susceptibility in Men Is Partially Related to Adiponectin/Leptin Ratio

    Directory of Open Access Journals (Sweden)

    Gloria Lena Vega

    2013-01-01

    Full Text Available Background. High adiponectin/leptin ratio may be protective from metabolic risks imparted by high triglyceride, low HDL, and insulin resistance. Methods. This cross-sectional study examines plasma adipokine levels in 428 adult men who were subgrouped according to low (<6.5 μg/mLand high (≥6.5 μg/mLadiponectin levels or a low or high ratio of adiponectin/leptin. Results. Men with high adiponectin/leptin ratio had lower plasma triglyceride and higher HDL cholesterol than those with low ratio. Similarly, those with high adiponectin/leptin ratio had lower TG/HDL cholesterol ratio and HOMA2-IR than those with low ratio. In contrast, levels of adiponectin or the ratio of adiponectin/leptin did not associate with systolic blood pressure. But the ratio of adiponectin/leptin decreased progressively with the increase in the number of risk factors for metabolic syndrome. Conclusion. Adipokine levels may reflect adipose tissue triglyceride storage capacity and insulin sensitivity. Leptin is an index of fat mass, and adiponectin is a biomarker of triglyceride metabolism and insulin sensitivity. Men with high adiponectin/leptin ratios have better triglyceride profile and insulin sensitivity than men with a low ratio regardless of waist girth.

  4. Rational Design of Glucose-Responsive Insulin Using Pharmacokinetic Modeling.

    Science.gov (United States)

    Bakh, Naveed A; Bisker, Gili; Lee, Michael A; Gong, Xun; Strano, Michael S

    2017-11-01

    A glucose responsive insulin (GRI) is a therapeutic that modulates its potency, concentration, or dosing of insulin in relation to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. Current GRI design lacks a theoretical basis on which to base fundamental design parameters such as glucose reactivity, dissociation constant or potency, and in vivo efficacy. In this work, an approach to mathematically model the relevant parameter space for effective GRIs is induced, and design rules for linking GRI performance to therapeutic benefit are developed. Well-developed pharmacokinetic models of human glucose and insulin metabolism coupled to a kinetic model representation of a freely circulating GRI are used to determine the desired kinetic parameters and dosing for optimal glycemic control. The model examines a subcutaneous dose of GRI with kinetic parameters in an optimal range that results in successful glycemic control within prescribed constraints over a 24 h period. Additionally, it is demonstrated that the modeling approach can find GRI parameters that enable stable glucose levels that persist through a skipped meal. The results provide a framework for exploring the parameter space of GRIs, potentially without extensive, iterative in vivo animal testing. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lepob/ob mice

    International Nuclear Information System (INIS)

    Sekiya, Motohiro; Yahagi, Naoya; Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko; Yagyu, Hiroaki; Gotoda, Takanari; Nagai, Ryozo; Shimano, Hitoshi; Yamada, Nobuhiro

    2009-01-01

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic β-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep ob/ob /HSL -/- ) and explored the role of HSL in pancreatic β-cells in the setting of obesity. Lep ob/ob /HSL -/- developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep ob/ob /HSL +/+ in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep +/+ background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep ob/ob islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep ob/ob mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  6. Insulin sensitivity and secretion in Arab Americans with glucose intolerance.

    Science.gov (United States)

    Salinitri, Francine D; Pinelli, Nicole R; Martin, Emily T; Jaber, Linda A

    2013-12-01

    This study examined the pathophysiological abnormalities in Arab Americans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). Homeostasis model assessment of insulin resistance (HOMA-IR), homeostasis model assessment of insulin secretion (HOMA-%β), and the Matsuda Insulin Sensitivity Index composite (ISIcomposite) were calculated from the fasting and stimulated glucose and insulin concentrations measured during the oral glucose tolerance test in a population-based, representative, cross-sectional sample of randomly selected Arab Americans. In total, 497 individuals (42±14 years old; 40% males; body mass index [BMI], 29±6 kg/m(2)) were studied. Multivariate linear regression models were performed to compare HOMA-IR, HOMA-%β, and ISIcomposite among individuals with normal glucose tolerance (NGT) (n=191) versus isolated IFG (n=136), isolated IGT (n=22), combined IFG/IGT (n=43), and diabetes (n=105). Compared with individuals with NGT (2.9±1.6), HOMA-IR progressively increased in individuals with isolated IFG (4.8±2.7, Psex and BMI, these associations remained unchanged. Whole-body insulin sensitivity as measured by ISIcomposite was significantly lower in individuals with isolated IFG (3.9±2.3, Psex, and BMI, isolated IFG (146.6±80.2) was also significantly associated with a decline in HOMA-%β relative to NGT (P=0.005). This study suggests that differences in the underlying metabolic defects leading to diabetes in Arab Americans with IFG and/or IGT exist and may require different strategies for the prevention of diabetes.

  7. Variability of insulin-stimulated myocardial glucose uptake in healthy elderly subjects

    DEFF Research Database (Denmark)

    Kofoed, Klaus F; Hove, Jens D; Freiberg, Jacob

    2002-01-01

    The aim of this study was to assess regional and global variability of insulin-stimulated myocardial glucose uptake in healthy elderly subjects and to evaluate potentially responsible factors. Twenty men with a mean age of 64 years, no history of cardiovascular disease, and normal blood pressure...... rest and hyperaemic blood flow during dipyridamole infusion were measured with nitrogen-13 ammonia and positron emission tomography in 16 left ventricular myocardial segments. Intra-individual and inter-individual variability of insulin-stimulated myocardial glucose uptake [relative dispersion...... = (standard deviation/mean)] was 13% and 29% respectively. Although inter-individual variability of glucose uptake and blood flow at rest was of the same magnitude, no correlation was found between these measures. Regional and global insulin-stimulated myocardial glucose uptake correlated linearly with whole...

  8. Insulin-sensitive phospholipid signaling systems and glucose transport. Update II.

    Science.gov (United States)

    Farese, R V

    2001-04-01

    Insulin provokes rapid changes in phospholipid metabolism and thereby generates biologically active lipids that serve as intracellular signaling factors that regulate glucose transport and glycogen synthesis. These changes include: (i) activation of phosphatidylinositol 3-kinase (PI3K) and production of PIP3; (ii) PIP3-dependent activation of atypical protein kinase Cs (PKCs); (iii) PIP3-dependent activation of PKB; (iv) PI3K-dependent activation of phospholipase D and hydrolysis of phosphatidylcholine with subsequent increases in phosphatidic acid (PA) and diacylglycerol (DAG); (v) PI3K-independent activation of glycerol-3-phosphate acylytansferase and increases in de novo synthesis of PA and DAG; and (vi) activation of DAG-sensitive PKCs. Recent findings suggest that atypical PKCs and PKB serve as important positive regulators of insulin-stimulated glucose metabolism, whereas mechanisms that result in the activation of DAG-sensitive PKCs serve mainly as negative regulators of insulin signaling through PI3K. Atypical PKCs and PKB are rapidly activated by insulin in adipocytes, liver, skeletal muscles, and other cell types by a mechanism requiring PI3K and its downstream effector, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), which, in conjunction with PIP3, phosphorylates critical threonine residues in the activation loops of atypical PKCs and PKB. PIP3 also promotes increases in autophosphorylation and allosteric activation of atypical PKCs. Atypical PKCs and perhaps PKB appear to be required for insulin-induced translocation of the GLUT 4 glucose transporter to the plasma membrane and subsequent glucose transport. PKB also appears to be the major regulator of glycogen synthase. Together, atypical PKCs and PKB serve as a potent, integrated PI3K/PDK-1-directed signaling system that is used by insulin to regulate glucose metabolism.

  9. PROXIMITY TO DELIVERY ALTERS INSULIN SENSITIVITY AND GLUCOSE METABOLISM IN PREGNANT MICE

    OpenAIRE

    Musial, Barbara; Fernandez-Twinn, Denise S.; Vaughan, Owen R.; Ozanne, Susan E.; Voshol, Peter; Sferruzzi-Perri, Amanda N.; Fowden, Abigail L.

    2016-01-01

    In late pregnancy, maternal insulin resistance occurs to support fetal growth but little is known about insulin-glucose dynamics close to delivery. This study measured insulin sensitivity in mice in late pregnancy, day (D) 16, and near term, D19, (term 20.5D). Non-pregnant (NP) and pregnant mice were assessed for metabolite and hormone concentrations, body composition by dual energy X-ray absorptiometry, tissue insulin signalling protein abundance by Western blotting, glucose tolerance and ut...

  10. Refractory hyperglycaemia induced by glucose-insulin-potassium infusion in acute myocardial infarction

    NARCIS (Netherlands)

    Svilaas, Tone; van der Horst, I.C.C.; Nijsten, M.W.N.; Zijlstra, F.

    2006-01-01

    Background. Recent randomised clinical trials have not confirmed the beneficial effects of glucose-insulin-potassium (GIK) infusion observed in experimental models of myocardial ischaemia and infarction. Methods. We investigated glucose levels and insulin dose in 107 patients treated with

  11. Radioimmunoassay of Plasma Insulin during Oral Glucose Tolerance Test in Thyrotoxicosis

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hong Kyu; Koh, Chang Soon; Lee, Mun Ho [Seoul National University College of Medicine, Seoul (Korea, Republic of)

    1971-03-15

    Blood glucose and immunoreactive insulin (IRI) were measured during oral glucose tolerance test in 15 thyrotoxic patients and 8 normal controls, to study the glucose metabolism in thyrotoxicosis. Following were the results;1) In thyrotoxicosis, there is noticed late rise and late fall of plasma IRI during oral glucose tolerance test, like as phenomenon of mild diabetes mellitus. 2) When the thyrotoxic patients were divided into normal and abnormal responsive groups after the level of blood glucose by Wilkerson Criteria, no significant difference in plasma IRI levels were noticed between two groups. 3) This result may be interpreted as relative deficiency of insulin secretion from panaceas and suggest genetically related defects.

  12. Exercise Protects Against Defective Insulin Signaling and Insulin Resistance of Glucose Transport in Skeletal Muscle of Angiotensin II-Infused Rat

    Directory of Open Access Journals (Sweden)

    Juthamard Surapongchai

    2018-04-01

    Full Text Available Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII infusion.Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR groups. Following a 6-week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR, insulin receptor substrate 1 (IRS-1, Akt, Akt substrate of 160 kDa (AS160, AMPKα, c-Jun NH2-terminal kinase (JNK, p38 MAPK, angiotensin converting enzyme (ACE, ANGII type 1 receptor (AT1R, ACE2, Mas receptor (MasR and oxidative stress marker in the soleus muscle, were evaluated.Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43% and decreases in oxidative stress marker (31% and insulin-induced p38 MAPK Thr180/Tyr182 (45% and SAPK/JNK Thr183/Tyr185 (25%, without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles.Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII.

  13. Restraint stress impairs glucose homeostasis through altered insulin ...

    African Journals Online (AJOL)

    The study investigated the potential alteration in the level of insulin and adiponectin, as well as the expression of insulin receptors (INSR) and glucose transporter 4 GLUT-4 in chronic restraint stress rats. Sprague-Dawley rats were randomly divided into two groups: the control group and stress group in which the rats were ...

  14. Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women.

    Directory of Open Access Journals (Sweden)

    Maria A Matuszek

    Full Text Available To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities.Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians.There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000, triglycerides (P = .050, low density lipoprotein (P = .009 and non-fasting blood glucose (15 min (P = .024 were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC. Non-fasting insulin in South Asians (15-120 min, in South East/East Asians (60-120 min, and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006. The molar ratio of C-peptide AUC/Insulin AUC (P = .045 and adiponectin (P = .037 were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022 and rs10830963 (P = 0.009, which are both near the melatonin receptor MTNR1B.Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

  15. Increased Insulin following an Oral Glucose Load, Genetic Variation near the Melatonin Receptor MTNR1B, but No Biochemical Evidence of Endothelial Dysfunction in Young Asian Men and Women.

    Science.gov (United States)

    Matuszek, Maria A; Anton, Angelyn; Thillainathan, Sobana; Armstrong, Nicola J

    2015-01-01

    To identify biochemical and genetic variation relating to increased risk of developing type 2 diabetes mellitus and cardiovascular disease in young, lean male and female adults of different ethnicities. Fasting blood and urine and non-fasting blood following oral glucose intake were analysed in 90 Caucasians, South Asians and South East/East Asians. There were no differences in age, birthweight, blood pressure, body mass index, percent body fat, total energy, percentage of macronutrient intake, microalbumin, leptin, cortisol, adrenocorticotropic hormone, nitric oxide metabolites, C-reactive protein, homocysteine, tumor necrosis factor-α, interleukin-6, von Willebrand factor, vascular cell adhesion molecule-1, plasminogen activator inhibitor-1, and tissue plasminogen activator. Fasting total cholesterol (P = .000), triglycerides (P = .050), low density lipoprotein (P = .009) and non-fasting blood glucose (15 min) (P = .024) were elevated in South Asians compared with Caucasians, but there was no significant difference in glucose area under curve (AUC). Non-fasting insulin in South Asians (15-120 min), in South East/East Asians (60-120 min), and insulin AUC in South Asians and South East/East Asians, were elevated compared with Caucasians (P≤0.006). The molar ratio of C-peptide AUC/Insulin AUC (P = .045) and adiponectin (P = .037) were lower in South Asians compared with Caucasians. A significant difference in allele frequency distributions in Caucasians and South Asians was found for rs2166706 (P = 0.022) and rs10830963 (P = 0.009), which are both near the melatonin receptor MTNR1B. Elevated non-fasting insulin exists in young South Asians of normal fasting glucose and insulin. Hepatic clearance of insulin may be reduced in South Asians. No current biochemical evidence exists of endothelial dysfunction at this stage of development. MTNR1B signalling may be a useful therapeutic target in Asian populations in the prevention of type 2 diabetes mellitus.

  16. Solutes transport characteristics in peritoneal dialysis: variations in glucose and insulin serum levels.

    Science.gov (United States)

    da Silva, Dirceu R; Figueiredo, Ana E; Antonello, Ivan C; Poli de Figueiredo, Carlos E; d'Avila, Domingos O

    2008-01-01

    Differences in small solutes transport rate (SSTR) during peritoneal dialysis (PD) may affect water and solutes removal. Patients with high SSTR must rely on shorter dwell times and increased dialysate glucose concentrations to keep fluid balance. Glucose absorption during peritoneal dialysis (PD), besides affecting glucose and insulin metabolism, may induce weight gain. The study aimed at examining acute glucose and insulin serum level changes and other potential relationships in PD patients with diverse SSTR. This cross-sectional study used a modified peritoneal equilibration test (PET) that enrolled 34 prevalent PD patients. Zero, 15, 30, 60, 120, 180, and 240-minute glucose and insulin serum levels were measured. Insulin resistance index was assessed by the homeostasis model assessment (HOMA-IR) formula. SSTR categories were classified by quartiles of the four-hour dialysate/serum creatinine ratio (D(4)/P(Cr)). Demographic and clinical variables were evaluated, and the body mass index (BMI) was estimated. Correlations among variables of interest and categories of SSTR were explored. Glucose serum levels were significantly different at 15, 30, and 60 minutes between high and low SSTR categories (p = 0.014, 0.009, and 0.022). Increased BMI (25.5 +/- 5.1) and insulin resistance [HOMA-IR = 2.60 (1.40-4.23)] were evidenced overall. Very strong to moderate correlations between insulin levels along the PET and HOMA-IR (r = 0.973, 0.834, 0.766, 0.728, 0.843, 0.857, 0.882) and BMI (r = 0.562, 0.459, 0.417, 0.370, 0.508, 0.514, 0.483) were disclosed. CONCLUSIONS; Early glucose serum levels were associated with SSTR during a PET. Overweight or obesity and insulin resistance were prevalent. An association between insulin serum levels and BMI was demonstrated.

  17. Effect of Artemisia dracunculus Administration on Glycemic Control, Insulin Sensitivity, and Insulin Secretion in Patients with Impaired Glucose Tolerance.

    Science.gov (United States)

    Méndez-Del Villar, Miriam; Puebla-Pérez, Ana M; Sánchez-Peña, María J; González-Ortiz, Luis J; Martínez-Abundis, Esperanza; González-Ortiz, Manuel

    2016-05-01

    To evaluate the effect of Artemisia dracunculus on glycemic control, insulin sensitivity, and insulin secretion in patients with impaired glucose tolerance (IGT). A randomized, double blind, placebo-controlled clinical trial was performed in 24 patients with diagnosis of IGT. Before and after the intervention, glucose and insulin levels were measured every 30 min for 2 h after a 75-g dextrose load, along with glycated hemoglobin A1c (A1C) and lipid profile. Twelve patients received A. dracunculus (1000 mg) before breakfast and dinner for 90 days; the remaining 12 patients received placebo. Area under the curve (AUC) of glucose and insulin, total insulin secretion, first phase of insulin secretion, and insulin sensitivity were calculated. Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests were used for statistical analyses. The institutional ethics committee approved the protocol. After A. dracunculus administration, there were significant decreases in systolic blood pressure (SBP; 120.0 ± 11.3 vs. 113.0 ± 11.2 mmHg, P AUC of insulin (56,136.0 ± 27,426.0 vs. 44,472.0 ± 23,370.0 pmol/L, P AUC of insulin, and total insulin secretion with a significant increase in HDL-C levels.

  18. Coffee Consumption Attenuates Insulin Resistance and Glucose ...

    African Journals Online (AJOL)

    olayemitoyin

    Alzheimer's disease (CBS 2012), dementia (Health news 2012) and ... the effects of coffee on insulin resistance and glucose tolerance as ..... mortality among patients with type 2 diabetes. ... transporter family: Structure, function and tissue-.

  19. Circulating leptin concentrations do not distinguish menstrual status in exercising women.

    Science.gov (United States)

    Corr, M; De Souza, M J; Toombs, R J; Williams, N I

    2011-03-01

    Low concentrations of leptin secondary to low body fat or other modulators are thought to be a key signal whereby an energy deficit suppresses the reproductive axis in exercising women resulting in functional hypothalamic amenorrhea (FHA). The purpose of this study was to first examine leptin concentrations in exercising women with and without FHA to address whether there is a threshold concentration of leptin below which reproductive function is suppressed. Secondly, we examined the role of adiposity and other possible modulators of leptin to ascertain whether leptin regulation differs depending on reproductive status. This study assessed 50 exercising, premenopausal women (aged 18-30 years) over the course of one menstrual cycle (eumenorrheic women) or one 28-day monitoring period (amenorrheic women). Quantification of daily urinary ovarian steroids and menstrual history were used to determine menstrual status. Body composition was assessed using dual energy X-ray absorptiometry, and leptin was determined by enzyme-linked immunoassay. Key modulators of leptin such as serum insulin concentration, carbohydrate intake, glucose availability, indirect indices of sympathetic nervous activity and other factors were assessed using linear regression. Percentage body fat (%BF) (21.0 ± 1.0 versus 26.8 ± 0.7%; P exercising women with amenorrhea (ExAmen; n = 24) compared with the exercising ovulatory women (ExOvul; n = 26). However, the ranges in leptin were similar for each group (ExAmen: 0.30-16.98 ng/ml; ExOvul: 2.57-18.28 ng/ml), and after adjusting for adiposity the difference in leptin concentration was no longer significant. Significant predictors of log leptin in ExAmen included %BF (β = 0.826, P exercising women, but the modulation of leptin concentrations may differ depending on reproductive status.

  20. Valsartan Improves β-Cell Function and Insulin Sensitivity in Subjects With Impaired Glucose Metabolism

    Science.gov (United States)

    van der Zijl, Nynke J.; Moors, Chantalle C.M.; Goossens, Gijs H.; Hermans, Marc M.H.; Blaak, Ellen E.; Diamant, Michaela

    2011-01-01

    OBJECTIVE Recently, the Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research Trial demonstrated that treatment with the angiotensin receptor blocker (ARB) valsartan for 5 years resulted in a relative reduction of 14% in the incidence of type 2 diabetes in subjects with impaired glucose metabolism (IGM). We investigated whether improvements in β-cell function and/or insulin sensitivity underlie these preventive effects of the ARB valsartan in the onset of type 2 diabetes. RESEARCH DESIGN AND METHODS In this randomized controlled, double-blind, two-center study, the effects of 26 weeks of valsartan (320 mg daily; n = 40) or placebo (n = 39) on β-cell function and insulin sensitivity were assessed in subjects with impaired fasting glucose and/or impaired glucose tolerance, using a combined hyperinsulinemic-euglycemic and hyperglycemic clamp with subsequent arginine stimulation and a 2-h 75-g oral glucose tolerance test (OGTT). Treatment effects were analyzed using ANCOVA, adjusting for center, glucometabolic status, and sex. RESULTS Valsartan increased first-phase (P = 0.028) and second-phase (P = 0.002) glucose-stimulated insulin secretion compared with placebo, whereas the enhanced arginine-stimulated insulin secretion was comparable between groups (P = 0.25). In addition, valsartan increased the OGTT-derived insulinogenic index (representing first-phase insulin secretion after an oral glucose load; P = 0.027). Clamp-derived insulin sensitivity was significantly increased with valsartan compared with placebo (P = 0.049). Valsartan treatment significantly decreased systolic and diastolic blood pressure compared with placebo (P valsartan treatment increased glucose-stimulated insulin release and insulin sensitivity in normotensive subjects with IGM. These findings may partly explain the beneficial effects of valsartan in the reduced incidence of type 2 diabetes. PMID:21330640

  1. Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin

    DEFF Research Database (Denmark)

    Henriksen, Jens Henrik Sahl; Holst, J J; Moller, S

    2000-01-01

    Leptin, a peptide hormone produced mainly in fat cells, appears to be important for the regulation of metabolism, insulin secretion/sensitivity and body weight. Recently, elevated plasma leptin levels have been reported in patients with arterial hypertension. Because a change in circulating leptin...... concentrations in such patients could be caused by altered rates of production or disposal, or both, the aim of the present study was to identify regions of leptin overflow into the bloodstream and of leptin extraction. Patients with arterial hypertension (n=12) and normotensive controls (n=20) were studied...... during catheterization with elective blood sampling from different vascular beds (artery, and renal, hepatic, iliac and cubital veins). Plasma leptin was determined by a radioimmunoassay. Patients with hypertension had significantly elevated levels of circulating leptin (12.8 ng/l, compared with 4.1 ng...

  2. Zinc Status Affects Glucose Homeostasis and Insulin Secretion in Patients with Thalassemia

    Directory of Open Access Journals (Sweden)

    Ellen B. Fung

    2015-06-01

    Full Text Available Up to 20% of adult patients with Thalassemia major (Thal live with diabetes, while 30% may be zinc deficient. The objective of this study was to explore the relationship between zinc status, impaired glucose tolerance and insulin sensitivity in Thal patients. Charts from thirty subjects (16 male, 27.8 ± 9.1 years with Thal were reviewed. Patients with low serum zinc had significantly lower fasting insulin, insulinogenic and oral disposition indexes (all p < 0.05 and elevated glucose response curve, following a standard 75 g oral load of glucose compared to those with normal serum zinc after controlling for baseline (group × time interaction p = 0.048. Longitudinal data in five patients with a decline in serum zinc over a two year follow up period (−19.0 ± 9.6 μg/dL, showed consistent increases in fasting glucose (3.6 ± 3.2 mg/dL and insulin to glucose ratios at 120 min post glucose dose (p = 0.05. Taken together, these data suggest that the frequently present zinc deficiency in Thal patients is associated with decreased insulin secretion and reduced glucose disposal. Future zinc trials will require modeling of oral glucose tolerance test data and not simply measurement of static indices in order to understand the complexities of pancreatic function in the Thal patient.

  3. Therapeutic effects of the allosteric protein tyrosine phosphatase 1B inhibitor KY-226 on experimental diabetes and obesity via enhancements in insulin and leptin signaling in mice

    Directory of Open Access Journals (Sweden)

    Yuma Ito

    2018-05-01

    Full Text Available The anti-diabetic and anti-obesity effects of the allosteric protein tyrosine phosphatase 1B (PTP1B inhibitor 4-(biphenyl-4-ylmethylsulfanylmethyl-N-(hexane-1-sulfonylbenzoylamide (KY-226 were pharmacologically evaluated. KY-226 inhibited human PTP1B activity (IC50 = 0.28 μM, but did not exhibit peroxisome proliferator-activated receptor γ (PPARγ agonist activity. In rodent preadipocytes (3T3-L1, KY-226 up to 10 μM had no effects on adipocyte differentiation, whereas pioglitazone, a PPARγ agonist, markedly promoted it. In human hepatoma-derived cells (HepG2, KY-226 (0.3–10 μM increased the phosphorylated insulin receptor (pIR produced by insulin. In db/db mice, the oral administration of KY-226 (10 and 30 mg/kg/day, 4 weeks significantly reduced plasma glucose and triglyceride levels as well as hemoglobin A1c values without increasing body weight gain, while pioglitazone exerted similar effects with increases in body weight gain. KY-226 attenuated plasma glucose elevations in the oral glucose tolerance test. KY-226 also increased pIR and phosphorylated Akt in the liver and femoral muscle. In high-fat diet-induced obese mice, the oral administration of KY-226 (30 and 60 mg/kg/day, 4 weeks decreased body weight gain, food consumption, and fat volume gain with increases in phosphorylated STAT3 in the hypothalamus. In conclusion, KY-226 exerted anti-diabetic and anti-obesity effects by enhancing insulin and leptin signaling, respectively. Keywords: PTP1B inhibitor, Diabetes, Obesity, Allosteric inhibitor, db/db mouse

  4. Effects of Bisphenol A on glucose homeostasis and brain insulin signaling pathways in male mice.

    Science.gov (United States)

    Fang, Fangfang; Chen, Donglong; Yu, Pan; Qian, Wenyi; Zhou, Jing; Liu, Jingli; Gao, Rong; Wang, Jun; Xiao, Hang

    2015-02-01

    The potential effects of Bisphenol A (BPA) on peripheral insulin resistance have recently gained more attention, however, its functions on brain insulin resistance are still unknown. The aim of the present study was to investigate the effects of BPA on insulin signaling and glucose transport in mouse brain. The male mice were administrated of 100 μg/kg/day BPA or vehicle for 15 days then challenged with glucose and insulin tolerance tests. The insulin levels were detected with radioimmunoassay (RIA), and the insulin signaling pathways were investigated by Western blot. Our results revealed that BPA significantly increased peripheral plasma insulin levels, and decreased the insulin signals including phosphorylated insulin receptor (p-IR), phosphorylated insulin receptor substrate 1 (p-IRS1), phosphorylated protein kinase B (p-AKT), phosphorylated glycogen synthase kinase 3β (p-GSK3β) and phosphorylated extracellular regulated protein kinases (p-ERK1/2) in the brain, though insulin expression in both hippocampus and profrontal cortex was increased. In parallel, BPA exposure might contribute to glucose transport disturbance in the brain since the expression of glucose transporters were markedly decreased. In conclusion, BPA exposure perturbs the insulin signaling and glucose transport in the brain, therefore, it might be a risk factor for brain insulin resistance. Copyright © 2015 Elsevier Inc. All rights reserved.

  5. Analysis of the relationship of leptin, high-sensitivity C-reactive protein, adiponectin, insulin, and uric acid to metabolic syndrome in lean, overweight, and obese young females.

    Science.gov (United States)

    Abdullah, Abdul Ridha; Hasan, Haydar A; Raigangar, Veena L

    2009-02-01

    Over the last decade there has been a steady rise in obesity and co-morbidity, but little is known about the rate of metabolic dysfunction among young adults in the United Arab Emirates. Various factors have been implicated as biomarkers of metabolic syndrome. The objective of this study was to analyze the relationships of leptin, C-reactive protein (CRP), adiponectin, insulin, and uric acid to the metabolic syndrome components in lean, overweight, and obese young females. This was a cross-sectional study of 69 apparently healthy young females, who were classified according to their body mass index (BMI) (kg/m(2)) into three groups: lean (25 and or=30). Estimated biomarkers were: leptin, insulin, adiponectin, high-sensitivity [hs]-CRP, uric acid, blood sugar, high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol, and triglycerides (TG). Anthropometric measures, blood pressure, and homeostasis model assessment-insulin resistance (HOMA-IR) were also measured. Serum leptin, hs-CRP, insulin, and uric acid increased significantly (p syndrome components was found in lean subjects (leptin vs. waist circumference r = 0.48) as opposed to six in the obese group (hs-CRP vs. waist circumference and systolic blood pressure [SBP], r = 0.45 and r = -0.41, respectively; insulin vs. diastolic blood pressure [DBP], r = 0.47; adiponectin vs. blood sugar, r = -0.44; and uric acid vs. waist circumference and TG, r = 0.5 and r = 0.51, respectively). Estimation of the levels of studied biomarkers could be an important tool for early detection of metabolic syndrome before the appearance of its frank components. Uric acid seems to be the most reliable biomarker to identify obese subjects with metabolic syndrome.

  6. Overweight is associated with lower serum leptin in Peruvian Indian than in Caucasian women: A dissociation contributing to low blood pressure?

    Science.gov (United States)

    Lindgärde, F; Söderberg, S; Olsson, T; Ercilla, M B; Correa, L R; Ahrén, B

    2001-03-01

    We tested whether plasma levels of leptin and insulin are associated with the lower blood pressure in women of Peruvian Indian heritage compared with Caucasian women. A total of 181 women from Peru and 85 from Sweden, aged 20 to 60 years, with normal plasma glucose levels participated in the study. Measurements of anthropometry, blood pressure, and blood tests were performed after overnight fasting. Compared with women from Umeå in Sweden, women from Lima, Peru had higher body mass index (BMI) (26.2 +/- 4.9 v 24.4 +/- 3.8 kg/m(2)), waist circumference (85 +/- 11 v 79 +/- 10 cm), lower systolic blood pressure (99 +/- 15 v 114 +/- 14 mm; P <.001) and diastolic blood pressure (67 +/- 7 v 74 +/- 10 mm; P <.001). In addition, they had a reduction of the ratio of plasma leptin to BMI (0.52 +/- 0.22 v 0.61 +/- 0.36; P <.001), greater plasma insulin (80 +/- 42 v 41 +/- 21 pmol/L), but lower plasma glucose (4.2 +/- 0.5 v 5.1 +/- 0.5 mmol/L; P <.001). Furthermore, the 181 women from Lima had higher plasma triglyceride levels (1.5 +/- 0.8 v 1.3 +/- 0.7; P =.039), but lower plasma high-density lipoprotein (HDL)-cholesterol (1.0 +/- 0.2 v 1.5 +/- 0.4 mmol/L; P <.001) and total plasma cholesterol (5.0 +/- 1.1 v 5.9 +/- 1.3 mmol/L; P <.001) levels. Plasma leptin correlated with blood pressure and BMI in both populations (P <.001). In multiple regression analysis, BMI, but not log leptin, emerged as the determinant for systolic blood pressure. We concluded that women living in Lima have significant lower blood pressure levels in association with elevated plasma insulin concentrations, but lower plasma leptin values adjusted for BMI in comparison with women from northern Sweden. This may suggest that the concept of metabolic syndrome is different among women with Peruvian Indian heritage in comparison to a Caucasian population. Copyright 2001 by W.B. Saunders Company

  7. Insulin-dependent glucose metabolism in dairy cows with variable fat mobilization around calving.

    Science.gov (United States)

    Weber, C; Schäff, C T; Kautzsch, U; Börner, S; Erdmann, S; Görs, S; Röntgen, M; Sauerwein, H; Bruckmaier, R M; Metges, C C; Kuhla, B; Hammon, H M

    2016-08-01

    Dairy cows undergo significant metabolic and endocrine changes during the transition from pregnancy to lactation, and impaired insulin action influences nutrient partitioning toward the fetus and the mammary gland. Because impaired insulin action during transition is thought to be related to elevated body condition and body fat mobilization, we hypothesized that over-conditioned cows with excessive body fat mobilization around calving may have impaired insulin metabolism compared with cows with low fat mobilization. Nineteen dairy cows were grouped according to their average concentration of total liver fat (LFC) after calving in low [LLFC; LFC 24.4% total fat/DM; n=10) fat-mobilizing cows. Blood samples were taken from wk 7 antepartum (ap) to wk 5 postpartum (pp) to determine plasma concentrations of glucose, insulin, glucagon, and adiponectin. We applied euglycemic-hyperinsulinemic (EGHIC) and hyperglycemic clamps (HGC) in wk 5 ap and wk 3 pp to measure insulin responsiveness in peripheral tissue and pancreatic insulin secretion during the transition period. Before and during the pp EGHIC, [(13)C6] glucose was infused to determine the rate of glucose appearance (GlucRa) and glucose oxidation (GOx). Body condition, back fat thickness, and energy-corrected milk were greater, but energy balance was lower in HLFC than in LLFC. Plasma concentrations of glucose, insulin, glucagon, and adiponectin decreased at calving, and this was followed by an immediate increase of glucagon and adiponectin after calving. Insulin concentrations ap were higher in HLFC than in LLFC cows, but the EGHIC indicated no differences in peripheral insulin responsiveness among cows ap and pp. However, GlucRa and GOx:GlucRa during the pp EGHIC were greater in HLFC than in LLFC cows. During HGC, pancreatic insulin secretion was lower, but the glucose infusion rate was higher pp than ap in both groups. Plasma concentrations of nonesterified fatty acids decreased during HGC and EGHIC, but in both

  8. Insulin response to oral glucose in healthy, lean young women and patients with polycystic ovary syndrome.

    Science.gov (United States)

    Kulshreshtha, Bindu; Ganie, Mohammed Ashraf; Praveen, Edavan Pulikkanath; Gupta, Nandita; Lal Khurana, Madan; Seith, Ashu; Dwivedi, Sadanand N; Kumar, Guresh; Ammini, Ariachery C

    2008-11-01

    Insulin resistance and consequent hyperinsulinemia are common among patients with polycystic ovary syndrome (PCOS). Ethnicity and dietary habits affect insulin levels. There is little published information from India on insulin levels in PCOS patients. Thus the present study aimed to determine the insulin response to oral glucose in women with PCOS and healthy women. In a case-control study design, women with PCOS and lean healthy women without a family history of diabetes mellitus underwent oral glucose tolerance testing. Samples were collected at 0, 1 and 2 h after glucose ingestion. Two hundred and eighty-five women with PCOS and 27 lean healthy young women were enrolled into the study. The mean age of controls was 22.8 +/- 4.5 years (range 15-32 years) and their mean body mass index (BMI) was 19.7 +/- 2.6 kg/m(2). Mean blood glucose at 0, 1 and 2 h was 88.2 +/- 7.2, 115.5 +/- 25.5 and 91.8 +/- 20.5 mg/dl, respectively. Corresponding plasma insulin levels were 5.8 +/- 1.1, 32.7 +/- 26.5 and 14.6 +/- 9.6 mIU/l. Peak insulin levels were seen at 1 h and these came down to less than 40% of the peak value by 2 h. Glucose/insulin ratio at 0, 1 and 2 h was 15.6 +/- 3.1, 7.0 +/- 3.1 and 11.4 +/- 7.0. Homeostasis model assessment of insulin resistance (HOMA-IR) was 1.2 +/- 0.2. The age of the PCOS women ranged from 15 to 40 years (mean 23.4 +/- 6.2 years) and their BMI ranged from 16.4 to 50.4 kg/m(2) (mean 27.7 +/- 6.3 kg/m(2)). One hundred and seventy-six (62%) PCOS patients had normal glucose tolerance (NGT), 39 (14%) had impaired fasting glucose (IFG), 49 (17%) had impaired glucose tolerance (IGT) and 21 (7%) had type 2 diabetes mellitus (T2DM). Insulin response was higher in women with PCOS. Peak insulin was observed at 1 h. The difference between 1-h and 2-h post-glucose insulin decreased with worsening glucose tolerance. Both plasma insulin and BMI showed a rising trend from NGT to IFG to IGT. There was no further increase in either insulin or BMI from IGT to T2DM

  9. Maternal serum leptin concentration in gestational diabetes

    Directory of Open Access Journals (Sweden)

    Sedigheh Soheilykhah

    2011-06-01

    Conclusion: Our data showed that serum leptin level was higher in GDM and had a positive correlation with insulin resistance. Our findings suggest that high leptin levels might be a risk factor for GDM and IGT in pregnant women.

  10. Peripheral Blood Transcriptomic Signatures of Fasting Glucose and Insulin Concentrations

    Science.gov (United States)

    Chen, Brian H.; Hivert, Marie-France; Peters, Marjolein J.; Pilling, Luke C.; Hogan, John D.; Pham, Lisa M.; Harries, Lorna W.; Fox, Caroline S.; Bandinelli, Stefania; Dehghan, Abbas; Hernandez, Dena G.; Hofman, Albert; Hong, Jaeyoung; Joehanes, Roby; Johnson, Andrew D.; Munson, Peter J.; Rybin, Denis V.; Singleton, Andrew B.; Uitterlinden, André G.; Ying, Saixia; Melzer, David; Levy, Daniel; van Meurs, Joyce B.J.; Ferrucci, Luigi; Florez, Jose C.; Dupuis, Josée

    2016-01-01

    Genome-wide association studies (GWAS) have successfully identified genetic loci associated with glycemic traits. However, characterizing the functional significance of these loci has proven challenging. We sought to gain insights into the regulation of fasting insulin and fasting glucose through the use of gene expression microarray data from peripheral blood samples of participants without diabetes in the Framingham Heart Study (FHS) (n = 5,056), the Rotterdam Study (RS) (n = 723), and the InCHIANTI Study (Invecchiare in Chianti) (n = 595). Using a false discovery rate q fasting glucose and 433 transcripts associated with fasting insulin levels after adjusting for age, sex, technical covariates, and complete blood cell counts. Among the findings, circulating IGF2BP2 transcript levels were positively associated with fasting insulin in both the FHS and RS. Using 1000 Genomes–imputed genotype data, we identified 47,587 cis-expression quantitative trait loci (eQTL) and 6,695 trans-eQTL associated with the 433 significant insulin-associated transcripts. Of note, we identified a trans-eQTL (rs592423), where the A allele was associated with higher IGF2BP2 levels and with fasting insulin in an independent genetic meta-analysis comprised of 50,823 individuals. We conclude that integration of genomic and transcriptomic data implicate circulating IGF2BP2 mRNA levels associated with glucose and insulin homeostasis. PMID:27625022

  11. Plasma insulin levels are increased by sertraline in rats under oral glucose overload

    Directory of Open Access Journals (Sweden)

    Gomez R.

    2001-01-01

    Full Text Available Recognition and control of depression symptoms are important to increase patient compliance with treatment and to improve the quality of life of diabetic patients. Clinical studies indicate that selective serotonin reuptake inhibitors (SSRI are better antidepressants for diabetic patients than other drugs. However, preclinical trials have demonstrated that not all SSRI reduce plasma glucose levels. In fact, fluoxetine increases and sertraline decreases glycemia in diabetic and non-diabetic rats. In the present study we evaluated plasma insulin levels during fasting and after glucose overload after treatment with sertraline. Adult male Wistar rats were fasted and treated with saline or 30 mg/kg sertraline and submitted or not to glucose overload (N = 10. Blood was collected and plasma insulin was measured. The mean insulin levels were: fasting group: 25.9 ± 3.86, sertraline + fasting group: 31.10 ± 2.48, overload group: 34.1 ± 3.40, and overload + sertraline group: 43.73 ± 5.14 µU/ml. Insulinemia was significantly increased in the overload + sertraline group. There were no differences between the other groups. No difference in glucose/insulin ratios could be detected between groups. The overload + sertraline group was the only one in which a significant number of individuals exceeded the upper confidence limit of insulin levels. This study demonstrates that sertraline increases glucose-stimulated insulin secretion without any change in peripheral insulin sensitivity.

  12. Insulin-stimulated conversion of D-[5-3H] glucose to 3HOH in the perifused isolated rat adipocyte

    International Nuclear Information System (INIS)

    Duckworth, W.C.; Peavy, D.E.; Frechette, P.; Solomon, S.S.

    1986-01-01

    Characteristics of basal and insulin-stimulated glucose utilization by perifused adipocytes have been investigated by measuring the formation of 3 HOH from D-(5- 3 H) glucose. At a glucose concentration of 0.55 mmol/L, basal glucose utilization ranged from 0.5 to 1.0 nmol/min/10(6) cells. Perifused adipocytes showed a maximal response to insulin of a threefold to fourfold increase in the conversion of (5- 3 H) glucose to 3 HOH with a half-maximal response at an insulin concentration of 20 microU/mL. The response to insulin was blocked by phlorizin and cytochalasin B, competitive inhibitors of glucose transport, consistent with an effect of insulin on glucose transport. Insulin increased the Vmax for glucose metabolism but had no effect on the apparent affinity for glucose utilization. The characteristics of glucose utilization and the stimulation of glucose metabolism by insulin in the perifused adipocyte are therefore similar to characteristics previously observed with incubated adipocytes. Because insulin can readily be removed from the system, perifused adipocytes are especially suited for studying the termination of insulin action. The termination of insulin-stimulated glucose metabolism occurred at the same rate in the presence of tracer (1 nmol/L) (5- 3 H)-glucose alone as when 0.55 mmol/L glucose or 2 mmol/L pyruvate were added to the perifusion buffer. The halftime for this process in both cases was approximately 40 minutes. These data suggest that the presence of metabolizable substrate is not required for the termination of the insulin response, but the time course suggests that termination requires more than simply insulin-receptor dissociation

  13. Metabolic surgery for non-obese type 2 diabetes: incretins, adipocytokines, and insulin secretion/resistance changes in a 1-year interventional clinical controlled study.

    Science.gov (United States)

    Geloneze, Bruno; Geloneze, Sylka Rodovalho; Chaim, Elinton; Hirsch, Fernanda Filgueira; Felici, Ana Claudia; Lambert, Giselle; Tambascia, Marcos Antonio; Pareja, José Carlos

    2012-07-01

    To compare duodenal-jejunal bypass (DJB) with standard medical care in nonobese patients with type 2 diabetes and evaluate surgically induced endocrine and metabolic changes. Eighteen patients submitted to a DJB procedure met the following criteria: overweight, diabetes diagnosis less than 15 years, current insulin treatment, residual β-cell function, and absence of autoimmunity. Patients who refused surgical treatment received standard medical care (control group). At baseline, 3, 6, and 12 months after surgery, insulin sensitivity and production of glucagon-like peptide-1 and glucose-insulinotropic polypeptide were assessed during a meal tolerance test. Fasting adipocytokines and dipeptidyl-peptidase-4 concentrations were measured. The mean age of the patients was 50 (5) years, time of diagnosis: 9 (2) years, time of insulin usage: 6 (5) months, fasting glucose: 9.9 (2.5) mmol/dL, and HbA1c (glycosylated hemoglobin) level: 8.9% (1.2%). Duodenal-jejunal bypass group showed greater reductions in fasting glucose (22% vs 6% in control group, P < 0.05) and daily insulin requirement (93% vs 15%, P < 0.01). Twelve patients from DJB group stopped using insulin and showed improvements in insulin sensitivity and β-cell function (P < 0.01), and reductions in glucose-insulinotropic polypeptide levels (P < 0.001), glucagon during the first 30 minutes after meal (P < 0.05), and leptin levels (P < 0.05). Dipeptidyl-peptidase-4 levels increased after surgery (P < 0.01), but glucagon-like peptide-1 levels did not change. Duodenal-jejunal bypass improved insulin sensitivity and β-cell function and reduced glucose-insulinotropic polypeptide, leptin, and glucagon production. Hence, DJB resulted in better glycemic control and reduction in insulin requirement but DJB did not result in remission of diabetes.

  14. [Obesity and leptin association in three Chilean aboriginal populations].

    Science.gov (United States)

    Pérez, F; Santos, J L; Albala, C; Calvillán, M; Carrasco, E

    2000-01-01

    Although there is a clear relationship between body mass index and leptin levels, few authors have addressed the possible influence of ethnic factors on these levels. To measure serum leptin in three different Chilean aboriginal populations. Fasting serum leptin and insulin levels were measured by radioimmunoassay in 345 rural mapuche individuals, 247 rural aymara subjects and 162 urban mapuche subjects. A body mass index of 27.5 kg/m2 was used as cutoff point to classify study subjects. Among the three ethnic groups, women had serum leptin levels three times higher than men. In all three ethnic groups, there was a significant association between leptin levels, body mass index and gender (r2 = 0.32 and 0.5 p mapuche, r2 = 0.32 and 0.5 p mapuche populations). No differences in leptin levels were observed for the interaction between age and insulin. The increments per quartile in leptin levels were lower among mapuche than aymara individuals. Rural mapuche individuals have a high frequency of obesity. However their leptin levels are lower than those of aymara or urban mapuche populations. The higher leptin levels observed in urban mapuche subjects could be due to environmental influences.

  15. Alteration of postprandial glucose and insulin concentrations with meal frequency and composition.

    Science.gov (United States)

    Kanaley, Jill A; Heden, Timothy D; Liu, Ying; Fairchild, Timothy J

    2014-11-14

    A frequent eating pattern may alter glycaemic control and augment postprandial insulin concentrations in some individuals due to the truncation of the previous postprandial period by a subsequent meal. The present study examined glucose, insulin, C-peptide and glucose-dependent insulinotropic peptide (GIP) responses in obese individuals when meals were ingested in a high-frequency pattern (every 2 h, 6M) or in a low-frequency pattern (every 4 h, 3M) over 12 h. It also examined these postprandial responses to high-frequency, high-protein meals (6MHP). In total, thirteen obese subjects completed three 12 h study days during which they consumed 6276 kJ (1500 kcal): (1) 3M - 15 % protein and 65 % carbohydrate; (2) 6M - 15 % protein and 65 % carbohydrate; (3) 6MHP - 45 % protein and 35 % carbohydrate. Blood samples were collected every 10 min and analysed for glucose, insulin, C-peptide and GIP. Insulin total AUC (tAUC) and peak insulin concentrations (Pmeal frequency or composition. In obese subjects, ingestion of meals in a low-frequency pattern does not alter glucose tAUC, but increases postprandial insulin responses. The substitution of carbohydrates with protein in a frequent meal pattern results in tighter glycaemic control and reduced postprandial insulin responses.

  16. A novel insulin receptor-binding protein from Momordica charantia enhances glucose uptake and glucose clearance in vitro and in vivo through triggering insulin receptor signaling pathway.

    Science.gov (United States)

    Lo, Hsin-Yi; Ho, Tin-Yun; Li, Chia-Cheng; Chen, Jaw-Chyun; Liu, Jau-Jin; Hsiang, Chien-Yun

    2014-09-10

    Diabetes, a common metabolic disorder, is characterized by hyperglycemia. Insulin is the principal mediator of glucose homeostasis. In a previous study, we identified a trypsin inhibitor, named Momordica charantia insulin receptor (IR)-binding protein (mcIRBP) in this study, that might interact with IR. The physical and functional interactions between mcIRBP and IR were clearly analyzed in the present study. Photo-cross-linking coupled with mass spectrometry showed that three regions (17-21, 34-40, and 59-66 residues) located on mcIRBP physically interacted with leucine-rich repeat domain and cysteine-rich region of IR. IR-binding assay showed that the binding behavior of mcIRBP and insulin displayed a cooperative manner. After binding to IR, mcIRBP activated the kinase activity of IR by (5.87 ± 0.45)-fold, increased the amount of phospho-IR protein by (1.31 ± 0.03)-fold, affected phosphoinositide-3-kinase/Akt pathways, and consequently stimulated the uptake of glucose in 3T3-L1 cells by (1.36 ± 0.12)-fold. Intraperitoneal injection of 2.5 nmol/kg mcIRBP significantly decreased the blood glucose levels by 20.9 ± 3.2% and 10.8 ± 3.6% in normal and diabetic mice, respectively. Microarray analysis showed that mcIRBP affected genes involved in insulin signaling transduction pathway in mice. In conclusion, our findings suggest that mcIRBP is a novel IRBP that binds to sites different from the insulin-binding sites on IR and stimulates both the glucose uptake in cells and the glucose clearance in mice.

  17. Effect of Human Myotubes-Derived Media on Glucose-Stimulated Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Maria L. Mizgier

    2017-01-01

    Full Text Available Fasting to postprandial transition requires a tight adjustment of insulin secretion to its demand, so tissue (e.g., skeletal muscle glucose supply is assured while hypo-/hyperglycemia are prevented. High muscle glucose disposal after meals is pivotal for adapting to increased glycemia and might drive insulin secretion through muscle-released factors (e.g., myokines. We hypothesized that insulin influences myokine secretion and then increases glucose-stimulated insulin secretion (GSIS. In conditioned media from human myotubes incubated with/without insulin (100 nmol/L for 24 h, myokines were qualitatively and quantitatively characterized using an antibody-based array and ELISA-based technology, respectively. C57BL6/J mice islets and Wistar rat beta cells were incubated for 24 h with control and conditioned media from noninsulin- and insulin-treated myotubes prior to GSIS determination. Conditioned media from insulin-treated versus nontreated myotubes had higher RANTES but lower IL6, IL8, and MCP1 concentration. Qualitative analyses revealed that conditioned media from noninsulin- and insulin-treated myotubes expressed 32 and 23 out of 80 myokines, respectively. Islets incubated with conditioned media from noninsulin-treated myotubes had higher GSIS versus control islets (p<0.05. Meanwhile, conditioned media from insulin-treated myotubes did not influence GSIS. In beta cells, GSIS was similar across conditions. In conclusion, factors being present in noninsulin-stimulated muscle cell-derived media appear to influence GSIS in mice islets.

  18. The interrelation between aPKC and glucose uptake in the skeletal muscle during contraction and insulin stimulation.

    Science.gov (United States)

    Santos, J M; Benite-Ribeiro, S A; Queiroz, G; Duarte, J A

    2014-12-01

    Contraction and insulin increase glucose uptake in skeletal muscle. While the insulin pathway, better characterized, requires activation of phosphoinositide 3-kinase (PI3K) and atypical protein kinase (aPKC), muscle contraction seems to share insulin-activated components to increase glucose uptake. This study aimed to investigate the interrelation between the pathway involved in glucose uptake evoked by insulin and muscle contraction. Isolated muscle of rats was treated with solvent (control), insulin, wortmannin (PI3K inhibitor) and the combination of insulin plus wortmannin. After treatment, muscles were electrically stimulated (contracted) or remained at rest. Glucose transporter 4 (GLUT4) localization, glucose uptake and phospho-aPKC (aPKC activated form) were assessed. Muscle contraction and insulin increased glucose uptake in all conditions when compared with controls not stimulating an effect that was accompanied by an increase in GLUT4 and of phospho-aPKC at the muscle membrane. Contracted muscles treated with insulin did not show additive effects on glucose uptake or aPKC activity compared with the response when these stimuli were applied alone. Inhibition of PI3K blocked insulin effect on glucose uptake and aPKC but not in the contractile response. Thus, muscle contraction seems to stimulate aPKC and glucose uptake independently of PI3K. Therefore, aPKC may be a convergence point and a rate limit step in the pathway by which, insulin and contraction, increase glucose uptake in skeletal muscle. Copyright © 2014 John Wiley & Sons, Ltd.

  19. P21-activated kinase 2 (PAK2) regulates glucose uptake and insulin sensitivity in neuronal cells.

    Science.gov (United States)

    Varshney, Pallavi; Dey, Chinmoy Sankar

    2016-07-05

    P21-activated kinases (PAKs) are recently reported as important players of insulin signaling and glucose homeostasis in tissues like muscle, pancreas and liver. However, their role in neuronal insulin signaling is still unknown. Present study reports the involvement of PAK2 in neuronal insulin signaling, glucose uptake and insulin resistance. Irrespective of insulin sensitivity, insulin stimulation decreased PAK2 activity. PAK2 downregulation displayed marked enhancement of GLUT4 translocation with increase in glucose uptake whereas PAK2 over-expression showed its reduction. Treatment with Akti-1/2 and wortmannin suggested that Akt and PI3K are mediators of insulin effect on PAK2 and glucose uptake. Rac1 inhibition demonstrated decreased PAK2 activity while inhibition of PP2A resulted in increased PAK2 activity, with corresponding changes in glucose uptake. Taken together, present study demonstrates an inhibitory role of insulin signaling (via PI3K-Akt) and PP2A on PAK2 activity and establishes PAK2 as a Rac1-dependent negative regulator of neuronal glucose uptake and insulin sensitivity. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Study on the relationship between serum levels of leptin and microangiopathy in patients with type 2 diabetes

    International Nuclear Information System (INIS)

    Cao Huiling; Guo Dongmei

    2004-01-01

    Objective: To evaluate the relationship between serum levels of leptin and microangiopathy in patients with type 2 diabetes. Methods: Fasting serum leptin (with RIA), insulin (with RIA) and fasting blood glucose (with oxidase method) levels were measured in 30 controls, 30 diabetic patients without microangiopathy and 30 patients with diabetic microangiopathy. Correlations between levels of serum leptin and other parameters were analyzed. Results: The levels of serum leptin in controls, diabetic patients without microangiopathy and patients with diabetic microangiopathy were (7.20 ± 2.11) μg/L, (7.95 ± 3.78) μg/L and (19.26 ± 4.37) μg/L respectively. The patients with diabetic microangiopathy had higher serum leptin levels than those in the diabetic patients without microangiopathy (t=2.18, P<0.05) and controls (t = 2.71, P<0.01), while the serum leptin levels in diabetic patients without microangiopathy were not significantly different from those in controls. The serum leptin levels were positively correlated with BMI and FINS (r=0.29, P<0.05; r=0.34, P<0.01). Conclusion: Serum leptin levels were elevated in patients with diabetic microangiopathy and were closely related with the development of diabetic microangiopathy. (authors)

  1. Leptin as a Marker of Body Fat and Hyperinsulinemia in College Students

    Science.gov (United States)

    Kempf, Angela M.; Strother, Myra L.; Li, Chaoyang; Kaur, Harsohena; Huang, Terry T-K.

    2006-01-01

    Little is known about obesity and insulin resistance in college students. Leptin is a hormone secreted by fat cells and has been shown to strongly correlate with both obesity and insulin resistance in children and adults. We investigated associations of leptin with insulin secretion and action in 119 normal-weight students aged 18-24 years. Leptin…

  2. Proportional Insulin Infusion in Closed-Loop Control of Blood Glucose

    NARCIS (Netherlands)

    Grasman, Johan; Callender, Hannah L.; Mensink, Marco; Pietropaolo, Massimo

    2017-01-01

    A differential equation model is formulated that describes the dynamics of glucose concentration in blood circulation. The model accounts for the intake of food, expenditure of calories and the control of glucose levels by insulin and glucagon. These and other hormones affect the blood glucose level

  3. Severe energy deficit upregulates leptin receptors, leptin signaling, and PTP1B in human skeletal muscle.

    Science.gov (United States)

    Perez-Suarez, Ismael; Ponce-González, Jesús Gustavo; de La Calle-Herrero, Jaime; Losa-Reyna, Jose; Martin-Rincon, Marcos; Morales-Alamo, David; Santana, Alfredo; Holmberg, Hans-Christer; Calbet, Jose A L

    2017-11-01

    In obesity, leptin receptors (OBR) and leptin signaling in skeletal muscle are downregulated. To determine whether OBR and leptin signaling are upregulated with a severe energy deficit, 15 overweight men were assessed before the intervention (PRE), after 4 days of caloric restriction (3.2 kcal·kg body wt -1 ·day -1 ) in combination with prolonged exercise (CRE; 8 h walking + 45 min single-arm cranking/day) to induce an energy deficit of ~5,500 kcal/day, and following 3 days of control diet (isoenergetic) and reduced exercise (CD). During CRE, the diet consisted solely of whey protein ( n = 8) or sucrose ( n = 7; 0.8 g·kg body wt -1 ·day -1 ). Muscle biopsies were obtained from the exercised and the nonexercised deltoid muscles and from the vastus lateralis. From PRE to CRE, serum glucose, insulin, and leptin were reduced. OBR expression was augmented in all examined muscles associated with increased maximal fat oxidation. Compared with PRE, after CD, phospho-Tyr 1141 OBR, phospho-Tyr 985 OBR, JAK2, and phospho-Tyr 1007/1008 JAK2 protein expression were increased in all muscles, whereas STAT3 and phospho-Tyr 705 STAT3 were increased only in the arms. The expression of protein tyrosine phosphatase 1B (PTP1B) in skeletal muscle was increased by 18 and 45% after CRE and CD, respectively ( P < 0.05). Suppressor of cytokine signaling 3 (SOCS3) tended to increase in the legs and decrease in the arm muscles (ANOVA interaction: P < 0.05). Myosin heavy chain I isoform was associated with OBR protein expression ( r  = -0.75), phospho-Tyr 985 OBR ( r  = 0.88), and phospho-Tyr 705 STAT3/STAT3 ( r = 0.74). In summary, despite increased PTP1B expression, skeletal muscle OBR and signaling are upregulated by a severe energy deficit with greater response in the arm than in the legs likely due to SOCS3 upregulation in the leg muscles. NEW & NOTEWORTHY This study shows that the skeletal muscle leptin receptors and their corresponding signaling cascade are upregulated in

  4. The influence of INS VNTR class III allele on auxological parameters, glucose, insulin, lipids, and adipocytokines secretion in prepubertal children born small for gestational age.

    Science.gov (United States)

    Stawerska, Renata; Szałapska, Małgorzata; Borowiec, Maciej; Antosik, Karolina; Młynarski, Wojciech; Lewiński, Andrzej

    2016-01-01

    The insulin gene variable number of tandem repeats (INS VNTR) class III allele has been implicated in lower birth weight, obesity, and insulin resistance. We assessed its influence on birth weight in the Polish population and on the current body mass and metabolic profile in prepubertal children born small for gestational age (SGA). DNA for genotyping of INS VNTR was available for 123 subjects born SGA and 132 born appropriate for gestational age (AGA). We identified two alleles: class I and class III. Next, in 112 prepubertal (aged: 6.8 ± 1.38 years) SGA children, the auxological measurements, fasting serum C-peptide, triglycerides, cholesterol, ghrelin, leptin, adiponectin, resistin, cortisol, and insulin-like growth factor type I (IGF-I) concentrations, as well as glucose and insulin during oral glucose tolerance test (OGTT), were assessed and insulin resistance indices were calculated. The results were analysed depending on INS VNTR variants. The occurrence of individual INS VNTR variants were similar in the SGA and AGA groups. In prepubertal SGA children, we did not observe any statistical differences as regards birth weight, body mass, lipids, or adipocytokine concentrations among I/I, I/III, and III/III class groups. The concentration of insulin in 120' of OGTT was significantly higher in class III homozygous than in class I homozygous individuals. Variant INS VNTR class III was shown not to be associated in any essential way with birth weight in the Polish population. Among prepubertal SGA children, the presence of INS VNTR class III is related to higher insulin secretion during OGTT. (Endokrynol Pol 2016; 67 (6): 585-591).

  5. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens Juul

    2003-01-01

    not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes.......We examined the simultaneous effects of a 24-h low-grade Intralipid infusion on peripheral glucose disposal, intracellular glucose partitioning and insulin secretion rates in twenty young men, by 2-step hyperinsulinemic euglycemic clamp [low insulin clamp (LI), 10 mU/m(2) x min; high insulin clamp...

  6. Molecular aspects of glucose homeostasis in skeletal muscle--A focus on the molecular mechanisms of insulin resistance.

    Science.gov (United States)

    Carnagarin, Revathy; Dharmarajan, Arun M; Dass, Crispin R

    2015-12-05

    Among all the varied actions of insulin, regulation of glucose homeostasis is the most critical and intensively studied. With the availability of glucose from nutrient metabolism, insulin action in muscle results in increased glucose disposal via uptake from the circulation and storage of excess, thereby maintaining euglycemia. This major action of insulin is executed by redistribution of the glucose transporter protein, GLUT4 from intracellular storage sites to the plasma membrane and storage of glucose in the form of glycogen which also involves modulation of actin dynamics that govern trafficking of all the signal proteins of insulin signal transduction. The cellular mechanisms responsible for these trafficking events and the defects associated with insulin resistance are largely enigmatic, and this review provides a consolidated overview of the various molecular mechanisms involved in insulin-dependent glucose homeostasis in skeletal muscle, as insulin resistance at this major peripheral site impacts whole body glucose homeostasis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  7. Mitochondrial GTP Regulates Glucose-Induced Insulin Secretion

    OpenAIRE

    Kibbey, Richard G.; Pongratz, Rebecca L.; Romanelli, Anthony J.; Wollheim, Claes B.; Cline, Gary W.; Shulman, Gerald I.

    2007-01-01

    Substrate-level mitochondrial GTP (mtGTP) and ATP (mtATP) synthesis occurs by nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl CoA synthetase (SCS). Unlike mtATP, each molecule of glucose metabolized produces approximately one mtGTP in pancreatic β-cells independent of coupling with oxidative phosphorylation making mtGTP a potentially important fuel signal. siRNA suppression of the GTP-producing pathway (ΔSCS-GTP) reduced glucose-stimulated insulin secretion ...

  8. Intake of Lactobacillus reuteri Improves Incretin and Insulin Secretion in Glucose-Tolerant Humans

    DEFF Research Database (Denmark)

    Simon, Marie-Christine; Strassburger, Klaus; Nowotny, Bettina

    2015-01-01

    production. Muscle and hepatic lipid contents were assessed by (1)H-magnetic resonance spectroscopy, and immune status, cytokines, and endotoxin were measured with specific assays. RESULTS: In glucose-tolerant volunteers, daily administration of L. reuteri SD5865 increased glucose-stimulated GLP-1 and GLP-2....... reuteri SD5865 or placebo over 4 weeks. Oral glucose tolerance and isoglycemic glucose infusion tests were used to assess incretin effect and GLP-1 and GLP-2 secretion, and euglycemic-hyperinsulinemic clamps with [6,6-(2)H2]glucose were used to measure peripheral insulin sensitivity and endogenous glucose...... cytokines. CONCLUSIONS: Enrichment of gut microbiota with L. reuteri increases insulin secretion, possibly due to augmented incretin release, but does not directly affect insulin sensitivity or body fat distribution. This suggests that oral ingestion of one specific strain may serve as a novel therapeutic...

  9. Leptin expression in ruminants: nutritional and physiological regulations in relation with energy metabolism.

    Science.gov (United States)

    Chilliard, Y; Delavaud, C; Bonnet, M

    2005-07-01

    Leptin, mainly produced in adipose tissue (AT), is a protein involved in the central and/or peripheral regulation of body homeostasis, energy intake, storage and expenditure, fertility and immune functions. Its role is well documented in rodent and human species, but less in ruminants. This review is focused on some intrinsic and extrinsic factors which regulate adipose tissue leptin gene expression and leptinemia in cattle, sheep, goat and camel: age, physiological status (particularly pregnancy and lactation) in interaction with long-term (adiposity) and short-term effects of feeding level, energy intake and balance, diet composition, specific nutrients and hormones (insulin, glucose and fatty acids), and seasonal non-dietary factors such as photoperiod. Body fatness strongly regulates leptin and its responses to other factors. For example, leptinemia is higher after underfeeding or during lactation in fat than in lean animals. Physiological status per se also modulates leptin expression, with lactation down-regulating leptinemia, even when energy balance (EB) is positive. These results suggest that leptin could be a link between nutritional history and physiological regulations, which integrates the animal's requirements (e.g., for a pregnancy-lactation cycle), predictable food availability (e.g., due to seasonal variations) and potential for survival (e.g., body fatness level). Reaching permissive leptin thresholds should be necessary for pubertal or postpartum reproductive activity. In addition to the understanding of leptin yield regulation, these data are helpful to understand the physiological significance of changes in leptin secretion and leptin effects, and how husbandry strategies could integrate the adaptative capacities of ruminant species to their environment.

  10. Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic β-cells

    Directory of Open Access Journals (Sweden)

    Muto Takashi

    2011-04-01

    Full Text Available Abstract Background Glycated albumin (GA is an Amadori product used as a marker of hyperglycemia. In this study, we investigated the effect of GA on insulin secretion from pancreatic β cells. Methods Islets were collected from male Wistar rats by collagenase digestion. Insulin secretion in the presence of non-glycated human albumin (HA and GA was measured under three different glucose concentrations, 3 mM (G3, 7 mM (G7, and 15 mM (G15, with various stimulators. Insulin secretion was measured with antagonists of inducible nitric oxide synthetase (iNOS, and the expression of iNOS-mRNA was investigated by real-time PCR. Results Insulin secretion in the presence of HA and GA was 20.9 ± 3.9 and 21.6 ± 5.5 μU/3 islets/h for G3 (P = 0.920, and 154 ± 9.3 and 126.1 ± 7.3 μU/3 islets/h (P = 0.046, for G15, respectively. High extracellular potassium and 10 mM tolbutamide abrogated the inhibition of insulin secretion by GA. Glyceraldehyde, dihydroxyacetone, methylpyruvate, GLP-1, and forskolin, an activator of adenylate cyclase, did not abrogate the inhibition. Real-time PCR showed that GA did not induce iNOS-mRNA expression. Furthermore, an inhibitor of nitric oxide synthetase, aminoguanidine, and NG-nitro-L-arginine methyl ester did not abrogate the inhibition of insulin secretion. Conclusion GA suppresses glucose-induced insulin secretion from rat pancreatic β-cells through impairment of intracellular glucose metabolism.

  11. Adipocytokines, neuropeptide Y and insulin resistance in overweight women with gynoid and android type of adipose tissue distribution.

    Science.gov (United States)

    Orbetzova, Maria M; Koleva, Daniela I; Mitkov, Mitko D; Atanassova, Iliana B; Nikolova, Julia G; Atanassova, Pepa K; Genchev, Gencho D

    2012-01-01

    The AIM of the study was to compare the levels of certain adipose tissue hormones in women with the two main morphological types of obesity - android and gynoid obesity. The study included 2 groups of age- and weight-matched women with android (n = 32) and gynoid (n = 27) type of obesity, and a group of age-matched healthy women (n = 24) with normal weight and body constitution. Leptin, resistin, tumour necrosis factor alpha (TNFalpha), neuropeptide Y (NPY), glucose and insulin were measured. HOMA index was calculated. Leptin levels in the women with gynoid obesity did not differ significantly from those in the controls and the women with android obesity. The controls had significantly lower leptin levels compared with the android obesity women. NPY was significantly higher in the control women compared to the women with android obesity and did not differ significantly between the two groups of obese women. TNFalpha levels in all groups were very similar. Resistin did not show significant differences between all groups but tended to have the lowest levels in the controls. In the women with android obesity, insulin was significantly higher than that in the women with gynoid obesity and the controls. Insulin resistance was found in the women with android obesity only. Basal insulin and HOMA index in the women with gynoid obesity did not differ significantly from the values in the control group. The results from this study contribute to understanding the association of adipose tissue hormones and insulin resistance in obesity. When adipose tissue is predominantly distributed in the abdominal area at similar amount and percentage of body fats, leptin production is higher and insulin resistance develops. In the gynoid type of adipose tissue predisposition, overt insulin resistance is not found, leptin levels does not differ significantly from those in the control group.

  12. Effect of vitamin K supplementation on insulin sensitivity: a meta-analysis

    Directory of Open Access Journals (Sweden)

    Suksomboon N

    2017-05-01

    Full Text Available Naeti Suksomboon,1 Nalinee Poolsup,2 Htoo Darli Ko Ko1 1Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand; 2Department of Pharmacy, Faculty of Pharmacy, Silpakorn University, Nakhon-Pathom, Thailand Objective: To perform a systematic review and meta-analysis of randomized, placebo-controlled trials to assess the effect of vitamin K supplementation on insulin sensitivity.Data sources: MEDLINE, the Cochrane Library, CINAHL, Web of Science, Scopus, clinicaltrials.gov, and clinicaltrialresults.org were searched up to January 2017. Reference lists of related papers were also scanned.Study selection: Randomized controlled trials were selected if they compared vitamin K supplementation with placebo or no treatment and reported homeostasis model assessment of insulin resistance, fasting plasma glucose, fasting plasma insulin, C-reactive protein, adiponectin, leptin, or interleukin-6 levels.Data extraction: Data extraction and study quality assessment were performed independently by two investigators using a standardized data extraction form. Any inconsistencies were resolved by a third reviewer. Effect estimates were pooled using inverse-variance weighted method. Heterogeneity was assessed by the I2 and Q statistic.Results: A total of eight trials involving 1,077 participants met the inclusion criteria. A wide variety of participants were enrolled, including older men, postmenopausal women, prediabetic premenopausal women, and participants with a history of diabetes, hypertension, or vascular disease. Vitamin K1 and vitamin K2 (MK-4 and MK-7 subtypes were assessed. Supplementation period ranged from 4 weeks to 3 years. Vitamin K supplementation did not affect insulin sensitivity as measured by homeostasis model assessment of insulin resistance, fasting plasma glucose, fasting plasma insulin, C-reactive protein, adiponectin, leptin, and interleukin-6 levels.Conclusion: Our analysis suggests no effect of vitamin K

  13. The triglyceride-glucose index, an insulin resistance marker in newborns?

    Science.gov (United States)

    Gesteiro, Eva; Bastida, Sara; Barrios, Laura; Sánchez-Muniz, Francisco J

    2018-04-01

    The study aims to assess the utility of the triglyceride-glucose index (TyG) as a marker of insulin resistance (IR) in neonates. TyG and the homeostatic model assessment (HOMA-IR) values were compared in 196 singleton, term normoweight and without distress newborns. A Decision Tree procedure (CHAID) was used to classify cases into groups or predict values of a dependent (Ln HOMA-IR) variable. Three nodes were drawn for TyG: ≤ 6.7, > 6.7-7.8 and > 7.8 (p glucose challenge test (p = 0.138) classifications nor by the TyG node* glucose challenge test and TyG node*gender interactions (p = 0.456 and p = 0.209, respectively). Glucose, HOMA-IR, and the triglyceride/HDL cholesterol ratio increased progressively from node 1 to 3 for TyG while QUICKI decreased. In conclusion, TyG appears to be a suitable tool for identifying IR at birth, justifying the further insulin determination in those neonates. TyG ≥ 7.8 is recommended as cut-off point in neonates. The need for a follow-up study to confirm the TyG as early IR marker is desirable. • HOMA-IR and the triglyceride-glucose index (TyG) show a high correlation. • The TyG has been used as an insulin resistance marker in adults. • This is the first study where TyG has been assessed in neonates. • TyG appears to be a suitable and cheap tool for identifying insulin resistance at birth.

  14. Superior Glycemic Control with a Glucose-Responsive Insulin Analog: Hepatic and Nonhepatic Impacts.

    Science.gov (United States)

    Moore, Mary Courtney; Kelley, David E; Camacho, Raul C; Zafian, Peter; Ye, Tian; Lin, Songnian; Kaarsholm, Niels C; Nargund, Ravi; Kelly, Terri M; Van Heek, Margaret; Previs, Stephen F; Moyes, Christopher; Smith, Marta S; Farmer, Ben; Williams, Phil; Cherrington, Alan D

    2018-03-14

    We evaluated the hepatic and nonhepatic responses to glucose-responsive insulin (GRI). Eight dogs received GRI or regular human insulin (HI) in random order. A primed, continuous intravenous infusion of [3- 3 H]glucose began at -120 min. Basal sampling (-30 to 0 min) was followed by 2 study periods (150 min each), P1 and P2. At 0 min, somatostatin and GRI (36±3 pmol/kg/min) or HI (1.8 pmol/kg/min) were infused IV; basal glucagon was replaced intraportally. Glucose was infused intravenously to clamp plasma glucose at 80 mg/dL (P1) and 240 mg/dL (P2). Whole body insulin clearance (WBIC) and insulin concentrations were not different in P1 vs P2 with HI, but WBIC was 23% higher and arterial insulin 16% lower in P1 vs P2 with GRI. Net hepatic glucose output was similar between treatments in P1. In P2, both treatments induced net hepatic glucose uptake (2.1±0.5 [HI] vs 3.3±0.4 [GRI] mg/kg/min). Nonhepatic glucose uptake (nonHGU, mg/kg/min) in P1 and P2, respectively, differed between treatments (2.6±0.3 and 7.4±0.6 with HI; 2.0±0.2 and 8.1±0.8 with GRI). Thus, glycemia impacted GRI but not HI clearance, with resultant differential effects on HGU and nonHGU. GRI holds promise for decreasing hypoglycemia risk while enhancing glucose uptake under hyperglycemic conditions. © 2018 by the American Diabetes Association.

  15. Scoparia dulcis (SDF7) endowed with glucose uptake properties on L6 myotubes compared insulin.

    Science.gov (United States)

    Beh, Joo Ee; Latip, Jalifah; Abdullah, Mohd Puad; Ismail, Amin; Hamid, Muhajir

    2010-05-04

    Insulin stimulates glucose uptake and promotes the translocation of glucose transporter 4 (Glut 4) to the plasma membrane on L6 myotubes. The aim of this study is to investigate affect of Scoparia dulcis Linn water extracts on glucose uptake activity and the Glut 4 translocation components (i.e., IRS-1, PI 3-kinase, PKB/Akt2, PKC and TC 10) in L6 myotubes compared to insulin. Extract from TLC fraction-7 (SDF7) was used in this study. The L6 myotubes were treated by various concentrations of SDF7 (1 to 50 microg/ml) and insulin (1 to 100 nM). The glucose uptake activities of L6 myotubes were evaluated using 2-Deoxy-D-glucose uptake assay in with or without fatty acid-induced medium. The Glut 4 translocation components in SDF7-treated L6 myotubes were detected using immunoblotting and quantified by densitometry compared to insulin. Plasma membrane lawn assay and glycogen colorimetry assay were carried out in SDF7- and insulin-treated L6 myotubes in this study. Here, our data clearly shows that SDF7 possesses glucose uptake properties on L6 myotubes that are dose-dependent, time-dependent and plasma membrane Glut 4 expression-dependent. SDF7 successfully stimulates glucose uptake activity as potent as insulin at a maximum concentration of 50 microg/ml at 480 min on L6 myotubes. Furthermore, SDF7 stimulates increased Glut 4 expression and translocation to plasma membranes at equivalent times. Even in the insulin resistance stage (free fatty acids-induced), SDF7-treated L6 myotubes were found to be more capable at glucose transport than insulin treatment. Thus, we suggested that Scoparia dulcis has the potential to be categorized as a hypoglycemic medicinal plant based on its good glucose transport properties. (c) 2010 Elsevier Ireland Ltd. All rights reserved.

  16. Interaction between exogenous insulin, endogenous insulin, and glucose in type 2 diabetes patients

    DEFF Research Database (Denmark)

    Janukonyté, Jurgita; Parkner, Tina; Bruun, Niels Henrik

    2015-01-01

    insulin aspart (s-IAsp), and blood glucose levels in an experimental short-term crossover design. STUDY DESIGN AND METHODS: Eight T2DM patients (63.52 years old; range, 49-69 years; mean body mass index, 28.8±3.8 kg/m2) were randomized to treatment with individual fixed doses of insulin aspart (0.5-1.5 IU......-IAsp, and s-EI were equal within visit TH and within visit CH, but variances were significantly higher during visit CH compared with visit TH. The s-IAsp reached lower levels at visit CH compared with visit TH (test for slope=1, P=0.005). The s-EI depended on p-glucose in a nonlinear fashion during the first...

  17. Insulin Sensitivity and Glucose Homeostasis Can Be Influenced by Metabolic Acid Load

    Directory of Open Access Journals (Sweden)

    Lucio Della Guardia

    2018-05-01

    Full Text Available Recent epidemiological findings suggest that high levels of dietary acid load can affect insulin sensitivity and glucose metabolism. Consumption of high protein diets results in the over-production of metabolic acids which has been associated with the development of chronic metabolic disturbances. Mild metabolic acidosis has been shown to impair peripheral insulin action and several epidemiological findings suggest that metabolic acid load markers are associated with insulin resistance and impaired glycemic control through an interference intracellular insulin signaling pathways and translocation. In addition, higher incidence of diabetes, insulin resistance, or impaired glucose control have been found in subjects with elevated metabolic acid load markers. Hence, lowering dietary acid load may be relevant for improving glucose homeostasis and prevention of type 2 diabetes development on a long-term basis. However, limitations related to patient acid load estimation, nutritional determinants, and metabolic status considerably flaws available findings, and the lack of solid data on the background physiopathology contributes to the questionability of results. Furthermore, evidence from interventional studies is very limited and the trials carried out report no beneficial results following alkali supplementation. Available literature suggests that poor acid load control may contribute to impaired insulin sensitivity and glucose homeostasis, but it is not sufficiently supportive to fully elucidate the issue and additional well-designed studies are clearly needed.

  18. TCPTP Regulates Insulin Signalling in AgRP Neurons to Coordinate Glucose Metabolism with Feeding.

    Science.gov (United States)

    Dodd, Garron T; Lee-Young, Robert S; Brüning, Jens C; Tiganis, Tony

    2018-04-30

    Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signalling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signalling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons ( Agrp -Cre; Ptpn2 fl/fl ) enhanced insulin sensitivity as assessed by the increased glucose infusion rates and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [ 14 C]-2-deoxy-D-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp -Cre; Ptpn2 fl/fl mice was corrected by IR heterozygosity ( Agrp -Cre; Ptpn2 fl/fl ; Insr fl/+ ), causally linking the effects on glucose metabolism with the IR signalling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signalling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting. © 2018 by the American Diabetes Association.

  19. Acute activation of GLP-1-expressing neurons promotes glucose homeostasis and insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Xuemei Shi

    2017-11-01

    Conclusions: We conclude that acute activation of PPG neurons in the brainstem reduces basal glucose production, enhances intraperitoneal glucose tolerance, and augments hepatic insulin sensitivity, suggesting an important physiological role of PPG neurons-mediated circuitry in promoting glycemic control and insulin sensitivity.

  20. A randomized clinical trial comparing the effect of basal insulin and inhaled mealtime insulin on glucose variability and oxidative stress

    NARCIS (Netherlands)

    Siegelaar, S. E.; Kulik, W.; van Lenthe, H.; Mukherjee, R.; Hoekstra, J. B. L.; DeVries, J. H.

    2009-01-01

    To assess the effect of three times daily mealtime inhaled insulin therapy compared with once daily basal insulin glargine therapy on 72-h glucose profiles, glucose variability and oxidative stress in type 2 diabetes patients. In an inpatient crossover study, 40 subjects with type 2 diabetes were

  1. Insulin-coated gold nanoparticles as a new concept for personalized and adjustable glucose regulation

    Science.gov (United States)

    Shilo, Malka; Berenstein, Peter; Dreifuss, Tamar; Nash, Yuval; Goldsmith, Guy; Kazimirsky, Gila; Motiei, Menachem; Frenkel, Dan; Brodie, Chaya; Popovtzer, Rachela

    2015-12-01

    Diabetes mellitus is a chronic metabolic disease, characterized by high blood glucose levels, affecting millions of people around the world. Currently, the main treatment for diabetes requires multiple daily injections of insulin and self-monitoring of blood glucose levels, which markedly affect patients' quality of life. In this study we present a novel strategy for controlled and prolonged glucose regulation, based on the administration of insulin-coated gold nanoparticles (INS-GNPs). We show that both intravenous and subcutaneous injection of INS-GNPs into a mouse model of type 1 diabetes decreases blood glucose levels for periods over 3 times longer than free insulin. We further showed that conjugation of insulin to GNPs prevented its rapid degradation by the insulin-degrading-enzyme, and thus allows controlled and adjustable bio-activity. Moreover, we assessed different sizes and concentrations of INS-GNPs, and found that both parameters have a critical effect in vivo, enabling specific adjustment of blood glucose levels. These findings have the potential to improve patient compliance in diabetes mellitus.

  2. Ablation of ghrelin receptor in leptin-deficient ob/ob mice has paradoxical effects on glucose homeostasis when compared with ablation of ghrelin in ob/ob mice

    Science.gov (United States)

    The orexigenic hormone ghrelin is important in diabetes because it has an inhibitory effect on insulin secretion. Ghrelin ablation in leptin-deficient ob/ob (Ghrelin(-/-):ob/ob) mice increases insulin secretion and improves hyperglycemia. The physiologically relevant ghrelin receptor is the growth ...

  3. Is reducing variability of blood glucose the real but hidden target of intensive insulin therapy?

    Science.gov (United States)

    Egi, Moritoki; Bellomo, Rinaldo; Reade, Michael C

    2009-01-01

    Since the first report that intensive insulin therapy reduced mortality in selected surgical critically ill patients, lowering of blood glucose levels has been recommended as a means of improving patient outcomes. In this initial Leuven trial, blood glucose control by protocol using insulin was applied to 98.7% of patients in the intensive group but to only 39.2% (P dimension of glucose management, a possible mechanism by which an intensive insulin protocol exerts its putative beneficial effects, and an important goal of glucose management in the intensive care unit. Clinicians need to be aware of this controversy when considering the application of intensive insulin therapy and interpreting future trials.

  4. Effect of HCV on fasting glucose, fasting insulin and peripheral insulin resistance in first 5 years of infection.

    Science.gov (United States)

    Ahmed, Naeema; Rashid, Amir; Naveed, Abdul Khaliq; Bashir, Qudsia

    2016-02-01

    To assess the effects of hepatitis C virus infection in the first 5 years on fasting glucose, fasting insulin and peripheral insulin resistance. The case-control study was conducted at the Army Medical College, Rawalpindi, from December 2011 to November 2012, and comprised subjects recruited from a government hospital in Rawalpindi. The subjects included known cases of hepatitis C virus infection for at least 5 years, and normal healthy controls. Fasting blood samples of all the subjects were collected and analysed for serum fasting insulin and serum fasting glucose levels. Homeostatic model assessment-Insulin resistance was calculated SPSS 11 was used for statistical analysis. Of the 30 subjects, 20(66.6%) were cases, while 10(33.3%) were controls. Serum fasting glucose mean level in cases was 89.55±9.53 compared to 84.40±9.80 in the controls (p=0.188). The mean serum fasting insulin in controls was 7.52±3.23 and 6.79±3.30 in cases (p=0.567). Homeostatic model assessment-Insulin resistance level in controls was 1.60±0.76 and In the cases it was 1.49±0.74 (p=0.695). Peripheral insulin resistance and development of type 2 diabetes as a complication of hepatitis C virus infection was not likely at least within the first five years of infection.

  5. The Effects of Fetal Gender on Maternal and Fetal Insulin Resistance.

    Directory of Open Access Journals (Sweden)

    Jennifer M Walsh

    Full Text Available Gender plays a role in the development of a number of cardiovascular and metabolic diseases and it has been suggested that females may be more insulin resistant in utero. We sought to assess the relationship between infant gender and insulin resistance in a large pregnancy cohort.This is a secondary analysis of a cohort from the ROLO randomized control trial of low GI diet in pregnancy. Serum insulin, glucose and leptin were measured in early pregnancy and at 28 weeks. At delivery cord blood C-peptide and leptin were measured. A comparison of maternal factors, fetal biometry, insulin resistance and leptin was made between male and female offspring. A multivariate regression model was built to account for the possible effects of maternal BMI, birthweight and original study group assignment on findings.A total of 582 women were included in this secondary analysis, of whom 304 (52.2% gave birth to male and 278 (47.8% gave birth to female infants. Compared to male infants at birth, female infants were significantly lighter, (3945 ± 436 vs. 4081± 549g, p<0.001, shorter in length (52.36 ± 2.3 vs. 53.05 ± 2.4cm, p<0.001 and with smaller head circumferences (35.36 ± 1.5 vs. 36.10 ± 1.1cm, p<0.001 than males. On multiple regression analysis, women pregnant with female fetuses were less insulin resistant in early pregnancy, i.e. had lower HOMA indices (B = -0.19, p = 0.01. Additionally female fetuses had higher concentrations of both cord blood leptin and C-peptide at birth when compared to male offspring (B = 0.38, p<0.001 and B = 0.31, p = 0.03 respectively.These findings suggest gender is a risk factor for insulin resistance in-utero. Additionally, carrying a female fetus decreases the risk of insulin resistance in the mother, from as early as the first trimester.

  6. The Effects of Fetal Gender on Maternal and Fetal Insulin Resistance.

    Science.gov (United States)

    Walsh, Jennifer M; Segurado, Ricardo; Mahony, Rhona M; Foley, Michael E; McAuliffe, Fionnuala M

    2015-01-01

    Gender plays a role in the development of a number of cardiovascular and metabolic diseases and it has been suggested that females may be more insulin resistant in utero. We sought to assess the relationship between infant gender and insulin resistance in a large pregnancy cohort. This is a secondary analysis of a cohort from the ROLO randomized control trial of low GI diet in pregnancy. Serum insulin, glucose and leptin were measured in early pregnancy and at 28 weeks. At delivery cord blood C-peptide and leptin were measured. A comparison of maternal factors, fetal biometry, insulin resistance and leptin was made between male and female offspring. A multivariate regression model was built to account for the possible effects of maternal BMI, birthweight and original study group assignment on findings. A total of 582 women were included in this secondary analysis, of whom 304 (52.2%) gave birth to male and 278 (47.8%) gave birth to female infants. Compared to male infants at birth, female infants were significantly lighter, (3945 ± 436 vs. 4081± 549g, p<0.001), shorter in length (52.36 ± 2.3 vs. 53.05 ± 2.4cm, p<0.001) and with smaller head circumferences (35.36 ± 1.5 vs. 36.10 ± 1.1cm, p<0.001) than males. On multiple regression analysis, women pregnant with female fetuses were less insulin resistant in early pregnancy, i.e. had lower HOMA indices (B = -0.19, p = 0.01). Additionally female fetuses had higher concentrations of both cord blood leptin and C-peptide at birth when compared to male offspring (B = 0.38, p<0.001 and B = 0.31, p = 0.03 respectively). These findings suggest gender is a risk factor for insulin resistance in-utero. Additionally, carrying a female fetus decreases the risk of insulin resistance in the mother, from as early as the first trimester.

  7. Light Control of Insulin Release and Blood Glucose Using an Injectable Photoactivated Depot.

    Science.gov (United States)

    Sarode, Bhagyesh R; Kover, Karen; Tong, Pei Y; Zhang, Chaoying; Friedman, Simon H

    2016-11-07

    In this work we demonstrate that blood glucose can be controlled remotely through light stimulated release of insulin from an injected cutaneous depot. Human insulin was tethered to an insoluble but injectable polymer via a linker, which was based on the light cleavable di-methoxy nitrophenyl ethyl (DMNPE) group. This material was injected into the skin of streptozotocin-treated diabetic rats. We observed insulin being released into the bloodstream after a 2 min trans-cutaneous irradiation of this site by a compact LED light source. Control animals treated with the same material, but in which light was blocked from the site, showed no release of insulin into the bloodstream. We also demonstrate that additional pulses of light from the light source result in additional pulses of insulin being absorbed into circulation. A significant reduction in blood glucose was then observed. Together, these results demonstrate the feasibility of using light to allow for the continuously variable control of insulin release. This in turn has the potential to allow for the tight control of blood glucose without the invasiveness of insulin pumps and cannulas.

  8. Leptin Increases Striatal Dopamine D2 Receptor Binding in Leptin-Deficient Obese (ob/ob) Mice

    Energy Technology Data Exchange (ETDEWEB)

    Pfaffly, J.; Michaelides, M.; Wang, G-J.; Pessin, J.E.; Volkow, N.D.; Thanos, P.K.

    2010-06-01

    Peripheral and central leptin administration have been shown to mediate central dopamine (DA) signaling. Leptin-receptor deficient rodents show decreased DA D2 receptor (D2R) binding in striatum and unique DA profiles compared to controls. Leptin-deficient mice show increased DA activity in reward-related brain regions. The objective of this study was to examine whether basal D2R-binding differences contribute to the phenotypic behaviors of leptin-deficient ob/ob mice, and whether D2R binding is altered in response to peripheral leptin treatment in these mice. Leptin decreased body weight, food intake, and plasma insulin concentration in ob/ob mice but not in wild-type mice. Basal striatal D2R binding (measured with autoradiography [{sup 3}H] spiperone) did not differ between ob/ob and wild-type mice but the response to leptin did. In wild-type mice, leptin decreased striatal D2R binding, whereas, in ob/ob mice, leptin increased D2R binding. Our findings provide further evidence that leptin modulates D2R expression in striatum and that these effects are genotype/phenotype dependent.

  9. Effects of Curcuma longa (turmeric) on postprandial plasma glucose and insulin in healthy subjects.

    Science.gov (United States)

    Wickenberg, Jennie; Ingemansson, Sandra Lindstedt; Hlebowicz, Joanna

    2010-10-12

    Previous animal studies have shown that Curcuma (C.) longa lowers plasma glucose. C. longa may thus be a promising ingredient in functional foods aimed at preventing type 2 diabetes. The purpose of the study is to study the effect of C. longa on postprandial plasma glucose, insulin levels and glycemic index (GI) in healthy subjects. Fourteen healthy subjects were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT) was administered together with capsules containing a placebo or C. longa. Finger-prick capillary and venous blood samples were collected before, and 15, 30, 45, 60, 90, and 120 min after the start of the OGTT to measure the glucose and insulin levels, respectively. The ingestion of 6 g C. longa had no significant effect on the glucose response. The change in insulin was significantly higher 30 min (P = 0.03) and 60 min (P = 0.041) after the OGTT including C. longa. The insulin AUCs were also significantly higher after the ingestion of C. longa, 15 (P = 0.048), 30 (P = 0.035), 90 (P = 0.03), and 120 (P = 0.02) minutes after the OGTT. The ingestion of 6 g C. longa increased postprandial serum insulin levels, but did not seem to affect plasma glucose levels or GI, in healthy subjects. The results indicate that C. longa may have an effect on insulin secretion.

  10. Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    International Nuclear Information System (INIS)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine; Halimi, Serge; Demongeot, Jacques

    2007-01-01

    Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using 125 I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

  11. Assessment of insulin resistance in fructose-fed rats with 125I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    Science.gov (United States)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Danièle; Halimi, Serge; Demongeot, Jacques; Fagret, Daniel; Ghezzi, Catherine

    2007-01-01

    Purpose Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state and it has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats with 125I-6-Deoxy-6-Iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Methods Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood were assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Results Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady-state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p<0.01; muscle, p<0.05; heart, p<0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p<0.001; muscle, p<0.001; heart, p<0.01) and whereas no significant changes were observed in fructose-fed rats. Conclusion This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. PMID:17171359

  12. HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients.

    Science.gov (United States)

    Grasso, Alessandro; Malfatti, Federica; Andraghetti, Gabriella; Marenco, Simona; Mazzucchelli, Chiara; Labanca, Sara; Cordera, Renzo; Testa, Roberto; Picciotto, Antonino

    2015-01-01

    Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P = 0.033 and 0.048, resp.) in patients who achieved an early viral load decay (EVR), a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

  13. HOMA, BMI, and Serum Leptin Levels Variations during Antiviral Treatment Suggest Virus-Related Insulin Resistance in Noncirrhotic, Nonobese, and Nondiabetic Chronic Hepatitis C Genotype 1 Patients

    Directory of Open Access Journals (Sweden)

    Alessandro Grasso

    2015-01-01

    Full Text Available Objective. To investigate the relationship between insulin resistance and viral load decay in nondiabetic and noncirrhotic genotype 1 chronic HCV patients during peginterferon and ribavirin treatment and the possible influence of BMI and leptin as metabolic confounders. Methods. 75 consecutive noncirrhotic, nonobese, and nondiabetic patients with genotype 1 chronic hepatitis C treated with peginterferon alpha 2a plus ribavirin were evaluated. HOMA-IR, serum leptin, and BMI were measured in all patients at baseline and at weeks 12 and 48, whereas viral load was measured at the same time points and then 24 weeks after the end of treatment. Results. HOMA-IR was significantly associated with both BMI and leptin at baseline. During peginterferon plus ribavirin treatment, there was a significant reduction of HOMA-IR at weeks 12 and 48 from baseline (P=0.033 and 0.048, resp. in patients who achieved an early viral load decay (EVR, a trend not observed in patients who not achieved EVR. No variations during treatment were observed regarding BMI and leptin irrespective of EVR. Conclusion. The early reduction of HOMA-IR but not of BMI and leptin during antiviral treatment in noncirrhotic, chronic hepatitis C genotype 1 patients who achieved EVR suggests a viral genesis of insulin resistance in patients with nonmetabolic phenotype.

  14. Interactions of obesity and glucose-stimulated insulin secretion in familial hypertriglyceridemia.

    Science.gov (United States)

    Maruhama, Y; Abe, R; Okuguchi, F; Oikawa, S; Ohneda, A; Goto, Y

    1978-06-01

    Plasma lipids and lipoproteins, glucose tolerance, plasma insulin response to glucose load, and liver function were examined in 81 relatives of 12 index cases with primary endogenous hypertriglyceridemia, hyperinsulinemia, and hepatic steatosis, as well as in 90 nonrelatives, including the spouses, as controls. Insulin hypersecretion (with or without glucose intolerance), endogenous hypertriglyceridemia, and abnormal liver function suggesting hepatic steatosis were shown to exist in the relatives mostly in combined fashion. Correlation analysis and stepwise multiple regression analysis revealed that the combined disorder developed on the basis of obesity. The incidence of diabetes mellitus was significantly high in the relatives (14.8 per cent) as compared with the normal Japanese population (3.5 per cent). Although the vertical transmission of the combined disorder was noted in almost all pedigrees, the frequency distribution analysis of insulin response, glucose tolerance, and plasma triglyceride showed the histograms of these variables similarly skewed to the right as compared with those of the controls, with no apparent bimodality. In view of the hitherto suggested role of insulin in triglyceride metabolism, it is concluded that hyperinsulinemia coupled with obesity seems to be the basic trait of this form of familial hypertriglyceridemia and hepatic steatosis, though the mode of transmission remains to be elucidated.

  15. Glucose and insulin induce Ca2+ signaling in nesfatin-1 neurons in the hypothalamic paraventricular nucleus.

    Science.gov (United States)

    Gantulga, Darambazar; Maejima, Yuko; Nakata, Masanori; Yada, Toshihiko

    2012-04-20

    Nucleobindin-2 derived nesfatin-1 in the hypothalamic paraventricular nucleus (PVN) plays a role in inhibition of feeding. The neural pathways downstream of PVN nesfatin-1 have been extensively investigated. However, regulation of the PVN nesfatin-1 neurons remains unclear. Since starvation decreases and refeeding stimulates nesfatin-1 expression specifically in the PVN, this study aimed to clarify direct effects of meal-evoked metabolic factors, glucose and insulin, on PVN nesfatin-1 neurons. High glucose (10mM) and insulin (10(-13)M) increased cytosolic calcium concentration ([Ca(2+)](i)) in 55 of 331 (16.6%) and 32 of 249 (12.9%) PVN neurons, respectively. Post [Ca(2+)](i) measurement immunocytochemistry identified that 58.2% of glucose-responsive and 62.5% of insulin-responsive neurons were immunoreactive to nesfatin-1. Furthermore, a fraction of the glucose-responsive nesfatin-1 neurons also responded to insulin, and vice versa. Some of the neurons that responded to neither glucose nor insulin were recruited to [Ca(2+)](i) increases by glucose and insulin in combination. Our data demonstrate that glucose and insulin directly interact with and increase [Ca(2+)](i) in nesfatin-1 neurons in the PVN, and that the nesfatin-1 neuron is the primary target for them in the PVN. The results suggest that high glucose- and insulin-induced activation of PVN nesfatin-1 neurons serves as a mechanism through which meal ingestion stimulates nesfatin-1 neurons in the PVN and thereby produces satiety. Copyright © 2012 Elsevier Inc. All rights reserved.

  16. Effects of Higher Dietary Protein and Fiber Intakes at Breakfast on Postprandial Glucose, Insulin, and 24-h Interstitial Glucose in Overweight Adults.

    Science.gov (United States)

    Amankwaah, Akua F; Sayer, R Drew; Wright, Amy J; Chen, Ningning; McCrory, Megan A; Campbell, Wayne W

    2017-04-02

    Dietary protein and fiber independently influence insulin-mediated glucose control. However, potential additive effects are not well-known. Men and women ( n = 20; age: 26 ± 5 years; body mass index: 26.1 ± 0.2 kg/m²; mean ± standard deviation) consumed normal protein and fiber (NPNF; NP = 12.5 g, NF = 2 g), normal protein and high fiber (NPHF; NP = 12.5 g, HF = 8 g), high protein and normal fiber (HPNF; HP = 25 g, NF = 2 g), or high protein and fiber (HPHF; HP = 25 g, HF = 8 g) breakfast treatments during four 2-week interventions in a randomized crossover fashion. On the last day of each intervention, meal tolerance tests were completed to assess postprandial (every 60 min for 240 min) serum glucose and insulin concentrations. Continuous glucose monitoring was used to measure 24-h interstitial glucose during five days of the second week of each intervention. Repeated-measures ANOVA was applied for data analyses. The HPHF treatment did not affect postprandial glucose and insulin responses or 24-h glucose total area under the curve (AUC). Higher fiber intake reduced 240-min insulin AUC. Doubling the amount of protein from 12.5 g to 25 g/meal and quadrupling fiber from 2 to 8 g/meal at breakfast was not an effective strategy for modulating insulin-mediated glucose responses in these young, overweight adults.

  17. Synthesis, characterization, and preclinical evaluation of new thiazolidin-4-ones substituted with p-chlorophenoxy acetic acid and clofibric acid against insulin resistance and metabolic disorder.

    Science.gov (United States)

    Gowdra, Vasantharaju S; Mudgal, Jayesh; Bansal, Punit; Nayak, Pawan G; Manohara Reddy, Seethappa A; Shenoy, Gautham G; Valiathan, Manna; Chamallamudi, Mallikarjuna R; Nampurath, Gopalan K

    2014-01-01

    We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

  18. Glucose clearance in aged trained skeletal muscle during maximal insulin with superimposed exercise

    DEFF Research Database (Denmark)

    Dela, Flemming; Mikines, K J; Larsen, J J

    1999-01-01

    Insulin and muscle contractions are major stimuli for glucose uptake in skeletal muscle and have in young healthy people been shown to be additive. We studied the effect of superimposed exercise during a maximal insulin stimulus on glucose uptake and clearance in trained (T) (1-legged bicycle tra...

  19. Twenty-four-hour endocrine and metabolic profiles following consumption of high-fructose corn syrup-, sucrose-, fructose-, and glucose-sweetened beverages with meals.

    Science.gov (United States)

    Stanhope, Kimber L; Griffen, Steven C; Bair, Brandi R; Swarbrick, Michael M; Keim, Nancy L; Havel, Peter J

    2008-05-01

    We have reported that, compared with glucose-sweetened beverages, consuming fructose-sweetened beverages with meals results in lower 24-h circulating glucose, insulin, and leptin concentrations and elevated triacylglycerol (TG). However, pure fructose and glucose are not commonly used as sweeteners. High-fructose corn syrup (HFCS) has replaced sucrose as the predominant sweetener in beverages in the United States. We compared the metabolic/endocrine effects of HFCS with sucrose and, in a subset of subjects, with pure fructose and glucose. Thirty-four men and women consumed 3 isocaloric meals with either sucrose- or HFCS-sweetened beverages, and blood samples were collected over 24 h. Eight of the male subjects were also studied when fructose- or glucose-sweetened beverages were consumed. In 34 subjects, 24-h glucose, insulin, leptin, ghrelin, and TG profiles were similar between days that sucrose or HFCS was consumed. Postprandial TG excursions after HFCS or sucrose were larger in men than in women. In the men in whom the effects of 4 sweeteners were compared, the 24-h glucose and insulin responses induced by HFCS and sucrose were intermediate between the lower responses during consumption of fructose and the higher responses during glucose. Unexpectedly, postprandial TG profiles after HFCS or sucrose were not intermediate but comparably high as after pure fructose. Sucrose and HFCS do not have substantially different short-term endocrine/metabolic effects. In male subjects, short-term consumption of sucrose and HFCS resulted in postprandial TG responses comparable to those induced by fructose.

  20. Childhood craniopharyngioma: greater hypothalamic involvement before surgery is associated with higher homeostasis model insulin resistance index

    Science.gov (United States)

    Trivin, Christine; Busiah, Kanetee; Mahlaoui, Nizar; Recasens, Christophe; Souberbielle, Jean-Claude; Zerah, Michel; Sainte-Rose, Christian; Brauner, Raja

    2009-01-01

    Background Obesity seems to be linked to the hypothalamic involvement in craniopharyngioma. We evaluated the pre-surgery relationship between the degree of this involvement on magnetic resonance imaging and insulin resistance, as evaluated by the homeostasis model insulin resistance index (HOMA). As insulin-like growth factor 1, leptin, soluble leptin receptor (sOB-R) and ghrelin may also be involved, we compared their plasma concentrations and their link to weight change. Methods 27 children with craniopharyngioma were classified as either grade 0 (n = 7, no hypothalamic involvement), grade 1 (n = 8, compression without involvement), or grade 2 (n = 12, severe involvement). Results Despite having similar body mass indexes (BMI), the grade 2 patients had higher glucose, insulin and HOMA before surgery than the grade 0 (P = 0.02, craniopharyngioma before surgery seems to determine the degree of insulin resistance, regardless of the BMI. The pre-surgery HOMA values were correlated with the post-surgery weight gain. This suggests that obesity should be prevented by reducing inn secretion in those cases with hypothalamic involvement. PMID:19341477

  1. Study on the changes of serum adiponectin (APN), insulin, C-reactive protein (CRP) and leptin levels after one year treatment in patients with type 2 diabetes

    International Nuclear Information System (INIS)

    Du Tongxin; Wang Zizheng; Wang Shukui; Li Yan; Fu Lei; Lin Yanli; Qu Wei; Qi Shaokang; Tao Xiaojun

    2005-01-01

    Objective: To investigate the β-cell function status and possible mechanism of insulin resistance in patients with type 2 diabetes through studies on the changes of serum APN, insulin, CRP, leptin, insulin antibody and glutamic acid decarboxylase antibody (GAD-Ab) levels after one year of treatment. Methods: Serum levels of the above four parameters and the positive rate of the two antibodies were measured (with CLIA, ELISA and RIA as appropriately) in 184 patients with type 2 diabetes and 30 controls as well as in 75 patients after one year of treatment. Results: The serum contents of insulin, leptin, CRP, insulin antibody in patients with type 2 diabetes were significantly higher (P<0.01) and APN levels significantly lower (P<0.001) than those in controls. Levels of APN were negatively correlated with those of the other parameters. In the 75 treated patients, levels of those parameters (with the exception of APN and insulin-antibody) decreased significantly. However, the APN levels were significantly increased (vs before treatment, P<0.001). Conclusion: Further study on the dynamic changes of these parameters in the diabetic patients might elucidate certain key-points in the pathogenesis of the disease. (authors)

  2. Effects of Curcuma longa (turmeric on postprandial plasma glucose and insulin in healthy subjects

    Directory of Open Access Journals (Sweden)

    Ingemansson Sandra

    2010-10-01

    Full Text Available Abstract Background Previous animal studies have shown that Curcuma (C. longa lowers plasma glucose. C. longa may thus be a promising ingredient in functional foods aimed at preventing type 2 diabetes. The purpose of the study is to study the effect of C. longa on postprandial plasma glucose, insulin levels and glycemic index (GI in healthy subjects. Methods Fourteen healthy subjects were assessed in a crossover trial. A standard 75 g oral glucose tolerance test (OGTT was administered together with capsules containing a placebo or C. longa. Finger-prick capillary and venous blood samples were collected before, and 15, 30, 45, 60, 90, and 120 min after the start of the OGTT to measure the glucose and insulin levels, respectively. Results The ingestion of 6 g C. longa had no significant effect on the glucose response. The change in insulin was significantly higher 30 min (P = 0.03 and 60 min (P = 0.041 after the OGTT including C. longa. The insulin AUCs were also significantly higher after the ingestion of C. longa, 15 (P = 0.048, 30 (P = 0.035, 90 (P = 0.03, and 120 (P = 0.02 minutes after the OGTT. Conclusions The ingestion of 6 g C. longa increased postprandial serum insulin levels, but did not seem to affect plasma glucose levels or GI, in healthy subjects. The results indicate that C. longa may have an effect on insulin secretion. Trial registration number NCT01029327

  3. Rates and tissue sites of non-insulin- and insulin-mediated glucose uptake in humans

    International Nuclear Information System (INIS)

    Baron, A.D.; Brechtel, G.; Wallace, P.; Edelman, S.V.

    1988-01-01

    In vivo glucose uptake can occur via two mechanisms, namely, insulin-mediated glucose uptake (IMGU) and non-insulin-mediated glucose uptake (NIMGU). Although the principal tissue sites for IMGU are skeletal muscle, the tissue sites for NIMGU at a given serum glucose concentration are not known. To examine this issue, rates of whole body glucose uptake (Rd) were measured at basal and during glucose clamp studies performed at euglycemia (approximately 90 mg/dl) and hyperglycemia (approximately 220 mg/dl) in six lean healthy men. Studies were performed during hyperinsulinemia (approximately 70 microU/ml) and during somatostatin-induced insulinopenia to measure IMGU and NIMGU, respectively. During each study, leg glucose balance (arteriovenous catheter technique) was also measured. With this approach, rates of whole body skeletal muscle IMGU and NIMGU can be estimated, and the difference between overall Rd and skeletal muscle glucose uptake represents non-skeletal muscle Rd. The results indicate that approximately 20% of basal Rd is into skeletal muscle. During insulinopenia approximately 86% of body NIMGU occurs in non-skeletal muscle tissues at euglycemia. When hyperglycemia was created, whole body NIMGU increased from 128 +/- 6 to 213 +/- 18 mg/min (P less than 0.01); NIMGU into non-skeletal muscle tissues was 134 +/- 11 and 111 +/- 6 mg/min at hyperglycemia and euglycemia, respectively, P = NS. Therefore, virtually all the hyperglycemia induced increment in NIMGU occurred in skeletal muscle. During hyperinsulinemia, IMGU in skeletal muscle represented 75 and 95% of body Rd, at euglycemia and hyperglycemia, respectively

  4. Action of Phytochemicals on Insulin Signaling Pathways Accelerating Glucose Transporter (GLUT4 Protein Translocation

    Directory of Open Access Journals (Sweden)

    Abu Sadat Md Sayem

    2018-01-01

    Full Text Available Diabetes is associated with obesity, generally accompanied by a chronic state of oxidative stress and redox imbalances which are implicated in the progression of micro- and macro-complications like heart disease, stroke, dementia, cancer, kidney failure and blindness. All these complications rise primarily due to consistent high blood glucose levels. Insulin and glucagon help to maintain the homeostasis of glucose and lipids through signaling cascades. Pancreatic hormones stimulate translocation of the glucose transporter isoform 4 (GLUT4 from an intracellular location to the cell surface and facilitate the rapid insulin-dependent storage of glucose in muscle and fat cells. Malfunction in glucose uptake mechanisms, primarily contribute to insulin resistance in type 2 diabetes. Plant secondary metabolites, commonly known as phytochemicals, are reported to have great benefits in the management of type 2 diabetes. The role of phytochemicals and their action on insulin signaling pathways through stimulation of GLUT4 translocation is crucial to understand the pathogenesis of this disease in the management process. This review will summarize the effects of phytochemicals and their action on insulin signaling pathways accelerating GLUT4 translocation based on the current literature.

  5. Fabrication of Glucose-Sensitive Layer-by-Layer Films for Potential Controlled Insulin Release Applications

    Directory of Open Access Journals (Sweden)

    Talusan Timothy Jemuel E.

    2015-01-01

    Full Text Available Self-regulated drug delivery systems (DDS are potential alternative to the conventional method of introducing insulin to the body due to their controlled drug release mechanism. In this study, Layer-by-Layer technique was utlized to manufacture drug loaded, pH responsive thin films. Insulin was alternated with pH-sensitive, [2-(dimethyl amino ethyl aminoacrylate] (PDMAEMA and topped of with polymer/glucose oxidase (GOD layers. Similarly, films using a different polymer, namely Poly(Acrylic Acid (PAA were also fabricated. Exposure of the films to glucose solutions resulted to the production of gluconic acid causing a polymer conformation change due to protonation, thus releasing the embedded insulin. The insulin release was monitored by subjecting the dipping glucose solutions to Bradford Assay. Films exhibited a reversal in drug release profile in the presence of glucose as compared to without glucose. PAA films were also found out to release more insulin compared to that of the PDMAEMA films.The difference in the profile of the two films were due to different polymer-GOD interactions, since both films exhibited almost identical profiles when embedded with Poly(sodium 4-styrenesulfonate (PSS instead of GOD.

  6. The effect of a prenatal lifestyle intervention on glucose metabolism: results of the Norwegian Fit for Delivery randomized controlled trial.

    Science.gov (United States)

    Sagedal, Linda R; Vistad, Ingvild; Øverby, Nina C; Bere, Elling; Torstveit, Monica K; Lohne-Seiler, Hilde; Hillesund, Elisabet R; Pripp, Are; Henriksen, Tore

    2017-06-02

    The effectiveness of prenatal lifestyle intervention to prevent gestational diabetes and improve maternal glucose metabolism remains to be established. The Norwegian Fit for Delivery (NFFD) randomized, controlled trial studied the effect of a combined lifestyle intervention provided to a general population, and found significantly lower gestational weight gain among intervention participants but no improvement in obstetrical outcomes or the proportion of large infants. The aim of the present study is to examine the effect of the NFFD intervention on glucose metabolism, including an assessment of the subgroups of normal-weight and overweight/obese participants. Healthy, non-diabetic women expecting their first child, with pre-pregnancy body mass index (BMI) ≥19 kg/m 2 , age ≥ 18 years and a singleton pregnancy of ≤20 gestational-weeks were enrolled from healthcare clinics in southern Norway. Gestational weight gain was the primary endpoint. Participants (n = 606) were individually randomized to intervention (two dietary consultations and access to twice-weekly exercise groups) or control group (routine prenatal care). The effect of intervention on glucose metabolism was a secondary endpoint, measuring glucose (fasting and 2-h following 75-g glucose load), insulin, homeostatic assessment of insulin resistance (HOMA-IR) and leptin levels at gestational-week 30. Blood samples from 557 (91.9%) women were analyzed. For the total group, intervention resulted in reduced insulin (adj. Mean diff -0.91 mU/l, p = 0.045) and leptin levels (adj. Mean diff -207 pmol/l, p = 0.021) compared to routine care, while glucose levels were unchanged. However, the effect of intervention on both fasting and 2-h glucose was modified by pre-pregnancy BMI (interaction p = 0.030 and p = 0.039, respectively). For overweight/obese women (n = 158), intervention was associated with increased risk of at least one glucose measurement exceeding International Association of

  7. Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test

    DEFF Research Database (Denmark)

    Solomon, Thomas; Malin, Steven K; Karstoft, Kristian

    2014-01-01

    Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index...

  8. Effect Of Leptin Status On Neuroendocrine- Reproductive ...

    African Journals Online (AJOL)

    The brain of each rat was harvested and processed into whole homogenate, and was used for some biochemicals assays (i.e isolation and purification of RNA, reverse transcription polymerase chain reaction (PCR), and leptin assay). The results showed that insulin increased the secretion of leptin, which in turn, reduced ...

  9. Cord Blood Leptin Levels in Gestational Diabetes

    Directory of Open Access Journals (Sweden)

    Özlem Şengül

    2010-08-01

    CONCLUSION: In this study there is a minimal clinical effect of cord blood leptin on macrosomia in women with GD, although it is increased in GD and associated with birthweight. Therefore overgrowth may be a result of direct anabolic effect of insulin, rather than indirect effect via leptin.

  10. Continuous glucose monitoring-enabled insulin-pump therapy in diabetic pregnancy

    DEFF Research Database (Denmark)

    Secher, Anna L; Schmidt, Signe; Nørgaard, Kirsten

    2010-01-01

    We describe the feasibility of continuous glucose monitoring (CGM)-enabled insulin-pump therapy during pregnancy in a woman with type 1 diabetes, who was treated with CGM-enabled insulin-pump therapy in her third pregnancy. During her first pregnancy, the woman was treated with multiple daily inj...

  11. An ancestral role for the mitochondrial pyruvate carrier in glucose-stimulated insulin secretion

    OpenAIRE

    McCommis, Kyle S.; Hodges, Wesley T.; Bricker, Daniel K.; Wisidagama, Dona R.; Compan, Vincent; Remedi, Maria S.; Thummel, Carl S.; Finck, Brian N.

    2016-01-01

    Objective: Transport of pyruvate into the mitochondrial matrix by the Mitochondrial Pyruvate Carrier (MPC) is an important and rate-limiting step in its metabolism. In pancreatic β-cells, mitochondrial pyruvate metabolism is thought to be important for glucose sensing and glucose-stimulated insulin secretion. Methods: To evaluate the role that the MPC plays in maintaining systemic glucose homeostasis, we used genetically-engineered Drosophila and mice with loss of MPC activity in insulin-prod...

  12. Changes in blood glucose and insulin responses to intravenous glucose tolerance tests and blood biochemical values in adult female Japanese black bears (Ursus thibetanus japonicus).

    Science.gov (United States)

    Kamine, Akari; Shimozuru, Michito; Shibata, Haruki; Tsubota, Toshio

    2012-02-01

    The metabolic mechanisms to circannual changes in body mass of bears have yet to be elucidated. We hypothesized that the Japanese black bear (Ursus thibetanus japonicus) has a metabolic mechanism that efficiently converts carbohydrates into body fat by altering insulin sensitivity during the hyperphagic stage before hibernation. To test this hypothesis, we investigated the changes in blood biochemical values and glucose and insulin responses to intravenous glucose tolerance tests (IVGTT) during the active season (August, early and late November). Four, adult, female bears (5-17 years old) were anesthetized with 6 mg/kg TZ (tiletamine HCl and zolazepam HCl) in combination with 0.1 mg/kg acepromazine maleate. The bears were injected intravenously with glucose (0.5 g/kg of body mass), and blood samples were obtained before, at, and intermittently after glucose injection. The basal triglycerides concentration decreased significantly with increase in body mass from August to November. Basal levels of plasma glucose and serum insulin concentrations were not significantly different among groups. The results of IVGTT demonstrated the increased peripheral insulin sensitivity and glucose tolerance in early November. In contrast, peripheral insulin resistance was indicated by the exaggerated insulin response in late November. Our findings suggest that bears shift their glucose and lipid metabolism from the stage of normal activity to the hyperphagic stage in which they show lipogenic-predominant metabolism and accelerate glucose uptake by increasing the peripheral insulin sensitivity.

  13. Sweet taste of saccharin induces weight gain without increasing caloric intake, not related to insulin-resistance in Wistar rats.

    Science.gov (United States)

    Foletto, Kelly Carraro; Melo Batista, Bruna Aparecida; Neves, Alice Magagnin; de Matos Feijó, Fernanda; Ballard, Cíntia Reis; Marques Ribeiro, Maria Flávia; Bertoluci, Marcello Casaccia

    2016-01-01

    In a previous study, we showed that saccharin can induce weight gain when compared with sucrose in Wistar rats despite similar total caloric intake. We now question whether it could be due to the sweet taste of saccharin per se. We also aimed to address if this weight gain is associated with insulin-resistance and to increases in gut peptides such as leptin and PYY in the fasting state. In a 14 week experiment, 16 male Wistar rats received either saccharin-sweetened yogurt or non-sweetened yogurt daily in addition to chow and water ad lib. We measured daily food intake and weight gain weekly. At the end of the experiment, we evaluated fasting leptin, glucose, insulin, PYY and determined insulin resistance through HOMA-IR. Cumulative weight gain and food intake were evaluated through linear mixed models. Results showed that saccharin induced greater weight gain when compared with non-sweetened control (p = 0.027) despite a similar total caloric intake. There were no differences in HOMA-IR, fasting leptin or PYY levels between groups. We conclude that saccharin sweet taste can induce mild weight gain in Wistar rats without increasing total caloric intake. This weight gain was not related with insulin-resistance nor changes in fasting leptin or PYY in Wistar rats. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. Assessment of insulin resistance in fructose-fed rats with {sup 125}I-6-deoxy-6-iodo-D-glucose, a new tracer of glucose transport

    Energy Technology Data Exchange (ETDEWEB)

    Perret, Pascale; Slimani, Lotfi; Briat, Arnaud; Villemain, Daniele; Fagret, Daniel; Ghezzi, Catherine [INSERM, E340, 38000 Grenoble, (France); Univ Grenoble, 38000 Grenoble, (France); Halimi, Serge [CHRU Grenoble, Hopital Michallon, Service de Diabetologie, 38000 Grenoble, (France); Demongeot, Jacques [Univ Grenoble, 38000 Grenoble, (France); CNRS, UMR 5525, 38000 Grenoble, (France)

    2007-05-15

    Insulin resistance, characterised by an insulin-stimulated glucose transport defect, is an important feature of the pre-diabetic state that has been observed in numerous pathological disorders. The purpose of this study was to assess variations in glucose transport in rats using {sup 125}I-6-deoxy-6-iodo-D-glucose (6DIG), a new tracer of glucose transport proposed as an imaging tool to assess insulin resistance in vivo. Two protocols were performed, a hyperinsulinaemic-euglycaemic clamp and a normoinsulinaemic-normoglycaemic protocol, in awake control and insulin-resistant fructose-fed rats. The tracer was injected at steady state, and activity in 11 tissues and the blood was assessed ex vivo at several time points. A multicompartmental mathematical model was developed to obtain fractional transfer coefficients of 6DIG from the blood to the organs. Insulin sensitivity of fructose-fed rats, estimated by the glucose infusion rate, was reduced by 40% compared with control rats. At steady state, 6DIG uptake was significantly stimulated by insulin in insulin-sensitive tissues of control rats (basal versus insulin: diaphragm, p < 0.01; muscle, p < 0.05; heart, p < 0.001), whereas insulin did not stimulate 6DIG uptake in insulin-resistant fructose-fed rats. Moreover, in these tissues, the fractional transfer coefficients of entrance were significantly increased with insulin in control rats (basal vs insulin: diaphragm, p < 0.001; muscle, p < 0.001; heart, p < 0.01) whereas no significant changes were observed in fructose-fed rats. This study sets the stage for the future use of 6DIG as a non-invasive means for the evaluation of insulin resistance by nuclear imaging. (orig.)

  15. Gestational Protein Restriction Impairs Insulin-Regulated Glucose Transport Mechanisms in Gastrocnemius Muscles of Adult Male Offspring

    Science.gov (United States)

    Blesson, Chellakkan S.; Sathishkumar, Kunju; Chinnathambi, Vijayakumar

    2014-01-01

    Type II diabetes originates from various genetic and environmental factors. Recent studies showed that an adverse uterine environment such as that caused by a gestational low-protein (LP) diet can cause insulin resistance in adult offspring. The mechanism of insulin resistance induced by gestational protein restriction is not clearly understood. Our aim was to investigate the role of insulin signaling molecules in gastrocnemius muscles of gestational LP diet–exposed male offspring to understand their role in LP-induced insulin resistance. Pregnant Wistar rats were fed a control (20% protein) or isocaloric LP (6%) diet from gestational day 4 until delivery and a normal diet after weaning. Only male offspring were used in this study. Glucose and insulin responses were assessed after a glucose tolerance test. mRNA and protein levels of molecules involved in insulin signaling were assessed at 4 months in gastrocnemius muscles. Muscles were incubated ex vivo with insulin to evaluate insulin-induced phosphorylation of insulin receptor (IR), Insulin receptor substrate-1, Akt, and AS160. LP diet-fed rats gained less weight than controls during pregnancy. Male pups from LP diet–fed mothers were smaller but exhibited catch-up growth. Plasma glucose and insulin levels were elevated in LP offspring when subjected to a glucose tolerance test; however, fasting levels were comparable. LP offspring showed increased expression of IR and AS160 in gastrocnemius muscles. Ex vivo treatment of muscles with insulin showed increased phosphorylation of IR (Tyr972) in controls, but LP rats showed higher basal phosphorylation. Phosphorylation of Insulin receptor substrate-1 (Tyr608, Tyr895, Ser307, and Ser318) and AS160 (Thr642) were defective in LP offspring. Further, glucose transporter type 4 translocation in LP offspring was also impaired. A gestational LP diet leads to insulin resistance in adult offspring by a mechanism involving inefficient insulin-induced IR, Insulin receptor

  16. Dissociation of in vitro sensitivities of glucose transport and antilipolysis to insulin in NIDDM

    International Nuclear Information System (INIS)

    Yki-Jaervinen, H.; Kubo, K.; Zawadzki, J.; Lillioja, S.; Young, A.; Abbott, W.; Foley, J.E.

    1987-01-01

    It is unclear from previous studies whether qualitative or only quantitative differences exist in insulin action in adipocytes obtained from obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) when compared with equally obese nondiabetic subjects. In addition, the role of changes in insulin binding as a cause of insulin resistance in NIDDM is still controversial. The authors compared the sensitivities of [ 14 C]-glucose transport and antilipolysis to insulin and measured [ 125 I]-insulin binding in abdominal adipocytes obtained from 45 obese nondiabetic, obese diabetic, and 15 nonobese female southwestern American Indians. Compared with the nonobese group, the sensitivities of glucose transport antilipolysis were reduced in both the obese nondiabetic and obese diabetic groups. Compared with the obese nondiabetic subjects, the ED 50 for stimulation of glucose transport was higher in the obese patients with NIDDM. In contrast, the ED 50 S for antilipolysis were similar in obese diabetic patients and obese nondiabetic subjects. No differences was found in insulin binding in patients with NIDDM when compared with the equally obese nondiabetic subjects. These data indicate 1) the mechanism of insulin resistance differs in NIDDM and obesity, and 2) the selective loss of insulin sensitivity in NIDDM precludes changes in insulin binding as a cause of insulin resistance in this disorder

  17. Differentiation of the insulin-sensitive glucose transporter in 3T3-L1 adipocytes

    International Nuclear Information System (INIS)

    Frost, S.C.; Baly, D.L.; Cushman, S.W.; Lane, M.D.; Simpson, I.A.

    1986-01-01

    3T3-L1 fibroblasts differentiate in culture to resemble adipocytes both morphologically and biochemically. Insulin-sensitive glucose transport, as measured by 2-deoxy-[1- 14 C]- glucose uptake in the undifferentiated cell is small (2X). In contrast, the rate of glucose transport in fully differentiated cells is elevated 15-fold over basal in the presence of insulin. To determine if this is due to an increase in the number of transporters/cell or accessibility to the transporters, the number of transporters was measured in subcellular fractions over differentiation using a 3 H-cytochalasin B binding assay. The increase in the rate of insulin-sensitive glucose transport directly parallels an increase in the number of transporters which reside in an insulin-responsive intracellular compartment. This observation was confirmed by identifying the transporters by immunoblotting using an antibody generated against the human erythrocyte transporter. The molecular weight of this transporter increases over differentiation from a single band of 40kDa to a heterogeneous triplet of 40, 44 and 48kDa. These data suggest that the transporter undergoes differential processing and that the functional, insulin-responsive transporter may be different from the insulin-insensitive (basal) transporter

  18. Acute stimulation of brain mu opioid receptors inhibits glucose-stimulated insulin secretion via sympathetic innervation.

    Science.gov (United States)

    Tudurí, Eva; Beiroa, Daniel; Stegbauer, Johannes; Fernø, Johan; López, Miguel; Diéguez, Carlos; Nogueiras, Rubén

    2016-11-01

    Pancreatic insulin-secreting β-cells express opioid receptors, whose activation by opioid peptides modulates hormone secretion. Opioid receptors are also expressed in multiple brain regions including the hypothalamus, where they play a role in feeding behavior and energy homeostasis, but their potential role in central regulation of glucose metabolism is unknown. Here, we investigate whether central opioid receptors participate in the regulation of insulin secretion and glucose homeostasis in vivo. C57BL/6J mice were acutely treated by intracerebroventricular (i.c.v.) injection with specific agonists for the three main opioid receptors, kappa (KOR), delta (DOR) and mu (MOR) opioid receptors: activation of KOR and DOR did not alter glucose tolerance, whereas activation of brain MOR with the specific agonist DAMGO blunted glucose-stimulated insulin secretion (GSIS), reduced insulin sensitivity, increased the expression of gluconeogenic genes in the liver and, consequently, impaired glucose tolerance. Pharmacological blockade of α2A-adrenergic receptors prevented DAMGO-induced glucose intolerance and gluconeogenesis. Accordingly, DAMGO failed to inhibit GSIS and to impair glucose tolerance in α2A-adrenoceptor knockout mice, indicating that the effects of central MOR activation on β-cells are mediated via sympathetic innervation. Our results show for the first time a new role of the central opioid system, specifically the MOR, in the regulation of insulin secretion and glucose metabolism. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Hypoglycemia in type 2 diabetes patients treated with insulin: the advantages of continuous glucose monitoring

    Directory of Open Access Journals (Sweden)

    Vadim Valer'evich Klimontov

    2014-03-01

    Full Text Available Aims.  To determine the incidence and risk factors for hypoglycemia in elderly insulin-treated type 2 diabetes mellitus (T2DM patients by means of continuous glucose monitoring (CGM. Materials and Methods.  We observed seventy-six hospitalized patients with T2DM, aged 65 to 79 years. Treatment with basal insulin (n=36, premixed insulin (n=12 or basal-bolus insulin regimen (n=28 was followed by metformin (n=44, glimepiride (n=14 and dipeptidyl peptidase-4 inhibitors (n=14. 2-days CGM with retrospective data analysis was performed in all patients. During CGM, three fasting and three 2-h postprandial finger-prick glucose values were obtained daily with portable glucose meter. Results.  Hypoglycemia (identified as blood glucose

  20. Glucose-stimulated insulin response in pregnant sheep following acute suppression of plasma non-esterified fatty acid concentrations

    Directory of Open Access Journals (Sweden)

    Sriskandarajah Nadarajah

    2004-09-01

    Full Text Available Abstract Background Elevated non-esterified fatty acids (NEFA concentrations in non-pregnant animals have been reported to decrease pancreatic responsiveness. As ovine gestation advances, maternal insulin concentrations fall and NEFA concentrations increase. Experiments were designed to examine if the pregnancy-associated rise in NEFA concentration is associated with a reduced pancreatic sensitivity to glucose in vivo. We investigated the possible relationship of NEFA concentrations in regulating maternal insulin concentrations during ovine pregnancy at three physiological states, non-pregnant, non-lactating (NPNL, 105 and 135 days gestational age (dGA, term 147+/- 3 days. Methods The plasma concentrations of insulin, growth hormone (GH and ovine placental lactogen (oPL were determined by double antibody radioimmunoassay. Insulin responsiveness to glucose was measured using bolus injection and hyperglycaemic clamp techniques in 15 non-pregnant, non-lactating ewes and in nine pregnant ewes at 105 dGA and near term at 135 dGA. Plasma samples were also collected for hormone determination. In addition to bolus injection glucose and insulin Area Under Curve calculations, the Mean Plasma Glucose Increment, Glucose Infusion Rate and Mean Plasma Insulin Increment and Area Under Curve were determined for the hyperglycaemic clamp procedures. Statistical analysis of data was conducted with Students t-tests, repeated measures ANOVA and 2-way ANOVA. Results Maternal growth hormone, placental lactogen and NEFA concentrations increased, while basal glucose and insulin concentrations declined with advancing gestation. At 135 dGA following bolus glucose injections, peak insulin concentrations and insulin area under curve (AUC profiles were significantly reduced in pregnant ewes compared with NPNL control ewes (p Conclusions Results suggest that despite an acute suppression of circulating NEFA concentrations during pregnancy, the associated steroids and hormones

  1. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol

    DEFF Research Database (Denmark)

    Nøhr, Mark K; Dudele, Anete; Poulsen, Morten M

    2016-01-01

    we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered...... through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b......, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during...

  2. Modelling of glucose-insulin-glucagon pharmacodynamics in man

    DEFF Research Database (Denmark)

    Wendt, Sabrina Lyngbye; Møller, Jan Kloppenborg; Haidar, A.

    The purpose is to build a simulation model of the glucoregulatory system in man. We estimate individual human parameters of a physiological glucose-insulin-glucagon model. We report posterior probability distributions and correlations of model parameters....

  3. Are the beneficial cardiovascular effects of simvastatin and metformin also associated with a hormone-dependent mechanism improving insulin sensitivity?

    Directory of Open Access Journals (Sweden)

    C. Bulcão

    Full Text Available In addition to lipid-lowering and cardiovascular protective actions, statins may have beneficial effects on insulin sensitivity. The objective of the present study was to evaluate the effect of simvastatin therapy on insulin resistance and on leptin, adiponectin, and C-reactive protein (CRP levels, as compared to metformin, in overweight pre-diabetic subjects. Forty-one subjects with BMI >25 kg/m² and impaired fasting glucose or impaired glucose tolerance were randomized to take simvastatin, 20 mg/day (N = 20 or metformin, 1.7 g/day (N = 21 for 16 weeks. Blood samples for the determination of metabolic, hormonal, and inflammatory parameters were obtained at baseline and after each treatment. After metformin therapy, significant reductions in mean BMI and waist circumference were observed, and after simvastatin treatment LDL and triglyceride levels were significantly reduced. Insulin resistance determined by the homeostasis model assessment decreased only with metformin. Independently of the type of medication, a significant decrease in CRP levels was detected from baseline to the end of the study. CRP showed a mean reduction of 0.12 ± 0.04 mg/dL (P = 0.002 over time. No change in leptin or adiponectin levels was induced by any therapy. The data suggest that a low dose of simvastatin does not affect insulin resistance in overweight pre-diabetic subjects and has no effect on leptin or adiponectin levels. Further studies including a larger sample size, higher doses of statins, and a placebo control group are necessary to confirm the present data.

  4. Systemic Glucoregulation by Glucose-Sensing Neurons in the Ventromedial Hypothalamic Nucleus (VMH).

    Science.gov (United States)

    Shimazu, Takashi; Minokoshi, Yasuhiko

    2017-05-01

    The ventromedial hypothalamic nucleus (VMH) regulates glucose production in the liver as well as glucose uptake and utilization in peripheral tissues, including skeletal muscle and brown adipose tissue, via efferent sympathetic innervation and neuroendocrine mechanisms. The action of leptin on VMH neurons also increases glucose uptake in specific peripheral tissues through the sympathetic nervous system, with improved insulin sensitivity. On the other hand, subsets of VMH neurons, such as those that express steroidogenic factor 1 (SF1), sense changes in the ambient glucose concentration and are characterized as glucose-excited (GE) and glucose-inhibited (GI) neurons whose action potential frequency increases and decreases, respectively, as glucose levels rise. However, how these glucose-sensing (GE and GI) neurons in the VMH contribute to systemic glucoregulation remains poorly understood. In this review, we provide historical background and discuss recent advances related to glucoregulation by VMH neurons. In particular, the article describes the role of GE neurons in the control of peripheral glucose utilization and insulin sensitivity, which depend on mitochondrial uncoupling protein 2 of the neurons, as well as that of GI neurons in the control of hepatic glucose production through hypoglycemia-induced counterregulatory mechanisms.

  5. Role of leptin resistance in the development of obesity in older patients

    Directory of Open Access Journals (Sweden)

    Carter S

    2013-07-01

    Full Text Available Sophie Carter,1,* Alexandre Caron,2,* Denis Richard,2 Frédéric Picard1 1Faculty of Pharmacy, 2Faculty of Medicine, Dept Anatomy and Physiology, Université Laval, Québec, QC, Canada *These authors contributed equally to the work Abstract: Obesity is a global epidemic associated with aging-like cellular processes; in both aging and obesity, resistance to hormones such as insulin and leptin can be observed. Leptin is a circulating hormone/cytokine with central and peripheral effects that is released mainly by subcutaneous white adipose tissue. Centrally, leptin controls food intake, energy expenditure, and fat distribution, whereas it controls (among several others insulin sensitivity, free fatty acids (FFAs oxidation, and lipolysis in the periphery. Aging is associated with important changes in both the distribution and the composition of adipose tissue. Fat is redistributed from the subcutaneous to the visceral depot and increased inflammation participates in adipocyte dysfunction. This redistribution of adipose tissue in favor of visceral fat influences negatively both longevity and healthy aging as shown in numerous animal models. These modifications observed during aging are also associated with leptin resistance. This resistance blunts normal central and peripheral functions of leptin, which leads to a decrease in neuroendocrine function and insulin sensitivity, an imbalance in energy regulation, and disturbances in lipid metabolism. Here, we review how age-related leptin resistance triggers metabolic disturbances and affects the longevity of obese patients. Furthermore, we discuss the potential impacts of leptin resistance on the decline of brown adipose tissue thermogenesis observed in elderly individuals. Keywords: leptin, obesity, aging, insulin sensitivity, brown adipose tissue

  6. Mathematical modeling of the glucose-insulin system

    DEFF Research Database (Denmark)

    Palumbo, Pasquale; Ditlevsen, Susanne; Bertuzzi, Alessandro

    2013-01-01

    of pancreatic insulin production, with a oarser/finer level of detail ranging over cellular and subcellular scales, to short-term organ/tissue models accounting for the intra-venous and the oral glucose tolerance tests as well as for the euglycemic hyperinsulinemic clamp, to total-body, long-term diabetes...

  7. The clinical significance of serum Leptin in the pathogenesis of 2DM and obesity

    International Nuclear Information System (INIS)

    Liu Chunyu; Lu Kuan; Gao Yanyan

    2001-01-01

    Objective: To study the relationship between serum Leptin ad insulin, body fat distribution and testosterone in 2-DM patients. Methods: The fasting blood serum Leptin and insulin levels in 65 2DM patients and 42 controls were measured by radioimmunoassay. Abdominal subcutaneous adipose tissue volume (ASF) and abdominal visceral adipose tissue volume (AVF) were measured by spiral CT SSD soft-ware in 32 2DM patients. The authors also measured the Leptin before and 2h after a 75 g OGTT in 34 2DM patients and fasting plasma testosterone in 30 2DM males. Results: DM group and normal group had equal number of females and were matched in BMI. Baseline plasma Leptin concentrations were not significantly different between the groups (P 14 mmol/L) had lower Leptin levels (P < 0.05). Sex, BMI, ASF were important factors contributing to the serum Leptin. The Leptin concentrations were significantly positively correlated with BMI (r 0.57, P0.0001), ASF(r = 0.67 P0.025) and insulin (r = 0.47, P0.0013) and was negative correlated with the serum testosterone (r = -0.061, P0.025). Conclusion: There were no abnormal Leptin levels in 2DM implies, suggesting that Leptin might not be the main causing factor in 2DM. The poorly metabolic controlled patients might have lack of Leptin. The lower Leptin levels in men might be caused by testosterone, sex BMI, ASF were important factors contributing to the serum Leptin levels

  8. Overexpression of the ped/pea-15 Gene Causes Diabetes by Impairing Glucose-Stimulated Insulin Secretion in Addition to Insulin Action

    OpenAIRE

    Vigliotta, Giovanni; Miele, Claudia; Santopietro, Stefania; Portella, Giuseppe; Perfetti, Anna; Maitan, Maria Alessandra; Cassese, Angela; Oriente, Francesco; Trencia, Alessandra; Fiory, Francesca; Romano, Chiara; Tiveron, Cecilia; Tatangelo, Laura; Troncone, Giancarlo; Formisano, Pietro

    2004-01-01

    Overexpression of the ped/pea-15 gene is a common feature of type 2 diabetes. In the present work, we show that transgenic mice ubiquitously overexpressing ped/pea-15 exhibited mildly elevated random-fed blood glucose levels and decreased glucose tolerance. Treatment with a 60% fat diet led ped/pea-15 transgenic mice to develop diabetes. Consistent with insulin resistance in these mice, insulin administration reduced glucose levels by only 35% after 45 min, compared to 70% in control mice. In...

  9. Inhibition of insulin-dependent glucose uptake by trivalent arsenicals: possible mechanism of arsenic-induced diabetes

    International Nuclear Information System (INIS)

    Walton, Felecia S.; Harmon, Anne W.; Paul, David S.; Drobna, Zuzana; Patel, Yashomati M.; Styblo, Miroslav

    2004-01-01

    Chronic exposures to inorganic arsenic (iAs) have been associated with increased incidence of noninsulin (type-2)-dependent diabetes mellitus. Although mechanisms by which iAs induces diabetes have not been identified, the clinical symptoms of the disease indicate that iAs or its metabolites interfere with insulin-stimulated signal transduction pathway or with critical steps in glucose metabolism. We have examined effects of iAs and methylated arsenicals that contain trivalent or pentavalent arsenic on glucose uptake by 3T3-L1 adipocytes. Treatment with inorganic and methylated pentavalent arsenicals (up to 1 mM) had little or no effect on either basal or insulin-stimulated glucose uptake. In contrast, trivalent arsenicals, arsenite (iAs III ), methylarsine oxide (MAs III O), and iododimethylarsine (DMAs III O) inhibited insulin-stimulated glucose uptake in a concentration-dependent manner. Subtoxic concentrations of iAs III (20 μM), MAs III O (1 μM), or DMAs III I (2 μM) decreased insulin-stimulated glucose uptake by 35-45%. Basal glucose uptake was significantly inhibited only by cytotoxic concentrations of iAs III or MAs III O. Examination of the components of the insulin-stimulated signal transduction pathway showed that all trivalent arsenicals suppressed expression and possibly phosphorylation of protein kinase B (PKB/Akt). The concentration of an insulin-responsive glucose transporter (GLUT4) was significantly lower in the membrane region of 3T3-L1 adipocytes treated with trivalent arsenicals as compared with untreated cells. These results suggest that trivalent arsenicals inhibit insulin-stimulated glucose uptake by interfering with the PKB/Akt-dependent mobilization of GLUT4 transporters in adipocytes. This mechanism may be, in part, responsible for the development of type-2 diabetes in individuals chronically exposed to iAs

  10. Divergent effects of glucose and fructose on hepatic lipogenesis and insulin signaling.

    Science.gov (United States)

    Softic, Samir; Gupta, Manoj K; Wang, Guo-Xiao; Fujisaka, Shiho; O'Neill, Brian T; Rao, Tata Nageswara; Willoughby, Jennifer; Harbison, Carole; Fitzgerald, Kevin; Ilkayeva, Olga; Newgard, Christopher B; Cohen, David E; Kahn, C Ronald

    2017-11-01

    Overconsumption of high-fat diet (HFD) and sugar-sweetened beverages are risk factors for developing obesity, insulin resistance, and fatty liver disease. Here we have dissected mechanisms underlying this association using mice fed either chow or HFD with or without fructose- or glucose-supplemented water. In chow-fed mice, there was no major physiological difference between fructose and glucose supplementation. On the other hand, mice on HFD supplemented with fructose developed more pronounced obesity, glucose intolerance, and hepatomegaly as compared to glucose-supplemented HFD mice, despite similar caloric intake. Fructose and glucose supplementation also had distinct effects on expression of the lipogenic transcription factors ChREBP and SREBP1c. While both sugars increased ChREBP-β, fructose supplementation uniquely increased SREBP1c and downstream fatty acid synthesis genes, resulting in reduced liver insulin signaling. In contrast, glucose enhanced total ChREBP expression and triglyceride synthesis but was associated with improved hepatic insulin signaling. Metabolomic and RNA sequence analysis confirmed dichotomous effects of fructose and glucose supplementation on liver metabolism in spite of inducing similar hepatic lipid accumulation. Ketohexokinase, the first enzyme of fructose metabolism, was increased in fructose-fed mice and in obese humans with steatohepatitis. Knockdown of ketohexokinase in liver improved hepatic steatosis and glucose tolerance in fructose-supplemented mice. Thus, fructose is a component of dietary sugar that is distinctively associated with poor metabolic outcomes, whereas increased glucose intake may be protective.

  11. The glucose-dependent insulinotropic polypeptide and glucose-stimulated insulin response to exercise training and diet in obesity

    OpenAIRE

    Kelly, Karen R.; Brooks, Latina M.; Solomon, Thomas P. J.; Kashyap, Sangeeta R.; O'Leary, Valerie B.; Kirwan, John P.

    2009-01-01

    Aging and obesity are characterized by decreased β-cell sensitivity and defects in the potentiation of nutrient-stimulated insulin secretion by GIP. Exercise and diet are known to improve glucose metabolism and the pancreatic insulin response to glucose, and this effect may be mediated through the incretin effect of GIP. The purpose of this study was to assess the effects of a 12-wk exercise training intervention (5 days/wk, 60 min/day, 75% V̇o2 max) combined with a eucaloric (EX, n = 10) or ...

  12. Effects of hydroalcoholic extract of Rhus coriaria seed on glucose and insulin related biomarkers, lipid profile, and hepatic enzymes in nicotinamide-streptozotocin-induced type II diabetic male mice.

    Science.gov (United States)

    Ahangarpour, Akram; Heidari, Hamid; Junghani, Majid Salehizade; Absari, Reza; Khoogar, Mehdi; Ghaedi, Ehsan

    2017-10-01

    Type 2 diabetes often leads to dislipidemia and abnormal activity of hepatic enzymes. The purpose of this study was to evaluate the antidiabetic and hypolipidemic properties of Rhus coriaria ( R. coriaria ) seed extrac on nicotinamide-streptozotocin induced type 2 diabetic mice. In this experimental study, 56 male Naval Medical Research Institute mice (30-35 g) were randomly separated into seven groups: control, diabetic group, diabetic mice treated with glibenclamide (0.25 mg/kg, as standard antidiabetic drug) or R. coriaria seed extract in doses of 200 and 300 mg/kg, and control groups received these two doses of extract orally for 28 days. Induction of diabetes was done by intraperitoneal injection of nicotinamide and streptozotocin. Ultimately, body weight of mice, blood levels of glucose, insulin, hepatic enzymes, leptin, and lipid profile were assayed. After induction of type 2 diabetes, level of glucose, cholesterol, low density lipoprotein, serum glutamic oxaloacetic transaminase, and serum glutamic pyruvic transaminase increased and level of insulin and high density lipoprotein decreased remarkably. Administration of both doses of extract decreased level of glucose and cholesterol significantly in diabetic mice. LDL level decreased in treated group with dose of 300 mg/kg of the extract. Although usage of the extract improved level of other lipid profiles, insulin and hepatic enzymes, changes weren't significant. This study showed R. coriaria seeds administration has a favorable effect in controlling some blood parameters in type 2 diabetes. Therefore it may be beneficial in the treatment of diabetes.

  13. Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

    Science.gov (United States)

    2015-01-01

    Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise. PMID:26487009

  14. The impact of transsphenoidal surgery on glucose homeostasis and insulin resistance in acromegaly.

    Science.gov (United States)

    Stelmachowska-Banaś, Maria; Zieliński, Grzegorz; Zdunowski, Piotr; Podgórski, Jan; Zgliczyński, Wocjiech

    2011-01-01

    Impaired glucose tolerance and overt diabetes mellitus are frequently associated with acro-megaly. The aim of this study was to find out whether these alterations could be reversed after transsphenoidal surgery. Two hundred and thirty-nine acromegalic patients were studied before and 6-12 months after transsphenoidal surgery. Diagnosis of active acromegaly was established on the basis of widely recognized criteria. In each patient, glucose and insulin concentrations were assessed during the 75 γ oral glucose tolerance test (OGTT). To estimate insulin resistance, we used homeostasis model assessment (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI). At the moment of diagnosis, diabetes mellitus was present in 25% of the acromegalic patients. After surgery, the pre-valence of diabetes mellitus normalized to the level present in the general Polish population. We found a statistically significant reduction after surgery in plasma glucose levels both fasting (89.45 ± 13.92 mg/dL vs. 99.12 ± 17.33 mg/dL, p surgery compared to the moment of diagnosis (15.44 ± 8.80 mIU/mL vs. 23.40 ± 10.24 mIU/mL, p transsphenoidal surgery, there was a significant reduction in HOMA-IR (3.08 vs. 6.76, p surgery in fasting glucose and insulin levels between patients with controlled and in-adequately controlled disease. We conclude that in acromegalic patients glucose homeostasis alterations and insulin sensitivity can be normalized after transsphenoidal surgery, even if strict biochemical cure criteria are not fulfilled.

  15. Probiotics modulate gut microbiota and improve insulin sensitivity in DIO mice.

    Science.gov (United States)

    Bagarolli, Renata A; Tobar, Natália; Oliveira, Alexandre G; Araújo, Tiago G; Carvalho, Bruno M; Rocha, Guilherme Z; Vecina, Juliana F; Calisto, Kelly; Guadagnini, Dioze; Prada, Patrícia O; Santos, Andrey; Saad, Sara T O; Saad, Mario J A

    2017-12-01

    Obesity and type 2 diabetes are characterized by subclinical inflammatory process. Changes in composition or modulation of the gut microbiota may play an important role in the obesity-associated inflammatory process. In the current study, we evaluated the effects of probiotics (Lactobacillus rhamnosus, L. acidophilus and Bifidobacterium bifidumi) on gut microbiota, changes in permeability, and insulin sensitivity and signaling in high-fat diet and control animals. More importantly, we investigated the effects of these gut modulations on hypothalamic control of food intake, and insulin and leptin signaling. Swiss mice were submitted to a high-fat diet (HFD) with probiotics or pair-feeding for 5 weeks. Metagenome analyses were performed on DNA samples from mouse feces. Blood was drawn to determine levels of glucose, insulin, LPS, cytokines and GLP-1. Liver, muscle, ileum and hypothalamus tissue proteins were analyzed by Western blotting and real-time polymerase chain reaction. In addition, liver and adipose tissues were analyzed using histology and immunohistochemistry. The HFD induced huge alterations in gut microbiota accompanied by increased intestinal permeability, LPS translocation and systemic low-grade inflammation, resulting in decreased glucose tolerance and hyperphagic behavior. All these obesity-related features were reversed by changes in the gut microbiota profile induced by probiotics. Probiotics also induced an improvement in hypothalamic insulin and leptin resistance. Our data demonstrate that the intestinal microbiome is a key modulator of inflammatory and metabolic pathways in both peripheral and central tissues. These findings shed light on probiotics as an important tool to prevent and treat patients with obesity and insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Central inhibition of IKKβ/NF-κB signaling attenuates high-fat diet-induced obesity and glucose intolerance.

    Science.gov (United States)

    Benzler, Jonas; Ganjam, Goutham K; Pretz, Dominik; Oelkrug, Rebecca; Koch, Christiane E; Legler, Karen; Stöhr, Sigrid; Culmsee, Carsten; Williams, Lynda M; Tups, Alexander

    2015-06-01

    Metabolic inflammation in the central nervous system might be causative for the development of overnutrition-induced metabolic syndrome and related disorders, such as obesity, leptin and insulin resistance, and type 2 diabetes. Here we investigated whether nutritive and genetic inhibition of the central IκB kinase β (IKKβ)/nuclear factor-κB (NF-κB) pathway in diet-induced obese (DIO) and leptin-deficient mice improves these metabolic impairments. A known prominent inhibitor of IKKβ/NF-κB signaling is the dietary flavonoid butein. We initially determined that oral, intraperitoneal, and intracerebroventricular administration of this flavonoid improved glucose tolerance and hypothalamic insulin signaling. The dose-dependent glucose-lowering capacity was profound regardless of whether obesity was caused by leptin deficiency or high-fat diet (HFD). To confirm the apparent central role of IKKβ/NF-κB signaling in the control of glucose and energy homeostasis, we genetically inhibited this pathway in neurons of the arcuate nucleus, one key center for control of energy homeostasis, via specific adeno-associated virus serotype 2-mediated overexpression of IκBα, which inhibits NF-κB nuclear translocation. This treatment attenuated HFD-induced body weight gain, body fat mass accumulation, increased energy expenditure, and reduced arcuate suppressor of cytokine signaling 3 expression, indicative for enhanced leptin signaling. These results reinforce a specific role of central proinflammatory IKKβ/NF-κB signaling in the development and potential treatment of DIO-induced comorbidities. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  17. The influence of GLP-1 on glucose-stimulated insulin secretion

    DEFF Research Database (Denmark)

    Kjems, Lise L; Holst, Jens Juul; Vølund, Aage

    2003-01-01

    . However, the dose-response relationship between GLP-1 and basal and glucose-stimulated prehepatic insulin secretion rate (ISR) is currently not known. Seven patients with type 2 diabetes and seven matched nondiabetic control subjects were studied. ISR was determined during a graded glucose infusion of 2...

  18. Cytokines and their association with insulin resistance in obese pregnant women with different levels of physical activity.

    Science.gov (United States)

    Nayak, Minakshi; Eekhoff, Marelise E W; Peinhaupt, Miriam; Heinemann, Akos; Desoye, Gernot; van Poppel, Mireille N M

    2016-01-01

    Cytokines contribute to insulin resistance in pregnancy, but the role of distinct cytokines is not fully understood. To study whether cytokines produced by tissues other than skeletal muscle are associated with glucose and insulin metabolism activity in overweight and obese women and to study whether these associations can be modified by physical activity. A longitudinal study with 44 overweight and obese pregnant women was conducted. Changes in cytokines levels (IFN-γ, IP-10, IL1-α, MIP1-α, adiponectin and leptin) and ICAM1 from early (15wk) to late (32wk) pregnancy were determined. Physical activity was measured objectively with accelerometers. In linear regression models, the associations between (changes in) cytokine levels and fasting glucose, fasting insulin and HOMA-IR were studied. Both IFN-γ and IP-10 levels increased from early to late pregnancy, and adiponectin levels decreased. IFN-γ and IP-10 were positively associated with fasting glucose, whereas IL-1α, ICAM1 and adiponectin were inversely associated with insulin and insulin resistance. The association of IL-1α with insulin and insulin resistance was only found in women with low levels of physical activity. IFN-γ, IP-10, IL1-α, ICAM1, and adiponectin may play a role in glucose and insulin metabolism in pregnancy. The relationship of IL-1α with insulin and insulin resistance might be moderated by levels of physical activity. Further studies are required to confirm the role of these cytokines in glucose and insulin metabolism in obese pregnant women. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. The role of ghrelin, leptin and insulin in foetal development

    Directory of Open Access Journals (Sweden)

    Magdalena Warchoł

    2014-06-01

    Full Text Available introduction and objective. The growing epidemic of childhood obesity has forced scientists to search for methods to prevent feeding disorders. Increasing interest in appetite regulating hormones has revealed their influence on energy homeostasis after birth or even in[i] utero[/i]. state of knowledge. The presence of ghrelin in the stomach of human foetuses and the distinctive production in the pancreas of neonates suggests the role of ghrelin in pre- and post-natal development. The neonatal period appears to be a critical time for the formation of adipose tissue-hypothalamus circuits, thus the amount of adipocytes in foetal life may be a major regulator of food intake. Insulin’s orexigenic effect in the arcuate nucleus of the hypothalamus can be a major modulator of foetal development. objective. This review, based on available literature, aims to analyses the role of appetite regulating hormones in foetal development. summary. Different concentrations of hormones, such as ghrelin, leptin and insulin during foetal life raises the question whether or not they can be modulated, thereby avoiding obesity before birth. Children with pancreas agenesis showed smaller body size at birth, which emphasises the probable role of insulin in foetal growth. Study of sheep foetuses with IUGR confirmed these finding. Appetite-regulating hormones show different roles in foetal development and seem to be essential in the perinatal period.

  20. Skeletal Muscle TRIB3 Mediates Glucose Toxicity in Diabetes and High- Fat Diet–Induced Insulin Resistance

    Science.gov (United States)

    Wu, Mengrui; Kim, Teayoun; Jariwala, Ravi H.; Garvey, W. John; Luo, Nanlan; Kang, Minsung; Ma, Elizabeth; Tian, Ling; Steverson, Dennis; Yang, Qinglin; Fu, Yuchang

    2016-01-01

    In the current study, we used muscle-specific TRIB3 overexpressing (MOE) and knockout (MKO) mice to determine whether TRIB3 mediates glucose-induced insulin resistance in diabetes and whether alterations in TRIB3 expression as a function of nutrient availability have a regulatory role in metabolism. In streptozotocin diabetic mice, TRIB3 MOE exacerbated, whereas MKO prevented, glucose-induced insulin resistance and impaired glucose oxidation and defects in insulin signal transduction compared with wild-type (WT) mice, indicating that glucose-induced insulin resistance was dependent on TRIB3. In response to a high-fat diet, TRIB3 MOE mice exhibited greater weight gain and worse insulin resistance in vivo compared with WT mice, coupled with decreased AKT phosphorylation, increased inflammation and oxidative stress, and upregulation of lipid metabolic genes coupled with downregulation of glucose metabolic genes in skeletal muscle. These effects were prevented in the TRIB3 MKO mice relative to WT mice. In conclusion, TRIB3 has a pathophysiological role in diabetes and a physiological role in metabolism. Glucose-induced insulin resistance and insulin resistance due to diet-induced obesity both depend on muscle TRIB3. Under physiological conditions, muscle TRIB3 also influences energy expenditure and substrate metabolism, indicating that the decrease and increase in muscle TRIB3 under fasting and nutrient excess, respectively, are critical for metabolic homeostasis. PMID:27207527

  1. Tumor necrosis factor-alpha inhibits insulin's stimulating effect on glucose uptake and endothelium-dependent vasodilation in humans

    DEFF Research Database (Denmark)

    Rask-Madsen, Christian; Domínguez, Helena; Ihlemann, Nikolaj

    2003-01-01

    BACKGROUND: Inflammatory mechanisms could be involved in the pathogenesis of both insulin resistance and atherosclerosis. Therefore, we aimed at examining whether the proinflammatory cytokine tumor necrosis factor (TNF)-alpha inhibits insulin-stimulated glucose uptake and insulin....../or TNF-alpha were coinfused. During infusion of insulin alone for 20 minutes, forearm glucose uptake increased by 220+/-44%. This increase was completely inhibited during coinfusion of TNF-alpha (started 10 min before insulin) with a more pronounced inhibition of glucose extraction than of blood flow....... Furthermore, TNF-alpha inhibited the ACh forearm blood flow response (Palpha...

  2. Abnormal transient rise in hepatic glucose production after oral glucose in non-insulin-dependent diabetic subjects.

    Science.gov (United States)

    Thorburn, A; Litchfield, A; Fabris, S; Proietto, J

    1995-05-01

    A transient rise in hepatic glucose production (HGP) after an oral glucosa load has been reported in some insulin-resistant states such as in obese fa/fa Zucker rats. The aim of this study was to determine whether this rise in HGP also occurs in subjects with established non-insulin-dependent diabetes mellitus (NIDDM). Glucose kinetics were measured basally and during a double-label oral glucose tolerance test (OGTT) in 12 NIDDM subjects and 12 non-diabetic 'control' subjects. Twenty minutes after the glucose load, HGP had increased 73% above basal in the NIDDM subjects (7.29 +/- 0.52 to 12.58 +/- 1.86 mumol/kg/min, P < 0.02). A transient rise in glucagon (12 pg/ml above basal, P < 0.004) occurred at a similar time. In contrast, the control subjects showed no rise in HGP or plasma glucagon. HGP began to suppress 40-50 min after the OGTT in both the NIDDM and control subjects. A 27% increase in the rate of gut-derived glucose absorption was also observed in the NIDDM group, which could be the result of increased gut glucose absorption or decreased first pass extraction of glucose by the liver. Therefore, in agreement with data in animal models of NIDDM, a transient rise in HGP partly contributes to the hyperglycemia observed after an oral glucose load in NIDDM subjects.

  3. Plasma Asprosin Concentrations Are Increased in Individuals with Glucose Dysregulation and Correlated with Insulin Resistance and First-Phase Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Yuren Wang

    2018-01-01

    Full Text Available Background. Adipokines are reported to participate in many common pathologic processes of glucose dysregulation, such as insulin resistance, β-cell dysfunction, and chronic inflammation. Objective. To detect the concentrations of plasma asprosin in subjects with impaired glucose regulation (IGR and newly diagnosed type 2 diabetes (nT2DM and its relationship to parameters of glucose and lipid metabolism, insulin resistance, and pancreatic β-cell function. Methods. 143 eligible participants were included and were divided into three groups including normal glucose regulation (NGR, n=52, IGR (n=40, and nT2DM group (n=51. The intravenous glucose tolerance test (IVGTT and clinical and biochemical parameters were measured in all participants. Results. Plasma asprosin levels were higher in IGR (82.40 ± 91.06 ng/mL, P<0.001 and nT2DM (73.25 ± 91.69 ng/mL, P<0.001 groups compared with those in the NGR (16.22 ± 9.27 ng/mL group, especially in IGR subjects. Correlation analysis showed that plasma asprosin levels were positively correlated with waist circumference (Wc, fasting plasma glucose (FPG, postchallenge plasma glucose (2hPG, HbA1c, triglyceride (TG, and homeostasis model assessment for insulin resistance (HOMA-IR and negatively correlated with homeostasis model assessment for β-cell function (HOMA-β, area under the curve of the first-phase (0–10 min insulin secretion (AUC, acute insulin response (AIR, and glucose disposition index (GDI (all P<0.05. Multiple logistical regression analyses revealed that plasma asprosin concentrations were significantly correlated with IGR and nT2DM after controlling for age, sex, BMI, and WHR. Conclusions. Circulating asprosin might be a predictor of early diagnosis in DM and might be a potential therapeutic target for prediabetes and T2DM.

  4. High passage MIN6 cells have impaired insulin secretion with impaired glucose and lipid oxidation.

    Directory of Open Access Journals (Sweden)

    Kim Cheng

    Full Text Available Type 2 diabetes is a metabolic disorder characterized by the inability of beta-cells to secrete enough insulin to maintain glucose homeostasis. MIN6 cells secrete insulin in response to glucose and other secretagogues, but high passage (HP MIN6 cells lose their ability to secrete insulin in response to glucose. We hypothesized that metabolism of glucose and lipids were defective in HP MIN6 cells causing impaired glucose stimulated insulin secretion (GSIS. HP MIN6 cells had no first phase and impaired second phase GSIS indicative of global functional impairment. This was coupled with a markedly reduced ATP content at basal and glucose stimulated states. Glucose uptake and oxidation were higher at basal glucose but ATP content failed to increase with glucose. HP MIN6 cells had decreased basal lipid oxidation. This was accompanied by reduced expressions of Glut1, Gck, Pfk, Srebp1c, Ucp2, Sirt3, Nampt. MIN6 cells represent an important model of beta cells which, as passage numbers increased lost first phase but retained partial second phase GSIS, similar to patients early in type 2 diabetes onset. We believe a number of gene expression changes occurred to produce this defect, with emphasis on Sirt3 and Nampt, two genes that have been implicated in maintenance of glucose homeostasis.

  5. Blood Glucose, Insulin and Inorganic Phosphorus in Healthy and Ketotic Dairy Cows after Intravenous Infusion of Glucose Solution

    Directory of Open Access Journals (Sweden)

    Radojica Djoković

    2009-01-01

    Full Text Available The aim of the present study was to determine the degree of blood glucose utilization by peripheral tissue on the basis of changes in blood concentrations of glucose, insulin and inorganic phosphorus in healthy (n = 10 and ketotic cows (n = 10 after intravenous infusion of glucose solution. Blood samples were taken in both groups of examined cows at the following time intervals: just before (time 0 and 30, 60, 120, 180 and 240 min after intravenous infusion of a total of 500 ml of 50% of glucose solution. Glucose and insulin blood serum values in both groups of cows increased significantly within 30 and 60 min of the experiment (p p p < 0.05 in the blood value of inorganic phosphorus in ketotic cows compared to the healthy ones. This is linked with the active entry of glucose into the glucolytic pathway of peripheral tissues. It can thus be concluded that there is a higher degree of blood glucose utilization by peripheral tissues in ketotic cows.

  6. Effect of cholecalciferol and levo carnitine on plasma glucose, plasma insulin and insulin resistance in type 2 diabetic rats

    International Nuclear Information System (INIS)

    Anwar, M. K.; Hussain, M. M.; Khan, M. A.; Ahmad, T.

    2013-01-01

    Objective: To compare the effects of combined and individual supplementation of cholecalciferol and levo carnitine on plasma glucose, plasma insulin and insulin resistance in type 2 diabetic rats. Methods: The randomised controlled trial was conducted at the Department of Physiology, Army Medical College, Rawalpindi, between October 2010 and April 2011. It comprised 80 healthy Sprague Dawley rats who were divided into four groups (n = 20 each). Rats were fed high-fat diet for 2 weeks followed by an intraperitoneal injection of streptozocin to induce type 2 diabetes mellitus. Group I served as diabetic control; group II was given cholecalciferol; group III; levo carnitine; and group IV was administered cholecalciferol and levo carnitine together. After 6 days of supplementation, terminal intracardiac blood extraction was done and samples were analysed for fasting plasma glucose and plasma insulin. Insulin resistance was calculated by homeostatic model assessment for insulin resistance. SPSS 17.0 was used for statistical analysis. Results: Fasting plasma glucose levels were significantly decreased (p <0.001) in the combined supplementation group compared to the diabetic control and individual supplementation groups. Combined supplementation showed a significant increase in fasting plasma insulin levels when compared with diabetic control and levo carnitine groups (p <0.001), and the effect of combined supplementation on ameliorating insulin resistance was significantly better (p <0.001) as compared to the individual supplementation of cholecalciferol and levo carnitine. Conclusions: The combined supplementation of cholecalciferol and levo carnitine for 6 days markedly improved the glycaemic control, insulin secretion and insulin resistance in type 2 diabetic rats on high-fat diet. A prolonged supplementation by both the compounds along with caloric restriction may yield a more promising outcome. (author)

  7. Synthesis, Characterization, and Preclinical Evaluation of New Thiazolidin-4-ones Substituted with p-Chlorophenoxy Acetic Acid and Clofibric Acid against Insulin Resistance and Metabolic Disorder

    Directory of Open Access Journals (Sweden)

    Vasantharaju S. Gowdra

    2014-01-01

    Full Text Available We synthesized twenty thiazolidin-4-one derivatives, which were then characterized by standard chromatographic and spectroscopic methods. From the in vitro glucose uptake assay, two compounds behaved as insulin sensitizers, where they enhanced glucose uptake in isolated rat diaphragm. In high-carbohydrate diet-induced insulin resistant mice, these two thiazolidin-4-ones attenuated hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia, and glucose intolerance. They raised the plasma leptin but did not reverse the diabetes-induced hypoadiponectinemia. Additionally, compound 3a reduced adiposity. The test compounds were also able to reverse the disturbed liver antioxidant milieu. To conclude, these two novel thiazolidin-4-ones modulated multiple mechanisms involved in metabolic disorders, reversing insulin resistance and thus preventing the development of type-2 diabetes.

  8. Akt and Rac1 signalling are jointly required for insulin-stimulated glucose uptake in skeletal muscle and downregulated in insulin resistance

    DEFF Research Database (Denmark)

    Sylow, Lykke; Kleinert, Maximilian; Pehmøller, Christian

    2014-01-01

    Skeletal muscle plays a major role in regulating whole body glucose metabolism. Akt and Rac1 are important regulators of insulin-stimulated glucose uptake in skeletal muscle. However the relative role of each pathway and how they interact is not understood. Here we delineate how Akt and Rac1...... pathways signal to increase glucose transport independently of each other and are simultaneously downregulated in insulin resistant muscle. Pharmacological inhibition of Rac1 and Akt signalling was used to determine the contribution of each pathway to insulin-stimulated glucose uptake in mouse muscles....... The actin filament-depolymerizing agent LatrunculinB was combined with pharmacological inhibition of Rac1 or Akt, to examine whether either pathway mediates its effect via the actin cytoskeleton. Akt and Rac1 signalling were investigated under each condition, as well as upon Akt2 knockout and in ob/ob mice...

  9. Weight loss after bariatric surgery reverses insulin-induced increases in brain glucose metabolism of the morbidly obese.

    Science.gov (United States)

    Tuulari, Jetro J; Karlsson, Henry K; Hirvonen, Jussi; Hannukainen, Jarna C; Bucci, Marco; Helmiö, Mika; Ovaska, Jari; Soinio, Minna; Salminen, Paulina; Savisto, Nina; Nummenmaa, Lauri; Nuutila, Pirjo

    2013-08-01

    Obesity and insulin resistance are associated with altered brain glucose metabolism. Here, we studied brain glucose metabolism in 22 morbidly obese patients before and 6 months after bariatric surgery. Seven healthy subjects served as control subjects. Brain glucose metabolism was measured twice per imaging session: with and without insulin stimulation (hyperinsulinemic-euglycemic clamp) using [18F]fluorodeoxyglucose scanning. We found that during fasting, brain glucose metabolism was not different between groups. However, the hyperinsulinemic clamp increased brain glucose metabolism in a widespread manner in the obese but not control subjects, and brain glucose metabolism was significantly higher during clamp in obese than in control subjects. After follow-up, 6 months postoperatively, the increase in glucose metabolism was no longer observed, and this attenuation was coupled with improved peripheral insulin sensitivity after weight loss. We conclude that obesity is associated with increased insulin-stimulated glucose metabolism in the brain and that this abnormality can be reversed by bariatric surgery.

  10. Glucose metabolism in pigs expressing human genes under an insulin promoter.

    Science.gov (United States)

    Wijkstrom, Martin; Bottino, Rita; Iwase, Hayoto; Hara, Hidetaka; Ekser, Burcin; van der Windt, Dirk; Long, Cassandra; Toledo, Frederico G S; Phelps, Carol J; Trucco, Massimo; Cooper, David K C; Ayares, David

    2015-01-01

    Xenotransplantation of porcine islets can reverse diabetes in non-human primates. The remaining hurdles for clinical application include safe and effective T-cell-directed immunosuppression, but protection against the innate immune system and coagulation dysfunction may be more difficult to achieve. Islet-targeted genetic manipulation of islet-source pigs represents a powerful tool to protect against graft loss. However, whether these genetic alterations would impair islet function is unknown. On a background of α1,3-galactosyltransferase gene-knockout (GTKO)/human (h)CD46, additional genes (hCD39, human tissue factor pathway inhibitor, porcine CTLA4-Ig) were inserted in different combinations under an insulin promoter to promote expression in islets (confirmed by immunofluorescence). Seven pigs were tested for baseline and glucose/arginine-challenged levels of glucose, insulin, C-peptide, and glucagon. This preliminary study did not show definite evidence of β-cell deficiencies, even when three transgenes were expressed under the insulin promoter. Of seven animals, all were normoglycemic at fasting, and five of seven had normal glucose disposal rates after challenge. All animals exhibited insulin, C-peptide, and glucagon responses to both glucose and arginine challenge; however, significant interindividual variation was observed. Multiple islet-targeted transgenic expression was not associated with an overtly detrimental effect on islet function, suggesting that complex genetic constructs designed for islet protection warrants further testing in islet xenotransplantation models. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  11. Optogenetic activation of leptin- and glucose-regulated GABAergic neurons in dorsomedial hypothalamus promotes food intake via inhibitory synaptic transmission to paraventricular nucleus of hypothalamus

    Directory of Open Access Journals (Sweden)

    Zesemdorj Otgon-Uul

    2016-08-01

    Full Text Available Objective: The dorsomedial hypothalamus (DMH has been considered an orexigenic nucleus, since the DMH lesion reduced food intake and body weight and induced resistance to diet-induced obesity. The DMH expresses feeding regulatory neuropeptides and receptors including neuropeptide Y (NPY, cocaine- and amphetamine-regulated transcript (CART, cholecystokinin (CCK, leptin receptor, and melanocortin 3/4 receptors. However, the principal neurons generating the orexigenic function in the DMH remain to be defined. This study aimed to clarify the role of the DMH GABAergic neurons in feeding regulation by using optogenetics and electrophysiological techniques. Methods: We generated the mice expressing ChRFR-C167A, a bistable chimeric channelrhodopsin, selectively in GABAergic neurons of DMH via locally injected adeno-associated virus 2. Food intake after optogenetic activation of DMH GABAergic neurons was measured. Electrophysiological properties of DMH GABAergic neurons were measured using slice patch clamp. Results: Optogenetic activation of DMH GABAergic neurons promoted food intake. Leptin hyperpolarized and lowering glucose depolarized half of DMH GABAergic neurons, suggesting their orexigenic property. Optical activation of axonal terminals of DMH GABAergic neurons at the paraventricular nucleus of hypothalamus (PVN, where anorexigenic neurons are localized, increased inhibitory postsynaptic currents on PVN neurons and promoted food intake. Conclusion: DMH GABAergic neurons are regulated by metabolic signals leptin and glucose and, once activated, promote food intake via inhibitory synaptic transmission to PVN. Keywords: Dorsomedial hypothalamus, GABAergic neuron, Feeding, Leptin, Glucose, Optogenetics

  12. Racl Signaling Is Required for Insulin-Stimulated Glucose Uptake and Is Dysregulated in Insulin-Resistant Murine and Human Skeletal Muscle

    DEFF Research Database (Denmark)

    Sylow, L.; Jensen, T. E.; Kleinert, M.

    2013-01-01

    The actin cytoskeleton-regulating GTPase Racl is required for insulin-stimulated GLUT4 translocation in cultured muscle cells. However, involvement of Racl and its downstream signaling in glucose transport in insulin-sensitive and insulin-resistant mature skeletal muscle has not previously been i...

  13. Effect of glycogen synthase overexpression on insulin-stimulated muscle glucose uptake and storage.

    Science.gov (United States)

    Fogt, Donovan L; Pan, Shujia; Lee, Sukho; Ding, Zhenping; Scrimgeour, Angus; Lawrence, John C; Ivy, John L

    2004-03-01

    Insulin-stimulated muscle glucose uptake is inversely associated with the muscle glycogen concentration. To investigate whether this association is a cause and effect relationship, we compared insulin-stimulated muscle glucose uptake in noncontracted and postcontracted muscle of GSL3-transgenic and wild-type mice. GSL3-transgenic mice overexpress a constitutively active form of glycogen synthase, which results in an abundant storage of muscle glycogen. Muscle contraction was elicited by in situ electrical stimulation of the sciatic nerve. Right gastrocnemii from GSL3-transgenic and wild-type mice were subjected to 30 min of electrical stimulation followed by hindlimb perfusion of both hindlimbs. Thirty minutes of contraction significantly reduced muscle glycogen concentration in wild-type (49%) and transgenic (27%) mice, although transgenic mice retained 168.8 +/- 20.5 micromol/g glycogen compared with 17.7 +/- 2.6 micromol/g glycogen for wild-type mice. Muscle of transgenic and wild-type mice demonstrated similar pre- (3.6 +/- 0.3 and 3.9 +/- 0.6 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) and postcontraction (7.9 +/- 0.4 and 7.0 +/- 0.4 micromol.g(-1).h(-1) for transgenic and wild-type, respectively) insulin-stimulated glucose uptakes. However, the [14C]glucose incorporated into glycogen was greater in noncontracted (151%) and postcontracted (157%) transgenic muscle vs. muscle of corresponding wild-type mice. These results indicate that glycogen synthase activity is not rate limiting for insulin-stimulated glucose uptake in skeletal muscle and that the inverse relationship between muscle glycogen and insulin-stimulated glucose uptake is an association, not a cause and effect relationship.

  14. Interrelations between glucose-induced insulin response, metabolic indicators, and time of first ovulation in high-yielding dairy cows.

    Science.gov (United States)

    Bossaert, P; Leroy, J L M R; De Vliegher, S; Opsomer, G

    2008-09-01

    High-yielding dairy cows are more susceptible to metabolic and reproductive disorders than low-yielding cows. Insulin plays a pivotal role in the development of both problems. In the present study, we aimed to assess the glucose-induced insulin responses of dairy cows at different time points relative to calving and to relate this to the metabolic status and the time of first ovulation. Twenty-three healthy, multiparous Holstein-Friesian cows with a high genetic merit for milk yield were studied from 14 d prepartum to 42 d postpartum. Intravenous glucose tolerance tests were performed on -14, 14, and 42 d relative to calving to evaluate the plasma insulin and glucose responses to a glucose load, as estimated by the peak concentration, the area under the curve (AUC), and the clearance rates of insulin and glucose. Blood samples were obtained at 3-d intervals and analyzed for glucose, insulin, and nonesterified fatty acids (NEFA). The time of first ovulation was defined by transrectal ultrasonography and plasma progesterone analysis. Glucose-induced insulin AUC and peak concentration decreased and glucose clearance increased during lactation compared with the dry period. Plasma NEFA concentrations were negatively related to insulin AUC and peak concentrations. Fourteen cows ovulated within 42 d postpartum, and the remaining 9 cows suffered from delayed resumption of ovarian function. Survival analysis demonstrated that cows with lower NEFA concentrations during the dry period tended to have earlier resumption of ovarian activity. In conclusion, our data suggest a decreased plasma insulin response to glucose postpartum in high-yielding dairy cows, possibly contributing to metabolic stress during the early postpartum period. It is hypothesized that NEFA impair glucose-induced insulin secretion in dairy cows. Additionally, our results suggest the importance of lipolysis during the transition period as a risk factor for delayed ovulation.

  15. Mitochondrial GTP Regulates Glucose-Induced Insulin Secretion

    Science.gov (United States)

    Kibbey, Richard G.; Pongratz, Rebecca L.; Romanelli, Anthony J.; Wollheim, Claes B.; Cline, Gary W.; Shulman, Gerald I.

    2007-01-01

    Summary Substrate-level mitochondrial GTP (mtGTP) and ATP (mtATP) synthesis occurs by nucleotide-specific isoforms of the tricarboxylic acid (TCA) cycle enzyme succinyl CoA synthetase (SCS). Unlike mtATP, each molecule of glucose metabolized produces approximately one mtGTP in pancreatic β-cells independent of coupling with oxidative phosphorylation making mtGTP a potentially important fuel signal. siRNA suppression of the GTP-producing pathway (ΔSCS-GTP) reduced glucose-stimulated insulin secretion (GSIS) by 50%, whereas suppression of the parallel ATP-producing isoform (ΔSCS-ATP) increased GSIS by two-fold in INS-1 832/13 cells and cultured rat islets. Insulin secretion correlated with increases in cytosolic calcium but not with changes in NAD(P)H or the ATP/ADP ratio. These data suggest an important role for mtGTP in mediating GSIS in β-cells by modulation of mitochondrial metabolism possibly via influencing mitochondrial calcium. Furthermore, by virtue of its tight coupling to TCA oxidation rates, mtGTP production may serve as an important molecular signal of TCA cycle activity. PMID:17403370

  16. Glucose Induces Mouse β-Cell Proliferation via IRS2, MTOR, and Cyclin D2 but Not the Insulin Receptor

    Science.gov (United States)

    Stamateris, Rachel E.; Sharma, Rohit B.; Kong, Yahui; Ebrahimpour, Pantea; Panday, Deepika; Ranganath, Pavana; Zou, Baobo; Levitt, Helena; Parambil, Nisha Abraham; O’Donnell, Christopher P.; García-Ocaña, Adolfo

    2016-01-01

    An important goal in diabetes research is to understand the processes that trigger endogenous β-cell proliferation. Hyperglycemia induces β-cell replication, but the mechanism remains debated. A prime candidate is insulin, which acts locally through the insulin receptor. Having previously developed an in vivo mouse hyperglycemia model, we tested whether glucose induces β-cell proliferation through insulin signaling. By using mice lacking insulin signaling intermediate insulin receptor substrate 2 (IRS2), we confirmed that hyperglycemia-induced β-cell proliferation requires IRS2 both in vivo and ex vivo. Of note, insulin receptor activation was not required for glucose-induced proliferation, and insulin itself was not sufficient to drive replication. Glucose and insulin caused similar acute signaling in mouse islets, but chronic signaling differed markedly, with mammalian target of rapamycin (MTOR) and extracellular signal–related kinase (ERK) activation by glucose and AKT activation by insulin. MTOR but not ERK activation was required for glucose-induced proliferation. Cyclin D2 was necessary for glucose-induced β-cell proliferation. Cyclin D2 expression was reduced when either IRS2 or MTOR signaling was lost, and restoring cyclin D2 expression rescued the proliferation defect. Human islets shared many of these regulatory pathways. Taken together, these results support a model in which IRS2, MTOR, and cyclin D2, but not the insulin receptor, mediate glucose-induced proliferation. PMID:26740601

  17. Glucose turnover during insulin-induced hypoglycemia in liver-denervated rats

    DEFF Research Database (Denmark)

    Mikines, K J; Sonne, B; Richter, Erik

    1985-01-01

    The role of hepatic autonomic nerves in glucose production during hypoglycemia was studied. Selective, surgical denervation of the liver was performed in rats, which reduced hepatic norepinephrine concentrations by 96%. Hypoglycemia was induced by 250 mU of insulin intra-arterially in anesthetized...... as well as in chronically catheterized, awake rats. Half of the anesthetized denervated or sham-operated rats had previously been adrenodemedullated. Glucose turnover was measured by primed, constant intravenous infusion of [3-3H]glucose. Before as well as during hypoglycemia the arterial glucose...

  18. A simple method for measuring glucose utilization of insulin-sensitive tissues by using the brain as a reference

    International Nuclear Information System (INIS)

    Namba, Hiroki; Nakagawa, Keiichi; Iyo, Masaomi; Fukushi, Kiyoshi; Irie, Toshiaki

    1994-01-01

    A simple method, without measurement of the plasma input function, to obtain semiquantitative values of glucose utilization in tissues other than the brain with radioactive deoxyglucose is reported. The brain, in which glucose utilization is essentially insensitive to plasma glucose and insulin concentrations, was used as an internal reference. The effects of graded doses of oral glucose loading (0.5, 1 and 2 mg/g body weight) on insulin-sensitive tissues (heart, muscle and fat tissue) were studied in the rat. By using the brain-reference method, dose-dependent increases in glucose utilization were clearly shown in all the insulin-sensitive tissues examined. The method seems to be of value for measurement of glucose utilization using radioactive deoxyglucose and positron emission tomography in the heart or other insulin-sensitive tissues, especially during glucose loading. (orig.)

  19. Time course and determinants of leptin decline during weight loss in obese boys and girls

    DEFF Research Database (Denmark)

    Holm, Jens-Christian; Gamborg, Michael; Kaas-Ibsen, Karsten

    2007-01-01

    OBJECTIVE: To investigate whether changes in leptin concentrations during weight loss can be explained by gender, puberty, baseline adiposity and changes in adiposity, body composition, rate of weight loss, physical activity and insulin concentrations. DESIGN: A longitudinal study with 9 repeated......, puberty, baseline adiposity or concomitant changes in BMI SDS, fat mass percentage, rate of weight loss, physical activity scores or insulin concentrations. CONCLUSION: The biphasic leptin decline, which exceeded the level expected, was independent of puberty, baseline adiposity and changes in adiposity...... size, physical activity scores, blood leptin (ng/ml) and insulin concentrations (pmol/l) were measured at baseline, and except for Tanner stage and testicular size, repeated regularly during the programme. RESULTS: The weight loss was accompanied by a steep decline in leptin concentrations during...

  20. Hypothalamic glycogen synthase kinase 3β has a central role in the regulation of food intake and glucose metabolism.

    Science.gov (United States)

    Benzler, Jonas; Ganjam, Goutham K; Krüger, Manon; Pinkenburg, Olaf; Kutschke, Maria; Stöhr, Sigrid; Steger, Juliane; Koch, Christiane E; Ölkrug, Rebecca; Schwartz, Michael W; Shepherd, Peter R; Grattan, David R; Tups, Alexander

    2012-10-01

    GSK3β (glycogen synthase kinase 3β) is a ubiquitous kinase that plays a key role in multiple intracellular signalling pathways, and increased GSK3β activity is implicated in disorders ranging from cancer to Alzheimer's disease. In the present study, we provide the first evidence of increased hypothalamic signalling via GSK3β in leptin-deficient Lep(ob/ob) mice and show that intracerebroventricular injection of a GSK3β inhibitor acutely improves glucose tolerance in these mice. The beneficial effect of the GSK3β inhibitor was dependent on hypothalamic signalling via PI3K (phosphoinositide 3-kinase), a key intracellular mediator of both leptin and insulin action. Conversely, neuron-specific overexpression of GSK3β in the mediobasal hypothalamus exacerbated the hyperphagia, obesity and impairment of glucose tolerance induced by a high-fat diet, while having little effect in controls fed standard chow. These results demonstrate that increased hypothalamic GSK3β signalling contributes to deleterious effects of leptin deficiency and exacerbates high-fat diet-induced weight gain and glucose intolerance.

  1. CaMKII regulates contraction- but not insulin-induced glucose uptake in mouse skeletal muscle.

    Science.gov (United States)

    Witczak, Carol A; Jessen, Niels; Warro, Daniel M; Toyoda, Taro; Fujii, Nobuharu; Anderson, Mark E; Hirshman, Michael F; Goodyear, Laurie J

    2010-06-01

    Studies using chemical inhibitors have suggested that the Ca(2+)-sensitive serine/threonine kinase Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) is a key regulator of both insulin- and contraction-stimulated glucose uptake in skeletal muscle. However, due to nonspecificity of these inhibitors, the specific role that CaMKII may play in the regulation of glucose uptake is not known. We sought to determine whether specific inhibition of CaMKII impairs insulin- and/or contraction-induced glucose uptake in mouse skeletal muscle. Expression vectors containing green fluorescent protein conjugated to a CaMKII inhibitory (KKALHRQEAVDCL) or control (KKALHAQERVDCL) peptide were transfected into tibialis anterior muscles by in vivo electroporation. After 1 wk, muscles were assessed for peptide expression, CaMK activity, insulin- and contraction-induced 2-[(3)H]deoxyglucose uptake, glycogen concentrations, and changes in intracellular signaling proteins. Expression of the CaMKII inhibitory peptide decreased muscle CaMK activity approximately 35% compared with control peptide. Insulin-induced glucose uptake was not changed in muscles expressing the inhibitory peptide. In contrast, expression of the inhibitory peptide significantly decreased contraction-induced muscle glucose uptake (approximately 30%). Contraction-induced decreases in muscle glycogen were not altered by the inhibitory peptide. The CaMKII inhibitory peptide did not alter expression of the glucose transporter GLUT4 and did not impair contraction-induced increases in the phosphorylation of AMP-activated protein kinase (Thr(172)) or TBC1D1/TBC1D4 on phospho-Akt substrate sites. These results demonstrate that CaMKII does not regulate insulin-stimulated glucose uptake in skeletal muscle. However, CaMKII plays a critical role in the regulation of contraction-induced glucose uptake in mouse skeletal muscle.

  2. Dual Regulation of Gluconeogenesis by Insulin and Glucose in the Proximal Tubules of the Kidney.

    Science.gov (United States)

    Sasaki, Motohiro; Sasako, Takayoshi; Kubota, Naoto; Sakurai, Yoshitaka; Takamoto, Iseki; Kubota, Tetsuya; Inagi, Reiko; Seki, George; Goto, Moritaka; Ueki, Kohjiro; Nangaku, Masaomi; Jomori, Takahito; Kadowaki, Takashi

    2017-09-01

    Growing attention has been focused on the roles of the proximal tubules (PTs) of the kidney in glucose metabolism, including the mechanism of regulation of gluconeogenesis. In this study, we found that PT-specific insulin receptor substrate 1/2 double-knockout mice, established by using the newly generated sodium-glucose cotransporter 2 (SGLT2)-Cre transgenic mice, exhibited impaired insulin signaling and upregulated gluconeogenic gene expression and renal gluconeogenesis, resulting in systemic insulin resistance. In contrast, in streptozotocin-treated mice, although insulin action was impaired in the PTs, the gluconeogenic gene expression was unexpectedly downregulated in the renal cortex, which was restored by administration of an SGLT1/2 inhibitor. In the HK-2 cells, the gluconeogenic gene expression was suppressed by insulin, accompanied by phosphorylation and inactivation of forkhead box transcription factor 1 (FoxO1). In contrast, glucose deacetylated peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α), a coactivator of FoxO1, via sirtuin 1, suppressing the gluconeogenic gene expression, which was reversed by inhibition of glucose reabsorption. These data suggest that both insulin signaling and glucose reabsorption suppress the gluconeogenic gene expression by inactivation of FoxO1 and PGC1α, respectively, providing insight into novel mechanisms underlying the regulation of gluconeogenesis in the PTs. © 2017 by the American Diabetes Association.

  3. Effect of glucose and insulin infusion on the myocardial extraction of a radioiodinated methyl-substituted fatty acid

    International Nuclear Information System (INIS)

    Bianco, J.A.; Elmaleh, D.R.; Leppo, J.A.; King, M.A.; Moring, A.; Livni, E.; Espinoza, E.; Alpert, J.S.; Strauss, H.W.; Massachusetts General Hospital, Boston

    1986-01-01

    We investigated the one-way. An extraction of 14-iodophenyl-tetradecanoic acid (BMTDA) in the canine heart under fasting conditions and during infusion of glucose plus insulin in eight an esthetized greyhound dogs. Myocardial extraction measurements were made with dual tracer approach, using Tc-99m albumin as reference tracer. Prior to, and during, infusion of 10% glucose and 25 units of regular insulin, heart rate, blood pressure, plasma glucose, insulin and free fatty acid levels were measured. Myocardial blood flow was determined using Sn-113 and Ru-103 radioactive microspheres. The mean extraction fraction of BMTDA was 0.38+-SEM 0.06 at baseline and increased to 0.44+-0.06 during hyperglycemia plus insulin (P<0.025). Plasma glucose and insulin were higher during the infusion (P<0.01) while plasma free fatty acids significantly declined (P<0.01). There were no changes in hemodynamics or myocardial blood flow during the infusion. We conclude that glucose and insulin infusion result in increased first-pass extraction fraction of radioiodinated BMTDA unaccompanied by changes in coronary flow or hemodynamics, implying an insulin-mediated augmented transport of BMTDA. (orig.)

  4. Leptin promoter gene polymorphism on -2549 position decreases plasma leptin and increases appetite in normal weight volunteers

    Directory of Open Access Journals (Sweden)

    Sandra Bragança Coelho

    2014-05-01

    Full Text Available Introduction: Investigate whether polymorphism in the promoter region encoding leptin and leptin receptor gene, in normal weight individuals, affects hormonal and appetite responses to peanuts.Materials and methods: Appetite, anthropometric indices, body composition, physical activity, dietary intake and leptin, ghrelin and insulin levels were monitored. Polymorphism analyses were also carried out.Results: None of the treatments led to statistical differences in the analyzed hormones. No polymorphism was found for leptin receptor gene, while for leptin gene, 50% of the volunteers presented one polymorphic allele and 13% presented both polymorphic alleles. These last ones presented lower body fat mass, leptin and ghrelin plasma concentrations, and fullness rates. They also presented higher hunger, desire to eat, and desire to eat sweet and salty foods.Conclusions: Peanut did not affect appetite and presented no different hormonal responses, compared to other foods studied. Polymorphic allele carriers in both alleles presented higher probability to develop obesity. However, the magnitude of this probability could not be measured.

  5. Autocrine effect of Zn²⁺ on the glucose-stimulated insulin secretion.

    Science.gov (United States)

    Slepchenko, Kira G; Daniels, Nigel A; Guo, Aili; Li, Yang V

    2015-09-01

    It is well known that zinc (Zn(2+)) is required for the process of insulin biosynthesis and the maturation of insulin secretory granules in pancreatic beta (β)-cells, and that changes in Zn(2+) levels in the pancreas have been found to be associated with diabetes. Glucose-stimulation causes a rapid co-secretion of Zn(2+) and insulin with similar kinetics. However, we do not know whether Zn(2+) regulates insulin availability and secretion. Here we investigated the effect of Zn(2+) on glucose-stimulated insulin secretion (GSIS) in isolated mouse pancreatic islets. Whereas Zn(2+) alone (control) had no effect on the basal secretion of insulin, it significantly inhibited GSIS. The application of CaEDTA, by removing the secreted Zn(2+) from the extracellular milieu of the islets, resulted in significantly increased GSIS, suggesting an overall inhibitory role of secreted Zn(2+) on GSIS. The inhibitory action of Zn(2+) was mostly mediated through the activities of KATP/Ca(2+) channels. Furthermore, during brief paired-pulse glucose-stimulated Zn(2+) secretion (GSZS), Zn(2+) secretion following the second pulse was significantly attenuated, probably by the secreted endogenous Zn(2+) after the first pulse. Such an inhibition on Zn(2+) secretion following the second pulse was completely reversed by Zn(2+) chelation, suggesting a negative feedback mechanism, in which the initial glucose-stimulated Zn(2+) release inhibits subsequent Zn(2+) secretion, subsequently inhibiting insulin co-secretion as well. Taken together, these data suggest a negative feedback mechanism on GSZS and GSIS by Zn(2+) secreted from β-cells, and the co-secreted Zn(2+) may act as an autocrine inhibitory modulator.

  6. An acute rat in vivo screening model to predict compounds that alter blood glucose and/or insulin regulation.

    Science.gov (United States)

    Brott, David A; Diamond, Melody; Campbell, Pam; Zuvich, Andy; Cheatham, Letitia; Bentley, Patricia; Gorko, Mary Ann; Fikes, James; Saye, JoAnne

    2013-01-01

    Drug-induced glucose dysregulation and insulin resistance have been associated with weight gain and potential induction and/or exacerbation of diabetes mellitus in the clinic suggesting they may be safety biomarkers when developing antipsychotics. Glucose and insulin have also been suggested as potential efficacy biomarkers for some oncology compounds. The objective of this study was to qualify a medium throughput rat in vivo acute Intravenous Glucose Tolerance Test (IVGTT) for predicting compounds that will induce altered blood glucose and/or insulin levels. Acute and sub-chronic studies were performed to qualify an acute IVGTT model. Double cannulated male rats (Han-Wistar and Sprague-Dawley) were administered vehicle, olanzapine, aripiprazole or other compounds at t=-44min for acute studies and at time=-44min on the last day of dosing for sub-chronic studies, treated with dextrose (time=0min; i.v.) and blood collected using an automated Culex® system for glucose and insulin analysis (time=-45, -1, 2, 10, 15, 30, 45, 60, 75, 90, 120, 150 and 180min). Olanzapine significantly increased glucose and insulin area under the curve (AUC) values while aripiprazole AUC values were similar to control, in both acute and sub-chronic studies. All atypical antipsychotics evaluated were consistent with literature references of clinical weight gain. As efficacy biomarkers, insulin AUC but not glucose AUC values were increased with a compound known to have insulin growth factor-1 (IGF-1) activity, compared to control treatment. These studies qualified the medium throughput acute IVGTT model to more quickly screen compounds for 1) safety - the potential to elicit glucose dysregulation and/or insulin resistance and 2) efficacy - as a surrogate for compounds affecting the glucose and/or insulin regulatory pathways. These data demonstrate that the same in vivo rat model and assays can be used to predict both clinical safety and efficacy of compounds. © 2013.

  7. Analysis of the variation levels of APN, insulin, sensitive C-reactive protein and leptin in the serum of patients with type 2 diabetes mellitus

    International Nuclear Information System (INIS)

    Du Tongxing; Wang Zizheng; Wang Shukui; Qi Shaokang; Tao Xiaojun

    2005-01-01

    To study the mechanism of pancreatic 13 cell dysfunction and tissue resistance to insulin, and to provide basis for early diagnosis and therapy of the disease, the levels of APN, insulin, sensitive C-reactive protein and leptin in the serum of patients with type 2 diabetes mellitus were determined. Altogether 184 untreatea type 2 diabetes mellitus patients, 30 normal people as the control group, and another 75 type 2 diabetes mellitus patients who have been treated for a year were enrolled in this study. The serum levels of the above indexes were determined by chemiluminescence immunoassay, enzyme immunoassay and radioimmunoassay. The results showed that there were obvious differences in the levels of insulin, leptin, C-reacting protein and insulin antibody between the normal control group and the group of the untreated type 2 diabetes mellitus patients (P<0.01), especially there was significant difference in the level of APN(P<0. 001). Among the 75 type 2 diabetes meltitus patients who have received a year's treatment, all the indexes except for APN and insulin antibody were decreased statistically, while the APN level was increased significantly (P<0.01) than that before the treatment. The determination of markers of type 2 diabetes mellitus is of great significance for its early diagnosis, therapy, prognosis and mechanism research. (authors)

  8. Programming of glucose-insulin homoeostasis

    DEFF Research Database (Denmark)

    Kongsted, Anna Hauntoft; Tygesen, M. P.; Husted, Sanne Vinter

    2014-01-01

    AIM: Exposure to adverse intra-uterine conditions can predispose for metabolic disorders later in life. By using a sheep model, we studied (i) how programming of glucose-insulin homoeostasis during late gestation is manifested later in life depending on the early post-natal dietary exposure and (ii......) whether dietary alteration in obese individuals can prevent adverse outcomes of early life programming. METHODS: During late gestation, twin-pregnant sheep were fed 100% (NORM) or 50% (LOW) of energy and protein requirements. After birth, offspring were exposed to a moderate (CONV) or high...

  9. Glucose homeostasis in rainbow trout fed a high-carbohydrate diet: metformin and insulin interact in a tissue-dependent manner.

    Science.gov (United States)

    Polakof, S; Moon, T W; Aguirre, P; Skiba-Cassy, S; Panserat, S

    2011-01-01

    Carnivorous fish species such as the rainbow trout (Oncorhynchus mykiss) are considered to be "glucose intolerant" because of the prolonged hyperglycemia experienced after intake of a carbohydrate-enriched meal. In the present study, we use this species to study glucose homeostasis in fish chronically infused with the hypoglycemic agents, insulin, and metformin, and fed with a high proportion of carbohydrates (30%). We analyzed liver, skeletal muscle, and white adipose tissue (WAT), which are insulin- and metformin-specific targets at both the biochemical and molecular levels. Trout infused with the combination of insulin and metformin can effectively utilize dietary glucose at the liver, resulting in lowered glycemia, increased insulin sensitivity, and glucose storage capacity, combined with reduced glucose output. However, in both WAT and skeletal muscle, we observed decreased insulin sensitivity with the combined insulin + metformin treatment, resulting in the absence of changes at the metabolic level in the skeletal muscle and an increased potential for glucose uptake and storage in the WAT. Thus, the poor utilization by rainbow trout of a diet with a high proportion of carbohydrate can at least be partially improved by a combined treatment with insulin and metformin, and the glucose intolerance observed in this species could be, in part, due to some of the downstream components of the insulin and metformin signaling pathways. However, the predominant effects of metformin treatment on the action of insulin in these three tissues thought to be involved in glucose homeostasis remain exclusive in this species.

  10. Preliminary evidence for obesity-associated insulin resistance in adolescents without elevations of inflammatory cytokines

    Directory of Open Access Journals (Sweden)

    Cohen Jessica I

    2012-06-01

    Full Text Available Abstract Background To ascertain whether the associations between obesity, inflammation, and insulin resistance established in human adult studies are found among adolescents. Methods We contrasted 36 obese and 24 lean youth on fasting glucose, insulin levels, lipid profile, hemoglobin A1C, markers of hepatic function, white blood cell count, C-reactive protein (CRP and fibrinogen levels. The cytokines IL-6, TNF-α, IFN-γ, IL-10 and IL-4 and the adipokines leptin, resistin, and adiponectin were also compared between the two groups. The fasting glucose and insulin values were used to estimate the degree of insulin resistance with the homeostatic model assessment of insulin resistance (HOMA-IR. T-tests and correlations were run to examine group differences and associations between groups. In addition, regression analyses were used to ascertain whether the markers of inflammation were predictive of the degree of insulin resistance. Results Although obese adolescents had clear evidence of insulin resistance, only CRP, fibrinogen and leptin were elevated; there were no group differences in pro- or anti-inflammatory cytokines nor adiponectin and resistin. Anthropometric measures of obesity and level of insulin resistance were highly correlated to the acute phase reactants CRP and fibrinogen; however, the degree of insulin resistance was not predicted by the pro- or anti-inflammatory cytokine markers. Obese adolescents had higher white blood cell counts. In addition they had higher circulating alanine aminotransferase concentrations and lower circulating albumin and total protein than lean adolescents, possibly as a result of hepatocyte damage from fatty liver. Conclusion Unlike rodent or adult studies, we found that wide-spread systemic inflammation is not necessarily associated with insulin resistance among adolescents. This finding does not support the current paradigm that the associations between obesity and insulin resistance are, to a

  11. Regulation of myosin light chain kinase during insulin-stimulated glucose uptake in 3T3-L1 adipocytes.

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    Shelly Woody

    Full Text Available Myosin II (MyoII is required for insulin-responsive glucose transporter 4 (GLUT4-mediated glucose uptake in 3T3-L1 adipocytes. Our previous studies have shown that insulin signaling stimulates phosphorylation of the regulatory light chain (RLC of MyoIIA via myosin light chain kinase (MLCK. The experiments described here delineate upstream regulators of MLCK during insulin-stimulated glucose uptake. Since 3T3-L1 adipocytes express two MyoII isoforms, we wanted to determine which isoform was required for insulin-stimulated glucose uptake. Using a siRNA approach, we demonstrate that a 60% decrease in MyoIIA protein expression resulted in a 40% inhibition of insulin-stimulated glucose uptake. We also show that insulin signaling stimulates the phosphorylation of MLCK. We further show that MLCK can be activated by calcium as well as signaling pathways. We demonstrate that adipocytes treated with the calcium chelating agent, 1,2-b (iso-aminophenoxy ethane-N,N,N',N'-tetra acetic acid, (BAPTA (in the presence of insulin impaired the insulin-induced phosphorylation of MLCK by 52% and the RLC of MyoIIA by 45% as well as impairing the recruitment of MyoIIA to the plasma membrane when compared to cells treated with insulin alone. We further show that the calcium ionophore, A23187 alone stimulated the phosphorylation of MLCK and the RLC associated with MyoIIA to the same extent as insulin. To identify signaling pathways that might regulate MLCK, we examined ERK and CaMKII. Inhibition of ERK2 impaired phosphorylation of MLCK and insulin-stimulated glucose uptake. In contrast, while inhibition of CaMKII did inhibit phosphorylation of the RLC associated with MyoIIA, inhibition of CAMKIIδ did not impair MLCK phosphorylation or translocation to the plasma membrane or glucose uptake. Collectively, our results are the first to delineate a role for calcium and ERK in the activation of MLCK and thus MyoIIA during insulin-stimulated glucose uptake in 3T3-L1 adipocytes.

  12. SOCS-1 deficiency does not prevent diet-induced insulin resistance

    DEFF Research Database (Denmark)

    Emanuelli, Brice; Macotela, Yazmin; Boucher, Jérémie

    2008-01-01

    Obesity is associated with inflammation and increased expression of suppressor of cytokine signaling (SOCS) proteins, which inhibit cytokine and insulin signaling. Thus, reducing SOCS expression could prevent the development of obesity-induced insulin resistance. Using SOCS-1 knockout mice, we...... investigated the contribution of SOCS-1 in the development of insulin resistance induced by a high-fat diet (HFD). SOCS-1 knockout mice on HFD gained 70% more weight, displayed a 2.3-fold increase in epididymal fat pads mass and increased hepatic lipid content. This was accompanied by increased mRNA expression...... of leptin and the macrophage marker CD68 in white adipose tissue and of SREBP1c and FAS in liver. HFD also induced hyperglycemia in SOCS-1 deficient mice with impairment of glucose and insulin tolerance tests. Thus, despite the role of SOCS proteins in obesity-related insulin resistance, SOCS-1 deficiency...

  13. Fructose replacement of glucose or sucrose in food or beverages lowers postprandial glucose and insulin without raising triglycerides: a systematic review and meta-analysis.

    Science.gov (United States)

    Evans, Rebecca A; Frese, Michael; Romero, Julio; Cunningham, Judy H; Mills, Kerry E

    2017-08-01

    Background: Conflicting evidence exists on the effects of fructose consumption in people with type 1 and type 2 diabetes mellitus. No systematic review has addressed the effect of isoenergetic fructose replacement of glucose or sucrose on peak postprandial glucose, insulin, and triglyceride concentrations. Objective: The objective of this study was to review the evidence for postprandial glycemic and insulinemic responses after isoenergetic replacement of either glucose or sucrose in foods or beverages with fructose. Design: We searched the Cochrane Library, MEDLINE, EMBASE, the WHO International Clinical Trials Registry Platform Search Portal, and clinicaltrials.gov The date of the last search was 26 April 2016. We included randomized controlled trials measuring peak postprandial glycemia after isoenergetic replacement of glucose, sucrose, or both with fructose in healthy adults or children with or without diabetes. The main outcomes analyzed were peak postprandial blood glucose, insulin, and triglyceride concentrations. Results: Replacement of either glucose or sucrose by fructose resulted in significantly lowered peak postprandial blood glucose, particularly in people with prediabetes and type 1 and type 2 diabetes. Similar results were obtained for insulin. Peak postprandial blood triglyceride concentrations did not significantly increase. Conclusions: Strong evidence exists that substituting fructose for glucose or sucrose in food or beverages lowers peak postprandial blood glucose and insulin concentrations. Isoenergetic replacement does not result in a substantial increase in blood triglyceride concentrations. © 2017 American Society for Nutrition.

  14. Lupanine Improves Glucose Homeostasis by Influencing KATP Channels and Insulin Gene Expression

    Directory of Open Access Journals (Sweden)

    Mats Wiedemann

    2015-10-01

    Full Text Available The glucose-lowering effects of lupin seeds involve the combined action of several components. The present study investigates the influence of one of the main quinolizidine alkaloids, lupanine, on pancreatic beta cells and in an animal model of type-2 diabetes mellitus. In vitro studies were performed with insulin-secreting INS-1E cells or islets of C57BL/6 mice. In the in vivo experiments, hyperglycemia was induced in rats by injecting streptozotocin (65 mg/kg body weight. In the presence of 15 mmol/L glucose, insulin secretion was significantly elevated by 0.5 mmol/L lupanine, whereas the alkaloid did not stimulate insulin release with lower glucose concentrations. In islets treated with l-arginine, the potentiating effect of lupanine already occurred at 8 mmol/L glucose. Lupanine increased the expression of the Ins-1 gene. The potentiating effect on secretion was correlated to membrane depolarization and an increase in the frequency of Ca2+ action potentials. Determination of the current through ATP-dependent K+ channels (KATP channels revealed that lupanine directly inhibited the channel. The effect was dose-dependent but, even with a high lupanine concentration of 1 mmol/L or after a prolonged exposure time (12 h, the KATP channel block was incomplete. Oral administration of lupanine did not induce hypoglycemia. By contrast, lupanine improved glycemic control in response to an oral glucose tolerance test in streptozotocin-diabetic rats. In summary, lupanine acts as a positive modulator of insulin release obviously without a risk for hypoglycemic episodes.

  15. Glucose but not insulin or insulin resistance is associated with memory performance in middle-aged non-diabetic women : a cross sectional study

    OpenAIRE

    Backeström, Anna; Eriksson, Sture; Nilsson, Lars-Göran; Olsson, Tommy; Rolandsson, Olov

    2015-01-01

    Background: Elevated concentrations of plasma glucose appear to play a role in memory impairment, and it has been suggested that insulin might also have a negative effect on cognitive function. Our aim was to study whether glucose, insulin or insulin resistance are associated with episodic or semantic memory in a non-diabetic and non-demented population.  Methods: We linked and matched two population-based data sets identifying 291 participants (127 men and 164 women, mean age of 50.7 +/- 8.0...

  16. Insulin secretion and cellular glucose metabolism after prolonged low-grade intralipid infusion in young men

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Holst, Jens Juul

    2003-01-01

    (HI), 40 mU/m(2) x min], 3-(3)H-glucose, indirect calorimetry, and iv glucose tolerance test. Free fatty acid concentrations were similar during basal steady state but 3.7- to 13-fold higher during clamps. P-glucagon increased and the insulin/glucagon ratio decreased at both LI and HI during...... not in the nonoxidative) glucose metabolism in young healthy men. Moreover, insulin hypersecretion perfectly countered the free-fatty acid-induced insulin resistance. Future studies are needed to determine the role of a prolonged moderate lipid load in subjects at increased risk of developing diabetes....

  17. Mitochondrial metabolism of pyruvate is essential for regulating glucose-stimulated insulin secretion.

    Science.gov (United States)

    Patterson, Jessica N; Cousteils, Katelyn; Lou, Jennifer W; Manning Fox, Jocelyn E; MacDonald, Patrick E; Joseph, Jamie W

    2014-05-09

    It is well known that mitochondrial metabolism of pyruvate is critical for insulin secretion; however, we know little about how pyruvate is transported into mitochondria in β-cells. Part of the reason for this lack of knowledge is that the carrier gene was only discovered in 2012. In the current study, we assess the role of the recently identified carrier in the regulation of insulin secretion. Our studies show that β-cells express both mitochondrial pyruvate carriers (Mpc1 and Mpc2). Using both pharmacological inhibitors and siRNA-mediated knockdown of the MPCs we show that this carrier plays a key role in regulating insulin secretion in clonal 832/13 β-cells as well as rat and human islets. We also show that the MPC is an essential regulator of both the ATP-regulated potassium (KATP) channel-dependent and -independent pathways of insulin secretion. Inhibition of the MPC blocks the glucose-stimulated increase in two key signaling molecules involved in regulating insulin secretion, the ATP/ADP ratio and NADPH/NADP(+) ratio. The MPC also plays a role in in vivo glucose homeostasis as inhibition of MPC by the pharmacological inhibitor α-cyano-β-(1-phenylindol-3-yl)-acrylate (UK5099) resulted in impaired glucose tolerance. These studies clearly show that the newly identified mitochondrial pyruvate carrier sits at an important branching point in nutrient metabolism and that it is an essential regulator of insulin secretion.

  18. Brain insulin action augments hepatic glycogen synthesis without suppressing glucose production or gluconeogenesis in dogs

    Science.gov (United States)

    Ramnanan, Christopher J.; Saraswathi, Viswanathan; Smith, Marta S.; Donahue, E. Patrick; Farmer, Ben; Farmer, Tiffany D.; Neal, Doss; Williams, Philip E.; Lautz, Margaret; Mari, Andrea; Cherrington, Alan D.; Edgerton, Dale S.

    2011-01-01

    In rodents, acute brain insulin action reduces blood glucose levels by suppressing the expression of enzymes in the hepatic gluconeogenic pathway, thereby reducing gluconeogenesis and endogenous glucose production (EGP). Whether a similar mechanism is functional in large animals, including humans, is unknown. Here, we demonstrated that in canines, physiologic brain hyperinsulinemia brought about by infusion of insulin into the head arteries (during a pancreatic clamp to maintain basal hepatic insulin and glucagon levels) activated hypothalamic Akt, altered STAT3 signaling in the liver, and suppressed hepatic gluconeogenic gene expression without altering EGP or gluconeogenesis. Rather, brain hyperinsulinemia slowly caused a modest reduction in net hepatic glucose output (NHGO) that was attributable to increased net hepatic glucose uptake and glycogen synthesis. This was associated with decreased levels of glycogen synthase kinase 3β (GSK3β) protein and mRNA and with decreased glycogen synthase phosphorylation, changes that were blocked by hypothalamic PI3K inhibition. Therefore, we conclude that the canine brain senses physiologic elevations in plasma insulin, and that this in turn regulates genetic events in the liver. In the context of basal insulin and glucagon levels at the liver, this input augments hepatic glucose uptake and glycogen synthesis, reducing NHGO without altering EGP. PMID:21865644

  19. Leptin and adiponectin in the female life course

    Directory of Open Access Journals (Sweden)

    S.B. Lecke

    2011-05-01

    Full Text Available Adipose tissue secretes a variety of adipokines, including leptin and adiponectin, which are involved in endocrine processes regulating glucose and fatty metabolism, energy expenditure, inflammatory response, immunity, cardiovascular function, and reproduction. The present article describes the fluctuations in circulating leptin and adiponectin as well as their patterns of secretion in women from birth to menopause. During pregnancy, leptin and adiponectin seem to act in an autocrine/paracrine fashion in the placenta and adipose tissue, playing a role in the maternal-fetal interface and contributing to glucose metabolism and fetal development. In newborns, adiponectin levels are two to three times higher than in adults. Full-term newborns have significantly higher leptin and adiponectin levels than preterms, whereas small-for-gestational-age infants have lower levels of these adipokines than adequate-for-gestational-age newborns. However, with weight gain, leptin concentrations increase significantly. Children between 5 and 8 years of age experience an increase in leptin and a decrease in adiponectin regardless of body mass index, with a reversal of the newborn pattern for adiponectin: plasma adiponectin levels at age five are inversely correlated with percentage of body fat. In puberty, leptin plays a role in the regulation of menstrual cycles. In adults, it has been suggested that obese individuals exhibit both leptin resistance and decreased serum adiponectin levels. In conclusion, a progressive increase in adiposity throughout life seems to influence the relationship between leptin and adiponectin in women.

  20. AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons.

    Science.gov (United States)

    Claret, Marc; Smith, Mark A; Batterham, Rachel L; Selman, Colin; Choudhury, Agharul I; Fryer, Lee G D; Clements, Melanie; Al-Qassab, Hind; Heffron, Helen; Xu, Allison W; Speakman, John R; Barsh, Gregory S; Viollet, Benoit; Vaulont, Sophie; Ashford, Michael L J; Carling, David; Withers, Dominic J

    2007-08-01

    Hypothalamic AMP-activated protein kinase (AMPK) has been suggested to act as a key sensing mechanism, responding to hormones and nutrients in the regulation of energy homeostasis. However, the precise neuronal populations and cellular mechanisms involved are unclear. The effects of long-term manipulation of hypothalamic AMPK on energy balance are also unknown. To directly address such issues, we generated POMC alpha 2KO and AgRP alpha 2KO mice lacking AMPK alpha2 in proopiomelanocortin- (POMC-) and agouti-related protein-expressing (AgRP-expressing) neurons, key regulators of energy homeostasis. POMC alpha 2KO mice developed obesity due to reduced energy expenditure and dysregulated food intake but remained sensitive to leptin. In contrast, AgRP alpha 2KO mice developed an age-dependent lean phenotype with increased sensitivity to a melanocortin agonist. Electrophysiological studies in AMPK alpha2-deficient POMC or AgRP neurons revealed normal leptin or insulin action but absent responses to alterations in extracellular glucose levels, showing that glucose-sensing signaling mechanisms in these neurons are distinct from those pathways utilized by leptin or insulin. Taken together with the divergent phenotypes of POMC alpha 2KO and AgRP alpha 2KO mice, our findings suggest that while AMPK plays a key role in hypothalamic function, it does not act as a general sensor and integrator of energy homeostasis in the mediobasal hypothalamus.

  1. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B

    DEFF Research Database (Denmark)

    Hribal, M L; Presta, I; Procopio, T

    2011-01-01

    The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry.......The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry....

  2. Correction of Diabetic Hyperglycemia and Amelioration of Metabolic Anomalies by Minicircle DNA Mediated Glucose-Dependent Hepatic Insulin Production.

    Directory of Open Access Journals (Sweden)

    Tausif Alam

    Full Text Available Type 1 diabetes mellitus (T1DM is caused by immune destruction of insulin-producing pancreatic β-cells. Commonly used insulin injection therapy does not provide a dynamic blood glucose control to prevent long-term systemic T1DM-associated damages. Donor shortage and the limited long-term success of islet transplants have stimulated the development of novel therapies for T1DM. Gene therapy-based glucose-regulated hepatic insulin production is a promising strategy to treat T1DM. We have developed gene constructs which cause glucose-concentration-dependent human insulin production in liver cells. A novel set of human insulin expression constructs containing a combination of elements to improve gene transcription, mRNA processing, and translation efficiency were generated as minicircle DNA preparations that lack bacterial and viral DNA. Hepatocytes transduced with the new constructs, ex vivo, produced large amounts of glucose-inducible human insulin. In vivo, insulin minicircle DNA (TA1m treated streptozotocin (STZ-diabetic rats demonstrated euglycemia when fasted or fed, ad libitum. Weight loss due to uncontrolled hyperglycemia was reversed in insulin gene treated diabetic rats to normal rate of weight gain, lasting ∼1 month. Intraperitoneal glucose tolerance test (IPGT demonstrated in vivo glucose-responsive changes in insulin levels to correct hyperglycemia within 45 minutes. A single TA1m treatment raised serum albumin levels in diabetic rats to normal and significantly reduced hypertriglyceridemia and hypercholesterolemia. Elevated serum levels of aspartate transaminase, alanine aminotransferase, and alkaline phosphatase were restored to normal or greatly reduced in treated rats, indicating normalization of liver function. Non-viral insulin minicircle DNA-based TA1m mediated glucose-dependent insulin production in liver may represent a safe and promising approach to treat T1DM.

  3. Glucose delays the insulin-induced increase in thyroid hormone-mediated signaling in adipose of prolong-fasted elephant seal pups

    Science.gov (United States)

    Soñanez-Organis, José G.; Viscarra, Jose A.; Jaques, John T.; MacKenzie, Duncan S.; Crocker, Daniel E.; Ortiz, Rudy M.

    2016-01-01

    Prolonged food deprivation in mammals typically reduces glucose, insulin, and thyroid hormone (TH) concentrations, as well as tissue deiodinase (DI) content and activity, which, collectively, suppress metabolism. However, in elephant seal pups, prolonged fasting does not suppress TH levels; it is associated with upregulation of adipose TH-mediated cellular mechanisms and adipose-specific insulin resistance. The functional relevance of this apparent paradox and the effects of glucose and insulin on TH-mediated signaling in an insulin-resistant tissue are not well defined. To address our hypothesis that insulin increases adipose TH signaling in pups during extended fasting, we assessed the changes in TH-associated genes in response to an insulin infusion in early- and late-fasted pups. In late fasting, insulin increased DI1, DI2, and THrβ-1 mRNA expression by 566%, 44%, and 267% at 60 min postinfusion, respectively, with levels decreasing by 120 min. Additionally, we performed a glucose challenge in late-fasted pups to differentiate between insulin- and glucose-mediated effects on TH signaling. In contrast to the insulin-induced effects, glucose infusion did not increase the expressions of DI1, DI2, and THrβ-1 until 120 min, suggesting that glucose delays the onset of the insulin-induced effects. The data also suggest that fasting duration increases the sensitivity of adipose TH-mediated mechanisms to insulin, some of which may be mediated by increased glucose. These responses appear to be unique among mammals and to have evolved in elephant seals to facilitate their adaptation to tolerate an extreme physiological condition. PMID:26739649

  4. Glucose-responsive insulin by molecular and physical design

    Science.gov (United States)

    Bakh, Naveed A.; Cortinas, Abel B.; Weiss, Michael A.; Langer, Robert S.; Anderson, Daniel G.; Gu, Zhen; Dutta, Sanjoy; Strano, Michael S.

    2017-10-01

    The concept of a glucose-responsive insulin (GRI) has been a recent objective of diabetes technology. The idea behind the GRI is to create a therapeutic that modulates its potency, concentration or dosing relative to a patient's dynamic glucose concentration, thereby approximating aspects of a normally functioning pancreas. From the perspective of the medicinal chemist, the GRI is also important as a generalized model of a potentially new generation of therapeutics that adjust potency in response to a critical therapeutic marker. The aim of this Perspective is to highlight emerging concepts, including mathematical modelling and the molecular engineering of insulin itself and its potency, towards a viable GRI. We briefly outline some of the most important recent progress toward this goal and also provide a forward-looking viewpoint, which asks if there are new approaches that could spur innovation in this area as well as to encourage synthetic chemists and chemical engineers to address the challenges and promises offered by this therapeutic approach.

  5. Role of sleep duration in the regulation of glucose metabolism and appetite

    OpenAIRE

    Morselli, Lisa; Leproult, Rachel; Balbo, Marcella; Spiegel, Karine

    2010-01-01

    Sleep curtailment has become a common behavior in modern society. This review summarizes the current laboratory evidence indicating that sleep loss may contribute to the pathophysiology of diabetes mellitus and obesity. Experimentally-induced sleep loss in healthy volunteers decreases insulin sensitivity without adequate compensation in beta-cell function, resulting in impaired glucose tolerance and increased diabetes risk. Lack of sleep also down-regulates the satiety hormone leptin, up-regu...

  6. Effects of Everyday Life Events on Glucose, Insulin, and Glucagon Dynamics in Continuous Subcutaneous Insulin Infusion–Treated Type 1 Diabetes: Collection of Clinical Data for Glucose Modeling

    DEFF Research Database (Denmark)

    Schmidt, Signe; Finan, Daniel Aaron; Duun-Henriksen, Anne Katrine

    2012-01-01

    metabolism, we designed and conducted a clinical study.Methods: Patients with insulin pump–treated T1D were recruited to perform everyday life events on two separate days. During the study, patients wore their insulin pumps and, in addition, a continuous glucose monitor and an activity monitor to estimate...

  7. Exponential increase in postprandial blood-glucose exposure with increasing carbohydrate loads using a linear carbohydrate-to-insulin ratio.

    Science.gov (United States)

    Marran, K J; Davey, B; Lang, A; Segal, D G

    2013-04-10

    Postprandial glucose excursions contribute significantly to average blood glucose, glycaemic variability and cardiovascular risk. Carbohydrate counting is a method of insulin dosing that balances carbohydrate load to insulin dose using a fixed ratio. Many patients and current insulin pumps calculate insulin delivery for meals based on a linear carbohydrate-to-insulin relationship. It is our hypothesis that a non-linear relationship exists between the amounts of carbohydrate consumed and the insulin required to cover it. To document blood glucose exposure in response to increasing carbohydrate loads on fixed carbohydrate-to-insulin ratios. Five type 1 diabetic subjects receiving insulin pump therapy with good control were recruited. Morning basal rates and carbohydrate- to-insulin ratios were optimised. A Medtronic glucose sensor was used for 5 days to collect data for area-under-the-curve (AUC) analysis, during which standardised meals of increasing carbohydrate loads were consumed. Increasing carbohydrate loads using a fixed carbohydrate-to-insulin ratio resulted in increasing glucose AUC. The relationship was found to be exponential rather than linear. Late postprandial hypoglycaemia followed carbohydrate loads of >60 g and this was often followed by rebound hyperglycaemia that lasted >6 hours. A non-linear relationship exists between carbohydrates consumed and the insulin required to cover them. This has implications for control of postprandial blood sugars, especially when consuming large carbohydrate loads. Further studies are required to look at the optimal ratios, duration and type of insulin boluses required to cover increasing carbohydrate loads.

  8. [Association of leptin receptor gene polymorphrism with metabolic syndrome in older Han adults from major cities in China].

    Science.gov (United States)

    Wu, Jinghuan; Zhuo, Qin; Chen, Xi; Tian, Yuan; Piao, Jianhua; Yang, Xiaoguang

    2016-05-01

    To investigate the relationship of leptin receptor gene rs1137100 and rs1137101 single nucleotide polymorphrism (SNP) with metabolic syndrome (MS) in older Han adults from major cities in China. A total of 2082 older Han adults were selected from 18 major cities including 15 provinces/municipalities of China National Nutrition and Health Survey in 2002. According to the MS definition proposed by Joint Interim Statement (JIS), the subjects were divided into MS and control groups. Plasma leptin and insulin levels were measured. The genotypes of rs1137100 and rs1137101 were detected by Taqman method. Association of genotypes of leptin receptor gene SNPs with MS was investigated. The MS group showed higher body mass index (BMI), waist circumference, fasting serum glucose, systolic blood pressure (SBP) and diastolic blood pressure (DBP), triglycerides (TG), serum total cholesterol (TC), insulin, homeostasis model of assessment for insulin resistence index (HOMA-IR) and leptin levels than those of control individuals, while the high density lipoprotein cholesterol (HDL-c) was significantly lower than the control group. The, GG, AA, GA genotypes distribution and the A allele frequency of rs1137100 and rs1137101 were similar between the two groups. The DBP and SBP level were obviously higher in AA genotype. The HDL-c concentration Was significantly lower in AA and GA + AA genotype. The AA and GA genotypes carriers in rs1137100 had similar risk for MS when comparing with the GG genotypes, and the OR values were 1.23 (95% CI 0.90-1.67) and 2.23 (95% CI 0.83-6.44), respectively. The AA and GA genotypes carriers in rs1137101 had similar risk for MS when comparing with the GG genotypes, and the OR values were 1.23 (95% CI 0.90-1.67) and 2.23 (95% CI 0.83-6.44), respectively. Leptin receptor genes rs1137100 and rs1137101 are not associated with pathogenesis of MS in older Han adults, but it may relate with hypertension or lipid abnormality.

  9. Curcumin reverses the depressive-like behavior and insulin resistance induced by chronic mild stress.

    Science.gov (United States)

    Shen, Ji-Duo; Wei, Yu; Li, Yu-Jie; Qiao, Jing-Yi; Li, Yu-Cheng

    2017-08-01

    Increasing evidence has demonstrated that patients with depression have a higher risk of developing type 2 diabetes. Insulin resistance has been identified as the key mechanism linking depression and diabetes. The present study established a rat model of depression complicated by insulin resistance using a 12-week exposure to chronic mild stress (CMS) and investigated the therapeutic effects of curcumin. Sucrose intake tests were used to evaluate depressive-like behaviors, and oral glucose tolerance tests (OGTT) and intraperitoneal insulin tolerance tests (IPITT) were performed to evaluate insulin sensitivity. Serum parameters were detected using commercial kits. Real-time quantitative PCR was used to examine mRNA expression. CMS rats exhibited reduced sucrose consumption, increased serum glucose, insulin, triglyceride (TG), low density lipoprotein-cholesterol (LDL-C), non-esterified fatty acid (NEFA), glucagon, leptin, and corticosterone levels, as well as impaired insulin sensitivity. Curcumin upregulated the phosphorylation of insulin receptor substrate (IRS)-1 and protein kinase B (Akt) in the liver, enhanced insulin sensitivity, and reversed the metabolic abnormalities and depressive-like behaviors mentioned above. Moreover, curcumin increased the hepatic glycogen content by inhibiting glycogen synthase kinase (GSK)-3β and prevented gluconeogenesis by inhibiting phosphoenolpyruvate carboxykinase (PEPCK) and glucose 6-phosphatase (G6Pase). These results suggest that curcumin not only exerted antidepressant-like effects, but also reversed the insulin resistance and metabolic abnormalities induced by CMS. These data may provide evidence to support the potential use of curcumin against depression and/or metabolic disorders.

  10. Maternal insulin sensitivity is associated with oral glucose-induced changes in fetal brain activity.

    Science.gov (United States)

    Linder, Katarzyna; Schleger, Franziska; Ketterer, Caroline; Fritsche, Louise; Kiefer-Schmidt, Isabelle; Hennige, Anita; Häring, Hans-Ulrich; Preissl, Hubert; Fritsche, Andreas

    2014-06-01

    Fetal programming plays an important role in the pathogenesis of type 2 diabetes. The aim of the present study was to investigate whether maternal metabolic changes during OGTT influence fetal brain activity. Thirteen healthy pregnant women underwent an OGTT (75 g). Insulin sensitivity was determined by glucose and insulin measurements at 0, 60 and 120 min. At each time point, fetal auditory evoked fields were recorded with a fetal magnetoencephalographic device and response latencies were determined. Maternal insulin increased from a fasting level of 67 ± 25 pmol/l (mean ± SD) to 918 ± 492 pmol/l 60 min after glucose ingestion and glucose levels increased from 4.4 ± 0.3 to 7.4 ± 1.1 mmol/l. Over the same time period, fetal response latencies decreased from 297 ± 99 to 235 ± 84 ms (p = 0.01) and then remained stable until 120 min (235 ± 84 vs 251 ± 91 ms, p = 0.39). There was a negative correlation between maternal insulin sensitivity and fetal response latencies 60 min after glucose ingestion (r = 0.68, p = 0.02). After a median split of the group based on maternal insulin sensitivity, fetuses of insulin-resistant mothers showed a slower response to auditory stimuli (283 ± 79 ms) than those of insulin-sensitive mothers (178 ± 46 ms, p = 0.03). Lower maternal insulin sensitivity is associated with slower fetal brain responses. These findings provide the first evidence of a direct effect of maternal metabolism on fetal brain activity and suggest that central insulin resistance may be programmed during fetal development.

  11. Assessment of insulin resistance and impaired glucose tolerance in lean women with polycystic ovary syndrome.

    Science.gov (United States)

    Stovall, Dale William; Bailey, Amelia Purser; Pastore, Lisa M

    2011-01-01

    To analyze insulin resistance (IR) and determine the need for a 2-hour oral glucose tolerance test (OGTT) for the identification of IR and impaired glucose tolerance (IGT) in lean nondiabetic women with polycystic ovary syndrome (PCOS). This was a cross-sectional analysis of treatment-naive women with PCOS who enrolled in a university-based clinical trial. Nondiabetic women with PCOS based on the Eunice Kennedy Shriven National Institute of Child Health and Human Development (NICHD) definition, aged 18-43 years and weighing ≤113 kg, were evaluated. Glucose and insulin levels were assessed at times 0, 30, 60, 90, and 120 minutes after a 75-g glucose load. Lean was defined as body mass index (BMI) women was studied. The prevalence of IR was 0% among lean women vs. 21% among nonlean subjects based on fasting insulin I(0) and 40%-68% based on two different homeostatic model assessment (HOMA) cutoff points (p women with IR had a BMI ≥ 28. Controlling for age and race, BMI explained over 57% of the variation in insulin fasting (I(o)), glucose fasting/Io (G(o)/I(o)), the qualitative insulin sensitivity check index (QUICKI), and HOMA and was a highly significant predictor of these outcomes (p lean PCOS women had IGT based on a 2-hour OGTT, and no lean subjects had IGT based on their fasting blood glucose. Diabetes mellitus, IGT, and IR are far less common in young lean women with PCOS compared with obese women with PCOS. These data imply that it is unnecessary to routinely perform either IR testing or 2-hour OGTT in lean women with PCOS; however, greater subject accumulation is needed to determine if OGTT is necessary in lean women with PCOS. BMI is highly predictive of both insulin and glucose levels in women with PCOS.

  12. Effect of test meals of varying dietary fiber content on plasma insulin and glucose response.

    Science.gov (United States)

    Potter, J G; Coffman, K P; Reid, R L; Krall, J M; Albrink, M J

    1981-03-01

    To assess the effect of dietary fiber on glucose tolerance four different meals of varying fiber content but identical protein fat and carbohydrate content were fed to eight healthy men aged 22 to 45. Each meal provided 75 g of carbohydrate as liquid glucose formula, as brown rice, pinto beans, or All Bran. The mean plasma glucose and insulin responses were highest following the formula, and least for All Bran and pinto beans. Rice produced nearly as great a rise in insulin and glucose as did the formula. The rank of each meal by content of neutral detergent fiber was nearly the inverse of the rank by magnitude of the insulin response evoked, fiber content being greatest in All Bran (18 g) and pinto beans (16.2 g), low in rice (2.8 g) and absent from the formula. It was concluded that dietary fiber dampened the insulin response to a high carbohydrate meal.

  13. Glucagon-insulin interaction on fat cell metabolism using c14 glucose

    International Nuclear Information System (INIS)

    Zewail, M.A.; Nielsen, J.H.

    1984-01-01

    Glucagon is known to stimulate the lipolysis in isolated fat cells from young rats, but not in fat cells from old heavy rate (Manganiello 1972). Insulin is known to counteract the lipolytic effect and to stimulate the synthesis of fatty acids from glucose. However, little is known about the interaction between the two hormones on the glucose metabolism. Experiments based on the use of various inhibitors of lipolysis have however, clearly shown that glucagon can also stimulate the entry and overall oxidation of glucose by mechanism which is distinct from its lipolysis stimulating mechanism (M. Blecher et al. 1969). Fat cells from old heavy rats are known to be less responsive to both the lipogenic action of insulin and the lipolytic action of glucagon than fat cells from young lean rats (E.G. Hansen, Nielsen and Gliemann, 1974). The aim of the present study was to see how glucagon affects glucose metabolism in fat cells, and whether this effect was dependent on the lipolytic action of glucagon

  14. Circulating ghrelin, leptin, and soluble leptin receptor concentrations and cardiometabolic risk factors in a community-based sample.

    Science.gov (United States)

    Ingelsson, Erik; Larson, Martin G; Yin, Xiaoyan; Wang, Thomas J; Meigs, James B; Lipinska, Izabella; Benjamin, Emelia J; Keaney, John F; Vasan, Ramachandran S

    2008-08-01

    The conjoint effects and relative importance of ghrelin, leptin, and soluble leptin receptor (sOB-R), adipokines involved in appetite control and energy expenditure in mediating cardiometabolic risk, is unknown. The objective of the study was to study the cross-sectional relations of these adipokines to cardiometabolic risk factors in a community-based sample. We measured circulating ghrelin, leptin, and sOB-R in 362 participants (mean age 45 yr; 54% women) of the Framingham Third Generation Cohort. Body mass index, waist circumference (WC), blood pressure, lipid measures, fasting glucose, smoking, and metabolic syndrome (MetS) were measured. Ghrelin and leptin concentrations were significantly higher in women (P risk.

  15. Effects of Endogenous Androgens and Abdominal Fat Distribution on the Interrelationship Between Insulin and Non-Insulin-Mediated Glucose Uptake in Females

    Science.gov (United States)

    Ezeh, Uche; Pall, Marita; Mathur, Ruchi; Dey, Damini; Berman, Daniel; Chen, Ida Y.; Dumesic, Daniel A.

    2013-01-01

    Background: Polycystic ovary syndrome (PCOS) is associated with hyperandrogenism and insulin resistance. Glucose disposal occurs via noninsulin-mediated glucose uptake (NIMGU) and insulin-mediated glucose uptake (IMGU). It is unknown whether in PCOS NIMGU increases to compensate for declining IMGU and whether androgens and fat distribution influence this relationship. Objectives: The objective of the study was to compare in women with PCOS and controls the interrelationship between NIMGU [ie, glucose effectiveness (Sg)] and IMGU [ie, the insulin sensitivity index (Si)] and the role of androgens and fat distribution. Participants: Twenty-eight PCOS (by National Institutes of Health 1990 criteria) and 28 control (age, race, and body mass index matched) women were prospectively studied. A subset of 16 PCOS subjects and 16 matched controls also underwent abdominal computed tomography. Main Outcome Measures: Glucose disposal (by a frequently sampled iv glucose tolerance test), circulating androgens, and abdominal fat distribution [by waist to hip ratio and visceral (VAT) and sc (SAT) adipose tissue content] were measured. Results: PCOS women had lower mean Si and similar Sg and abdominal fat distribution compared with controls. PCOS women with Si below the PCOS median (more insulin resistant) had a lower mean Sg than controls with Si above the control median (more insulin sensitive). In PCOS only, body mass index, free T, modified Ferriman-Gallwey score, and waist to hip ratio independently predicted Sg, whereas Si did not. In PCOS, VAT and SAT independently and negatively predicted Si and Sg, respectively. Conclusion: The decreased IMGU in PCOS is not accompanied by a compensatory increase in NIMGU or associated with excessive VAT accumulation. Increased general obesity, SAT, and hyperandrogenism are primary predictors of the deterioration of NIMGU in PCOS. PMID:23450052

  16. Glucose Control: non-insulin therapies* 9.1: Drug Summary ...

    African Journals Online (AJOL)

    Glucose Control: non-insulin therapies in 2017 SEMDSA Guideline for the Management of Type 2 Diabetes. Guideline ... Weight neutral or causes modest weight loss (-1.2kg). No weight ..... Older patients with multiple comorbidities. • Patients ...

  17. Effects of Acute Exercise and Chronic Exercise on the Liver Leptin-AMPK-ACC Signaling Pathway in Rats with Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Xuejie Yi

    2013-01-01

    Full Text Available Aim. To investigate the effects of acute and chronic exercise on glucose and lipid metabolism in liver of rats with type 2 diabetes caused by a high fat diet and low dose streptozotocin (STZ. Methods. Animals were classified into control (CON, diabetes (DC, diabetic chronic exercise (DCE, and diabetic acute exercise (DAE groups. Results. Compared to CON, the leptin levels in serum and liver and ACC phosphorylation were significantly higher in DC, but the levels of liver leptin receptor, AMPKα1/2, AMPKα1, and ACC proteins expression and phosphorylation were significantly lower in DC. In addition, the levels of liver glycogen reduced significantly, and the levels of TG and FFA increased significantly in DC compared to CON. Compared to DC, the levels of liver AMPKα1/2, AMPKα2, AMPKα1, and ACC phosphorylation significantly increased in DCE and DAE. However, significant increase of the level of liver leptin receptor and glycogen as well as significant decrease of the level of TG and FFA were observed only in DEC. Conclusion. Our study demonstrated that both acute and chronic exercise indirectly activated the leptin-AMPK-ACC signaling pathway and increased insulin sensitivity in the liver of type 2 diabetic rats. However, only chronic and long-term exercise improved glucose and lipid metabolism of the liver.

  18. Decrease of glucose-induced insulin secretion of rat pancreatic islets after irradiation in vitro

    Energy Technology Data Exchange (ETDEWEB)

    Heinzmann, D; Nadrowitz, R; Besch, W; Schmidt, W; Hahn, H J [Zentralinstitut fuer Diabetes, Karlsburg (German Democratic Republic); Ernst-Moritz-Arndt-Universitaet, Greifswald (German Democratic Republic). Radiologische Klinik)

    1983-01-01

    In vitro irradiation of rat pancreatic islets up to a dose of 2.5 Gy did neither alter glucose- nor isobutylmethyl xanthine (IBMX)-induced insulin secretion. Insulin as well as glucagon content of irradiated islets corresponded to that of the control tissue. So it was in islets irradiated with 25 Gy which were characterized by a decreased insulin secretion in the presence of glucose and IBMX, respectively. There was no indication of an enhanced hormone output in the radiation medium and it is to be suggested that higher radiation doses affect the insulin release of pancreatic islets in vitro. This must be taken into consideration for radioimmunosuppression experiments.

  19. Insulin monotherapy compared with the addition of oral glucose-lowering agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control

    NARCIS (Netherlands)

    Vos, Rimke C; van Avendonk, Mariëlle JP; Jansen, Hanneke; Goudswaard, Alexander N; van den Donk, Maureen; Gorter, Kees; Kerssen, Anneloes; Rutten, Guy EHM

    2016-01-01

    BACKGROUND: It is unclear whether people with type 2 diabetes mellitus on insulin monotherapy who do not achieve adequate glycaemic control should continue insulin as monotherapy or can benefit from adding oral glucose-lowering agents to the insulin therapy. OBJECTIVES: To assess the effects of

  20. Response of plasma glucose, insulin, and nonesterified fatty acids to intravenous glucose tolerance tests in dairy cows during a 670-day lactation.

    Science.gov (United States)

    Marett, L C; Auldist, M J; Moate, P J; Wales, W J; Macmillan, K L; Dunshea, F R; Leury, B J

    2015-01-01

    This experiment investigated the metabolic response of dairy cows undergoing an extended lactation to a frequently sampled intravenous glucose tolerance test. The experiment used 12 multiparous Holstein cows that calved in late winter in a seasonally calving pasture-based system and were managed for a 670-d lactation by delaying rebreeding. In each of four 5-wk experimental periods commencing at approximately 73, 217, 422, and 520 (±9.1) days in milk (DIM), cows were offered a diet of perennial ryegrass (73 and 422 DIM) or pasture hay and silage (217 and 520 DIM) supplemented with 1kg of DM grain (control; CON) or 6kg of DM grain (GRN) as a ration. Daily energy intake was approximately 160 and 215 MJ of metabolizable energy/cow for the CON and GRN treatments, respectively. At all other times, cows were managed as a single herd and grazed pasture supplemented with grain to an estimated minimum daily total intake of 180 MJ of metabolizable energy/cow. Cows were fitted with an indwelling jugular catheter during the final week of each experimental period. The standard intravenous glucose tolerance test using 0.3g of glucose per kilogram of body weight was performed on each cow at approximately 100, 250, 460, and 560 DIM. Plasma concentrations of glucose, insulin, and nonesterified fatty acids (NEFA) responses were measured. Milk yield, milk solids yield, body weight, and basal plasma glucose were greater in the GRN compared with the CON treatment. The area under the plasma response curve relative to baseline (AUC) for glucose, insulin, and NEFA and their apparent fractional clearance rates indicated varied whole body responsiveness to insulin in terms of glucose metabolism throughout the 670-d lactation. The glucose AUC 0 to 20 min postinfusion was increased at 560 DIM, indicating reduced utilization of glucose by the mammary gland at this stage of lactation. The NEFA clearance rate, 6 to 30 min postinfusion, was greater at 460 and 560 DIM. These data indicated an