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Sample records for resistance insulin secretion

  1. Studies on insulin secretion and insulin resistance in non-insulin-dependent diabetes in young Indians

    International Nuclear Information System (INIS)

    Naidoo, C.

    1986-01-01

    Patients with Non-insulin-dependent diabetes mellitus (NIDDM) have defects in insulin secretion and insulin action. In the discrete genetic syndrome of NIDDY (non-insulin-dependent diabetes in the young), the situation is less clear and these aspects is the subject of this thesis. This study included Indian pasients with three generation transmission of NIDDM via one parent. The insulin and C-peptide responses to oral and intravenous glucose in patients with NIDDY were studied. The insulin and glucose responses to non-glucose secretogogues glucagon, tolbutamide and arginine, in NIDDY were also investigated. The following aspects with regard to insulin resistance in NIDDY were examined: glucose and free fatty acid response to intravenous insulin administration, insulin binding to circulating erythrocytes and monocytes, 125 I-insulin binding to the solubilized erythrocyte membrane receptor and 125 I-insulin binding to fibroblasts in culture

  2. Macrophage-secreted factors induce adipocyte inflammation and insulin resistance

    International Nuclear Information System (INIS)

    Permana, Paska A.; Menge, Christopher; Reaven, Peter D.

    2006-01-01

    Macrophage infiltration into adipose tissue increases with obesity, a condition associated with low-grade inflammation and insulin resistance. We investigated the direct effects of macrophage-secreted factors on adipocyte inflammation and insulin resistance. 3T3-L1 adipocytes incubated with media conditioned by RAW264.7 macrophages (RAW-CM) showed dramatically increased transcription of several inflammation-related genes, greater nuclear factor kappa B (NF-κB) activity, and enhanced binding of U937 monocytes. All of these effects were prevented by co-incubation with pyrrolidinedithiocarbamate, an NF-κB inhibitor. Adipocytes incubated with RAW-CM also released more non-esterified fatty acids and this increased lipolysis was not suppressed by insulin. In addition, RAW-CM treatment decreased insulin-stimulated glucose uptake in adipocytes. Taken together, these results indicate that macrophage-secreted factors induce inflammatory responses and reduce insulin responsiveness in adipocytes. These effects of macrophage-secreted factors on adipocytes may contribute significantly to the systemic inflammation and insulin resistance associated with obesity

  3. Association of Nocturnal Melatonin Secretion With Insulin Resistance in Nondiabetic Young Women

    OpenAIRE

    McMullan, Ciaran J.; Curhan, Gary C.; Schernhammer, Eva S.; Forman, John P.

    2013-01-01

    Exogenous melatonin ameliorates insulin resistance in animals, while among humans, polymorphisms in the melatonin receptor gene are associated with insulin resistance. We aimed to investigate the association of endogenous nocturnal melatonin secretion with insulin resistance in humans. We analyzed the association between endogenous nocturnal melatonin secretion, estimated by measuring the main melatonin metabolite, 6-sulfatoxymelatonin, from the first morning urinary void, and the prevalence ...

  4. Tacrolimus reversibly reduces insulin secretion, induces insulin resistance, and causes islet cell damage in rats.

    Science.gov (United States)

    Xu, Chun; Niu, Yu-Jian; Liu, Xiao-Jun; Teng, Ya-Qin; Li, Chun-Feng; Wang, Hong-Yu; Yin, Jun-Ping; Wang, Le-Tian; Shen, Zhong-Yang

    2014-07-01

    To investigate the diabetogenic effects of the immunosuppressive agent tacrolimus, the reversibility of these effects upon treatment discontinuation, and the underlying mechanisms in a rat model. 60 healthy male rats were randomly divided into three groups for intragastric administration of tacrolimus either at 4 mg/kg/d or 2 mg/kg/d or an equal volume of normal saline (control). The treatment was administered for 5 months, followed by a 5-month period of no intervention. Fasting plasma glucose and insulin levels were used to calculate the homeostasis model assessment of ß-cell function (HOMA-ß) and insulin sensitivity index (ISI). Tacrolimus treatment significantly increased blood glucose concentrations (p insulin secretion pathway, local and/or systemic insulin resistance, and islet cell damage.

  5. Insulin and Insulin Resistance

    Science.gov (United States)

    2005-01-01

    As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the complex biological mechanisms of insulin action and insulin resistance, we need to consider the dramatic social changes of the past century with respect to physical activity, diet, work, socialisation and sleep patterns. Rapid globalisation, urbanisation and industrialisation have spawned epidemics of obesity, diabetes and their attendant co-morbidities, as physical inactivity and dietary imbalance unmask latent predisposing genetic traits. PMID:16278749

  6. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance.

    Science.gov (United States)

    Pereira, Renata Oliveira; Tadinada, Satya M; Zasadny, Frederick M; Oliveira, Karen Jesus; Pires, Karla Maria Pereira; Olvera, Angela; Jeffers, Jennifer; Souvenir, Rhonda; Mcglauflin, Rose; Seei, Alec; Funari, Trevor; Sesaki, Hiromi; Potthoff, Matthew J; Adams, Christopher M; Anderson, Ethan J; Abel, E Dale

    2017-07-14

    Mitochondrial dynamics is a conserved process by which mitochondria undergo repeated cycles of fusion and fission, leading to exchange of mitochondrial genetic content, ions, metabolites, and proteins. Here, we examine the role of the mitochondrial fusion protein optic atrophy 1 (OPA1) in differentiated skeletal muscle by reducing OPA1 gene expression in an inducible manner. OPA1 deficiency in young mice results in non-lethal progressive mitochondrial dysfunction and loss of muscle mass. Mutant mice are resistant to age- and diet-induced weight gain and insulin resistance, by mechanisms that involve activation of ER stress and secretion of fibroblast growth factor 21 (FGF21) from skeletal muscle, resulting in increased metabolic rates and improved whole-body insulin sensitivity. OPA1-elicited mitochondrial dysfunction activates an integrated stress response that locally induces muscle atrophy, but via secretion of FGF21 acts distally to modulate whole-body metabolism. © 2017 The Authors.

  7. Effect of almonds on insulin secretion and insulin resistance in nondiabetic hyperlipidemic subjects: a randomized controlled crossover trial.

    Science.gov (United States)

    Jenkins, David J A; Kendall, Cyril W C; Marchie, Augustine; Josse, Andrea R; Nguyen, Tri H; Faulkner, Dorothea A; Lapsley, Karen G; Singer, William

    2008-07-01

    Nuts appear to have a marked effect in cohort studies in reducing the risk of coronary heart disease (CHD), but their demonstrated ability to lower cholesterol can only explain a proportion of the reduction in risk. Our aim was to assess whether improvement in carbohydrate metabolism provides a further explanation for the effect of nuts in reducing CHD. The effects of whole almonds, taken as snacks, were compared with the effects of low saturated fat (<5% energy) whole-wheat muffins (control) in the therapeutic diets of hyperlipidemic subjects. In a randomized crossover study, 27 hyperlipidemic men and women consumed 3 isoenergetic (mean, 423 kcal/d) supplements each for 1 month. Supplements provided 22.2% of energy and consisted of full-dose almonds (73 +/- 3 g/d), half-dose almonds plus half-dose muffins, and full-dose muffins. Subjects were assessed at weeks 0, 2, and 4 and fasting blood samples were obtained. Twenty-four-hour urinary output was collected at the end of week 4 on each treatment. Mean body weights differed by less than 300 g between treatments. No differences were seen in baseline or treatment values for fasting glucose, insulin, C-peptide, or insulin resistance as measured by homeostasis model assessment of insulin resistance. However, 24-hour urinary C-peptide output as a marker of 24-hour insulin secretion was significantly reduced on the half-and full-dose almonds by comparison to the control after adjustment for urinary creatinine output (P = .002 and P = .004, respectively). We conclude that reductions in 24-hour insulin secretion appear to be a further metabolic advantage of nuts that in the longer term may help to explain the association of nut consumption with reduced CHD risk.

  8. Insulin secretion in lipodystrophic HIV-infected patients is associated with high levels of nonglucose secretagogues and insulin resistance of beta-cells

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Storgaard, Heidi

    2004-01-01

    We examined whether plasma concentrations of nonglucose insulin secretagogues are associated with prehepatic insulin secretion rates (ISR) in nondiabetic, insulin-resistant, human immunodeficiency virus (HIV)-infected, lipodystrophic patients (LIPO). Additionally, the negative feedback of insulin...... on ISR was evaluated. ISR were estimated by deconvolution of plasma C-peptide concentrations during fasting (basal) and during the last 30 min of a 120-min euglycemic insulin clamp (40 mU.m(-2).min(-1)). Eighteen normoglycemic LIPO were compared with 25 normoglycemic HIV-infected patients without...... lipodystrophy (controls). Thirty minutes before start of the clamp, a bolus of glucose was injected intravenously to stimulate endogenous insulin secretion. Insulin sensitivity index (SiRd) was estimated from glucose tracer analysis. LIPO displayed increased basal ISR (69%), clamp ISR (114%), basal insulin (130...

  9. Differential pattern for regulating insulin secretion, insulin resistance, and lipid metabolism by osteocalcin in male and female T2DM patients.

    Science.gov (United States)

    Rui, Xuefei; Xu, Bei; Su, Junlei; Pan, Chunping; Zhan, Chenyu; Su, Bin; Li, Hong; Wang, Jiying; Sheng, Hui; Qu, Shen

    2014-05-01

    Osteocalcin has been reported to be relevant to glucose and lipid metabolism, indicating it may stimulate insulin secretion and improve insulin resistance. Yet the difference between male and female patients is still not clear. We aimed to investigate the difference in serum osteocalcin, and its association with glucose, lipid metabolism, pancreatic function, insulin sensitivity, and resistance in male and female middle-aged and elderly type 2 diabetic (T2DM) patients. 739 T2DM patients were included. After measurement of body mass index (BMI), the levels of fasting plasma glucose (FPG), insulin (FINS), C peptide (FC-P), 2-h post-OGTT plasma glucose (2h-PG), HbA1C, and osteocalcin were determined. Homeostasis model assessment of β-cell function (HOMA-%B), homeostasis model assessment of insulin sensitivity (HOMA-%S), and homeostasis model assessment of insulin resistance (HOMA-IR) were calculated. Females had higher osteocalcin concentration than males (Pinsulin (2h-INS), and HOMA-%B (Pmetabolism through enhancing insulin secretion in males, and through increasing insulin secretion and improving insulin resistance in females with T2DM. Osteocalcin probably also plays an important role in lipid metabolism.

  10. Jejunal proteins secreted by db/db mice or insulin-resistant humans impair the insulin signaling and determine insulin resistance.

    Directory of Open Access Journals (Sweden)

    Serenella Salinari

    Full Text Available Two recent studies demonstrated that bariatric surgery induced remission of type 2 diabetes very soon after surgery and far too early to be attributed to weight loss. In this study, we sought to explore the mechanism/s of this phenomenon by testing the effects of proteins from the duodenum-jejunum conditioned-medium (CM of db/db or Swiss mice on glucose uptake in vivo in Swiss mice and in vitro in both Swiss mice soleus and L6 cells. We studied the effect of sera and CM proteins from insulin resistant (IR and insulin-sensitive subjects on insulin signaling in human myoblasts.db/db proteins induced massive IR either in vivo or in vitro, while Swiss proteins did not. In L6 cells, only db/db proteins produced a noticeable increase in basal (473Ser-Akt phosphorylation, lack of GSK3β inhibition and a reduced basal (389Thr-p70-S6K1 phosphorylation. Human IR serum markedly increased basal (473Ser-Akt phosphorylation in a dose-dependent manner. Human CM IR proteins increased by about twofold both basal and insulin-stimulated (473Ser-Akt. Basal (9Ser-GSK3β phosphorylation was increased by IR subjects serum with a smaller potentiating effect of insulin.These findings show that jejunal proteins either from db/db mice or from insulin resistant subjects impair muscle insulin signaling, thus inducing insulin resistance.

  11. Insulin Resistance and Prediabetes

    Science.gov (United States)

    ... in the normal range. What happens with insulin resistance? In insulin resistance, muscle, fat, and liver cells do not ... they do not usually test specifically for insulin resistance. Insulin resistance can be assessed by measuring the level ...

  12. Insulin Resistance

    DEFF Research Database (Denmark)

    Jensen, Benjamin Anderschou Holbech

    Insulin resistance (IR) is escalating with alarming pace and is no longer restricted to westernized countries. As a forerunner for some of the most serious threats to human health including metabolic syndrome, cardiovascular diseases, and type 2-diabetes, the need for new treatment modalities...... interventions. We further show that improving the inflammatory toning, using fish oil as fat source, protects mice against diet induced obesity and -inflammation while preserving insulin sensitivity, even in the absence of free fatty acid receptor 4. Conversely, HFD-induced intestinal dysbiosis is associated...

  13. The T-allele of TCF7L2 rs7903146 associates with a reduced compensation of insulin secretion for insulin resistance induced by 9 days of bed rest

    DEFF Research Database (Denmark)

    Alibegovic, Amra C; Sonne, Mette P; Højbjerre, Lise

    2010-01-01

    , the TCF7L2 rs7903146 did not influence peripheral insulin action or the rate of lipolysis before or after bed rest. CONCLUSIONS: Healthy carriers of the T-allele of TCF7L2 rs7903146 exhibit a diminished increase of insulin secretion in response to intravenous glucose to compensate for insulin resistance......OBJECTIVE: The aim of this study was to determine whether the type 2 diabetes-associated T-allele of transcription factor 7-like 2 (TCF7L2) rs7903146 associates with impaired insulin secretion to compensate for insulin resistance induced by bed rest. RESEARCH DESIGN AND METHODS: A total of 38....... The genetic analyses were done assuming a dominant model of inheritance. RESULTS: The first-phase insulin response (FPIR) was significantly lower in carriers of the T-allele compared with carriers of the CC genotype before bed rest, with and without correction for insulin resistance. The incremental rise...

  14. Fatty acid-induced insulin resistance

    DEFF Research Database (Denmark)

    Le Marchand-Brustel, Y; Gual, P; Grémeaux, T

    2003-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterized by a decrease in the insulin effect on glucose transport in muscle and adipose tissue. Tyrosine phosphorylation of IRS-1 (insulin receptor subs...

  15. 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.

  16. Insulin Resistance and Mitochondrial Dysfunction.

    Science.gov (United States)

    Gonzalez-Franquesa, Alba; Patti, Mary-Elizabeth

    2017-01-01

    Insulin resistance precedes and predicts the onset of type 2 diabetes (T2D) in susceptible humans, underscoring its important role in the complex pathogenesis of this disease. Insulin resistance contributes to multiple tissue defects characteristic of T2D, including reduced insulin-stimulated glucose uptake in insulin-sensitive tissues, increased hepatic glucose production, increased lipolysis in adipose tissue, and altered insulin secretion. Studies of individuals with insulin resistance, both with established T2D and high-risk individuals, have consistently demonstrated a diverse array of defects in mitochondrial function (i.e., bioenergetics, biogenesis and dynamics). However, it remains uncertain whether mitochondrial dysfunction is primary (critical initiating defect) or secondary to the subtle derangements in glucose metabolism, insulin resistance, and defective insulin secretion present early in the course of disease development. In this chapter, we will present the evidence linking mitochondrial dysfunction and insulin resistance, and review the potential for mitochondrial targets as a therapeutic approach for T2D.

  17. Aβ-Induced Insulin Resistance and the Effects of Insulin on the Cholesterol Synthesis Pathway and Aβ Secretion in Neural Cells.

    Science.gov (United States)

    Najem, Dema; Bamji-Mirza, Michelle; Yang, Ze; Zhang, Wandong

    2016-06-01

    Alzheimer's disease (AD) is characterized by amyloid-β (Aβ) toxicity, tau pathology, insulin resistance, neuroinflammation, and dysregulation of cholesterol homeostasis, all of which play roles in neurodegeneration. Insulin has polytrophic effects on neurons and may be at the center of these pathophysiological changes. In this study, we investigated possible relationships among insulin signaling and cholesterol biosynthesis, along with the effects of Aβ42 on these pathways in vitro. We found that neuroblastoma 2a (N2a) cells transfected with the human gene encoding amyloid-β protein precursor (AβPP) (N2a-AβPP) produced Aβ and exhibited insulin resistance by reduced p-Akt and a suppressed cholesterol-synthesis pathway following insulin treatment, and by increased phosphorylation of insulin receptor subunit-1 at serine 612 (p-IRS-S612) as compared to parental N2a cells. Treatment of human neuroblastoma SH-SY5Y cells with Aβ42 also increased p-IRS-S612, suggesting that Aβ42 is responsible for insulin resistance. The insulin resistance was alleviated when N2a-AβPP cells were treated with higher insulin concentrations. Insulin increased Aβ release from N2a-AβPP cells, by which it may promote Aβ clearance. Insulin increased cholesterol-synthesis gene expression in SH-SY5Y and N2a cells, including 24-dehydrocholesterol reductase (DHCR24) and 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR) through sterol-regulatory element-binding protein-2 (SREBP2). While Aβ42-treated SH-SY5Y cells exhibited increased HMGCR expression and c-Jun phosphorylation as pro-inflammatory responses, they also showed down-regulation of neuro-protective/anti-inflammatory DHCR24. These results suggest that Aβ42 may cause insulin resistance, activate JNK for c-Jun phosphorylation, and lead to dysregulation of cholesterol homeostasis, and that enhancing insulin signaling may relieve the insulin-resistant phenotype and the dysregulated cholesterol-synthesis pathway to promote A

  18. Maternal Moderate Physical Training during Pregnancy Attenuates the Effects of a Low-Protein Diet on the Impaired Secretion of Insulin in Rats: Potential Role for Compensation of Insulin Resistance and Preventing Gestational Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Carol Góis Leandro

    2012-01-01

    Full Text Available The effects of pregestational and gestational low-to-moderate physical training on insulin secretion in undernourished mothers were evaluated. Virgin female Wistar rats were divided into four groups as follows: control (C, n=5; trained (T, n=5; low-protein diet (LP, n=5; trained with a low-protein diet (T + LP, n=5. Trained rats ran on a treadmill over a period of 4 weeks before mate (5 days week−1 and 60 min day−1, at 65% of VO2max. At pregnancy, the intensity and duration of the exercise were reduced. Low-protein groups were provided with an 8% casein diet, and controls were provided with a 17% casein diet. At third day after delivery, mothers and pups were killed and islets were isolated by collagenase digestion of pancreas and incubated for a further 1 h with medium containing 5.6 or 16.7 mM glucose. T mothers showed increased insulin secretion by isolated islets incubated with 16.7 mM glucose, whereas LP group showed reduced secretion of insulin by isolated islets when compared with both C and LP + T groups. Physical training before and during pregnancy attenuated the effects of a low-protein diet on the secretion of insulin, suggesting a potential role for compensation of insulin resistance and preventing gestational diabetes mellitus.

  19. Sensitive and specific markers for insulin resistance, hyperandrogenemia, and inappropriate gonadotrophin secretion in women with polycystic ovary syndrome: a case-control study from Bahrain

    Directory of Open Access Journals (Sweden)

    Al-Ayadhi MA

    2012-05-01

    Full Text Available Jamal Golbahar,1,2,* Maha Al-Ayadhi,2,* Negalla Mohan Das,2 Khalid Gumaa,2 1Department of Molecular Medicine, Al-Jawhara Centre for Genetic Diagnosis and Research, 2Department of Medical Biochemistry, College of Medicine and Medical Sciences, AGU, Manama, Bahrain *These authors contributed equally to this articleBackground: In women with polycystic ovary syndrome (PCOS, despite a high prevalence of insulin resistance, hyperandrogenemia, and disturbances in the secretion of gonadotrophin, the principal causes of biochemical abnormalities and the best endocrine markers for PCOS have not been fully identified.Subjects and methods: Serum levels of insulin, glucose, follicle-stimulating hormone (FSH, luteinizing hormone (LH, total testosterone, estrogen, sex hormone-binding capacity (SHBG, and other related indices such as homeostasis model assessment, insulin glucose ratios, LH/FSH ratios, and the free androgen index (FAI were determined and compared in women with PCOS (n = 50 and women without PCOS (n = 50.Results: In multivariate logistic regression analyses, among all insulin resistance indices, only hyperinsulinemia (odds ratio [OR] = 2.6; confidence interval [CI]: 1.3–5.2; P = 0.008 was significantly and independently associated with PCOS when adjusted for body mass index (BMI, hyperandrogenemia, and LH/FSH ratios. The LH/FSH ratio (OR = 5.4; CI: 1.2–23.0, P = 0.03 was the only marker among those indices for inappropriate gonadotrophin secretion that significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. Among those indices for hyperandrogenemia, FAI (OR = 1.1; CI: 1.0–2.7; P = 0.02 and SHBG (OR = 1.2; CI: 1.2–3.4; P = 0.03 were significantly and independently associated with PCOS when adjusted for BMI and hyperinsulinemia. In addition, receiver operating characteristic analysis showed that the best predictive markers for PCOS were insulin (area under the curve [AUC] = 0.944; CI: 0.887–0

  20. Glycosphingolipids and insulin resistance

    NARCIS (Netherlands)

    Langeveld, Mirjam; Aerts, Johannes M. F. G.

    2009-01-01

    Obesity is associated with an increased risk for insulin resistance, a state characterized by impaired responsiveness of liver, muscle and adipose tissue to insulin. One class of lipids involved in the development of insulin resistance are the (glyco)sphingolipids. Ceramide, the most simple

  1. High normal HbA(1c) levels were associated with impaired insulin secretion without escalating insulin resistance in Japanese individuals: the Toranomon Hospital Health Management Center Study 8 (TOPICS 8).

    Science.gov (United States)

    Heianza, Y; Arase, Y; Fujihara, K; Tsuji, H; Saito, K; Hsieh, S D; Kodama, S; Shimano, H; Yamada, N; Hara, S; Sone, H

    2012-10-01

    We aimed to characterize the association of insulin resistance, impaired insulin secretion and β-cell dysfunction in relation to HbA(1c) levels in a non-diabetic range in Japanese individuals without clinically diagnosed diabetes. This cross-sectional study included 1444 individuals without a history of outpatient treatment of diabetes or use of insulin or oral hypoglycaemic agents. The homeostasis model assessment of insulin resistance and beta-cell function, insulinogenic index, Matsuda index and disposition index were calculated using data from 75-g oral glucose tolerance tests and compared across quintile (Q) categories of HbA(1c) levels. Fasting plasma glucose and 30-min and 60-min plasma glucose (PG) levels were significantly higher when HbA(1c) exceeded 36 mmol/mol (5.4%). A HbA(1c) concentration of 36-37 mmol/mol (5.4-5.5%) (Q3) was significantly associated with a 15% lower homeostasis model assessment of β-cell function value and 31% lower insulinogenic index value compared with HbA(1c) ≤ 32 mmol/mol (≤ 5.1%) (Q1) (P insulin resistance was not significantly elevated and the Matsuda index was not significantly lower unless HbA(1c) exceeded 41 mmol/mol (5.9%). Individuals with HbA(1c) ≥ 41 mmol/mol (≥ 5.9%) (Q5) had a 69% lower disposition index than those with a HbA(1c) concentration of ≤ 32 mmol/mol (≤ 5.1%) (Q1). Elevated HbA(1c) levels ≥ 41 mmol/mol (≥ 5.9%) were associated with substantial reductions in insulin secretion, insulin sensitivity and β-cell dysfunction in Japanese individuals not treated for diabetes. High normal HbA(1c) levels of 36-40 mmol/mol (5.4-5.8%) were also associated with impaired insulin secretion without marked insulin resistance in Japanese individuals. © 2012 The Authors. Diabetic Medicine © 2012 Diabetes UK.

  2. [Hypertension and insulin resistance].

    Science.gov (United States)

    Voiculescu, A; Kutkuhn, B; Rösen, P; Grabensee, B

    1997-10-17

    Non insulin dependent diabetes mellitus (NIDDM) and obesity are defined as classical insulin resistant states. Essential hypertension is now also considered to be an insulin resistant state, even in absence of NIDDM or obesity, as shown in epidemiological, clinical and experimental studies. Neither the underlying mechanism nor a direct causality between the two phenomena has been detected as yet, but different hypotheses have been postulated where, on the one hand, insulin resistance and hypertension are considered to be causally related and, on the other hand, they are considered to be parallel phenomena due to genetic and acquired factors. The clarification of the connection between hypertension and insulin resistance seems to be of great clinical importance, since they are both independent risk factors for cardiovascular disease and mortality from cardiovascular complications. This paper gives an overview of the results of recent research on the possible underlying pathogenetic mechanisms linking hypertension and insulin resistance.

  3. Evaluation of insulin secretion and action in New World camelids.

    Science.gov (United States)

    Firshman, Anna M; Cebra, Christopher K; Schanbacher, Barbara J; Seaquist, Elizabeth R

    2013-01-01

    To measure and compare insulin secretion and sensitivity in healthy alpacas and llamas via glucose clamping techniques. 8 llamas and 8 alpacas. Hyperinsulinemic euglycemic clamping (HEC) and hyperglycemic clamping (HGC) were performed on each camelid in a crossover design with a minimum 48-hour washout period between clamping procedures. The HEC technique was performed to measure insulin sensitivity. Insulin was infused IV at 6 mU/min/kg for 4 hours, and an IV infusion of glucose was adjusted to maintain blood glucose concentration at 150 mg/dL. Concentrations of blood glucose and plasma insulin were determined throughout. The HGC technique was performed to assess insulin secretion in response to exogenous glucose infusion. An IV infusion of glucose was administered to maintain blood glucose concentration at 320 mg/dL for 3 hours, and concentrations of blood glucose and plasma insulin were determined throughout. Alpacas and llamas were not significantly different with respect to whole-body insulin sensitivity during HEC or in pancreatic β-cell response during HGC. Alpacas and llamas had markedly lower insulin sensitivity during HEC and markedly lower pancreatic β-cell response during HGC, in comparison with many other species. New World camelids had lower glucose-induced insulin secretion and marked insulin resistance in comparison with other species. This likely contributes to the disorders of fat and glucose metabolism that are common to camelids.

  4. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes.

    Science.gov (United States)

    Satin, Leslie S; Butler, Peter C; Ha, Joon; Sherman, Arthur S

    2015-04-01

    Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern, has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM. Copyright © 2015 Elsevier Ltd. All rights reserved.

  5. Pulsatile insulin secretion, impaired glucose tolerance and type 2 diabetes

    Science.gov (United States)

    Satin, Leslie S.; Butler, Peter C.; Ha, Joon; Sherman, Arthur S.

    2015-01-01

    Type 2 diabetes (T2DM) results when increases in beta cell function and/or mass cannot compensate for rising insulin resistance. Numerous studies have documented the longitudinal changes in metabolism that occur during the development of glucose intolerance and lead to T2DM. However, the role of changes in insulin secretion, both amount and temporal pattern has been understudied. Most of the insulin secreted from pancreatic beta cells of the pancreas is released in a pulsatile pattern, which is disrupted in T2DM. Here we review the evidence that changes in beta cell pulsatility occur during the progression from glucose intolerance to T2DM in humans, and contribute significantly to the etiology of the disease. We review the evidence that insulin pulsatility improves the efficacy of secreted insulin on its targets, particularly hepatic glucose production, but also examine evidence that pulsatility alters or is altered by changes in peripheral glucose uptake. Finally, we summarize our current understanding of the biophysical mechanisms responsible for oscillatory insulin secretion. Understanding how insulin pulsatility contributes to normal glucose homeostasis and is altered in metabolic disease states may help improve the treatment of T2DM. PMID:25637831

  6. [Insulin resistance in children].

    Science.gov (United States)

    Stąpor, Natalia; Beń-Skowronek, Iwona

    2015-01-01

    Insulin resistance is the state of reduced tissue sensitivity to insulin. The frequency of this occurrence is increasing dramatically in developed countries. Both, environmental and genetic factors are involved in the pathogenesis of insulin resistance. Sedentary lifestyle and the excessive calorie intake cause the substantial increase of the fat issue, leading to overweight and obesity. Insulin resistance occurs physiologically during puberty, but it is also a pathological condition predisposing children to develop abnormal glucose tolerance, diabetes, hypertension and polycystic ovary syndrome among girls. More frequent occurrence of metabolic syndrome can be observed among children born small for gestational age (SGA). The article presents the current views on risk factors, etiology, diagnosis and consequences insulin resistance and disorders of glucose tolerance. © Polish Society for Pediatric Endocrinology and Diabetology.

  7. [Alteration of insulin secretion in the elderly].

    Science.gov (United States)

    Aizawa, Toru

    2006-01-01

    Aging per se is associated with reduced insulin secretion, which is an important contributing factor for pandemic of diabetes worldwide. Although underlying mechanism for it is not fully elucidated, a combination of reduced beta cell mass and impairment of insulin granule handing in the cell is most likely which may be due to age-related mitochondrial dysfunction and/or dysregulation of transcriptional factors. For effective prevention of diabetes in the elderly population, restoration of beta cell function is desired. Meanwhile, identification of insulin-deficient elderly patients with diabetes and an earlier institution of insulin therapy for them are recommended for improvement of treatment outcome.

  8. Decreased insulin secretion and increased risk of type 2 diabetes associated with allelic variations of the WFS1 gene: the Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) prospective study.

    Science.gov (United States)

    Cheurfa, N; Brenner, G M; Reis, A F; Dubois-Laforgue, D; Roussel, R; Tichet, J; Lantieri, O; Balkau, B; Fumeron, F; Timsit, J; Marre, M; Velho, G

    2011-03-01

    We investigated associations of allelic variations in the WFS1 gene with insulin secretion and risk of type 2 diabetes in a general population prospective study. We studied 5,110 unrelated French men and women who participated in the prospective Data from Epidemiological Study on the Insulin Resistance Syndrome (DESIR) study. Additional cross-sectional analyses were performed on 4,472 French individuals with type 2 diabetes and 3,065 controls. Three single nucleotide polymorphisms (SNPs) were genotyped: rs10010131, rs1801213/rs7672995 and rs734312. We observed statistically significant associations between the major alleles of the three variants and prevalent type 2 diabetes in the DESIR cohort at baseline. Cox analyses showed an association between the G-allele of rs10010131 and incident type 2 diabetes (HR 1.34, 95% CI 1.08-1.70, p = 0.007). Similar results were observed for the G-allele of rs1801213 and the A-allele of rs734312. The GGA haplotype was associated with an increased risk of diabetes as compared with the ACG haplotype (HR 1.26, 95% CI 1.04-1.42, p = 0.02). We also observed statistically significant associations of the three SNPs with plasma glucose, HbA(1c) levels and insulin secretion at baseline and throughout the study in individuals with type 2 diabetes or at risk of developing diabetes. However, no association was observed in those who remained normoglycaemic at the end of the follow-up. Associations between the three variants and type 2 diabetes were replicated in cross-sectional studies of type 2 diabetic patients in comparison with a non-diabetic control group. The most frequent haplotype at the haplotype block containing the WFS1 gene modulated insulin secretion and was associated with an increased risk of type 2 diabetes.

  9. Variants within the calpain-10 gene on chromosome 2q37 (NIDDM1) and relationships to type 2 diabetes, insulin resistance, and impaired acute insulin secretion among Scandinavian Caucasians

    DEFF Research Database (Denmark)

    Rasmussen, Søren K; Urhammer, Søren A; Berglund, Lars Erik

    2002-01-01

    Variations in the calpain-10 gene (CAPN10) have been identified among Mexican-Americans, and an at-risk haplotype combination (112/121) defined by three polymorphisms, UCSNP-43, -19, and -63, confers increased risk of type 2 diabetes. Here we examine the three polymorphisms in 1,594 Scandinavian...... subjects, including 409 type 2 diabetic patients, 200 glucose-tolerant control subjects, 322 young healthy subjects, 206 glucose-tolerant offspring of diabetic patients, and 457 glucose-tolerant 70-year-old men. The frequency of the 112/121 combination was not significantly different in 409 type 2 diabetic...... the CAPN10 variants and type 2 diabetes, insulin resistance, or impaired insulin secretion....

  10. Depression and Insulin Resistance

    Science.gov (United States)

    Pearson, Sue; Schmidt, Mike; Patton, George; Dwyer, Terry; Blizzard, Leigh; Otahal, Petr; Venn, Alison

    2010-01-01

    OBJECTIVE To examine the association between depressive disorder and insulin resistance in a sample of young adults using the Composite International Diagnostic Interview to ascertain depression status. RESEARCH DESIGN AND METHODS Cross-sectional data were collected from 1,732 participants aged between 26 and 36 years. Insulin resistance was derived from blood chemistry measures of fasting insulin and glucose using the homeostasis model assessment method. Those identified with mild, moderate, or severe depression were classified as having depressive disorder. RESULTS The 12-month prevalence of depressive disorder was 5.4% among men and 11.7% among women. In unadjusted models mean insulin resistance was 17.2% (95% CI 0.7–36.0%, P = 0.04) higher in men and 11.4% (1.5–22.0%, P = 0.02) higher in women with depressive disorder. After adjustment for behavioral and dietary factors, the increased level of insulin resistance associated with depressive disorder was 13.2% (−3.1 to 32.3%, P = 0.12) in men and 6.1% (−4.1 to 17.4%, P = 0.25) in women. Waist circumference was identified as a mediator in the relationship between depression and insulin resistance, reducing the β coefficient in the fully adjusted models in men by 38% and in women by 42%. CONCLUSIONS A positive association was found between depressive disorder and insulin resistance in this population-based sample of young adult men and women. The association seemed to be mediated partially by waist circumference. PMID:20185745

  11. Factors influencing insulin secretion from encapsulated islets

    NARCIS (Netherlands)

    de Haan, BJ; Faas, MM; de Vos, P

    2003-01-01

    Adequate regulation of glucose levels by a microencapsulated pancreatic islet graft requires a minute-to-minute regulation of blood glucose. To design such a transplant, it is mandatory to have sufficient insight in factors influencing the kinetics of insulin secretion by encapsulated islets. The

  12. Insulin resistance alters islet morphology in nondiabetic humans

    DEFF Research Database (Denmark)

    Mezza, Teresa; Muscogiuri, Giovanna; Sorice, Gian Pio

    2014-01-01

    Type 2 diabetes is characterized by poor glucose uptake in metabolic tissues and manifests when insulin secretion fails to cope with worsening insulin resistance. In addition to its effects on skeletal muscle, liver, and adipose tissue metabolism, it is evident that insulin resistance also affects...... pancreatic β-cells. To directly examine the alterations that occur in islet morphology as part of an adaptive mechanism to insulin resistance, we evaluated pancreas samples obtained during pancreatoduodenectomy from nondiabetic subjects who were insulin-resistant or insulin-sensitive. We also compared...... insulin sensitivity, insulin secretion, and incretin levels between the two groups. We report an increased islet size and an elevated number of β- and α-cells that resulted in an altered β-cell-to-α-cell area in the insulin- resistant group. Our data in this series of studies suggest that neogenesis from...

  13. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    independent phosphorylation of PKCε causes this reduction in insulin receptor gene expression. One of the pathways through which fatty acid can induce insulin resistance in insulin target cells is suggested by these studies. We provide an overview of ...

  14. Molecular mechanisms of insulin resistance

    African Journals Online (AJOL)

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

  15. Impact of objectively measured sedentary behaviour on changes in insulin resistance and secretion over 3 years in the RISC study

    DEFF Research Database (Denmark)

    Lahjibi, E; Heude, B; Dekker, J M

    2013-01-01

    The importance of reducing sedentary time is increasingly being recognized in the prevention of diabetes and cardiovascular disease. Despite this, the prospective association between sedentary time and physical activity with insulin sensitivity and cardiometabolic risk factors has been little stu...

  16. Insulin secretion and sensitivity in space flight: diabetogenic effects

    Science.gov (United States)

    Tobin, Brian W.; Uchakin, Peter N.; Leeper-Woodford, Sandra K.

    2002-01-01

    Nearly three decades of space flight research have suggested that there are subclinical diabetogenic changes that occur in microgravity. Alterations in insulin secretion, insulin sensitivity, glucose tolerance, and metabolism of protein and amino acids support the hypothesis that insulin plays an essential role in the maintenance of muscle mass in extended-duration space flight. Experiments in flight and after flight and ground-based bedrest studies have associated microgravity and its experimental paradigms with manifestations similar to those of diabetes, physical inactivity, and aging. We propose that these manifestations are characterized best by an etiology that falls into the clinical category of "other" causes of diabetes, including, but not restricted to, genetic beta-cell defects, insulin action defects, diseases of the endocrine pancreas, endocrinopathies, drug or chemically induced diabetes, infections, immune-mediated metabolic alteration, and a host of genetic related diseases. We present data showing alterations in tumor necrosis factor-alpha production, insulin secretion, and amino acid metabolism in pancreatic islets of Langerhans cultured in a ground-based cell culture bioreactor that mimics some of the effects of microgravity. Taken together, space flight research, ground-based studies, and bioreactor studies of pancreatic islets of Langerhans support the hypothesis that the pancreas is unable to overcome peripheral insulin resistance and amino acid dysregulation during space flight. We propose that measures of insulin secretion and insulin action will be necessary to design effective countermeasures against muscle loss, and we advance the "disposition index" as an essential model to be used in the clinical management of space flight-induced muscle loss.

  17. Insulin Resistance in Liver Diseases

    OpenAIRE

    Irshad, M

    2011-01-01

    Present report gives a brief and consolidated review of insulin resistance developed in chronic liver diseases. Insulin resistance remains an important feature of chronic liver diseases and progresses disease towards fibrogenesis. Of hepatitis viral infections, hepatitis C virus (HCV) was reported to have a significant role in inducing insulin resistance. Both viral particles as such, as well its structural components induce insulin resistance. Hepatitis C virus core protein, specially, cause...

  18. Insulin Resistance and Hypogonadism

    Directory of Open Access Journals (Sweden)

    Shahana Shermin

    2013-05-01

    Full Text Available Backgound: The number of hypogonads is increasing day by day. It may be due to sedentary life style with increased obesity, increased tension or stressed lifestyle among all groups of populations. Visceral obesity is associated with insulin resistance, diabetes mellitus and also with hypogonadism.Objective: This study was carried out to determine the proportion of insulin resistance among male subjects with hypogonadism in different age groups along with status of erectile quality among diabetics and non diabetics.Materials and method: This cross sectional study among 161 adult male subjects aged ≥ 20 to ≤ 60 years were purposively selected from Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders (BIRDEM, Dhaka, Bangladesh between May 2009 to September 2010. Glycemic status and insulin resistance (by HOMA-R were done and relevant history were documented.Results: The highest proportion (38.9% of hypogonadism was in ≥ 50 years age group whereas highest proportion (39.6% of the eugonads was in the age group of 40 to 49 years. More than half of the hypogonad subjects had weak erectile quality (54.0% which were followed by absent erectile quality in 32.7% and 13.3% subjects had normal erectile quality. Among the eugonad subjects 41.7% had normal erectile quality, 41.6% subjects had weak erectile quality and 16.7% subjects had no erectile quality. More than ninety percent of the hypogonad subjects and about 60% of the eugonad subjects had insulin resistance. The average HOMA-R was more in the subjects with hypogonadism with diabetes which was highly significant (p-value < 0.001.Conclusion: Hypogonadism is associated with insulin resistance.

  19. Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Tsubasa Omi

    2016-01-01

    Full Text Available We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose metabolism.

  20. Paliperidone Induced Hypoglycemia by Increasing Insulin Secretion

    OpenAIRE

    Omi, Tsubasa; Riku, Keisen; Fukumoto, Motoyuki; Kanai, Koji; Omura, Yumi; Takada, Hiromune; Matunaga, Hidenori

    2016-01-01

    We report the case of a 41-year-old woman with schizophrenia who developed persistent hypoglycemia following paliperidone administration. After discontinuing paliperidone, the hypoglycemia resolved, but symptoms of diabetes emerged. Therefore, it appears that the hypoglycemia induced by paliperidone may mask symptoms of diabetes. Paliperidone may induce hypoglycemia by increasing insulin secretion. This report could help elucidate the relationship between atypical antipsychotics and glucose m...

  1. Adiposity in Children Born Small for Gestational Age Is Associated With β-Cell Function, Genetic Variants for Insulin Resistance, and Response to Growth Hormone Treatment

    DEFF Research Database (Denmark)

    Thankamony, Ajay; Jensen, Rikke Beck; O'Connell, Susan M

    2016-01-01

    BACKGROUND: Genetic susceptibility to insulin resistance is associated with lower adiposity in adults. Insulin resistance, and therefore adiposity, may alter sensitivity to GH. We aimed to determine the relationship between adiposity, genetic susceptibility to insulin resistance or insulin secret...

  2. The relationship between bone turnover and insulin sensitivity and secretion

    DEFF Research Database (Denmark)

    Frost, Morten; Balkau, Beverley; Hatunic, Mensud

    2018-01-01

    Bone metabolism appears to influence insulin secretion and sensitivity, and insulin promotes bone formation in animals, but similar evidence in humans is limited. The objectives of this study are to explore if bone turnover markers were associated with insulin secretion and sensitivity and to det...

  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 Juul

    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. Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin?s Metabolic Action in the Presence of Insulin Resistance

    OpenAIRE

    Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.; Liu, Zhenqi

    2014-01-01

    Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid in...

  5. Bimodal effect on pancreatic β-cells of secretory products from normal or insulin-resistant human skeletal muscle

    DEFF Research Database (Denmark)

    Bouzakri, Karim; Plomgaard, Peter; Berney, Thierry

    2011-01-01

    Type 2 diabetes is characterized by insulin resistance with a relative deficiency in insulin secretion. This study explored the potential communication between insulin-resistant human skeletal muscle and primary (human and rat) β-cells....

  6. Insulin Resistance in Alzheimer's Disease

    Science.gov (United States)

    Dineley, Kelly T; Jahrling, Jordan B; Denner, Larry

    2014-01-01

    Insulin is a key hormone regulating metabolism. Insulin binding to cell surface insulin receptors engages many signaling intermediates operating in parallel and in series to control glucose, energy, and lipids while also regulating mitogenesis and development. Perturbations in the function of any of these intermediates, which occur in a variety of diseases, cause reduced sensitivity to insulin and insulin resistance with consequent metabolic dysfunction. Chronic inflammation ensues which exacerbates compromised metabolic homeostasis. Since insulin has a key role in learning and memory as well as directly regulating ERK, a kinase required for the type of learning and memory compromised in early Alzheimer's disease (AD), insulin resistance has been identified as a major risk factor for the onset of AD. Animal models of AD or insulin resistance or both demonstrate that AD pathology and impaired insulin signaling form a reciprocal relationship. Of note are human and animal model studies geared toward improving insulin resistance that have led to the identification of the nuclear receptor and transcription factor, peroxisome proliferator-activated receptor gamma (PPARγ) as an intervention tool for early AD. Strategic targeting of alternate nodes within the insulin signaling network has revealed disease-stage therapeutic windows in animal models that coalesce with previous and ongoing clinical trial approaches. Thus, exploiting the connection between insulin resistance and AD provides powerful opportunities to delineate therapeutic interventions that slow or block the pathogenesis of AD. PMID:25237037

  7. Insulin resistance and chronic inflammation

    Directory of Open Access Journals (Sweden)

    Natalia Matulewicz

    2016-12-01

    Full Text Available Insulin resistance is a condition of reduced biological response to insulin. Growing evidence indicates the role of the chronic low-grade inflammatory response in the pathogenesis of insulin resistance. Adipose tissue in obesity is characterized by increased lipolysis with the excessive release of free fatty acids, and is also a source of proinflammatory cytokines. Both these factors may inhibit insulin action. Proinflammatory cytokines exert their effect by stimulating major inflammatory NFκB and JNK pathways within the cells. Inflammatory processes in other insulin responsive tissues may also play a role in inducing insulin resistance. This paper is an overview of the chronic low-grade inflammation in adipose tissue, skeletal muscle, liver and endothelial cells during the development of insulin resistance.

  8. A Bayesian approach to estimating the prehepatic insulin secretion rate

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    The prehepatic insulin secretion rate of the pancreatic $beta$-cells is not directly measurable, since part of the secreted insulin is absorbed by the liver prior to entering the blood stream. However, C-peptide is co-secreted equimolarly and is not absorbed by the liver, allowing...... for the estimation of the prehepatic insulin secretion rate. We consider a stochastic differential equation model that combines both insulin and C-peptide concentrations in plasma to estimate the prehepatic insulin secretion rate. Previously this model has been analysed in an iterative deterministic set-up, where...... the time courses of insulin and C-peptide subsequently are used as known forcing functions. In this work we adopt a Bayesian graphical model to describe the unied model simultaneously. We develop a model that also accounts for both measurement error and process variability. The parameters are estimated...

  9. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However, the underlying mechanism involved is still unclear. In searching for the cause of the mechanism, it has been found that palmitate inhibits insulin receptor (IR) gene expression, ...

  10. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    PRAKASH

    Free fatty acids are known to play a key role in promoting loss of insulin sensitivity, thereby causing insulin resistance and type 2 diabetes. However ... PDK1-independent phosphorylation of PKCε causes this reduction in insulin receptor gene ... i.e. muscle, liver and fat, is extremely high (Brunetti et al 2001). However, there ...

  11. Selective Insulin Resistance in Adipocytes*

    Science.gov (United States)

    Tan, Shi-Xiong; Fisher-Wellman, Kelsey H.; Fazakerley, Daniel J.; Ng, Yvonne; Pant, Himani; Li, Jia; Meoli, Christopher C.; Coster, Adelle C. F.; Stöckli, Jacqueline; James, David E.

    2015-01-01

    Aside from glucose metabolism, insulin regulates a variety of pathways in peripheral tissues. Under insulin-resistant conditions, it is well known that insulin-stimulated glucose uptake is impaired, and many studies attribute this to a defect in Akt signaling. Here we make use of several insulin resistance models, including insulin-resistant 3T3-L1 adipocytes and fat explants prepared from high fat-fed C57BL/6J and ob/ob mice, to comprehensively distinguish defective from unaffected aspects of insulin signaling and its downstream consequences in adipocytes. Defective regulation of glucose uptake was observed in all models of insulin resistance, whereas other major actions of insulin such as protein synthesis and anti-lipolysis were normal. This defect corresponded to a reduction in the maximum response to insulin. The pattern of change observed for phosphorylation in the Akt pathway was inconsistent with a simple defect at the level of Akt. The only Akt substrate that showed consistently reduced phosphorylation was the RabGAP AS160 that regulates GLUT4 translocation. We conclude that insulin resistance in adipose tissue is highly selective for glucose metabolism and likely involves a defect in one of the components regulating GLUT4 translocation to the cell surface in response to insulin. PMID:25720492

  12. SIRT4 Is a Lysine Deacylase that Controls Leucine Metabolism and Insulin Secretion

    DEFF Research Database (Denmark)

    Anderson, Kristin A; Huynh, Frank K; Fisher-Wellman, Kelsey

    2017-01-01

    in leucine oxidation, and we show a primary role for SIRT4 in controlling this pathway in mice. Furthermore, we find that dysregulated leucine metabolism in SIRT4KO mice leads to elevated basal and stimulated insulin secretion, which progressively develops into glucose intolerance and insulin resistance...

  13. Insulin Resistance: Causes And Metabolic Implications | Igharo ...

    African Journals Online (AJOL)

    Insulin is an anabolic hormone that plays key roles in glucose metabolism. Insulin resistance is a decreased biological response to normal concentration of circulating insulin. In insulin resistance, normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle and liver cells. Insulin ...

  14. 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

    OBJECTIVE: Ingestion of probiotics can modify gut microbiota and alter insulin resistance and diabetes development in rodents. We hypothesized that daily intake of Lactobacillus reuteri increases insulin sensitivity by changing cytokine release and insulin secretion via modulation of the release...... 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....... 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...

  15. The evolutionary benefit of insulin resistance

    NARCIS (Netherlands)

    Soeters, Maarten R.; Soeters, Peter B.

    2012-01-01

    Insulin resistance is perceived as deleterious, associated with conditions as the metabolic syndrome, type 2 diabetes mellitus and critical illness. However, insulin resistance is evolutionarily well preserved and its persistence suggests that it benefits survival. Insulin resistance is important in

  16. Moderate alcohol consumption is associated with improved insulin sensitivity, reduced basal insulin secretion rate and lower fasting glucagon concentration in healthy women

    DEFF Research Database (Denmark)

    Bonnet, F; Disse, E; Laville, M

    2012-01-01

    Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes with a stronger effect in women. As the underlying mechanisms remain poorly characterised, we investigated its relationship with insulin resistance, insulin secretion, clearance of insulin and glucagon concentration....

  17. 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...

  18. 92 INSULIN RESISTANCE: CAUSES AND METABOLIC ...

    African Journals Online (AJOL)

    drclement

    2009-12-01

    Dec 1, 2009 ... ABSTRACT. Insulin is an anabolic hormone that plays key roles in glucose metabolism. Insulin resistance is a decreased biological response to normal concentration of circulating insulin. In insulin resistance, normal amounts of insulin are inadequate to produce a normal insulin response from fat, muscle ...

  19. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol.

    Science.gov (United States)

    Nøhr, Mark K; Dudele, Anete; Poulsen, Morten M; Ebbesen, Lene H; Radko, Yulia; Christensen, Lars P; Jessen, Niels; Richelsen, Bjørn; Lund, Sten; Pedersen, Steen B

    2016-01-01

    Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here 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 an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P insulin and glucose homeostasis was normalized by resveratrol. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

  20. LPS-Enhanced Glucose-Stimulated Insulin Secretion Is Normalized by Resveratrol.

    Directory of Open Access Journals (Sweden)

    Mark K Nøhr

    Full Text Available Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS resulting in endotoxemia could be a candidate. Here 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 an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose from 13.73 to 22.40 pmol/mmol (P < 0.001. This aberration in insulin and glucose homeostasis was normalized by resveratrol.Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

  1. Insulin Regulates Hepatic Triglyceride Secretion and Lipid Content via Signaling in the Brain.

    Science.gov (United States)

    Scherer, Thomas; Lindtner, Claudia; O'Hare, James; Hackl, Martina; Zielinski, Elizabeth; Freudenthaler, Angelika; Baumgartner-Parzer, Sabina; Tödter, Klaus; Heeren, Joerg; Krššák, Martin; Scheja, Ludger; Fürnsinn, Clemens; Buettner, Christoph

    2016-06-01

    Hepatic steatosis is common in obesity and insulin resistance and results from a net retention of lipids in the liver. A key mechanism to prevent steatosis is to increase secretion of triglycerides (TG) packaged as VLDLs. Insulin controls nutrient partitioning via signaling through its cognate receptor in peripheral target organs such as liver, muscle, and adipose tissue and via signaling in the central nervous system (CNS) to orchestrate organ cross talk. While hepatic insulin signaling is known to suppress VLDL production from the liver, it is unknown whether brain insulin signaling independently regulates hepatic VLDL secretion. Here, we show that in conscious, unrestrained male Sprague Dawley rats the infusion of insulin into the third ventricle acutely increased hepatic TG secretion. Chronic infusion of insulin into the CNS via osmotic minipumps reduced the hepatic lipid content as assessed by noninvasive (1)H-MRS and lipid profiling independent of changes in hepatic de novo lipogenesis and food intake. In mice that lack the insulin receptor in the brain, hepatic TG secretion was reduced compared with wild-type littermate controls. These studies identify brain insulin as an important permissive factor in hepatic VLDL secretion that protects against hepatic steatosis. © 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.

  2. 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

    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...... with IGT and we also examined this interrelation in relation to the 2 main incretins, glucagon-like peptide (GLP-1) and gastric inhibitory polypeptide (GIP). To that end, 13 women with IGT and 17 women with normal glucose tolerance (NGT) underwent an oral glucose tolerance test (OGTT) with measurements...... 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...

  3. [Effect of arotinolol on insulin secretion and insulin clearance rate in patients with Graves' disease].

    Science.gov (United States)

    Ohguni, S; Notsu, K; Tanaka, J; Sato, T; Kato, Y

    1993-08-20

    Glucose-induced insulin secretion, 24-h urinary C-peptide (CPR) and euglycemic clamp were examined in five patients with hyperthyroid Graves' disease before and 2 weeks after treatment with arotinolol (20 mg/day, p.o.). Plasma glucose and insulin responses to oral administration of 75 g glucose were not changed by arotinolol treatment. 24-h urinary CPR and basal posthepatic insulin delivery rate (BPIDR) as an indicator of insulin secretion were significantly suppressed by arotinolol. Glucose infusion rate (GIR) as an indicator of insulin sensitivity and glucose clearance rate (GCR) were not influenced by arotinolol therapy. Insulin clearance rate (ICR) was significantly suppressed by arotinolol. These findings suggest that arotinolol inhibits insulin secretion by decreasing ICR but does not attenuate insulin release induced by glucose in hyperthyroid patients, and that insulin sensitivity and GCR are not affected by arotinolol.

  4. Adipokines mediate inflammation and insulin resistance

    Directory of Open Access Journals (Sweden)

    Jeffrey E. Pessin

    2013-06-01

    Full Text Available For many years, adipose tissue was considered as an inert energy storage organ that accumulates and stores triacylglycerols during energy excess and releases fatty acids in times of systemic energy need. However, over the last two decades adipose tissue depots have been established as highly active endocrine and metabolically important organs that modulate energy expenditure and glucose homeostasis. In rodents, brown adipose tissue plays an essential role in non-shivering thermogenesis and in energy dissipation that can serve to protect against diet-induced obesity. White adipose tissue collectively referred too as either subcutaneous or visceral adipose tissue is responsible for the secretion of an array of signaling molecules, termed adipokines. These adipokines function as classic circulating hormones to communicate with other organs including brain, liver, muscle, the immune system and adipose tissue itself. The dysregulation of adipokines has been implicated in obesity, type 2 diabetes and cardiovascular disease. Recently, inflammatory responses in adipose tissue have been shown as a major mechanism to induce peripheral tissue insulin resistance. Although leptin and adiponectin regulate feeding behavior and energy expenditure, these adipokines are also involved in the regulation of inflammatory responses. Adipose tissue secrete various pro- and anti-inflammatory adipokines to modulate inflammation and insulin resistance. In obese humans and rodent models, the expression of pro-inflammatory adipokines is enhanced to induce insulin resistance. Collectively, these findings have suggested that obesity-induced insulin resistance may result, at least in part, from an imbalance in the expression of pro- and anti-inflammatory adipokines. Thus we will review the recent progress regarding the physiological and molecular functions of adipokines in the obesity-induced inflammation and insulin resistance with perspectives on future directions.

  5. Increase in homeostasis model assessment of insulin resistance (HOMA-IR) had a strong impact on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion: the Saku study.

    Science.gov (United States)

    Morimoto, Akiko; Tatsumi, Yukako; Soyano, Fumie; Miyamatsu, Naomi; Sonoda, Nao; Godai, Kayo; Ohno, Yuko; Noda, Mitsuhiko; Deura, Kijyo

    2014-01-01

    Our aim was to assess the impact of increase in homeostasis model assessment of insulin resistance (HOMA-IR) on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion (IIS). This study included 2,209 participants aged 30-69 without diabetes at baseline who underwent comprehensive medical check-ups between April 2006 and March 2007 at Saku Central Hospital. Participants were classified into eight groups according to the combination of baseline IIS status (non-IIS and IIS) and category of HOMA-IR change between the baseline and follow-up examinations (decrease, no change/small increase, moderate increase, and large increase). Type 2 diabetes was determined from fasting and 2 h post-load plasma glucose concentrations at the follow-up examination between April 2009 and March 2011. At baseline, 669 individuals (30.3%) were classified as having IIS. At follow-up, 74 individuals developed type 2 diabetes. After adjusting for confounding factors including baseline HOMA-IR values, the multivariable-adjusted odds ratios (95% confidence intervals) for type 2 diabetes in the non-IIS with a decrease (mean change in HOMA-IR: -0.47), non-IIS with a moderate increase (mean change in HOMA-IR: 0.28), non-IIS with a large increase (mean change in HOMA-IR: 0.83), IIS with a decrease (mean change in HOMA-IR: -0.36), IIS with no change/small increase (mean change in HOMA-IR: 0.08), IIS with a moderate increase (mean change in HOMA-IR: 0.27), and IIS with a large increase (mean change in HOMA-IR: 0.73) groups, relative to the non-IIS with no change/small increase (mean change in HOMA-IR: 0.08) group were 0.23 (0.04, 1.11), 1.22 (0.26, 5.72), 2.01 (0.70, 6.46), 1.37 (0.32, 4.28), 3.60 (0.83, 15.57), 5.24 (1.34, 20.52), and 7.01 (1.75, 24.18), respectively. Moderate and large increases in HOMA-IR had a strong impact on the development of type 2 diabetes among individuals with IIS in this Japanese population.

  6. Increase in homeostasis model assessment of insulin resistance (HOMA-IR had a strong impact on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion: the Saku study.

    Directory of Open Access Journals (Sweden)

    Akiko Morimoto

    Full Text Available Our aim was to assess the impact of increase in homeostasis model assessment of insulin resistance (HOMA-IR on the development of type 2 diabetes in Japanese individuals with impaired insulin secretion (IIS. This study included 2,209 participants aged 30-69 without diabetes at baseline who underwent comprehensive medical check-ups between April 2006 and March 2007 at Saku Central Hospital. Participants were classified into eight groups according to the combination of baseline IIS status (non-IIS and IIS and category of HOMA-IR change between the baseline and follow-up examinations (decrease, no change/small increase, moderate increase, and large increase. Type 2 diabetes was determined from fasting and 2 h post-load plasma glucose concentrations at the follow-up examination between April 2009 and March 2011. At baseline, 669 individuals (30.3% were classified as having IIS. At follow-up, 74 individuals developed type 2 diabetes. After adjusting for confounding factors including baseline HOMA-IR values, the multivariable-adjusted odds ratios (95% confidence intervals for type 2 diabetes in the non-IIS with a decrease (mean change in HOMA-IR: -0.47, non-IIS with a moderate increase (mean change in HOMA-IR: 0.28, non-IIS with a large increase (mean change in HOMA-IR: 0.83, IIS with a decrease (mean change in HOMA-IR: -0.36, IIS with no change/small increase (mean change in HOMA-IR: 0.08, IIS with a moderate increase (mean change in HOMA-IR: 0.27, and IIS with a large increase (mean change in HOMA-IR: 0.73 groups, relative to the non-IIS with no change/small increase (mean change in HOMA-IR: 0.08 group were 0.23 (0.04, 1.11, 1.22 (0.26, 5.72, 2.01 (0.70, 6.46, 1.37 (0.32, 4.28, 3.60 (0.83, 15.57, 5.24 (1.34, 20.52, and 7.01 (1.75, 24.18, respectively. Moderate and large increases in HOMA-IR had a strong impact on the development of type 2 diabetes among individuals with IIS in this Japanese population.

  7. Possible modulatory effect of endogenous islet catecholamines on insulin secretion

    Directory of Open Access Journals (Sweden)

    Gagliardino Juan J

    2001-10-01

    Full Text Available Abstract Background The possible participation of endogenous islet catecholamines (CAs in the control of insulin secretion was tested. Methods Glucose-induced insulin secretion was measured in the presence of 3-Iodo-L-Tyrosine (MIT, a specific inhibitor of tyrosine-hydroxylase activity, in fresh and precultured islets isolated from normal rats. Incubated islets were also used to measure CAs release in the presence of low and high glucose, and the effect of α2-(yohimbine [Y] and idazoxan [I] and α1-adrenergic antagonists (prazosin [P] and terazosin [T] upon insulin secretion elicited by high glucose. Results Fresh islets incubated with 16.7 mM glucose released significantly more insulin in the presence of 1 μM MIT (6.66 ± 0.39 vs 5.01 ± 0.43 ng/islet/h, p Conclusion Our results suggest that islet-originated CAs directly modulate insulin release in a paracrine manner.

  8. Retinol binding protein 4, obesity, and insulin resistance in adolescents

    Directory of Open Access Journals (Sweden)

    Ronaldi Noor

    2017-02-01

    Full Text Available Background Obesity is a global problem. Even in poor and developing countries, obesity has reached alarming levels. In childhood, obesity may lead to insulin resistance. Retinol binding protein (RBP4, secreted primarily by liver and adipose tissues, was recently proposed as a link between obesity and insulin resistance. The role of RBP4 in pediatric obesity and its relationship with insulin resistance have not been well elucidated. Objective To compare RBP4 levels in obese and lean adolescents and to assess for a relationship between RBP4 levels and insulin resistance. Method This cross-sectional study was conducted in three senior high schools in Padang, West Sumatera, Indonesia. Subjects were adolescents aged 14-18 years, who were obese or normal weight (n=56. We measured subjects’ body mass index (BMI and serum RBP4 concentrations. Insulin resistance was assessed using the homeostasis model assessment of insulin resistance (HOMA-IR index. Results Similar RBP4 levels were found in the obese and normoweight groups (P>0.05. Higher RBP4 levels were found in the insulin resistant compared to the non-insulin resistant group, but the difference was not significant (P > 0.05. Conclusion There is no significant difference in mean RBP4 levels in obese adolescents compared to normoweight adolescents. Nor are mean RBP4 levels significantly different between obese adolescents with and without insulin resistance.

  9. Influence of Flavonoids on Mechanism of Modulation of Insulin Secretion.

    Science.gov (United States)

    Soares, Juliana Mikaelly Dias; Pereira Leal, Ana Ediléia Barbosa; Silva, Juliane Cabral; Almeida, Jackson R G S; de Oliveira, Helinando Pequeno

    2017-01-01

    The development of alternatives for insulin secretion control in vivo or in vitro represents an important aspect to be investigated. In this direction, natural products have been progressively explored with this aim. In particular, flavonoids are potential candidates to act as insulin secretagogue. To study the influence of flavonoid on overall modulation mechanisms of insulin secretion. The research was conducted in the following databases and platforms: PubMed, Scopus, ISI Web of Knowledge, SciELO, LILACS, and ScienceDirect, and the MeSH terms used for the search were flavonoids, flavones, islets of Langerhans, and insulin-secreting cells. Twelve articles were included and represent the basis of discussion on mechanisms of insulin secretion of flavonoids. Papers in ISI Web of Knowledge were in number of 1, Scopus 44, PubMed 264, ScienceDirect 511, and no papers from LILACS and SciELO databases. According to the literature, the majority of flavonoid subclasses can modulate insulin secretion through several pathways, in an indication that corresponding molecule is a potential candidate for active materials to be applied in the treatment of diabetes. The action of natural products on insulin secretion represents an important investigation topic due to their importance in the diabetes controlIn addition to their typical antioxidant properties, flavonoids contribute to the insulin secretionThe modulation of insulin secretion is induced by flavonoids according to different mechanisms. Abbreviations used: K ATP channels: ATP-sensitive K + channels, GLUT4: Glucose transporter 4, ERK1/2: Extracellular signal-regulated protein kinases 1 and 2, L-VDCCs: L-type voltage-dependent Ca +2 channels, GLUT1: Glucose transporter 1, AMPK: Adenosine monophosphate-activated protein kinase, PTP1B: Protein tyrosine phosphatase 1B, GLUT2: Glucose transporter 2, cAMP: Cyclic adenosine monophosphate, PKA: Protein kinase A, PTK: Protein tyrosine kinase, CaMK II: Ca 2+ /calmodulin

  10. Insulin secretion and action in North Indian women during pregnancy

    DEFF Research Database (Denmark)

    Arora, G P; Almgren, P; Thaman, R G

    2017-01-01

    ) and adapted WHO 2013 (GDM2013) criteria, excluding the 1-h glucose value, in a high-risk Indian population from Punjab. METHODS: Insulin secretion (HOMA2-B) and insulin action (HOMA2-IR) were assessed in 4665 Indian women with or without gestational diabetes defined by the GDM1999 or adapted GDM2013 criteria...

  11. Getting closer to physiologic insulin secretion.

    Science.gov (United States)

    Heise, Tim

    2007-01-01

    The goal of insulin replacement therapy in diabetes mellitus (DM) is to recreate a normal physiologic insulin supply throughout the day. This article reviewed the use of rapid acting insulin analogues in recreating physiologic postprandial insulin responses. This review article was based on a presentation at a satellite symposium entitled "Realising the Value of Modern Insulins: Reaching Further with Rapid-Acting Insulin Analogues" that was convened during the XIXth World Diabetes Congress, December 3, 2006, in Cape Town, South Africa. In the context of mealtime insulin supply, recreating physiologic postprandial insulin responses requires rapid availability of insulin within a short time of eating and a duration of action that does not extend into the late postprandial period. Conventional human insulin is not ideally suited to SC injection, with its slow onset of action and dose-dependent duration of action. The rapid-acting insulin analogues have been designed to address these deficiencies, with more rapid onset of action, higher maximal effects, and consequently better postprandial glycemic control. These properties have been reported in patients with type 1 and type 2 DM, as well as in nondiabetic individuals in euglycemic clamp studies. Rapid-acting insulin analogues are also of particular interest in people with diabetic nephropathy, women with gestational DM, and elderly patients with DM. Compared with soluble human (regular) insulin, rapid-acting insulin analogues have a more rapid onset of action and a shorter duration of action. Their potential in special patient groups is now being established in clinical research and in everyday practice.

  12. TRPM5 regulates glucose-stimulated insulin secretion.

    Science.gov (United States)

    Brixel, Lili R; Monteilh-Zoller, Mahealani K; Ingenbrandt, Claudia S; Fleig, Andrea; Penner, Reinhold; Enklaar, Thorsten; Zabel, Bernhard U; Prawitt, Dirk

    2010-06-01

    Insulin secretion in beta-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of additional ion channels in this process. TRPM5 is a cation channel expressed in beta-cells and proposed to be involved in coupling intracellular Ca(2+) release to electrical activity and cellular responses. Here, we report that TRPM5 acts as an indispensable regulator of insulin secretion. In vivo glucose tolerance tests showed that Trpm5 (-/-) -mice maintain elevated blood glucose levels for over an hour compared to wild-type littermates, while insulin sensitivity is normal in Trpm5 (-/-) -mice. In pancreatic islets isolated from Trpm5 (-/-) -mice, hyperglycemia as well as arginine-induced insulin secretion was diminished. The presented results describe a major role for TRPM5 in glucose-induced insulin secretion beyond membrane depolarization. Dysfunction of the TRPM5 protein could therefore be an important factor in the etiology of some forms of type 2 diabetes, where disruption of the normal pattern of secretion is observed.

  13. Sunitinib specifically augments glucose-induced insulin secretion.

    Science.gov (United States)

    Lutz, Stefan Z; Ullrich, Axel; Häring, Hans-Ulrich; Ullrich, Susanne; Gerst, Felicia

    2017-08-01

    The tyrosine kinase inhibitor sunitinib is used for the treatment of numerous cancers in humans. In diabetic patients, sunitinib lowers blood glucose levels and improves glycaemic control. This study aims to analyse whether sunitinib has specific and direct effects on insulin secreting β-cells. Regulation of insulin secretion, of cellular cAMP levels and activation of signalling pathways were examined upon exposure of rat insulinoma INS-1E cells to sunitinib under specific stimulatory and inhibitory conditions. Secreted insulin and cellular cAMP levels were measured using RIA and ELISA, respectively. Protein phosphorylations were examined on western blots. Sunitinib enhanced glucose-induced insulin secretion (GIIS) concentration-dependently, reaching a maximal stimulation at 2μM. Sunitinib further augmented insulin secretion in the presence of elevated cAMP levels and the FFAR1 agonists. Adrenaline and the PKA inhibitor H89 counteracted the stimulatory effect of sunitinib on secretion. However, sunitinib altered neither the cellular levels of cAMP nor the phosphorylation of PKA. Sunitinib did not reduce IGF-1-induced phosphorylation of AKT/PKB and ERK1/2. In conclusion, these results suggest that sunitinib stimulates GIIS by a direct effect on β-cells, which may contribute to the glucose-lowering action of the tyrosine kinase inhibitor in humans. Copyright © 2017. Published by Elsevier Inc.

  14. Molecular Mechanisms of Insulin Resistance Development

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    Vsevolod Arsen'evich Tkachuk

    2014-05-01

    Full Text Available Insulin resistance (IR is a phenomenon associated with an impaired ability of insulin to stimulate glucose uptake by target cells and to reduce the blood glucose level. A response increase in insulin secretion by the pancreas and hyperinsulinemia are compensatory reactions of the body. The development of IR leads to the inability of target cells to respond to insulin that results in developing type 2 diabetes mellitus (T2DM and metabolic syndrome. For this reason, the metabolic syndrome is defined in practice as a combination of IR with one or more pathologies such as T2DM, arterial hypertension, dyslipidemia, abdominal obesity, non-alcoholic fatty liver disease, and some others. However, a combination of high blood glucose and insulin levels always serves as its physiological criterion.IR should be considered as a systemic failure of the endocrine regulation in the body. Physiological causes of IR are diverse. The main ones are nutritional overload and accumulation of certain lipids and their metabolites in cells, low physical activity, chronic inflammation and stress of various nature, including oxidative and endoplasmic reticulum stress (impairment of damaged protein degradation in the cell. Recent studies have demonstrated that these physiological mechanisms likely act through a single intracellular scenario. This is the impairment of signal transduction from the insulin receptor to its targets via the negative feedback mechanism in intracellular insulin-dependent signaling cascades.This review describes the physiological and intracellular mechanisms of insulin action and focuses on their abnormalities upon IR development. Finally, feasible trends in early molecular diagnosis and therapy of IR are discussed.

  15. Pancreatic islets of variable size - insulin secretion and glucose utilization

    International Nuclear Information System (INIS)

    Colella, R.M.; Bonner-Weir, S.; Braunstein, L.P.; Schwalke, M.; Weir, G.C.

    1985-01-01

    Glucose metabolism and insulin secretion were studied in isolated rat pacreatic islets of different sizes and the amount of tissue was quantitated by the measurement of DNA. It was found that larger islets (140-210 ng DNA/islet) utilized more glucose (based on the conversion of 3 H-5-glucose to 3 H 2 O) per ng of DNA than islets containing less DNA (60-120 ng/islet). However, the insulin secreted per ng of DNA in response to a given glucose concentration was the same in islets of all sizes. Also, the islet insulin and glucagon content when expressed in terms of DNA did not depend upon islet size. Thus, although glucose utilization rates expressed as a function of islet DNA content were greater in larger islets, no such relationship was found for glucose-induced insulin release or insulin and glucagon content. 17 reference, 1 figure, 3 tables

  16. Insulin resistance in obesity can be reliably identified from fasting plasma insulin

    NARCIS (Netherlands)

    ter Horst, K. W.; Gilijamse, P. W.; Koopman, K. E.; de Weijer, B. A.; Brands, M.; Kootte, R. S.; Romijn, J. A.; Ackermans, M. T.; Nieuwdorp, M.; Soeters, M. R.; Serlie, M. J.

    2015-01-01

    Insulin resistance is the major contributor to cardiometabolic complications of obesity. We aimed to (1) establish cutoff points for insulin resistance from euglycemic hyperinsulinemic clamps (EHCs), (2) identify insulin-resistant obese subjects and (3) predict insulin resistance from routinely

  17. Nutritional Modulation of Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Martin O. Weickert

    2012-01-01

    Full Text Available Insulin resistance has been proposed as the strongest single predictor for the development of Type 2 Diabetes (T2DM. Chronic oversupply of energy from food, together with inadequate physical activity, have been recognized as the most relevant factors leading to overweight, abdominal adiposity, insulin resistance, and finally T2DM. Conversely, energy reduced diets almost invariably to facilitate weight loss and reduce abdominal fat mass and insulin resistance. However, sustained weight loss is generally difficult to achieve, and distinct metabolic characteristics in patients with T2DM further compromise success. Therefore, investigating the effects of modulating the macronutrient composition of isoenergetic diets is an interesting concept that may lead to additional important insights. Metabolic effects of various different dietary concepts and strategies have been claimed, but results from randomized controlled studies and particularly from longer-term-controlled interventions in humans are often lacking. However, some of these concepts are supported by recent research, at least in animal models and short-term studies in humans. This paper provides an update of the current literature regarding the role of nutrition in the modulation of insulin resistance, which includes the discussion of weight-loss-independent metabolic effects of commonly used dietary concepts.

  18. Obesity genes and insulin resistance.

    Science.gov (United States)

    Belkina, Anna C; Denis, Gerald V

    2010-10-01

    The exploding prevalence of insulin resistance and Type 2 diabetes (T2D) linked to obesity has become an alarming public health concern. Worldwide, approximately 171 million people suffer from obesity-induced diabetes and public health authorities expect this situation to deteriorate rapidly. An interesting clinical population of 'metabolically healthy but obese' (MHO) cases is relatively protected from T2D and its associated cardiovascular risk. The molecular basis for this protection is not well understood but is likely to involve reduced inflammatory responses. The inflammatory cells and pathways that respond to overnutrition are the primary subject matter for this review. The chance discovery of a genetic mutation in the Brd2 gene, which is located in the class II major histocompatibility complex and makes mice enormously fat but protects them from diabetes, offers revolutionary new insights into the cellular mechanisms that link obesity to insulin resistance and T2D. These Brd2-hypomorphic mice have reduced inflammation in fat that is normally associated with insulin resistance, and resemble MHO patients, suggesting novel therapeutic pathways for obese patients at risk for T2D. Deeper understanding of the functional links between genes that control inflammatory responses to diet-induced obesity is crucial to the development of therapies for obese, insulin-resistant patients.

  19. Pathophysiological mechanisms of insulin resistance

    NARCIS (Netherlands)

    Brands, M.

    2013-01-01

    In this thesis we studied pathophysiological mechanisms of insulin resistance in different conditions in humans, i.e. in obesity, during lipid infusions, after hypercaloric feeding, and glucocorticoid treatment. We focused on 3 important hypotheses that are suggested to be implicated in the

  20. Genetics Home Reference: type A insulin resistance syndrome

    Science.gov (United States)

    ... Conditions Type A insulin resistance syndrome Type A insulin resistance syndrome Printable PDF Open All Close All Enable ... as energy. In people with type A insulin resistance syndrome , insulin resistance impairs blood sugar regulation and ultimately leads ...

  1. Incretins, insulin secretion and Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, Tina; Holst, Jens Møller

    2004-01-01

    the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism......When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response...... to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where...

  2. Insulin Resistance: From Theory To Practice

    OpenAIRE

    Srinivas Kakkilaya Bevinje

    2006-01-01

    Insulin resistance is at the core of the well recognised metabolic syndrome and possibly many other ailments commonly seen in the modern society. While the quantification of insulin resistance remains a difficult task, the problems associated with it are increasing in epidemic proportions. Need of the hour therefore is to develop concise dietary and pharmacotherapeutic guidelines for prevention and management of insulin resistance

  3. TRPM5 regulates glucose-stimulated insulin secretion

    OpenAIRE

    Brixel, Lili R.; Monteilh-Zoller, Mahealani K.; Ingenbrandt, Claudia S.; Fleig, Andrea; Penner, Reinhold; Enklaar, Thorsten; Zabel, Bernhard U.; Prawitt, Dirk

    2010-01-01

    Insulin secretion in β-pancreatic cells due to glucose stimulation requires the coordinated alteration of cellular ion concentrations and a substantial membrane depolarization to enable insulin vesicle fusion with the cellular membrane. The cornerstones of this cascade are well characterized, yet current knowledge argues for the involvement of additional ion channels in this process. TRPM5 is a cation channel expressed in β-cells and proposed to be involved in coupling intracellular Ca2+ rele...

  4. Effects of aging on insulin synthesis and secretion. Differential effects on preproinsulin messenger RNA levels, proinsulin biosynthesis, and secretion of newly made and preformed insulin in the rat.

    OpenAIRE

    Wang, S Y; Halban, P A; Rowe, J W

    1988-01-01

    Aging in men and rodents is associated with a marked decline in glucose stimulated insulin secretion by pancreatic beta cells (B cells). Secreted insulin is the end result of a series of steps along the biosynthetic protein-secretion pathway, including insulin gene transcription, processing of transcripts to preproinsulin mRNA, translation of mRNA, segregation and processing of newly made proinsulin in secretory vesicles, proinsulin to insulin conversion, transport of vesicles to the plasma m...

  5. Microvascular Recruitment in Insulin Resistance

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker

    the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...... hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...

  6. Microvascular Recruitment in Insulin Resistance

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker

    hormone glucagon-like-peptide-1 (GLP-1) in the microcirculation. Glucagon-like-peptide-1 analogs are drugs used for treatments of insulin resistance and type 2 diabetes but the vascular effects of GLP-1 in vivo are elusive. Here it was shown that GLP-1 rapidly increased the microvascular recruitment...... the resonating sound from the microbubbles in the systemic circulation were recorded for determination of microvascular recruitment in designated muscle segments. Results showed that microvascular recruitment increased with insulin stimulation by ~30% in rats and ~40% in humans (study I). Furthermore......, it was observed that muscle contractions increased muscle perfusion rapidly by 3-4 fold and by 1-2 fold compared to basal and insulin, respectively, in both rat and human skeletal muscle (study I). The real-time contrast-enhanced ultrasound method was applied to investigate the vaso-active effect of the incretin...

  7. Effect of alcohol on insulin secretion and viability of human pancreatic islets

    Directory of Open Access Journals (Sweden)

    Nikolić Dragan

    2017-01-01

    Full Text Available Introduction/Objective. There are controversial data in the literature on the topic of effects of alcohol on insulin secretion, apoptosis, and necrosis of the endocrine and exocrine pancreas. The goal of this research was to determine how alcohol affects the insulin secretion and viability of human adult pancreatic islets in vitro during a seven-day incubation. Methods. Human pancreatic tissue was digested with Collagenase XI, using a non-automated method. Cultures were incubated in Roswell Park Memorial Institute (RPMI medium containing alcohol (10 μl of alcohol in 100 ml of medium. Insulin stimulation index (SI and viability of the islets were determined on the first, third, and seventh day of cultivation. Results. Analysis of the viability of the islets showed that there wasn’t significant difference between the control and the test group. In the test group, viability of the cultures declined with the time of incubation. SI of the test group was higher compared to the control group, by 50% and 25% on the first and third day of cultivation, respectively. On the seventh day, insulin secretion was reduced by 25%. The difference was not statistically significant (p > 0.05. In the test group, significant decline in insulin secretion was found on the third and seventh day of incubation (p ≤ 0.05. Conclusion. Alcohol can increase or decrease insulin secretion of islets cultures, which may result in an inadequate response of pancreatic β-cells to blood glucose, leading to insulin resistance, and increased risk of developing type 2 diabetes. [Project of the Serbian Ministry of Education, Science and Technological Development, Grant no. 41002

  8. Targeting development of incretin-producing cells increases insulin secretion

    NARCIS (Netherlands)

    Petersen, Natalia; Reimann, Frank; van Es, Johan H; van den Berg, Bernard M; Kroone, Chantal; Pais, Ramona; Jansen, Erik; Clevers, Hans; Gribble, Fiona M; de Koning, Eelco J P

    Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing the

  9. Methylated trivalent arsenicals are potent inhibitors of glucose stimulated insulin secretion by murine pancreatic islets

    Energy Technology Data Exchange (ETDEWEB)

    Douillet, Christelle [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Currier, Jenna [Curriculum in Toxicology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Saunders, Jesse [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States); Bodnar, Wanda M. [Department of Environmental Sciences and Engineering, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7431 (United States); Matoušek, Tomáš [Institute of Analytical Chemistry of the ASCR, v.v.i., Veveří 97, 602 00 Brno (Czech Republic); Stýblo, Miroslav, E-mail: styblo@med.unc.edu [Department of Nutrition, Gillings School of Global Public Health, 2302 MHRC, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7461 (United States)

    2013-02-15

    Epidemiologic evidence has linked chronic exposure to inorganic arsenic (iAs) with an increased prevalence of diabetes mellitus. Laboratory studies have identified several mechanisms by which iAs can impair glucose homeostasis. We have previously shown that micromolar concentrations of arsenite (iAs{sup III}) or its methylated trivalent metabolites, methylarsonite (MAs{sup III}) and dimethylarsinite (DMAs{sup III}), inhibit the insulin-activated signal transduction pathway, resulting in insulin resistance in adipocytes. Our present study examined effects of the trivalent arsenicals on insulin secretion by intact pancreatic islets isolated from C57BL/6 mice. We found that 48-hour exposures to low subtoxic concentrations of iAs{sup III}, MAs{sup III} or DMAs{sup III} inhibited glucose-stimulated insulin secretion (GSIS), but not basal insulin secretion. MAs{sup III} and DMAs{sup III} were more potent than iAs{sup III} as GSIS inhibitors with estimated IC{sub 50} ≤ 0.1 μM. The exposures had little or no effects on insulin content of the islets or on insulin expression, suggesting that trivalent arsenicals interfere with mechanisms regulating packaging of the insulin transport vesicles or with translocation of these vesicles to the plasma membrane. Notably, the inhibition of GSIS by iAs{sup III}, MAs{sup III} or DMAs{sup III} could be reversed by a 24-hour incubation of the islets in arsenic-free medium. These results suggest that the insulin producing pancreatic β-cells are among the targets for iAs exposure and that the inhibition of GSIS by low concentrations of the methylated metabolites of iAs may be the key mechanism of iAs-induced diabetes. - Highlights: ► Trivalent arsenicals inhibit glucose stimulated insulin secretion by pancreatic islets. ► MAs{sup III} and DMAs{sup III} are more potent inhibitors than arsenite with IC{sub 50} ∼ 0.1 μM. ► The arsenicals have little or no effects on insulin expression in pancreatic islets. ► The inhibition of

  10. 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

    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.

  11. Insulin resistance and bone: a biological partnership.

    Science.gov (United States)

    Conte, Caterina; Epstein, Solomon; Napoli, Nicola

    2018-04-01

    Despite a clear association between type 2 diabetes (T2D) and fracture risk, the pathogenesis of bone fragility in T2D has not been clearly elucidated. Insulin resistance is the primary defect in T2D. Insulin signalling regulates both bone formation and bone resorption, but whether insulin resistance can affect bone has not been established. On the other hand, evidence exists that bone might play a role in the regulation of glucose metabolism. This article reviews the available experimental and clinical evidence on the interplay between bone and insulin resistance. Interestingly, a bilateral relationship between bone and insulin resistance seems to exist that unites them in a biological partnership.

  12. Altered pancreatic growth and insulin secretion in WSB/EiJ mice.

    Directory of Open Access Journals (Sweden)

    Maggie M Ho

    Full Text Available These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies also highlight the role of post-natal growth in determining adult β-cell mass. Mice are important animal models for the study of metabolic physiology and the genetics of complex traits. Wild-derived inbred mouse strains, such as WSB/EiJ (WSB, are unrelated to the commonly studied mouse strains and are valuable tools to identify novel genes that modify disease risk. We have previously shown that in contrast to C57BL/6J (B6 mice, WSB mice fed a high fat diet do not develop hyperinsulinemia or insulin resistance, and had nearly undetectable insulin secretion in response to an intraperitoneal glucose challenge. As hyperinsulinemia may drive obesity and insulin resistance, we examined whether defects in β-cell mass or function could contribute to the low insulin levels in WSB mice. In young WSB mice, β-cell mass was similar to B6 mice. However, we found that adult WSB mice had reduced β-cell mass due to reduced pancreatic weights. Pancreatic sizes were similar between the strains when normalized to body weight, suggesting their pancreatic size is appropriate to their body size in adults, but overall post-natal pancreatic growth was reduced in WSB mice compared to B6 mice. Islet architecture was normal in WSB mice. WSB mice had markedly increased insulin secretion from isolated islets in vitro. These data suggest that insulin secretion in WSB mice is blunted specifically in vivo, either due to a reduced insulin requirement and/or due to factors that are absent or destroyed in vitro. These studies suggest that WSB mice may provide novel insight into mechanisms regulating insulin secretion and also highlight the role of post-natal growth in determining adult β-cell mass.

  13. Mechanisms of insulin resistance in obesity

    Science.gov (United States)

    Ye, Jianping

    2014-01-01

    Obesity increases the risk for type 2 diabetes through induction of insulin resistance. Treatment of type 2 diabetes has been limited by little translational knowledge of insulin resistance although there have been several well-documented hypotheses for insulin resistance. In those hypotheses, inflammation, mitochondrial dysfunction, hyperinsulinemia and lipotoxicity have been the major concepts and have received a lot of attention. Oxidative stress, endoplasmic reticulum (ER) stress, genetic background, aging, fatty liver, hypoxia and lipodystrophy are active subjects in the study of these concepts. However, none of those concepts or views has led to an effective therapy for type 2 diabetes. The reason is that there has been no consensus for a unifying mechanism of insulin resistance. In this review article, literature is critically analyzed and reinterpreted for a new energy-based concept of insulin resistance, in which insulin resistance is a result of energy surplus in cells. The energy surplus signal is mediated by ATP and sensed by adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. Decreasing ATP level by suppression of production or stimulation of utilization is a promising approach in the treatment of insulin resistance. In support, many of existing insulin sensitizing medicines inhibit ATP production in mitochondria. The effective therapies such as weight loss, exercise, and caloric restriction all reduce ATP in insulin sensitive cells. This new concept provides a unifying cellular and molecular mechanism of insulin resistance in obesity, which may apply to insulin resistance in aging and lipodystrophy. PMID:23471659

  14. 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.

  15. Synaptotagmin-7 phosphorylation mediates GLP-1-dependent potentiation of insulin secretion from β-cells

    DEFF Research Database (Denmark)

    Wu, Bingbing; Wei, Shunhui; Petersen, Natalia

    2015-01-01

    Glucose stimulates insulin secretion from β-cells by increasing intracellular Ca(2+). Ca(2+) then binds to synaptotagmin-7 as a major Ca(2+) sensor for exocytosis, triggering secretory granule fusion and insulin secretion. In type-2 diabetes, insulin secretion is impaired; this impairment is amel...

  16. Importance of radioimmunoassay of insulin secretion disorder as atherogenic factor

    International Nuclear Information System (INIS)

    Knyazev, Yu.A.; Bespalova, V.A.; Vakhrusheva, L.L.; Kirbasova, N.P.; Severtseva, V.V.

    1984-01-01

    Using a radioimmunoassay a C-peptide levei was revealed in children, pregnant and lying-in women as well as in patients with insulin-dependent diabetes mellitus. After breakfast and insulin administration wich curative purposes the IRI concentration in children increased whereas the C-peptide level changed insignificantly. Changes of the insulin secretion were more noticeable in severe diabetes mejlitus with vascular complications and in disease decompensation. The atherogenic nature of the lipid metaboiism (an increase in the cholesterol, triglyceride and β-lipoprotein levels), changes in the liver and tendency to vascular involvement are results of insulin effect inadequacy. Such metabolic derangements in pregnant women create unfavorable conditions for the development of fetus and may lead to early atherogenic processes

  17. Periapical lesions decrease insulin signal and cause insulin resistance.

    Science.gov (United States)

    Astolphi, Rafael Dias; Curbete, Mariane Machado; Colombo, Natalia Helena; Shirakashi, Daisy Jaqueline; Chiba, Fernando Yamamoto; Prieto, Annelise Katrine Carrara; Cintra, Luciano Tavares Angelo; Bomfim, Suely Regina Mogami; Ervolino, Edilson; Sumida, Doris Hissako

    2013-05-01

    Inflammatory cytokines are associated with decreased insulin signal transduction. Moreover, local oral inflammation, such as that accompanying periodontal disease, is associated with insulin resistance and type 2 diabetes mellitus. The aim of this study was to evaluate the effect of periapical lesions (PLs) on insulin signaling and insulin sensitivity in rats. We hypothesized that PLs alter systemic insulin signaling and insulin sensitivity via elevated plasmatic tumor necrosis factor α (TNF-α). Wistar rats were divided into control (CN) and PL groups. PLs were induced by exposing pulpal tissue to the oral environment. After 30 days, insulin sensitivity was measured using the insulin tolerance test. After euthanization, maxillae were processed for histopathology. Plasmatic concentrations of tumor necrosis factor α (TNF-α) were determined via the enzyme-linked immunosorbent assay. Insulin signal transduction was evaluated using insulin receptor substrate tyrosine phosphorylation status and serine phosphorylation status in periepididymal white adipose tissue via Western blotting. For insulin signaling and insulin tolerance tests, the analyses performed were analysis of variance followed by the Tukey post hoc test. For TNF-α analysis, the Student's t test was used. In all tests, P change in serine phosphorylation status in white adipose tissue after insulin stimulation. PLs can cause alterations to both insulin signaling and insulin sensitivity, probably because of elevation of plasmatic TNF-α. The results from this study emphasize the importance of the prevention of local inflammatory diseases, such as PLs, with regard to the prevention of insulin resistance. Copyright © 2013 American Association of Endodontists. Published by Elsevier Inc. All rights reserved.

  18. Pathogenesis of Insulin Resistance in Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Muhammad A. Abdul-Ghani

    2010-01-01

    Full Text Available Insulin resistance in skeletal muscle is manifested by decreased insulin-stimulated glucose uptake and results from impaired insulin signaling and multiple post-receptor intracellular defects including impaired glucose transport, glucose phosphorylation, and reduced glucose oxidation and glycogen synthesis. Insulin resistance is a core defect in type 2 diabetes, it is also associated with obesity and the metabolic syndrome. Dysregulation of fatty acid metabolism plays a pivotal role in the pathogenesis of insulin resistance in skeletal muscle. Recent studies have reported a mitochondrial defect in oxidative phosphorylation in skeletal muscle in variety of insulin resistant states. In this review, we summarize the cellular and molecular defects that contribute to the development of insulin resistance in skeletal muscle.

  19. Insulin and insulin signaling play a critical role in fat induction of insulin resistance in mouse

    Science.gov (United States)

    Ning, Jie; Hong, Tao; Yang, Xuefeng; Mei, Shuang; Liu, Zhenqi; Liu, Hui-Yu

    2011-01-01

    The primary player that induces insulin resistance has not been established. Here, we studied whether or not fat can cause insulin resistance in the presence of insulin deficiency. Our results showed that high-fat diet (HFD) induced insulin resistance in C57BL/6 (B6) mice. The HFD-induced insulin resistance was prevented largely by the streptozotocin (STZ)-induced moderate insulin deficiency. The STZ-induced insulin deficiency prevented the HFD-induced ectopic fat accumulation and oxidative stress in liver and gastrocnemius. The STZ-induced insulin deficiency prevented the HFD- or insulin-induced increase in hepatic expression of long-chain acyl-CoA synthetases (ACSL), which are necessary for fatty acid activation. HFD increased mitochondrial contents of long-chain acyl-CoAs, whereas it decreased mitochondrial ADP/ATP ratio, and these HFD-induced changes were prevented by the STZ-induced insulin deficiency. In cultured hepatocytes, we observed that expressions of ACSL1 and -5 were stimulated by insulin signaling. Results in cultured cells also showed that blunting insulin signaling by the PI3K inhibitor LY-294002 prevented fat accumulation, oxidative stress, and insulin resistance induced by the prolonged exposure to either insulin or oleate plus sera that normally contain insulin. Finally, knockdown of the insulin receptor prevented the oxidative stress and insulin resistance induced by the prolonged exposure to insulin or oleate plus sera. Together, our results show that insulin and insulin signaling are required for fat induction of insulin resistance in mice and cultured mouse hepatocytes. PMID:21586696

  20. Insulin resistance causes inflammation in adipose tissue.

    Science.gov (United States)

    Shimobayashi, Mitsugu; Albert, Verena; Woelnerhanssen, Bettina; Frei, Irina C; Weissenberger, Diana; Meyer-Gerspach, Anne Christin; Clement, Nicolas; Moes, Suzette; Colombi, Marco; Meier, Jerome A; Swierczynska, Marta M; Jenö, Paul; Beglinger, Christoph; Peterli, Ralph; Hall, Michael N

    2018-03-12

    Obesity is a major risk factor for insulin resistance and type 2 diabetes. In adipose tissue, obesity-mediated insulin resistance correlates with the accumulation of proinflammatory macrophages and inflammation. However, the causal relationship of these events is unclear. Here, we report that obesity-induced insulin resistance in mice precedes macrophage accumulation and inflammation in adipose tissue. Using a mouse model that combines genetically induced, adipose-specific insulin resistance (mTORC2-knockout) and diet-induced obesity, we found that insulin resistance causes local accumulation of proinflammatory macrophages. Mechanistically, insulin resistance in adipocytes results in production of the chemokine monocyte chemoattractant protein 1 (MCP1), which recruits monocytes and activates proinflammatory macrophages. Finally, insulin resistance (high homeostatic model assessment of insulin resistance [HOMA-IR]) correlated with reduced insulin/mTORC2 signaling and elevated MCP1 production in visceral adipose tissue from obese human subjects. Our findings suggest that insulin resistance in adipose tissue leads to inflammation rather than vice versa.

  1. Associations between depressive symptoms and insulin resistance

    DEFF Research Database (Denmark)

    Adriaanse, M C; Dekker, J M; Nijpels, G

    2006-01-01

    AIMS/HYPOTHESIS: The association between depression and insulin resistance has been investigated in only a few studies, with contradictory results reported. The aim of this study was to determine whether the association between symptoms of depression and insulin resistance varies across glucose...... established type 2 diabetes mellitus. Main outcome measures were insulin resistance defined by the homeostasis model assessment for insulin resistance (HOMA-IR) and symptoms of depression using the Centre for Epidemiologic Studies Depression Scale (CES-D). RESULTS: In the total sample, we found a weak.......942). The association between depressive symptoms and insulin resistance was similar for men and women. CONCLUSIONS/INTERPRETATION: We found only weak associations between depressive symptoms and insulin resistance, which did not differ among different glucose metabolism subgroups or between men and women....

  2. Variations of Adipokines and Insulin Resistance in Primary Hypothyroidism.

    Science.gov (United States)

    Kar, Kaushik; Sinha, Satwika

    2017-08-01

    Hypothyroidism is a common concern in endocrinology practice, which plays a significant role in metabolic and development processes. Obesity, hyperlipidaemia and hypertension may complicate hypothyroidism. Recent studies have shown that cytokines like leptin and adiponectin, secreted by adipose tissue and exert their endocrinal functions by modulating appetite, obesity and insulin sensitivity in conjunction with thyroid hormones. Interrelation between thyroid hormone, insulin resistance and adipokines are not yet clear. To estimate serum leptin, adiponectin and insulin resistance in patients with hypothyroidism and to compare with control subjects and measure the relation between the mean value of one variable with others. Forty primary hypothyroidism patients and forty age and sex matched controls were selected for the study with informed consent. Fasting serum Thyroid Stimulating Hormone (TSH), leptin, adiponectin, glucose and insulin were estimated. Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) was evaluated from fasting plasma glucose and serum insulin levels. Statistical analysis was carried out using SPSS version 17.0. Unpaired t-test and regression analysis were used to compare and determine the dependence, pHOMA-IR were significantly higher (p<0.05) in patients with hypothyroidism (10.37±4.10, 10.97±0.60, 31.09±4.07, 3.64±0.40) than controls (2.41±2.09, 10.37±0.12, 33.32±1.44, 2.36±0.35). Regression analysis showed that leptin was significantly (p=0.054) dependent on adiponectin but not on others. Increased oxidative stress by hypothyroid mediated leptin secretion and increased insulin resistance can down-regulate the adiponectin secretion and future complications. Serum estimation and correction of imbalance of adipokines in hypothyroidism can prevent severe consequences.

  3. Targeting development of incretin-producing cells increases insulin secretion

    DEFF Research Database (Denmark)

    Petersen, Natalia; Reimann, Frank; van Es, Johan H

    2015-01-01

    Glucagon-like peptide-1-based (GLP-1-based) therapies improve glycemic control in patients with type 2 diabetes. While these agents augment insulin secretion, they do not mimic the physiological meal-related rise and fall of GLP-1 concentrations. Here, we tested the hypothesis that increasing....... Dibenzazepine also increased K cell numbers, resulting in increased gastric inhibitory polypeptide (GIP) secretion. Using a GLP-1 receptor antagonist, we determined that the insulinotropic effect of dibenzazepine was mediated through an increase in GLP-1 signaling. Together, our data indicate that modulation...

  4. Histone deacetylase 3 inhibition improves glycaemia and insulin secretion in obese diabetic rats

    DEFF Research Database (Denmark)

    Lundh, Morten; Galbo, Thomas; Poulsen, Steen Seier

    2015-01-01

    Failure of pancreatic β cells to compensate for insulin resistance is a prerequisite for the development of type 2 diabetes. Sustained elevated circulating levels of free fatty acids and glucose contribute to β-cell failure. Selective inhibition of Histone deacetylase (HDAC)-3 protects pancreatic β...... cells against inflammatory and metabolic insults in vitro. Here we tested the ability of a selective HDAC3 inhibitor, BRD3308, to reduce hyperglycemia and increase insulin secretion in an animal model of type 2 diabetes. At diabetes onset, an ambulatory hyperglycemic clamp was performed. HDAC3......3 as a key therapeutic target for β-cell protection in type 2 diabetes....

  5. Obesity and Insulin Resistance: Management in Diabetes

    OpenAIRE

    Suhel Ashraff; Muhammad A. Siddiqui; Thomas E. Carline

    2013-01-01

    Obesity today, is a major public health problem across the world. The rapid increase in the incidence of obesity and associated co-morbidities presents a major challenge to health care globally. Insulin resistance is commonly associated with obesity and other life style diseases. However, much uncertainty remains about the mechanism regarding the association between insulin resistance and human disease mainly because of the difficulties of defining insulin resistance in clinical terms and of ...

  6. Insulin Resistance: From Theory To Practice

    Directory of Open Access Journals (Sweden)

    Srinivas Kakkilaya Bevinje

    2006-07-01

    Full Text Available Insulin resistance is at the core of the well recognised metabolic syndrome and possibly many other ailments commonly seen in the modern society. While the quantification of insulin resistance remains a difficult task, the problems associated with it are increasing in epidemic proportions. Need of the hour therefore is to develop concise dietary and pharmacological guidelines for for prevention and management of insulin resistance

  7. Assessment of insulin sensitivity/resistance

    OpenAIRE

    Gutch, Manish; Kumar, Sukriti; Razi, Syed Mohd; Gupta, Kumar Keshav; Gupta, Abhinav

    2015-01-01

    Insulin resistance is one pretty troublesome entity which very commonly aggravates metabolic syndrome. Many methods and indices are available for the estimation of insulin resistance. It is essential to test and validate their reliability before they can be used as an investigation in patients. At present, hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance and are being used as a reference standard...

  8. Effects of glucose and insulin on secretion of amyloid?? by human adipose tissue cells

    OpenAIRE

    Tharp, William G.; Gupta, Dhananjay; Smith, Joshua; Jones, Karen P.; Jones, Amanda M.; Pratley, Richard E.

    2016-01-01

    Objective Obesity and type 2 diabetes mellitus are risk factors for developing Alzheimer disease. Overlapping patterns of metabolic dysfunction may be common molecular links between these complex diseases. Amyloid?? (A?) precursor protein and associated ?? and ??secretases are expressed in adipose tissue. A? precursor protein is up?regulated with obesity and correlated to insulin resistance. A? may be secreted by adipose tissue, its production may be regulated through metabolic pathways, and ...

  9. Antibody-Mediated Insulin Resistance: When Insulin and Insulin Receptor Act as Autoantigens in Humans.

    Science.gov (United States)

    Liminet, Christelle; Vouillarmet, Julien; Chikh, Karim; Disse, Emmanuel

    2016-10-01

    We report the case of a patient with diabetes presenting a severe insulin-resistance syndrome due to the production of insulin autoantibodies by a lymphocytic lymphoma. We describe the various mechanisms leading to the production of insulin autoantibodies and insulin receptor autoantibodies and review the therapeutic possibilities. Copyright © 2016 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

  10. Secretome Analysis of Lipid-Induced Insulin Resistance in Skeletal Muscle Cells by a Combined Experimental and Bioinformatics Workflow

    DEFF Research Database (Denmark)

    Deshmukh, Atul S; Cox, Juergen; Jensen, Lars Juhl

    2015-01-01

    the secretome of lipid-induced insulin-resistant skeletal muscle cells. Our workflow identified 1073 putative secreted proteins including 32 growth factors, 25 cytokines, and 29 metalloproteinases. In addition to previously reported proteins, we report hundreds of novel ones. Intriguingly, ∼40% of the secreted......-resistant conditions. Our study demonstrates an efficient combined experimental and bioinformatics workflow to identify putative secreted proteins from insulin-resistant skeletal muscle cells, which could easily be adapted to other cellular models....

  11. MiR-184 regulates insulin secretion through repression of Slc25a22

    Science.gov (United States)

    Morita, Sumiyo; Horii, Takuro; Kimura, Mika

    2013-01-01

    Insulin secretion from pancreatic β-cells plays an essential role in blood glucose homeostasis and type 2 diabetes. Many genes are involved in the secretion of insulin and most of these genes can be targeted by microRNAs (miRNAs). However, the role of miRNAs in insulin secretion and type 2 diabetes has not been exhaustively studied. The expression miR-184, a miRNA enriched in pancreatic islets, negatively correlates with insulin secretion, suggesting that it is a good candidate for miRNA-mediated regulation of insulin secretion. Here we report that miR-184 inhibits insulin secretion in the MIN6 pancreatic β-cell line through the repression of its target Slc25a22, a mitochondrial glutamate carrier. Our study provides new insight into the regulation of insulin secretion by glutamate transport in mitochondria. PMID:24109547

  12. Reconstruction of the insulin secretion rate by Bayesian deconvolution

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    of the insulin secretion rate (ISR) can be done by solving a highly ill-posed deconvolution problem. We present a Bayesian methodology for the estimation of scaled densities of phase-type distributions via Markov chain Monte Carlo techniques, whereby closed form evaluation of ISR is possible. We demonstrate...... the methodology on simulated data concluding that the method seems as a promising alternative to existing methods where the ISR is considered as piecewise constant....

  13. Sepsis-Induced Adipokine Change with regard to Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Andreas Hillenbrand

    2012-01-01

    Full Text Available Background. Assessment of white adipose tissue has changed in recent years, with WAT now being considered as an active endocrine organ, secreting a large number of bioactive mediators, so-called adipokines. Besides other functions, these adipokines are involved in inflammatory response thereby exhibiting predominantly proinflammatory or anti-inflammatory properties and contribute to insulin resistance. Methods. Comprehensive review of the literature of the role of adipokines relevant to critical care medicine using PubMed search. Results. Adiponectin—the prototype of an anti-inflammatory and insulin-sensitizing adipokine—is diminished in sepsis, while resistin—a protein with proinflammatory properties—is elevated. Plasminogen activator inhibitor-1, interleukin (IL-1, IL-6, IL-8, and IL-10, and tumor-necrosis-factor-alpha mediate insulin resistance and are elevated in sepsis, while retinol-binding protein-4 concentrations are significantly reduced in sepsis. Chemerin displays potent anti-inflammatory and insulin-resistance properties, while monocyte chemotactic protein-1—increased in sepsis—contributes to macrophage infiltration in adipose tissue and insulin resistance. Conclusions. The expression of adipokines in humans is altered as well in obese as in septic patients with elevated levels of proinflammatory adipokines. Changes in adipokine levels in acute sepsis could contribute to insulin resistance. Consequently, in critically ill patients, these alterations underline a possible contribution of adipokines in the development of hyperglycemia.

  14. Insulin resistance and cancer: the role of insulin and IGFs.

    Science.gov (United States)

    Djiogue, Sefirin; Nwabo Kamdje, Armel Hervé; Vecchio, Lorella; Kipanyula, Maulilio John; Farahna, Mohammed; Aldebasi, Yousef; Seke Etet, Paul Faustin

    2013-02-01

    Insulin, IGF1, and IGF2 are the most studied insulin-like peptides (ILPs). These are evolutionary conserved factors well known as key regulators of energy metabolism and growth, with crucial roles in insulin resistance-related metabolic disorders such as obesity, diseases like type 2 diabetes mellitus, as well as associated immune deregulations. A growing body of evidence suggests that insulin and IGF1 receptors mediate their effects on regulating cell proliferation, differentiation, apoptosis, glucose transport, and energy metabolism by signaling downstream through insulin receptor substrate molecules and thus play a pivotal role in cell fate determination. Despite the emerging evidence from epidemiological studies on the possible relationship between insulin resistance and cancer, our understanding on the cellular and molecular mechanisms that might account for this relationship remains incompletely understood. The involvement of IGFs in carcinogenesis is attributed to their role in linking high energy intake, increased cell proliferation, and suppression of apoptosis to cancer risks, which has been proposed as the key mechanism bridging insulin resistance and cancer. The present review summarizes and discusses evidence highlighting recent advances in our understanding on the role of ILPs as the link between insulin resistance and cancer and between immune deregulation and cancer in obesity, as well as those areas where there remains a paucity of data. It is anticipated that issues discussed in this paper will also recover new therapeutic targets that can assist in diagnostic screening and novel approaches to controlling tumor development.

  15. Depressive symptoms, insulin sensitivity and insulin secretion in the RISC cohort study

    DEFF Research Database (Denmark)

    Bot, M; Pouwer, F; De Jonge, P

    2013-01-01

    . highest quartile of beta-cell rate sensitivity was 2.04; P=0.01). Also, significant depressive symptoms were associated with a statistically significant decrease in the potentiation factor ratio in unadjusted models, but not in the fully adjusted model. CONCLUSION: Depressive symptoms were not related......AIM: This study explored the association of depressive symptoms with indices of insulin sensitivity and insulin secretion in a cohort of non-diabetic men and women aged 30 to 64 years. METHODS: The study population was derived from the 3-year follow-up of the Relationship between Insulin...... Sensitivity and Cardiovascular Disease Risk (RISC) study. Presence of significant depressive symptoms was defined as a Center for Epidemiologic Studies Depression Scale (CES-D) score ≥ 16. Standard oral glucose tolerance tests were performed. Insulin sensitivity was assessed with the oral glucose insulin...

  16. Incretins, insulin secretion and Type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Vilsbøll, T; Holst, Jens Juul

    2004-01-01

    the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism...... of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas...... the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown...

  17. Selective Insulin Resistance in the Kidney

    Science.gov (United States)

    Horita, Shoko; Nakamura, Motonobu; Suzuki, Masashi; Satoh, Nobuhiko; Suzuki, Atsushi; Seki, George

    2016-01-01

    Insulin resistance has been characterized as attenuation of insulin sensitivity at target organs and tissues, such as muscle and fat tissues and the liver. The insulin signaling cascade is divided into major pathways such as the PI3K/Akt pathway and the MAPK/MEK pathway. In insulin resistance, however, these pathways are not equally impaired. For example, in the liver, inhibition of gluconeogenesis by the insulin receptor substrate (IRS) 2 pathway is impaired, while lipogenesis by the IRS1 pathway is preserved, thus causing hyperglycemia and hyperlipidemia. It has been recently suggested that selective impairment of insulin signaling cascades in insulin resistance also occurs in the kidney. In the renal proximal tubule, insulin signaling via IRS1 is inhibited, while insulin signaling via IRS2 is preserved. Insulin signaling via IRS2 continues to stimulate sodium reabsorption in the proximal tubule and causes sodium retention, edema, and hypertension. IRS1 signaling deficiency in the proximal tubule may impair IRS1-mediated inhibition of gluconeogenesis, which could induce hyperglycemia by preserving glucose production. In the glomerulus, the impairment of IRS1 signaling deteriorates the structure and function of podocyte and endothelial cells, possibly causing diabetic nephropathy. This paper mainly describes selective insulin resistance in the kidney, focusing on the proximal tubule. PMID:27247938

  18. The Role of Taste in Cephalic Phase of Insulin Secretion

    Directory of Open Access Journals (Sweden)

    M. Dušková

    2013-01-01

    Full Text Available The effect of a short gustatory signal of a sweet solution was tested on 15 young male volunteers. The experiment consisted of mouth rinsing with either a sucrose or aspartate solution or pure water as a placebo. Blood was then taken in short intervals of 0, 5, 10, 15 and 20 min. Blood glucose, C-peptide, insulin and cortisol were determined. While C-peptide and glucose were unaffected, a short-term increase in insulin was observed after the sucrose, but not after the aspartate or placebo. The increase in insulin was significant, though it amounted to only 0.5 mIU/l and lasted approx. 15 min reaching then the starting value. The decline of cortisol level within 20 min of the experiment was approx. 40 nmol/l, although it was also observed after aspartate or placebo mouth rinsing and was probably caused by stress factors or anticipation. In conclusion, the contribution of taste to the cephalic phase of insulin secretion is small yet significant, and mouth rinsing with 5% sucrose causes an insulin increase of just under 1 IU/l, which returns to starting level within 15 min.

  19. Insulin resistance: vascular function and exercise

    OpenAIRE

    Moon-Hyon Hwang; Sewon Lee

    2016-01-01

    Insulin resistance associated with metabolic syndrome and Type 2 diabetes mellitus is an epidemic metabolic disorder, which increases the risk of cardiovascular complications. Impaired vascular endothelial function is an early marker for atherosclerosis, which causes cardiovascular complications. Both experimental and clinical studies indicate that endothelial dysfunction in vasculatures occurs with insulin resistance. The associated physiological mechanisms are not fully appreciated yet, how...

  20. Insulin resistance and maximal oxygen uptake

    DEFF Research Database (Denmark)

    Seibaek, Marie; Vestergaard, Henrik; Burchardt, Hans

    2003-01-01

    Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown.......Type 2 diabetes, coronary atherosclerosis, and physical fitness all correlate with insulin resistance, but the relative importance of each component is unknown....

  1. How to measure hepatic insulin resistance?

    Science.gov (United States)

    Choukem, S-P; Gautier, J-F

    2008-12-01

    The liver plays a pivotal role in energy metabolism. Under the control of hormones, especially insulin, the liver stores or releases glucose as needed by the body's systems. It is also responsible for an important part of non-esterified fatty-acid and aminoacid metabolism. Assessing hepatic insulin resistance is almost always synonymous with measuring hepatic glucose production (HGP) and calculating indices of hepatic insulin resistance. The most frequently used method to this end is the isotope dilution technique using a tracer. Among tracers, stable isotope-labelled glucose molecules are particularly advantageous over radioactive isotope-labelled glucose and are, therefore, the tracers of choice. The tracer is infused either on its own after an overnight fast to evaluate fasting HGP, or with some among the usual insulin-sensitivity tests to assess HGP suppression by insulin and/or glucose. In a fasting state, HGP is easily calculated whereas, during insulin or glucose infusion, some formula are needed to correct for the non-steady-state condition. The hepatic insulin-resistance index is the product of HGP and the corresponding plasma insulin concentration. Although subject to error, the isotope dilution method nevertheless remains an irreplaceable tool for assessing hepatic insulin resistance in clinical research. From a practical point of view, some easily obtainable indices and clinical or biochemical parameters can serve as surrogates or markers of hepatic insulin resistance in clinical practice. Finally, drugs such as metformin or glitazones can improve hepatic insulin resistance, hence their use in hepatic insulin-resistant states such as type 2 diabetes and non-alcoholic fatty liver disease.

  2. Treatment Approach to Patients With Severe Insulin Resistance

    Science.gov (United States)

    Church, Timothy J.

    2016-01-01

    In Brief Patients with severe insulin resistance require >2 units/kg of body weight or 200 units/day of insulin. Yet, many patients do not achieve glycemic targets despite using very high doses of insulin. Insulin can cause weight gain, which further contributes to worsening insulin resistance. This article describes the pharmacological options for managing patients with severe insulin resistance, including the use of U-500 insulin and newer agents in combination with insulin. PMID:27092020

  3. Standardized Mori ramulus extract improves insulin secretion and insulin sensitivity in C57BLKS/J db/db mice and INS-1 cells.

    Science.gov (United States)

    Park, Soo-Yeon; Jin, Bora; Shin, Jae-Ho; Adisakwattana, Sirichai; Kwon, Oran

    2017-08-01

    Abnormalities in the hyperbolic relationship between insulin sensitivity and insulin secretion may cause oxidative stress and non-enzymatic glycation, resulting in an increased risk of type 2 diabetes. Here, we performed a 14-week study to investigate the effects of ethanolic extract of Mori ramulus (MRE; 0, 800, and 1600mg/kg body weight) and its signature component oxyresveratrol (OXY; 800mg/kg body weight) on β-cell dysfunction and insulin resistance in C57BLKS/J db/db mice fed with a high-fat diet. Compared with the diabetic control group, the high-dose MRE group showed a significant decrease in fasting blood glucose (p=0.0024); a significant increase in insulin secretion as measured by insulin (p=0.0012) and C-peptide (p=0.0103) levels in plasma and insulin content (p=0.0440) and homeobox factor-1 protein expression (p=0.0148) in the pancreas; and a significant increase in insulin sensitivity as measured by insulin receptor mRNA expression in the liver (p=0.0179) and adipose tissue (p=0.0491). In addition, improvements in the reactive oxygen species level and inflammatory pancreatic and hepatic tissue damage were also observed in the MRE group as assessed by histological findings. A similar but weaker effect was found in the OXY group. Furthermore, we observed a potentiating effect of MRE and OXY on insulin secretion in INS-1 cells in the presence of 27mM glucose, together with an anti-glycation effect as indicated by methylglyoxal-trapping capacity and inhibition of advanced glycation end-product formation. Taken together, these data suggest that MRE could ameliorate β-cell dysfunction and insulin resistance by reducing oxidative damage and advanced glycation end-product (Wagenknecht et al., 2003) formation and that these effects are due, at least in part, to OXY. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

  4. Effect of Gymnema sylvestre Administration on Metabolic Syndrome, Insulin Sensitivity, and Insulin Secretion.

    Science.gov (United States)

    Zuñiga, Laura Y; González-Ortiz, Manuel; Martínez-Abundis, Esperanza

    2017-08-01

    Gymnema sylvestre is a medicinal plant whose consumption has demonstrated benefits on lipid and glucose levels, blood pressure, and body weight (BWt). The aim of this study was to evaluate the effect of G. sylvestre administration on metabolic syndrome (MetS), insulin secretion, and insulin sensitivity. A randomized, double-blind, placebo-controlled clinical trial was carried out in 24 patients (without pharmacological treatment), 30-60 years old, with diagnosis of MetS in accordance with the modified International Diabetes Federation criteria. Patients were randomly assigned to receive G. sylvestre or placebo twice daily before breakfast and dinner in 300 mg capsules for a total of 600 mg per day for 12 weeks. Before and after the intervention, the components of MetS were evaluated as well as BWt, body mass index (BMI), total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein (VLDL). Area under the curve of glucose and insulin, phases of insulin secretion, and insulin sensitivity were calculated. Statistical analysis was performed using Wilcoxon signed-rank, Mann-Whitney U, and chi-square tests; P ≤ .05 was considered statistically significant. After G. sylvestre administration, significant decreases in BWt (81.3 ± 10.6 kg vs. 77.9 ± 8.4 kg, P = .02), BMI (31.2 ± 2.5 kg/m 2 vs. 30.4 ± 2.2 kg/m 2 , P = .02), and VLDL levels (0.45 ± 0.15 mmol/dL vs. 0.35 ± 0.15 mmol/dL, P = .05) were observed, without modifying the components of MetS, insulin secretion, and insulin sensitivity. In conclusion, G. sylvestre administration decreased BWt, BMI, and VLDL levels in subjects with MetS, without changes in insulin secretion and insulin sensitivity.

  5. Dietary Sodium Restriction Decreases Insulin Secretion Without Affecting Insulin Sensitivity in Humans

    Science.gov (United States)

    Byrne, Loretta M.; Yu, Chang; Wang, Thomas J.; Brown, Nancy J.

    2014-01-01

    Context: Interruption of the renin-angiotensin-aldosterone system prevents incident diabetes in high-risk individuals, although the mechanism remains unclear. Objective: To test the hypothesis that activation of the endogenous renin-angiotensin-aldosterone system or exogenous aldosterone impairs insulin secretion in humans. Design: We conducted a randomized, blinded crossover study of aldosterone vs vehicle and compared the effects of a low-sodium versus a high-sodium diet. Setting: Academic clinical research center. Participants: Healthy, nondiabetic, normotensive volunteers. Interventions: Infusion of exogenous aldosterone (0.7 μg/kg/h for 12.5 h) or vehicle during low or high sodium intake. Low sodium (20 mmol/d; n = 12) vs high sodium (160 mmol/d; n = 17) intake for 5–7 days. Main Outcome Measures: Change in acute insulin secretory response assessed during hyperglycemic clamps while in sodium balance during a low-sodium vs high-sodium diet during aldosterone vs vehicle. Results: A low-sodium diet increased endogenous aldosterone and plasma renin activity, and acute glucose-stimulated insulin (−16.0 ± 5.6%; P = .007) and C-peptide responses (−21.8 ± 8.4%; P = .014) were decreased, whereas the insulin sensitivity index was unchanged (−1.0 ± 10.7%; P = .98). Aldosterone infusion did not affect the acute insulin response (+1.8 ± 4.8%; P = .72) or insulin sensitivity index (+2.0 ± 8.8%; P = .78). Systolic blood pressure and serum potassium were similar during low and high sodium intake and during aldosterone infusion. Conclusions: Low dietary sodium intake reduces insulin secretion in humans, independent of insulin sensitivity. PMID:25029426

  6. Midkine, a potential link between obesity and insulin resistance.

    Directory of Open Access Journals (Sweden)

    Nengguang Fan

    Full Text Available Obesity is associated with increased production of inflammatory mediators in adipose tissue, which contributes to chronic inflammation and insulin resistance. Midkine (MK is a heparin-binding growth factor with potent proinflammatory activities. We aimed to test whether MK is associated with obesity and has a role in insulin resistance. It was found that MK was expressed in adipocytes and regulated by inflammatory modulators (TNF-α and rosiglitazone. In addition, a significant increase in MK levels was observed in adipose tissue of obese ob/ob mice as well as in serum of overweight/obese subjects when compared with their respective controls. In vitro studies further revealed that MK impaired insulin signaling in 3T3-L1 adipocytes, as indicated by reduced phosphorylation of Akt and IRS-1 and decreased translocation of glucose transporter 4 (GLUT4 to the plasma membrane in response to insulin stimulation. Moreover, MK activated the STAT3-suppressor of cytokine signaling 3 (SOCS3 pathway in adipocytes. Thus, MK is a novel adipocyte-secreted factor associated with obesity and inhibition of insulin signaling in adipocytes. It may provide a potential link between obesity and insulin resistance.

  7. Ghrelin- and GH-induced insulin resistance

    DEFF Research Database (Denmark)

    Vestergaard, Esben Thyssen; Krag, Morten B; Poulsen, Morten M

    2013-01-01

    Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects.......Supraphysiological levels of ghrelin and GH induce insulin resistance. Serum levels of retinol-binding protein-4 (RBP4) correlate inversely with insulin sensitivity in patients with type 2 diabetes. We aimed to determine whether ghrelin and GH affect RBP4 levels in human subjects....

  8. 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 ...

  9. Insulin resistance in porphyria cutanea tarda.

    Science.gov (United States)

    Calcinaro, F; Basta, G; Lisi, P; Cruciani, C; Pietropaolo, M; Santeusanio, F; Falorni, A; Calafiore, R

    1989-06-01

    It has been reported that patients with porphyria cutanea tarda (PCT) develop carbohydrate (CHO) intolerance and manifest diabetes melitus (DM) more frequently than the normal population. In order to verify whether this is due to insulin resistance we studied 5 patients with PCT and 5 normal subjects matched for age, sex and weight. In all the patients an evaluation consisted of the glycemic curve and insulin response to an iv glucose tolerance test (IVGTT: 0.33 g/kg) as well as of an evaluation of the circulating monocyte insulin receptors. Blood samples were drawn in the basal state to measure plasma levels of NEFA, glycerol, and intermediate metabolites. The patients with PCT showed normal glucose tolerance which was obtained, however, at the expense of the elevated insulin levels: therefore a condition of insulin resistance was demonstrated in these subjects. An involvement of the lipid metabolism, observed by the raised levels of plasma NEFA and glycerol, was also evident. The insulin binding to circulating monocytes was reduced but not enough to justify the degree of insulin resistance observed. Therefore, it could be hypothesized, in agreement with similar studies, that a postreceptor defect is responsible for the insulin-resistance observed in patients with PCT and that the reduction of insulin receptors is determined by the down regulation in response to elevated insulinemic levels. An alteration of the porphyrin metabolism might be responsible for this disorder.

  10. Insulin resistance and muscle insulin receptor substrate‐1 serine hyperphosphorylation

    Science.gov (United States)

    Stuart, Charles A.; Howell, Mary E. A.; Cartwright, Brian M.; McCurry, Melanie P.; Lee, Michelle L.; Ramsey, Michael W.; Stone, Michael H.

    2014-01-01

    Abstract Insulin resistance in metabolic syndrome subjects is profound in spite of muscle insulin receptor and insulin‐responsive glucose transporter (GLUT4) expression being nearly normal. Insulin receptor tyrosine kinase phosphorylation of insulin receptor substrate‐1 (IRS‐1) at Tyr896 is a necessary step in insulin stimulation of translocation of GLUT4 to the cell surface. Serine phosphorylation of IRS‐1 by some kinases diminishes insulin action in mice. We evaluated the phosphorylation status of muscle IRS‐1 in 33 subjects with the metabolic syndrome and seventeen lean controls. Each underwent euglycemic insulin clamps and a thigh muscle biopsy before and after 8 weeks of either strength or endurance training. Muscle IRS‐1 phosphorylation at six sites was quantified by immunoblots. Metabolic syndrome muscle IRS‐1 had excess phosphorylation at Ser337 and Ser636 but not at Ser307, Ser789, or Ser1101. Ser337 is a target for phosphorylation by glycogen synthase kinase 3 (GSK3) and Ser636 is phosphorylated by c‐Jun N‐terminal kinase 1 (JNK1). Exercise training without weight loss did not change the IRS‐1 serine phosphorylation. These data suggest that baseline hyperphosphorylation of at least two key serines within muscle IRS‐1 diminishes the transmission of the insulin signal and thereby decreases the insulin‐stimulated translocation of GLUT4. Excess fasting phosphorylation of muscle IRS‐1 at Ser636 may be a major cause of the insulin resistance seen in obesity and might prevent improvement in insulin responsiveness when exercise training is not accompanied by weight loss. PMID:25472611

  11. Molecular mechanism of insulin resistance

    Indian Academy of Sciences (India)

    PRAKASH

    Diabetes is of two types. Type 1 or insulin-dependent diabetes mellitus (IDDM) is basically due to autoimmune- mediated destruction of the pancreatic β islets resulting in insulin deficiency. Patients with type 1 diabetes usually have to take exogenous insulin for survival and to prevent the development of ketoacidosis.

  12. Selective insulin resistance in hepatocyte senescence

    Energy Technology Data Exchange (ETDEWEB)

    Aravinthan, Aloysious [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Challis, Benjamin [Institute of Metabolic Sciences, University of Cambridge, Cambridge (United Kingdom); Shannon, Nicholas [Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Hoare, Matthew [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Cancer Research UK Cambridge Institute, Cambridge (United Kingdom); Heaney, Judith [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom); Foundation for Liver Research, Institute of Hepatology, London (United Kingdom); Alexander, Graeme J.M., E-mail: gja1000@doctors.org.uk [Division of Gastroenterology and Hepatology, Department of Medicine, University of Cambridge, Cambridge (United Kingdom)

    2015-02-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance.

  13. Selective insulin resistance in hepatocyte senescence

    International Nuclear Information System (INIS)

    Aravinthan, Aloysious; Challis, Benjamin; Shannon, Nicholas; Hoare, Matthew; Heaney, Judith; Alexander, Graeme J.M.

    2015-01-01

    Insulin resistance has been described in association with chronic liver disease for decades. Hepatocyte senescence has been demonstrated in chronic liver disease and as many as 80% of hepatocytes show a senescent phenotype in advanced liver disease. The aim of this study was to understand the role of hepatocyte senescence in the development of insulin resistance. Senescence was induced in HepG2 cells via oxidative stress. The insulin metabolic pathway was studied in control and senescent cells following insulin stimulation. GLUT2 and GLUT4 expressions were studied in HepG2 cells and human liver tissue. Further, GLUT2 and GLUT4 expressions were studied in three independent chronic liver disease cohorts. Signalling impairment distal to Akt in phosphorylation of AS160 and FoxO1 was evident in senescent HepG2 cells. Persistent nuclear localisation of FoxO1 was demonstrated in senescent cells despite insulin stimulation. Increased GLUT4 and decreased GLUT2 expressions were evident in senescent cells, human cirrhotic liver tissue and publically available liver disease datasets. Changes in GLUT expressions were associated with a poor clinical prognosis. In conclusion, selective insulin resistance is evident in senescent HepG2 cells and changes in GLUT expressions can be used as surrogate markers of hepatocyte senescence. - Highlights: • Senescent hepatocytes demonstrate selective insulin resistance. • GLUT changes act as markers of hepatocyte senescence and have prognostic value. • Study offers insight into long noticed intimacy of cirrhosis and insulin resistance

  14. Patients with psoriasis are insulin resistant

    DEFF Research Database (Denmark)

    Gyldenløve, Mette; Storgaard, Heidi; Holst, Jens Juul

    2015-01-01

    BACKGROUND: Patients with psoriasis have increased risk of type 2 diabetes. The pathophysiology is largely unknown, but it is hypothesized that systemic inflammation causes insulin resistance. Insulin sensitivity has only been sparsely investigated in patients with psoriasis, and previous studies...... no differences between groups in plasma glucose, insulin, C-peptide, and glucagon during the clamp. LIMITATIONS: The classic hyperinsulinemic euglycemic clamp technique does not allow assessment of endogenous glucose production. CONCLUSION: Patients with psoriasis were more insulin resistant compared...... have used suboptimal methodology. The hyperinsulinemic euglycemic clamp remains the gold standard for quantifying whole-body insulin sensitivity. OBJECTIVE: We sought to investigate if normal glucose-tolerant patients with psoriasis exhibit impaired insulin sensitivity. METHODS: Three...

  15. Does epigenetic dysregulation of pancreatic islets contribute to impaired insulin secretion and type 2 diabetes?

    Science.gov (United States)

    Dayeh, Tasnim; Ling, Charlotte

    2015-10-01

    β cell dysfunction is central to the development and progression of type 2 diabetes (T2D). T2D develops when β cells are not able to compensate for the increasing demand for insulin caused by insulin resistance. Epigenetic modifications play an important role in establishing and maintaining β cell identity and function in physiological conditions. On the other hand, epigenetic dysregulation can cause a loss of β cell identity, which is characterized by reduced expression of genes that are important for β cell function, ectopic expression of genes that are not supposed to be expressed in β cells, and loss of genetic imprinting. Consequently, this may lead to β cell dysfunction and impaired insulin secretion. Risk factors that can cause epigenetic dysregulation include parental obesity, an adverse intrauterine environment, hyperglycemia, lipotoxicity, aging, physical inactivity, and mitochondrial dysfunction. These risk factors can affect the epigenome at different time points throughout the lifetime of an individual and even before an individual is conceived. The plasticity of the epigenome enables it to change in response to environmental factors such as diet and exercise, and also makes the epigenome a good target for epigenetic drugs that may be used to enhance insulin secretion and potentially treat diabetes.

  16. Restructuring of pancreatic islets and insulin secretion in a postnatal critical window.

    Directory of Open Access Journals (Sweden)

    Cristina Aguayo-Mazzucato

    Full Text Available Function and structure of adult pancreatic islets are determined by early postnatal development, which in rats corresponds to the first month of life. We analyzed changes in blood glucose and hormones during this stage and their association with morphological and functional changes of alpha and beta cell populations during this period. At day 20 (d20, insulin and glucose plasma levels were two- and six-fold higher, respectively, as compared to d6. Interestingly, this period is characterized by physiological hyperglycemia and hyperinsulinemia, where peripheral insulin resistance and a high plasmatic concentration of glucagon are also observed. These functional changes were paralleled by reorganization of islet structure, cell mass and aggregate size of alpha and beta cells. Cultured beta cells from d20 secreted the same amount of insulin in 15.6 mM than in 5.6 mM glucose (basal conditions, and were characterized by a high basal insulin secretion. However, beta cells from d28 were already glucose sensitive. Understanding and establishing morphophysiological relationships in the developing endocrine pancreas may explain how events in early life are important in determining adult islet physiology and metabolism.

  17. Lipodystrophy: Syndrome of severe insulin resistance.

    Science.gov (United States)

    Bindlish, Shagun; Presswala, Lubaina S; Schwartz, Frank

    2015-06-01

    Lipodystrophy (LD) is a relatively rare complex collection of diseases that can be congenital or acquired. It is commonly missed in the clinical setting. Thus, the spectrum of disease presentation mandates clinician expertise in the pathophysiology and management of all forms of LD, obesity, and insulin resistance. An extensive literature search of clinical trials, systematic reviews, and narrative reviews was completed in PubMed for the years 1970 to 2013. The search terms were lipodystrophy, congenital LD, acquired LD, HIV-associated LD, severe insulin resistance, adiposity, obesity, and dyslipidemia. Lipodystrophies are a heterogeneous group of disorders with abnormal adipose tissue distribution, utilization, and metabolism. Adipose tissue can undergo significant changes in composition (hypertrophy and atrophy) in response to a nutritional state. Paradoxically, both excess and deficient adipose tissue is associated with insulin resistance and the metabolic syndrome. Bone density scan (DEXA) for body fat composition analysis or magnetic resonance imaging are optimal modalities for the assessment of abnormal adipose tissue distribution. Ongoing clinical studies suggest thiazolidinediones, insulin like growth factor-1, leptin, and growth hormone-releasing hormone as possible treatment for LPD; however, none of them is approved to reverse fat loss or treat severe insulin resistance due to LPD. The underlying mechanisms for LPD causing insulin resistance may be lipotoxicity and derangements in adipose tissue-derived proteins (adipocytokines). However, the lack of evidence to support this model means that clinicians are on their own as they navigate through the phenotypic presentation of lipodystrophies, obesity, insulin resistance, and the metabolic syndrome.

  18. Circulating interleukin-6 in relation to adiposity, insulin action, and insulin secretion

    DEFF Research Database (Denmark)

    Vozarova, B; Weyer, C; Hanson, K

    2001-01-01

    Plasma concentrations of interleukin-6 (IL-6), a proinflammatory cytokine produced and released in part by adipose tissue, are elevated in people with obesity and type 2 diabetes. Because recent studies suggest that markers of inflammation predict the development of type 2 diabetes, we examined w...... whether circulating plasma IL-6 concentrations were related to direct measures of insulin resistance and insulin secretory dysfunction in Pima Indians, a population with high rates of obesity and type 2 diabetes....

  19. Loss of inverse relationship between pulsatile insulin and glucagon secretion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Menge, Björn A; Grüber, Lena; Jørgensen, Signe M

    2011-01-01

    In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known.......In patients with type 2 diabetes, glucagon levels are often increased. Furthermore, pulsatile secretion of insulin is disturbed in such patients. Whether pulsatile glucagon secretion is altered in type 2 diabetes is not known....

  20. 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

  1. A novel surrogate index for hepatic insulin resistance.

    LENUS (Irish Health Repository)

    Vangipurapu, J

    2011-03-01

    In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance.

  2. Role of mitochondrial function in insulin resistance

    NARCIS (Netherlands)

    Brands, Myrte; Verhoeven, Arthur J.; Serlie, Mireille J.

    2012-01-01

    The obesity pandemic increases the prevalence of type 2 diabetes (DM2).DM2 develops when pancreatic β-cells fail and cannot compensate for the decrease in insulin sensitivity. How excessive caloric intake and weight gain cause insulin resistance has not completely been elucidated.Skeletal muscle is

  3. Increased CD19+CD24+CD27+ B regulatory cells are associated with insulin resistance in patients with type I Hashimoto's thyroiditis.

    Science.gov (United States)

    Yang, Min; Du, Changji; Wang, Yinping; Liu, Jun

    2017-06-01

    Hashimoto's thyroiditis (HT) is characterized by dysregulated immune responses and is commonly associated with insulin resistance. However, the mechanism of insulin resistance in HT remains to be fully elucidated. The aim of the present study was to investigate the correlation between the percentage of B regulatory lymphocytes (Bregs) and insulin resistance in patients with HT but with normal thyroid function (type I). A total of 59 patients with type I HT and 38 healthy volunteers were enrolled in the study. An oral glucose tolerance test was performed to measure insulin secretion and assess β‑cell functions. Flow cytometry was performed to examine the percentages of lymphocyte populations. The patients with HT exhibited normal fasting and postprandial glucose and fasting insulin secretion, but increased secretion of early‑phase and total insulin. The patients with HT also had insufficient β‑cell compensation for insulin resistance, indicated by a reduced disposition index, in the fasting state. An elevation in the percentage of CD19+CD24+CD27+ Bregs was also observed, which correlated positively with insulin secretion and insulin resistance in the fasting state. The patients with type I HT had postprandial insulin resistance and insufficient β‑cell compensation for fasting insulin resistance. Therefore, the increase in CD19+CD24+CD27+ Bregs was closely associated with fasting insulin secretion. These results provide novel insight into the mechanism of insulin resistance in HT.

  4. IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients

    DEFF Research Database (Denmark)

    Bouzakri, Karim; Karlsson, Håkan K R; Vestergaard, Henrik

    2006-01-01

    Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied....... In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia....... insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal...

  5. IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas tranplant recipient

    DEFF Research Database (Denmark)

    Bouzakri, K; Karlsson, HRK; Vestergaard, Henrik

    2006-01-01

    Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied....... In conclusion, peripheral insulin resistance in pancreas-kidney transplant recipients may arise from a negative feedback regulation of the canonical insulin-signaling cascade from excessive serine phosphorylation of IRS-1, possibly as a consequence of immunosuppressive therapy and hyperinsulinemia....... insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal...

  6. Calcineurin inhibitors acutely improve insulin sensitivity without affecting insulin secretion in healthy human volunteers

    DEFF Research Database (Denmark)

    Øzbay, Aygen; Møller, Niels; Juhl, Claus

    2012-01-01

    WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: New onset diabetes after transplantation is related to treatment with immunosuppressive medications. Clinical studies have shown that risk of new onset diabetes is greater with tacrolimus compared with ciclosporin. The diabetogenicity of ciclosporin...... of NODAT remains unclear. We sought to compare the impact of CsA and Tac on glucose metabolism in human subjects. METHODS: Ten healthy men underwent 5 h infusions of CsA, Tac and saline in a randomized, double-blind, crossover study. During infusion glucose metabolism was investigated using following.......047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were...

  7. [Primary study on characteristics of insulin secretion rate, metabolic clearance rate and sensitivity in non-insulin-dependent diabetic subjects from multiplex diabetic pedigrees].

    Science.gov (United States)

    Ran, J; Cheng, H; Li, F

    2000-01-01

    index (BMI) (P < 0.01), and MCR-I had significant negative correlation with AUCC (P < 0.01). There are obvious impaired first phase insulin secretion after glucose challenge in non-insulin-dependent diabetic subjects from MDP. Decrease in endogenous MCR-I might be an important factor to hyperinsulinemia and insulin resistance. Increased insulin secretion, decreased MCR-I and insulin sensitivity can be observed in abdominal obese subjects of control group.

  8. Insulin resistance: regression and clustering.

    Science.gov (United States)

    Yoon, Sangho; Assimes, Themistocles L; Quertermous, Thomas; Hsiao, Chin-Fu; Chuang, Lee-Ming; Hwu, Chii-Min; Rajaratnam, Bala; Olshen, Richard A

    2014-01-01

    In this paper we try to define insulin resistance (IR) precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI) or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ), a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT). We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be.

  9. Insulin resistance: regression and clustering.

    Directory of Open Access Journals (Sweden)

    Sangho Yoon

    Full Text Available In this paper we try to define insulin resistance (IR precisely for a group of Chinese women. Our definition deliberately does not depend upon body mass index (BMI or age, although in other studies, with particular random effects models quite different from models used here, BMI accounts for a large part of the variability in IR. We accomplish our goal through application of Gauss mixture vector quantization (GMVQ, a technique for clustering that was developed for application to lossy data compression. Defining data come from measurements that play major roles in medical practice. A precise statement of what the data are is in Section 1. Their family structures are described in detail. They concern levels of lipids and the results of an oral glucose tolerance test (OGTT. We apply GMVQ to residuals obtained from regressions of outcomes of an OGTT and lipids on functions of age and BMI that are inferred from the data. A bootstrap procedure developed for our family data supplemented by insights from other approaches leads us to believe that two clusters are appropriate for defining IR precisely. One cluster consists of women who are IR, and the other of women who seem not to be. Genes and other features are used to predict cluster membership. We argue that prediction with "main effects" is not satisfactory, but prediction that includes interactions may be.

  10. Mechanisms Linking Inflammation to Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Li Chen

    2015-01-01

    Full Text Available Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several signaling pathways, both of which are involved in the pathogenesis of insulin resistance by interfering with insulin signaling and action. It has been suggested that specific factors and signaling pathways are often correlated with each other; therefore, both of the fluctuation of cytokines and the status of relevant signaling pathways should be considered during studies analyzing inflammation-related insulin resistance. In this paper, we discuss how these factors and signaling pathways contribute to insulin resistance and the therapeutic promise targeting inflammation in insulin resistance based on the latest experimental studies.

  11. Insulin resistance in obese children and adolescents

    Directory of Open Access Journals (Sweden)

    Monica Cristina dos Santos Romualdo

    2014-11-01

    Conclusion: The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood.

  12. Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Marko Kostovski

    2018-03-01

    CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides.

  13. Insulin secretion and glucose uptake by isolated islets of the hamster

    International Nuclear Information System (INIS)

    Dunbar, J.C.; McLaughlin, W.J.; Walsh, M.F.J.; Foa, P.P.

    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- 14 C (1.0 μC/ml), the amount of insulin secreted and the 14 CO 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- 3 H into total extractable insulin (insulin + proinsulin). Thus, insulin and proinsulin appear to inhibit insulin release, but not insulin synthesis. (orig.) [de

  14. Metabolic endotoxemia initiates obesity and insulin resistance

    OpenAIRE

    Cani, Patrice D.; Amar, Jacques; Iglesias, Miguel Angel; Poggi, Marjorie; Knauf, Claude; Bastelica, Delphine; Neyrinck, Audrey M.; Fava, Francesca; Tuohy, Kieran; Chabo, Chantal; Waget, Aurélie; Delmée, Evelyne; Cousin, Béatrice; Sulpice, Thierry; Chamontin, Bernard

    2007-01-01

    Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration t...

  15. Insulin resistance and laminitis in horses

    OpenAIRE

    Horn, Isabella

    2009-01-01

    Laminitis is a common painful condition in horses that often has a poor outcome. The aetiology of laminitis has been widely studied, but still not completely understood. There is some evidence that pasture associated laminitis is one of the most common forms of laminitis , and this is most likely associated with underlying endocrine dysfunction i.e. insulin resistance. However, what the prevalence of insulin resistance in horses presented with laminitis is, that is currently unknown and it ha...

  16. Insulin signaling pathways in a patient with insulin resistance of difficult management - a case report

    OpenAIRE

    Taboada, Giselle F; de Freitas, Marta S; da S Corr?a, Fernanda H; Junior, Carlos RMA; de B Gomes, Mar?lia

    2009-01-01

    Insulin signalling pathways were investigated in a 33 year-old woman with immunologic insulin resistance. Her past medical history was remarkable for intermittent use of insulin and allergic reactions to several drugs, and measure of plasma anti-insulin antibodies level corroborated the clinical suspicion of immune mediated insulin resistance (8074 nU/ml - RIA - Ref value:

  17. [Molecular Mechanisms of Insulin Resistance: An Update].

    Science.gov (United States)

    Gutiérrez-Rodelo, Citlaly; Roura-Guiberna, Adriana; Olivares-Reyes, Jesús Alberto

    The biological actions of insulin are initiated by activating its membrane receptor, which triggers multiple signaling pathways to mediate their biological actions. Due to the importance of metabolic regulation and promoting functions of cell growth and proliferation, insulin actions are highly regulated to promote proper metabolic functioning and energy balance. If these mechanisms are altered, this can lead to a condition known as insulin resistance, which is the consequence of a deficient insulin signaling caused by mutations or post-translational modifications of the receptor or effector molecules located downstream. Insulin resistance is one of the main characteristics of pathological manifestations associated with type 2 diabetes mellitus, one of the leading causes of death in Mexico and worldwide. In recent years, it has been found that conditions such as inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction promote insulin resistance. The aim of this review is to elucidate the molecular aspects of insulin resistance and the mechanisms involved in regulating its effects, with particular emphasis on the role of inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction.

  18. Insulin resistance and serum parameters of iron status in type 2 diabetics

    International Nuclear Information System (INIS)

    Zafar, U.

    2011-01-01

    Background: Type 2 diabetes mellitus (T2DM) is a predominant public health concern worldwide, accounting for 90% of the cases of diabetes globally. Pathogenesis of T2DM involves insulin resistance, defective insulin secretion and increased glucose production by the liver. Subclinical haemochromatosis has been considered as one of the probable causes of insulin resistance and diabetes mellitus. The aim of this study was to determine and correlate insulin resistance and serum parameters of iron status (serum ferritin and transferrin saturation) in type 2 diabetics. Methods: It was a correlational study. This study was conducted on sixty male patients with type 2 diabetes mellitus. Fasting blood sample was taken from each subject and analysed for glucose, haemoglobin, insulin, iron, Total Iron Binding Capacity (TIBC) and ferritin. Insulin resistance was determined by HOMA-IR index. Transferrin saturation was calculated from serum iron and TIBC. Data was analysed using SPSS-17. Results: There was significant positive correlation between insulin resistance and transferrin saturation, but there was no significant correlation of insulin resistance with blood haemoglobin, serum iron and serum ferritin in type 2 diabetics. Conclusion: Correlation between insulin resistance and transferrin saturation reveals that iron has negative impact on insulin sensitivity in type 2 diabetics. (author)

  19. Topical insulin accelerates cutaneous wound healing in insulin-resistant diabetic rats

    OpenAIRE

    Yu, Tianyi; Gao, Min; Yang, Peilang; Pei, Qing; Liu, Dan; Wang, Di; Zhang, Xiong; Liu, Yan

    2017-01-01

    Insulin signaling defects could lead to insulin resistance in insulin target organs: typically, in the muscler, liver, and adipose tissue. We have observed that insulin accelerated diabetic wound healing in our previous works; to further elucidate the mechanism, we investigated the expression and activation of insulin and insulin-like growth factor (IGF)-1 signaling, compared insulin sensitivity in skin tissue with that in liver tissue, and also observed the regulation of insulin on inflammat...

  20. Evaluation of 25(OH) Vitamin D3 with Reference to Magnesium Status and Insulin Resistance in T2DM.

    Science.gov (United States)

    Gandhe, Mahendra Bhauraoji; Jain, Keerthi; Gandhe, Swapnali Mahendra

    2013-11-01

    Calcium is a recognized second messenger implicated in insulin secretion. Vitamin D (1,25-dihydroxycholecalciferol, Calcitriol) plays a role in calcium metabolism. This explains the indirect role of Vitamin D in insulin secretion and insulin sensitivity. Hence, low Vitamin D levels are implicated in decreased insulin secretion and increased insulin resistance. In this study, we tried to find out the probable association of Vitamin D3, calcium and magnesium with reference to insulin resistance in type 2 diabetes mellitus (T2DM) cases. It is well documented that measurement of circulating 25-Hydroxycholecalciferol {25 (OH)Vitamin D3} is a marker of total Vitamin D status. We measured 25(OH) Vitamin D3 levels in thirty T2DM subjects with thirty age and sex matched healthy controls. We estimated Vitamin D status, calcium and magnesium levels in the light of insulin resistance. Insulin resistance was measured by homeostasis model assessment of insulin resistance (HOMA-IR). Twenty five (OH) Vitamin-D3 level was significantly low among T2DM cases (12.29+2.32ng/ml) in comparison to healthy controls (19.55+0.50ng/ml) (pT2DM cases as compared to healthy controls (pinsulin levels, and insulin resistance (pinsulin levels suggest that the supplementation of Vitamin D has the potential to increase insulin sensitivity and lower the risk of developing type 2 diabetes mellitus.

  1. The possible mechanisms by which maternal hypothyroidism impairs insulin secretion in adult male offspring in rats.

    Science.gov (United States)

    Karbalaei, Narges; Ghasemi, Asghar; Hedayati, Mehdi; Godini, Aliashraf; Zahediasl, Saleh

    2014-04-01

    Previous studies have recently shown that maternal hypothyroidism leads to impaired glucose metabolism and reduced insulin secretion in adult offspring in rats. The aim of this study was to locate the defect in the insulin secretion pathway induced by maternal hypothyroidism. Pregnant Wistar rats were divided into two groups; the control group consumed water, while the hypothyroid (FH) group received water containing 0.025% 6-propyl-2-thiouracil during gestation. An intravenous glucose tolerance test was carried out on 5-month-old male offspring. In in vitro studies, the effects of various secretagogues and inhibitors acting at different levels of the insulin secretion cascade were investigated, and insulin content, insulin secretion and glucokinase activity of the islets were compared. Although insulin content of the FH islets did not differ from that of control islets, insulin secretion from FH islets was reduced when it was challenged by glucose or arginine. Compared with control islets, activities of both hexokinase and glucokinase were also significantly decreased in the FH islets. Although, in both groups, increasing glibenclamide and nifedipine concentrations in the presence of 16.7 mmol l(-1) glucose increased and decreased insulin secretion, respectively, the percentage of changes in secretion of FH islets was significantly lower compared with control islets. The response of FH islets to high extracellular potassium concentration and diazoxide was also significantly lower than that of the control islets. These findings demonstrate that impaired insulin secretion in the FH group is probably related to alterations in different steps of the insulin secretion pathway and not in the insulin pool of β-cells.

  2. Sex steroid hormones, upper body obesity, and insulin resistance.

    Science.gov (United States)

    Abate, Nicola; Haffner, Steven M; Garg, Abhimanyu; Peshock, Ronald M; Grundy, Scott M

    2002-10-01

    Low plasma levels of SHBG and free testosterone have been associated with increased insulin resistance and risk for type 2 diabetes in males. As truncal obesity, a condition accompanied by increased insulin resistance, is also associated with low SHBG and testosterone levels, the independent association of low free testosterone and SHBG with excessive insulin resistance remains to be determined. In this study we evaluated whether in normogonadic men, plasma levels of SHBG and free testosterone are primarily related to insulin resistance or to generalized and regional adiposity. Hyperinsulinemic-euglycemic clamps and iv glucose tolerance tests were performed in 24 healthy volunteer and 33 patients with mild type 2 diabetes. The 2 groups were chosen to have similar body mass index and were found to have similar body composition and fat distribution, assessed by underwater weighing, skinfold thickness, and magnetic resonance imaging of the abdomen. In the 2 groups combined, plasma levels of SHBG correlated inversely with fat accumulation in both sc and intraabdominal areas. Plasma levels of free testosterone correlated inversely with both truncal and peripheral skinfold thickness only in the nondiabetic men. No associations between plasma levels of sex steroid hormones and insulin resistance, hepatic glucose output, or insulin secretion were found to be independent of adiposity. Furthermore, although patients with diabetes were more insulin resistant than those without diabetes, the 2 groups had similar plasma concentrations of free testosterone (55 +/- 14 and 67 +/- 27 pmol/liter, respectively), SHBG (19 +/- 13 and 19 +/- 13 nmol/liter), estradiol (83 +/- 5 and 81 +/- 21 pmol/liter), and dehydroepiandrosterone sulfate (3.6 +/- 2.2 and 2.8 +/- 1.7 nmol/liter). We conclude that in normogonadal nondiabetic males, the variability in plasma bioavailable testosterone concentrations is predictive of the variability in fat deposition in the sc adipose tissue compartments of

  3. Serum acylated ghrelin is negatively correlated with the insulin resistance in the CODING study.

    Directory of Open Access Journals (Sweden)

    Peyvand Amini

    Full Text Available Ghrelin is a 28-amino acid orexigenic peptide synthesized mainly in the stomach. Acute administration of ghrelin has been found to decrease insulin secretion. However, little data is available regarding whether ghrelin contributes to the long-term regulation of insulin resistance at the population level. The aim of this study is to investigate the association between circulating ghrelin and insulin resistance in a large population based study.A total of 2082 CODING study (Complex Diseases in the Newfoundland population: Environment and Genetics subjects were assessed. Subjects were of at least third generation Newfoundland descent, between the ages of 20 and 79 years, and had no serious metabolic, cardiovascular, or endocrine diseases. Ghrelin was measured with an Enzyme Immunoassay method. Insulin and fasting glucose were measured by Immulite 2500 autoanalyzer and Lx20 clinical chemistry analyzer, respectively. Homeostatic Model Assessment of β cell function (HOMA-β and Insulin Resistance (HOMA-IR and Quantitative Insulin-sensitivity Check Index (QUICKI were used for measurement of insulin resistance.Partial correlation analyses showed a significant negative correlation between circulating ghrelin and insulin level and insulin resistance in the entire cohort and also in men and women separately. The aforementioned correlation was independent of age, percentage of trunk fat and HDL-cholesterol. According to menopausal status, only pre-menopausal women revealed negative correlations.Our results suggest that except for postmenopausal women, high circulating ghrelin level is associated with lower insulin resistance in the general population.

  4. Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves

    International Nuclear Information System (INIS)

    Kamal, M.M.; Van Eetvelde, M.; Bogaert, H.; Hostens, M.; Vandaele, L.; Shamsuddin, M.; Opsomer, G.

    2016-01-01

    Full text: The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves. Birth weight and gestational age of the calves at delivery were determined. On the next day, heart girth, wither height and diagonal length of both the calves and their dams were measured. Parity, body condition score and age at calving were recorded for all dams. For the cows, days open before last gestation, lactation length (LL), lenght of dry period (DP) and calving interval were also calculated. The magnitude and shape of the lactation curve both quantified using the MilkBot model based on monthly milk weights, were used to calculate the amount of milk produced during gestation. Using the same procedure, cumulative milk production from conception to drying off (MGEST) was calculated. A blood sample was collected from all calves (n=481; 169 born to heifers and 312 born to cows) at least 5 h after a milk meal on day 3 of life to measure basal glucose and insulin levels. In addition, an intravenous glucose-stimulated insulin secretion test was performed in a subset of the calves (n=316). After descriptive analysis, generalized linear mixed models were used to identify factors that were significantly associated with the major insulin traits (Insb, basal insulin level; QUICKI, quantitative insulin sensitivity check index; AIR, acute insulin response; DI, disposition index) of the newborn calves. The overall average birth weight of the calves was 42.7 ± 5.92 kg. The insulin traits were significantly associated with MGEST (P=0.076) and longer DP (P=0.034). The QUICKI was estimated to be lower in calves born to the cows having passed a higher MGEST (P=0.030) and longer DP (P=0.058). Moreover, the AIR (P=0.009) and DI (P=0.049) were estimated to be lower in male compared with female calves. Furthermore, the AIR

  5. Insulin resistance in obese children and adolescents.

    Science.gov (United States)

    Romualdo, Monica Cristina dos Santos; Nóbrega, Fernando José de; Escrivão, Maria Arlete Meil Schimith

    2014-01-01

    To evaluate the presence of insulin resistance and its association with other metabolic abnormalities in obese children and adolescents. Retrospective study of 220 children and adolescents aged 5-14 years. Anthropometric measurements were performed (weight, height, and waist circumference) and clinical (gender, age, pubertal stage, and degree of obesity) and biochemical (glucose, insulin, total cholesterol, and fractions, triglycerides) data were analyzed. Insulin resistance was identified by the homeostasis model assessment for insulin resistance (HOMA-IR) index. The analysis of the differences between the variables of interest and the HOMA-IR quartiles was performed by ANOVA or Kruskal-Wallis tests. Insulin resistance was diagnosed in 33.20% of the sample. It was associated with low levels of high-density lipoprotein cholesterol (HDL-C; p=0.044), waist circumference measurement (p=0.030), and the set of clinical and metabolic (p=0.000) alterations. Insulin-resistant individuals had higher mean age (p=0.000), body mass index (BMI; p=0.000), abdominal circumference (p=0.000), median triglycerides (p=0.001), total cholesterol (p≤0.042), and low-density lipoprotein cholesterol (LDL-C; p≤0.027); and lower HDL-C levels (p=0.005). There was an increase in mean BMI (p=0.000), abdominal circumference (p=0.000), and median triglycerides (p=0.002) as the values of HOMA -IR increased, with the exception of HDL-C, which decreased (p=0.001). Those with the highest number of simultaneous alterations were between the second and third quartiles of the HOMA-IR index (p=0.000). The results confirmed that insulin resistance is present in many obese children and adolescents, and that this condition is associated with alterations that represent an increased risk for developing metabolic disorders in adulthood. Copyright © 2014 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.

  6. Mechanisms Linking Inflammation to Insulin Resistance

    OpenAIRE

    Chen, Li; Chen, Rui; Wang, Hua; Liang, Fengxia

    2015-01-01

    Obesity is now widespread around the world. Obesity-associated chronic low-grade inflammation is responsible for the decrease of insulin sensitivity, which makes obesity a major risk factor for insulin resistance and related diseases such as type 2 diabetes mellitus and metabolic syndromes. The state of low-grade inflammation is caused by overnutrition which leads to lipid accumulation in adipocytes. Obesity might increase the expression of some inflammatory cytokines and activate several sig...

  7. AMPK, insulin resistance, and the metabolic syndrome

    OpenAIRE

    Ruderman, Neil B.; Carling, David; Prentki, Marc; Cacicedo, José M.

    2013-01-01

    Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. Regular exercise and calorie restriction have long been known to increase insulin sensitivity and decrease the prevalence of these disorders. The subsequent identification of AMP-activated protein kinase (AMPK) and its activation by exercise and fuel depr...

  8. Observations on the insulin-secretion function in the offsprings of patients with type II diabetes

    International Nuclear Information System (INIS)

    Xu Shujie; Tian Xiaoping; Wu Yan

    2004-01-01

    Objective: To investigate the disturbance of insulin-secretion function in the offsprings of patients with type II diabetes. Methods: Blood sugar (with oxidase method) and insulin (with RIA) levels were measured after overnight fasting and repeatedly measured 2h after 75g glucose per oral in the following subjects: 1) Group A, 23 non-obese offsprings of type II diabetics 2) group B, 18 obese offsprings (BMI ≥25kg/m 2 ) and 3) 27 controls. Homeostatic model assessment-insulin resistance (HOMA-IR) and β-cell function index (HCI) were calculated from the data (glucose and insulin levels) obtained. Results: For Group A subjects, the fasting blood sugar (FPG) levels were significantly higher and HBCI significantly lower than those in te controls (both P<0.05). For Group B obese subjects, in addition to the above two parameters (with HBCI P<0.01), 2h PG levels as well as HOMA-IR were also significantly higher (both P<0.05). Conclusion: Present study showed that in the offsprings of diabetics, HBCI was already lowered before definite impaired glucose tolerance (IGT) could be demonstrated, especially in the obese ones. (authors)

  9. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance

    DEFF Research Database (Denmark)

    Højlund, Kurt

    2014-01-01

    . These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes...... described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance....... Type 2 diabetes, obesity and PCOS are characterized by pronounced defects in the insulin-stimulated glucose uptake, in particular glycogen synthesis and to a lesser extent glucose oxidation, and the ability of insulin to suppress lipid oxidation. In inherited insulin resistance, however, only insulin...

  10. Insulin resistance and cancer: epidemiological evidence.

    Science.gov (United States)

    Tsugane, Shoichiro; Inoue, Manami

    2010-05-01

    Over the last 60 years, Japanese people have experienced a rapid and drastic change in lifestyle, including diet. Suspicions have been raised that so-called 'Westernization', characterized by a high-calorie diet and physical inactivity, is associated with increasing trends in the incidence of cancer of the colon, liver, pancreas, prostate, and breast, as well as type 2 diabetes. Epidemiological evidence from our prospective study, the Japan Public Health Center-based Prospective (JPHC) study, and systematic literature reviews generally support the idea that factors related to diabetes or insulin resistance are associated with an increased risk of colon (mostly in men), liver, and pancreatic cancers. These cancers are inversely associated with physical activity and coffee consumption, which are known to decrease the risk of type 2 diabetes. The suggested mechanism of these effects is that insulin resistance and the resulting chronic hyperinsulinemia and increase in bioavailable insulin-like growth factor 1 (IGF1) stimulate tumor growth. In contrast, associations with diabetes are less clear for cancer of the colon in women, and breast and prostate, which are known to be related to sex hormones. The effect of insulin resistance or body fat on sex-hormone production and bioavailability may modify their carcinogenic effect differently from cancers of the colon in men, and liver and pancreas. In conclusion, there is substantial evidence to show that cancers of the colon, liver, and pancreas are associated with insulin resistance, and that these cancers can be prevented by increasing physical activity, and possibly coffee consumption.

  11. Assessment of insulin sensitivity/resistance.

    Science.gov (United States)

    Gutch, Manish; Kumar, Sukriti; Razi, Syed Mohd; Gupta, Kumar Keshav; Gupta, Abhinav

    2015-01-01

    Insulin resistance is one pretty troublesome entity which very commonly aggravates metabolic syndrome. Many methods and indices are available for the estimation of insulin resistance. It is essential to test and validate their reliability before they can be used as an investigation in patients. At present, hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance and are being used as a reference standard. Some simple methods, from which indices can be derived, have been validated e.g. homeostasis model assessment (HOMA), quantitative insulin sensitivity check index (QUICKI). For the clinical uses HOMA-insulin resistance, QUIKI, and Matsuda are suitable, while HES, McAuley, Belfiore, Cederholm, Avignon and Stumvoll index are suitable for epidemiological/research purposes. With increasing number of these available indices of IR, it may be difficult for clinicians to select the most appropriate index for their studies. This review provides guidelines that must be considered before performing such studies.

  12. Assessment of insulin sensitivity/resistance

    Directory of Open Access Journals (Sweden)

    Manish Gutch

    2015-01-01

    Full Text Available Insulin resistance is one pretty troublesome entity which very commonly aggravates metabolic syndrome. Many methods and indices are available for the estimation of insulin resistance. It is essential to test and validate their reliability before they can be used as an investigation in patients. At present, hyperinsulinemic euglycemic clamp and intravenous glucose tolerance test are the most reliable methods available for estimating insulin resistance and are being used as a reference standard. Some simple methods, from which indices can be derived, have been validated e.g. homeostasis model assessment (HOMA, quantitative insulin sensitivity check index (QUICKI. For the clinical uses HOMA-insulin resistance, QUIKI, and Matsuda are suitable, while HES, McAuley, Belfiore, Cederholm, Avignon and Stumvoll index are suitable for epidemiological/research purposes. With increasing number of these available indices of IR, it may be difficult for clinicians to select the most appropriate index for their studies. This review provides guidelines that must be considered before performing such studies.

  13. Exercise Increases Insulin Content and Basal Secretion in Pancreatic Islets in Type 1 Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Han-Hung Huang

    2011-01-01

    Full Text Available Exercise appears to improve glycemic control for people with type 1 diabetes (T1D. However, the mechanism responsible for this improvement is unknown. We hypothesized that exercise has a direct effect on the insulin-producing islets. Eight-week-old mice were divided into four groups: sedentary diabetic, exercised diabetic, sedentary control, and exercised control. The exercised groups participated in voluntary wheel running for 6 weeks. When compared to the control groups, the islet density, islet diameter, and β-cell proportion per islet were significantly lower in both sedentary and exercised diabetic groups and these alterations were not improved with exercise. The total insulin content and insulin secretion were significantly lower in sedentary diabetics compared to controls. Exercise significantly improved insulin content and insulin secretion in islets in basal conditions. Thus, some improvements in exercise-induced glycemic control in T1D mice may be due to enhancement of insulin content and secretion in islets.

  14. Insulin Sensitivity Determines Effects of Insulin and Meal Ingestion on Systemic Vascular Resistance in Healthy Subjects

    NARCIS (Netherlands)

    Woerdeman, Jorn; Meijer, Rick I; Eringa, Etto C; Hoekstra, T.; Smulders, Yvo M; Serné, Erik H

    OBJECTIVE: In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined

  15. Sleep duration and insulin resistance in individuals without type 2 diabetes: the PPP-Botnia study.

    Science.gov (United States)

    Pyykkönen, Antti-Jussi; Isomaa, Bo; Pesonen, Anu-Katriina; Eriksson, Johan G; Groop, Leif; Tuomi, Tiinamaija; Räikkönen, Katri

    2014-08-01

    Both short and long sleep duration may increase risk of type 2 diabetes (diabetes). We studied if short and long sleep durations were associated with insulin resistance (IR) and insulin secretion in individuals without diabetes, and if the associations remained after we excluded individuals who reported more frequent and severe complaints of sleep apnea and insomnia. An oral glucose tolerance test (OGTT) was performed for 722 adults without diabetes. Indices of IR and insulin secretion were calculated. Sleep duration and complaints of sleep apnea and insomnia were self-reported. In comparison to average sleepers (6-9 h/night), short sleepers (< 6 h/night) had higher 120-min insulin and AUC glucose, and long sleepers (≥ 9 h/night) had higher fasting and 120-min insulin, 120-min glucose, and HOMAIR and lower Insulin Sensitivity Index. After adjusting for confounders and after excluding individuals who reported more frequent and severe complaints of sleep apnea and insomnia, long sleep duration remained significantly associated with IR and insulin secretion. Long but not short sleep duration is associated with IR and insulin secretion in individuals without diabetes whether or not accompanied by sleep complaints. Long sleepers may benefit from targeted preventions and interventions that aim at reducing risk of future diabetes.

  16. Molecular mechanisms of insulin resistance | Pillay | South African ...

    African Journals Online (AJOL)

    This review discusses recent advances in understanding of the structure and function of the insulin receptor and insulin action, and how these relate to the clinical aspects of insulin resistance associated with non-insulin-dependent diabetes and other disorders. Improved understanding of the molecular basis of insulin ...

  17. The role of fatty acids in insulin resistance

    OpenAIRE

    Sears, Barry; Perry, Mary

    2015-01-01

    Insulin resistance is a multi-faceted disruption of the communication between insulin and the interior of a target cell. The underlying cause of insulin resistance appears to be inflammation that can either be increased or decreased by the fatty acid composition of the diet. However, the molecular basis for insulin resistance can be quite different in various organs. This review deals with various types of inflammatory inputs mediated by fatty acids, which affect the extent of insulin resista...

  18. Impact of 9 days of bed rest on hepatic and peripheral insulin action, insulin secretion, and whole-body lipolysis in healthy young male offspring of patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Alibegovic, Amra C; Højbjerre, Lise; Sonne, Mette P

    2009-01-01

    OBJECTIVE: The aim of this study was to investigate the impact of 9 days of bed rest on insulin secretion, insulin action, and whole-body glucose and fat metabolism in first-degree relative (FDR) and matched control (CON) subjects. RESEARCH DESIGN AND METHODS: A total of 13 FDR and 20 CON subjects...... deteriorates with 9 days of bed rest, converging toward similar degrees of whole-body insulin resistance. FDR subjects exhibit hepatic insulin resistance (HIR), which, in contrast to CON subjects, deteriorates in response to physical inactivity. FDR subjects exhibit reduced insulin secretion when seen...... participated in the study. All were studied before and after 9 days of bed rest using the clamp technique combined with indirect calorimetry preceded by an intravenous glucose tolerance test. Glucose and glycerol turnover rates were studied using stable isotope kinetics. RESULTS: Bed rest caused a significant...

  19. Insulin resistance in the elderly: The Rotterdam Study

    NARCIS (Netherlands)

    R.P. Stolk (Ronald)

    1995-01-01

    textabstractInsulin resistance is a diminished ability to keep the serum glucose low with insulin levels in the normal range. Subjects with raised insulin resistance therefore usually have increased serum insulin levels. When the B-cells of the pancreas are no longer able to produce these increased

  20. Adipocyte CREB promotes insulin resistance in obesity.

    Science.gov (United States)

    Qi, Ling; Saberi, Maziyar; Zmuda, Erik; Wang, Yiguo; Altarejos, Judith; Zhang, Xinmin; Dentin, Renaud; Hedrick, Susie; Bandyopadhyay, Gautam; Hai, Tsonwin; Olefsky, Jerry; Montminy, Marc

    2009-03-01

    Increases in adiposity trigger metabolic and inflammatory changes that interfere with insulin action in peripheral tissues, culminating in beta cell failure and overt diabetes. We found that the cAMP Response Element Binding protein (CREB) is activated in adipose cells under obese conditions, where it promotes insulin resistance by triggering expression of the transcriptional repressor ATF3 and thereby downregulating expression of the adipokine hormone adiponectin as well as the insulin-sensitive glucose transporter 4 (GLUT4). Transgenic mice expressing a dominant-negative CREB transgene in adipocytes displayed increased whole-body insulin sensitivity in the contexts of diet-induced and genetic obesity, and they were protected from the development of hepatic steatosis and adipose tissue inflammation. These results indicate that adipocyte CREB provides an early signal in the progression to type 2 diabetes.

  1. Insulin-mediated increases in renal plasma flow are impaired in insulin-resistant normal subjects

    NARCIS (Netherlands)

    ter Maaten, JC; Bakker, SJL; Serne, EH; Moshage, HJ; Gans, ROB

    2000-01-01

    Background Impaired vasodilatation in skeletal muscle is a possible mechanism linking insulin resistance to blood pressure regulation. Increased renal vascular resistance has been demonstrated in the offspring of essential hypertensives. We assessed whether insulin-mediated renal vasodilatation is

  2. Role of reduced insulin-stimulated bone blood flow in the pathogenesis of metabolic insulin resistance and diabetic bone fragility.

    Science.gov (United States)

    Hinton, Pamela S

    2016-08-01

    Worldwide, 387 million adults live with type 2 diabetes (T2D) and an additional 205 million cases are projected by 2035. Because T2D has numerous complications, there is significant morbidity and mortality associated with the disease. Identification of early events in the pathogenesis of insulin resistance and T2D might lead to more effective treatments that would mitigate health and monetary costs. Here, we present our hypothesis that impaired bone blood flow is an early event in the pathogenesis of whole-body metabolic insulin resistance that ultimately leads to T2D. Two recent developments in different fields form the basis for this hypothesis. First, reduced vascular function has been identified as an early event in the development of T2D. In particular, before the onset of tissue or whole body metabolic insulin resistance, insulin-stimulated, endothelium-mediated skeletal muscle blood flow is impaired. Insulin resistance of the vascular endothelium reduces delivery of insulin and glucose to skeletal muscle, which leads to tissue and whole-body metabolic insulin resistance. Second is the paradigm-shifting discovery that the skeleton has an endocrine function that is essential for maintenance of whole-body glucose homeostasis. Specifically, in response to insulin signaling, osteoblasts secret osteocalcin, which stimulates pancreatic insulin production and enhances insulin sensitivity in skeletal muscle, adipose, and liver. Furthermore, the skeleton is not metabolically inert, but contributes to whole-body glucose utilization, consuming 20% that of skeletal muscle and 50% that of white adipose tissue. Without insulin signaling or without osteocalcin activity, experimental animals become hyperglycemic and insulin resistant. Currently, it is not known if insulin-stimulated, endothelium-mediated blood flow to bone plays a role in the development of whole body metabolic insulin resistance. We hypothesize that it is a key, early event. Microvascular dysfunction is a

  3. Selenoprotein P-neutralizing antibodies improve insulin secretion and glucose sensitivity in type 2 diabetes mouse models.

    Science.gov (United States)

    Mita, Yuichiro; Nakayama, Kaho; Inari, Shogo; Nishito, Yukina; Yoshioka, Yuya; Sakai, Naoko; Sotani, Kanade; Nagamura, Takahiro; Kuzuhara, Yuki; Inagaki, Kumi; Iwasaki, Miki; Misu, Hirofumi; Ikegawa, Masaya; Takamura, Toshinari; Noguchi, Noriko; Saito, Yoshiro

    2017-11-21

    Selenoprotein P (SeP) functions as a selenium (Se)-supply protein. SeP is identified as a hepatokine, promoting insulin resistance in type 2 diabetes. Thus, the suppression of Se-supply activity of SeP might improve glucose metabolism. Here, we develop an anti-human SeP monoclonal antibody AE2 as with neutralizing activity against SeP. Administration of AE2 to mice significantly improves glucose intolerance and insulin resistance that are induced by human SeP administration. Furthermore, excess SeP administration significantly decreases pancreas insulin levels and high glucose-induced insulin secretion, which are improved by AE2 administration. Epitope mapping reveals that AE2 recognizes a region of human SeP adjacent to the first histidine-rich region (FHR). A polyclonal antibody against the mouse SeP FHR improves glucose intolerance and insulin secretion in a mouse model of diabetes. This report describes a novel molecular strategy for the development of type 2 diabetes therapeutics targeting SeP.

  4. Hematopoietic-Derived Galectin-3 Causes Cellular and Systemic Insulin Resistance.

    Science.gov (United States)

    Li, Pingping; Liu, Shuainan; Lu, Min; Bandyopadhyay, Gautum; Oh, Dayoung; Imamura, Takeshi; Johnson, Andrew M F; Sears, Dorothy; Shen, Zhufang; Cui, Bing; Kong, Lijuan; Hou, Shaocong; Liang, Xiao; Iovino, Salvatore; Watkins, Steven M; Ying, Wei; Osborn, Olivia; Wollam, Joshua; Brenner, Martin; Olefsky, Jerrold M

    2016-11-03

    In obesity, macrophages and other immune cells accumulate in insulin target tissues, promoting a chronic inflammatory state and insulin resistance. Galectin-3 (Gal3), a lectin mainly secreted by macrophages, is elevated in both obese subjects and mice. Administration of Gal3 to mice causes insulin resistance and glucose intolerance, whereas inhibition of Gal3, through either genetic or pharmacologic loss of function, improved insulin sensitivity in obese mice. In vitro treatment with Gal3 directly enhanced macrophage chemotaxis, reduced insulin-stimulated glucose uptake in myocytes and 3T3-L1 adipocytes and impaired insulin-mediated suppression of glucose output in primary mouse hepatocytes. Importantly, we found that Gal3 can bind directly to the insulin receptor (IR) and inhibit downstream IR signaling. These observations elucidate a novel role for Gal3 in hepatocyte, adipocyte, and myocyte insulin resistance, suggesting that Gal3 can link inflammation to decreased insulin sensitivity. Inhibition of Gal3 could be a new approach to treat insulin resistance. Copyright © 2016 Elsevier Inc. All rights reserved.

  5. Osteocalcin improves insulin resistance and inflammation in obese mice: Participation of white adipose tissue and bone.

    Science.gov (United States)

    Guedes, J A C; Esteves, J V; Morais, M R; Zorn, T M; Furuya, D T

    2017-11-26

    The discovery of osteocalcin, a protein synthetized by osteoblasts, as a hormone that has positive effects on insulin resistance, contributed to support the concept of bone as an endocrine organ. However, very little is known about the molecular pathways involved in osteocalcin improved-insulin resistance. The present study aimed to investigate the mechanisms of action of osteocalcin on insulin resistance and inflammation in obese mice and 3T3-L1 adipocytes. Lean control, saline-treated obese and uncarboxylated osteocalcin (uOC)-treated obese mice were subjected to insulin tolerance test in vivo. Blood was collect for biochemical/metabolic profile analysis; and, skeletal muscle, white adipose tissue (WAT) and bone were collected for protein (Western blotting) and mRNA (RT-qPCR) analysis. uOC effects on insulin resistance and inflammation were also investigated in 3T3-L1 adipocytes challenged with tumor necrosis factor. Osteocalcin treatment improved in vivo insulin resistance in obese mice. In WAT, osteocalcin had positive effects such as (1) WAT weight reduction; (2) upregulation of glucose transporter (GLUT) 4 protein and its mRNA (Slc2a4); (3) improved insulin-induced AKT phosphorylation; (4) downregulation of several genes involved in inflammation and inflammassome transcriptional machinery, and (5) reduction of the density of macrophage in crown-like structures (histomorphometrical analysis). Notably, in 3T3-L1 adipocytes, osteocalcin restored Slc2a4/GLUT4 content and reduced the expression of inflammatory genes after TNF-a challenge; moreover, osteocalcin treatment increased AKT phosphorylation induced by insulin. Finally, it was observed that in bone, osteocalcin improves insulin resistance by increasing insulin-induced AKT phosphorylation and reducing the expression of genes involved in bone insulin resistance, resulting in increased secretion of uncarboxylated osteocalcin in circulation. We provided some mechanisms of action for osteocalcin in the

  6. Novel insulin from the bullfrog: its structure and function in protein secretion by hepatocytes

    International Nuclear Information System (INIS)

    Hulsebus, J.J.

    1987-01-01

    Bullfrog insulin was extracted and purified from the pancreas of Rana catesbeiana adults using gel filtration and reverse phase high performance liquid chromatography. Amino acid analysis of bullfrog insulin revealed 52 amino acids instead of the most common number of 51. The most unique features of bullfrog insulin is a two amino acid extension on the amino terminus (A1) of the A chain. This is the only insulin to date that has an extension at this position. Bullfrog and porcine insulin increase protein secretion from bullfrog adult and three developmental stages of tadpole hepatocytes in a totally defined, serum-free culture system. The hormone slightly stimulates protein secretion by premetamorphic and early prometamorphic tadpoles. Late prometamorphic tadpoles respond to bullfrog and porcine insulin with higher concentrations of secreted protein than either of the two previous developmental stages. Insulin treated adult hepatocytes secrete significantly higher concentrations of protein than any of the tadpole stages. 35 S-methionine and 35 S-cysteine were added to the culture medium for twelve hours. Proteins secreted into the medium were separated using SDS polyacrylamide linear gradient gels. Densitometer scans of autoradiograms did not show an increases in any specific proteins, but did show a generalized increase in all secreted proteins for both adults, and tadpoles

  7. The effect of thyroidectomy and propylthiouracil-induced hypothyroidism on insulin secretion in male rats.

    Science.gov (United States)

    Godini, A; Ghasemi, A; Karbalaei, N; Zahediasl, S

    2014-09-01

    Data available on thyroid dysfunction and insulin secretion are inconsistent. The aim of this study was to assess the effect of hypothyroidism on insulin secretion, in vivo and in vitro, in rats. Adult Wistar male rats were divided into 4 groups, the control, the propylthiouracyl (PTU)-treated hypothyroid, the surgically thyroidectomized, and the sham-operated thyroidectomized. After 5 weeks, intravenous glucose tolerance test (IVGTT) was performed and 3 weeks later pancreatic islets were isolated to assess glucose induced insulin secretion and insulin content. Fasting serum glucose and insulin levels did not differ between the groups, but serum glucose concentration during IVGTT in the PTU-induced hypothyroid group was significantly higher as compared to controls, throughout 5-60 min. The serum glucose concentration during IVGTT in the thyroidectomized rats was also significantly higher than in the sham-operated ones, except at 10 and 60 min. The area under the curve of the serum insulin was significantly lower during IVGTT in the PTU-treated (10,010 ± 1,380 pmol/l/60 min) and thyroidectomized (13,930 ± 2,786) groups vs. their comparable groups (19,150 ± 2,110), phypothyroidism leads to impaired glucose tolerance due to reduced glucose stimulated insulin secretion. Islets insulin secretion is positively correlated with serum T3 and T4 concentrations. © Georg Thieme Verlag KG Stuttgart · New York.

  8. Importance of hepatitis C virus-associated insulin resistance: Therapeutic strategies for insulin sensitization

    OpenAIRE

    Kawaguchi, Takumi; Sata, Michio

    2010-01-01

    Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection. Generally, persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases. However, these complications are not major causes of death in patients with HCV-associated insulin resistance. Indeed, insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection. ...

  9. Fine-mapping diabetes-related traits, including insulin resistance, in heterogeneous stock rats.

    Science.gov (United States)

    Solberg Woods, Leah C; Holl, Katie L; Oreper, Daniel; Xie, Yuying; Tsaih, Shirng-Wern; Valdar, William

    2012-11-01

    Type 2 diabetes (T2D) is a disease of relative insulin deficiency resulting from both insulin resistance and beta cell failure. We have previously used heterogeneous stock (HS) rats to fine-map a locus for glucose tolerance. We show here that glucose intolerance in the founder strains of the HS colony is mediated by different mechanisms: insulin resistance in WKY and an insulin secretion defect in ACI, and we demonstrate a high degree of variability for measures of insulin resistance and insulin secretion in HS rats. As such, our goal was to use HS rats to fine-map several diabetes-related traits within a region on rat chromosome 1. We measured blood glucose and plasma insulin levels after a glucose tolerance test in 782 male HS rats. Using 97 SSLP markers, we genotyped a 68 Mb region on rat chromosome 1 previously implicated in glucose and insulin regulation. We used linkage disequilibrium mapping by mixed model regression with inferred descent to identify a region from 198.85 to 205.9 that contains one or more quantitative trait loci (QTL) for fasting insulin and a measure of insulin resistance, the quantitative insulin sensitivity check index. This region also encompasses loci identified for fasting glucose and Insulin_AUC (area under the curve). A separate <3 Mb QTL was identified for body weight. Using a novel penalized regression method we then estimated effects of alternative haplotype pairings under each locus. These studies highlight the utility of HS rats for fine-mapping genetic loci involved in the underlying causes of T2D.

  10. Momordica charantia Administration Improves Insulin Secretion in Type 2 Diabetes Mellitus.

    Science.gov (United States)

    Cortez-Navarrete, Marisol; Martínez-Abundis, Esperanza; Pérez-Rubio, Karina G; González-Ortiz, Manuel; Villar, Miriam Méndez-Del

    2018-02-12

    An improvement in parameters of glycemic control has been observed with Momordica charantia in patients with type 2 diabetes mellitus (T2DM). It is unknown whether this improvement is through a modification of insulin secretion, insulin sensitivity, or both. We hypothesized that M. charantia administration can improve insulin secretion and/or insulin sensitivity in patients with T2DM, without pharmacological treatment. The objective of the study was to evaluate the effect of M. charantia administration on insulin secretion and sensitivity. A randomized, double-blinded, placebo-controlled, clinical trial was carried out in 24 patients who received M. charantia (2000 mg/day) or placebo for 3 months. A 2-h oral glucose tolerance test (OGTT) was done before and after the intervention to calculate areas under the curve (AUC) of glucose and insulin, total insulin secretion (insulinogenic index), first phase of insulin secretion (Stumvoll index), and insulin sensitivity (Matsuda index). In the M. charantia group, there were significant decreases in weight, body mass index (BMI), fat percentage, waist circumference (WC), glycated hemoglobin A1c (A1C), 2-h glucose in OGTT, and AUC of glucose. A significant increase in insulin AUC (56,562 ± 36,078 vs. 65,256 ± 42,720 pmol/L/min, P = .043), in total insulin secretion (0.29 ± 0.18 vs. 0.41 ± 0.29, P = .028), and during the first phase of insulin secretion (557.8 ± 645.6 vs. 1135.7 ± 725.0, P = .043) was observed after M. charantia administration. Insulin sensitivity was not modified with any intervention. In conclusion, M. charantia administration reduced A1C, 2-h glucose, glucose AUC, weight, BMI, fat percentage, and WC, with an increment of insulin AUC, first phase and total insulin secretion.

  11. Streptozotocin diabetes and insulin resistance impairment of ...

    African Journals Online (AJOL)

    olayemitoyin

    Streptozotocin diabetes and insulin resistance impairment of spermatogenesis in adult rat testis: central Vs local mechanism. *1. Arikawe A. P.,. 1. Oyerinde A.,. 2. Olatunji-Bello I.I., and. 3. Obika L.F.O. Department of Physiology, 1Faculty of Basic Medical Sciences, College of Medicine, University of Lagos, Idi-. Araba, Lagos ...

  12. Hippocampal insulin resistance and cognitive dysfunction

    NARCIS (Netherlands)

    Biessels, Geert Jan; Reagan, Lawrence P.

    2015-01-01

    Clinical studies suggest a link between type 2 diabetes mellitus (T2DM) and insulin resistance (IR) and cognitive dysfunction, but there are significant gaps in our knowledge of the mechanisms underlying this relationship. Animal models of IR help to bridge these gaps and point to hippocampal IR as

  13. Coffee Consumption Attenuates Insulin Resistance and Glucose ...

    African Journals Online (AJOL)

    Coffee Consumption Attenuates Insulin Resistance and Glucose Intolerance in Rats fed on High-Sucrose Diet. ... Summary: Several epidemiological evidences indicate that consumption of coffee is associated with a lower risk of type 2 diabetes mellitus (T2DM) however; there is dearth of experimental data to support these ...

  14. Streptozotocin diabetes and insulin resistance impairment of ...

    African Journals Online (AJOL)

    Group 7 > Insulin resistant-ginger treated group; fed ad libitum on a special diet as in group 4 above, and also treated with 500 mg/Kg Ginger extract orally. Hormonal and tissue biochemistry analyses revealed that both central and local mechanisms are implicated in the impairment of spermatogenesis by diabetes but the ...

  15. Coffee Consumption Attenuates Insulin Resistance and Glucose ...

    African Journals Online (AJOL)

    olayemitoyin

    J. Physiol. Sci. 28(December 2013) 179–185 www.njps.com.ng. Coffee Consumption Attenuates Insulin Resistance and Glucose. Intolerance in Rats fed on High-Sucrose Diet. Morakinyo AO*, Adekunbi DA, Dada KA and Adegoke OA. Department of Physiology, College of Medicine of the University of Lagos, Lagos. Nigeria.

  16. Insulin resistance induced by antiretroviral drugs: Current ...

    African Journals Online (AJOL)

    Treatment with highly active antiretroviral therapy (HAART) has improved the prognosis of patients with AIDS, but it has also increased the incidence of various metabolic disorders, in particular insulin resistance accompanied by dyslipidaemia, hyperglycaemia and lipodystrophy. This is often accompanied by frank type 2 ...

  17. Severe Insulin Resistance Improves Immediately After Sleeve Gastrectomy

    OpenAIRE

    Sharma, Rahul; Hassan, Chandra; Chaiban, Joumana T.

    2016-01-01

    Introduction. Obese individuals exhibit insulin resistance often leading to adverse health outcomes. When compared with intensive medical therapy, bariatric surgery has shown better outcomes mainly in terms of insulin resistance and glycemic control. Using the Homeostasis Model Assessment of insulin resistance (HOMA-IR), we report herein a case illustrating a drastic improvement in severe insulin resistance after sleeve gastrectomy in the immediate postoperative period. Case Report. A patient...

  18. 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.

  19. Effect of early life stress on pancreatic isolated islets' insulin secretion in young adult male rats subjected to chronic stress.

    Science.gov (United States)

    Sadeghimahalli, Forouzan; Karbaschi, Roxana; Zardooz, Homeira; Khodagholi, Fariba; Rostamkhani, Fatemeh

    2015-03-01

    Early stressful experiences may predispose organisms to certain disorders, including those of metabolic defects. This study aimed to explore the effects of early life stress on pancreatic insulin secretion and glucose transporter 2 (GLUT2) protein levels in stressed young adult male rats. Foot shock stress was induced in early life (at 2 weeks of age) and/or in young adulthood (at 8-10 weeks of age) for five consecutive days. Blood samples were taken before and after stress exposure in young adult rats. At the end of the experiment, glucose tolerance, isolated islets' insulin secretion, and pancreatic amounts of GLUT2 protein were measured. Our results show that early life stress has no effect on basal plasma corticosterone levels and adrenal weight, either alone or combined with young adulthood stress, but that early life + young adulthood stress could prevent weight gain, and cause an increase in basal plasma glucose and insulin. The homeostasis model assessment of insulin resistance index did not increase, when the rats were subjected to early life stress alone, but increased when combined with young adulthood stress. Moreover, glucose tolerance was impaired by the combination of early life + young adult stress. There was a decrease in islet's insulin secretion in rats subjected to early life stress in response to 5.6 mM glucose concentration, but an increase with a concentration of 16.7 mM glucose. However, in rats subjected to early life + young adulthood stress, islet's insulin secretion increased in response to both the levels of glucose concentrations. GLUT2 protein levels decreased in response to early life stress and early life + young adulthood stress, but there was a greater decrease in the early life stress group. In conclusion, perhaps early life stress sensitizes the body to stressors later in life, making it more susceptible to metabolic syndrome only when the two are in combination.

  20. 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)

  1. Association of type 2 diabetes candidate polymorphisms in KCNQ1 with incretin and insulin secretion

    DEFF Research Database (Denmark)

    Müssig, Karsten; Staiger, Harald; Machicao, Fausto

    2009-01-01

    OBJECTIVE: KCNQ1 gene polymorphisms are associated with type 2 diabetes. This linkage appears to be mediated by altered beta-cell function. In an attempt to study underlying mechanisms, we examined the effect of four KCNQ1 single nucleotide polymorphisms (SNPs) on insulin secretion upon different...... C-peptide levels during OGTT, first-phase insulin secretion, and insulinogenic index after adjustment in the dominant model (all P insulin secretion indexes (all P ... and basal or stimulated incretin levels (all P > or = 0.05). CONCLUSIONS: Common genetic variation in KCNQ1 is associated with insulin secretion upon oral glucose load in a German population at increased risk of type 2 diabetes. The discrepancy between orally and intravenously administered glucose seems...

  2. Aminophylline stimulates insulin secretion in patients with type 2 diabetes mellitus

    NARCIS (Netherlands)

    Arias, A. M.; Bisschop, P. H.; Ackermans, M. T.; Nijpels, G.; Endert, E.; Romijn, J. A.; Sauerwein, H. P.

    2001-01-01

    In healthy subjects, paracrine factors partly regulate insulin secretion and basal endogenous glucose production. Administration of pentoxifylline, an adenosine receptor antagonist, inhibits transiently endogenous glucose production in healthy humans without any changes in glucoregulatory hormone

  3. Pancreatic β-Cell Electrical Activity and Insulin Secretion: of Mice and Men

    Science.gov (United States)

    Rorsman, Patrik; Ashcroft, Frances M

    2018-01-01

    The pancreatic β-cell plays a key role in glucose homeostasis by secreting insulin, the only hormone capable of lowering the blood glucose concentration. Impaired insulin secretion results in the chronic hyperglycaemia that characterizes type 2 diabetes (T2DM), which currently afflicts >450 million people worldwide. The healthy β-cell acts as a glucose sensor matching its output to the circulating glucose concentration. It does so via metabolically induced changes in electrical activity, which culminate in an increase in the cytoplasmic Ca2+ concentration and initiation of Ca2+-dependent exocytosis of insulin-containing secretory granules. Here, we review recent advances in our understanding of the β-cell transcriptome, electrical activity and insulin exocytosis. We highlight salient differences between mouse and human β-cells, provide models of how the different ion channels contribute to their electrical activity and insulin secretion, and conclude by discussing how these processes become perturbed in T2DM. PMID:29212789

  4. Intra- and Inter-islet Synchronization of Metabolically Driven Insulin Secretion

    DEFF Research Database (Denmark)

    Pedersen, Morten Gram; Bertram, Richard; Sherman, Arthur

    2005-01-01

    Insulin secretion from pancreatic beta-cells is pulsatile with a period of 5-10 min and is believed to be responsible for plasma insulin oscillations with similar frequency. To observe an overall oscillatory insulin pro. le it is necessary that the insulin secretion from individual beta......-cells is synchronized within islets, and that the population of islets is also synchronized. We have recently developed a model in which pulsatile insulin secretion is produced as a result of calcium-driven electrical oscillations in combination with oscillations in glycolysis. We use this model to investigate possible...... mechanisms for intra-islet and inter-islet synchronization. We show that electrical coupling is sufficient to synchronize both electrical bursting activity and metabolic oscillations. We also demonstrate that islets can synchronize by mutually entraining each other by their effects on a simple model "liver...

  5. High uric acid directly inhibits insulin signalling and induces insulin resistance.

    Science.gov (United States)

    Zhu, Yuzhang; Hu, Yaqiu; Huang, Tianliang; Zhang, Yongneng; Li, Zhi; Luo, Chaohuan; Luo, Yinfeng; Yuan, Huier; Hisatome, Ichiro; Yamamoto, Tetsuya; Cheng, Jidong

    2014-05-16

    Accumulating clinical evidence suggests that hyperuricemia is strongly associated with abnormal glucose metabolism and insulin resistance. However, how high uric acid (HUA) level causes insulin resistance remains unclear. We aimed to determine the direct role of HUA in insulin resistance in vitro and in vivo in mice. An acute hyperuricemia mouse model was created by potassium oxonate treatment, and the impact of HUA level on insulin resistance was investigated by glucose tolerance test, insulin tolerance test and insulin signalling, including phosphorylation of insulin receptor substrate 1 (IRS1) and Akt. HepG2 cells were exposed to HUA treatment and N-acetylcysteine (NAC), reactive oxygen species scavenger; IRS1 and Akt phosphorylation was detected by Western blot analysis after insulin treatment. Hyperuricemic mice showed impaired glucose tolerance with insulin resistance. Hyperuricemia inhibited phospho-Akt (Ser473) response to insulin and increased phosphor-IRS1 (Ser307) in liver, muscle and fat tissues. HUA induced oxidative stress, and the antioxidant NAC blocked HUA-induced IRS1 activation and Akt inhibition in HepG2 cells. This study supplies the first evidence of HUA directly inducing insulin resistance in vivo and in vitro. Increased uric acid level may inhibit IRS1 and Akt insulin signalling and induce insulin resistance. The reactive oxygen species pathway plays a key role in HUA-induced insulin resistance. Copyright © 2014 Elsevier Inc. All rights reserved.

  6. Glucose and insulin modify thrombospondin 1 expression and secretion in primary adipocytes from diet-induced obese rats.

    Science.gov (United States)

    Garcia-Diaz, Diego F; Arellano, Arianna V; Milagro, Fermin I; Moreno-Aliaga, Maria Jesus; Portillo, Maria Puy; Martinez, J Alfredo; Campion, Javier

    2011-09-01

    Thrombospondin 1 (TSP-1), an antiangiogenic factor and transforming growth factor (TGF)-β activity regulator, has been recently recognized as an adipokine that correlates with obesity, inflammation and insulin resistance processes. In the present study, epididymal adipocytes of rats that were fed a chow or a high-fat diet (HFD) for 50 days were isolated and incubated (24-72 h) in low (5.6 mM) or high (HG; 25 mM) glucose, in the presence or absence of 1.6 nM insulin. Rats fed the HF diet showed an established obesity state. Serum TSP-1 levels and TSP-1 mRNA basal expression of adipocytes from HFD rats were higher than those from controls. Adipocytes from HFD animals presented an insulin resistance state, as suggested by the lower insulin-stimulated glucose uptake as compared to controls. TSP-1 expression in culture was higher in adipocytes from obese animals at 24 h, but when the adipocytes were treated with HG, these expression levels dropped dramatically. Later at 72 h, TSP-1 expression was lower in adipocytes from HFD rats, and no effects of the other treatments were observed. Surprisingly, the secretion levels of this protein at 72 h were increased significantly by the HG treatment in both types of adipocytes, although they were even higher in adipocytes from obese animals. Finally, cell viability was significantly reduced by HG treatment in both types of adipocytes. In summary, TSP-1 expression/secretion was modulated in an in vitro model of insulin-resistant adipocytes. The difference between expression and secretion patterns suggests a posttranscriptional regulation. The present study confirms that TPS-1 is closely associated with obesity-related mechanisms.

  7. Fatty Acids, Obesity and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Peter Arner

    2015-04-01

    Full Text Available Objective: Although elevated free fatty acid (FFA levels in obesity have been considered to be of importance for insulin resistance, a recent meta-analysis suggested normal FFA levels in obese subjects. We investigated fasting circulating FFA and glycerol levels in a large cohort of non-obese and obese subjects. Methods: Subjects recruited for a study on obesity genetics were investigated in the morning after an overnight fast (n = 3,888. Serum FFA (n = 3,306, plasma glycerol (n = 3,776, and insulin sensitivity index (HOMA-IR,n = 3,469 were determined. Obesity was defined as BMI ≥ 30 kg/m2 and insulin resistance as HOMA-IR ≥ 2.21. Results: In obese subjects, circulating FFA and glycerol levels were higher than in non-obese individuals (by 26% and 47%, respectively; both p Conclusion: Circulating FFA and glycerol levels are markedly elevated in obesity but only marginally influenced by insulin resistance and type 2 diabetes. Whether these differences persist during diurnal variations in circulating FFA/glycerol, remains to be established.

  8. MODELS OF INSULIN RESISTANCE AND HEART FAILURE

    Science.gov (United States)

    Velez, Mauricio; Kohli, Smita; Sabbah, Hani N.

    2013-01-01

    The incidence of heart failure (HF) and diabetes mellitus is rapidly increasing and is associated with poor prognosis. In spite of the advances in therapy, HF remains a major health problem with high morbidity and mortality. When HF and diabetes coexist, clinical outcomes are significantly worse. The relationship between these two conditions has been studied in various experimental models. However, the mechanisms for this interrelationship are complex, incompletely understood, and have become a matter of considerable clinical and research interest. There are only few animal models that manifest both HF and diabetes. However, the translation of results from these models to human disease is limited and new models are needed to expand our current understanding of this clinical interaction. In this review, we discuss mechanisms of insulin signaling and insulin resistance, the clinical association between insulin resistance and HF and its proposed pathophysiologic mechanisms. Finally, we discuss available animal models of insulin resistance and HF and propose requirements for future new models. PMID:23456447

  9. Enhanced insulin secretion and insulin sensitivity in young lambs with placental insufficiency-induced intrauterine growth restriction.

    Science.gov (United States)

    Camacho, Leticia E; Chen, Xiaochuan; Hay, William W; Limesand, Sean W

    2017-08-01

    Intrauterine growth restriction (IUGR) is associated with persistent metabolic complications, but information is limited for IUGR infants. We determined glucose-stimulated insulin secretion (GSIS) and insulin sensitivity in young lambs with placental insufficiency-induced IUGR. Lambs with hyperthermia-induced IUGR ( n = 7) were compared with control lambs ( n = 8). GSIS was measured at 8 ± 1 days of age, and at 15 ± 1 days, body weight-specific glucose utilization rates were measured with radiolabeled d-glucose during a hyperinsulinemic-euglycemic clamp (HEC). IUGR lambs weighed 23% less ( P insulin concentrations were not different between IUGR and controls for either study. First-phase insulin secretion was enhanced 2.3-fold in IUGR lambs compared with controls. However, second-phase insulin concentrations, glucose-potentiated arginine-stimulated insulin secretion, and β-cell mass were not different, indicating that IUGR β-cells have an intrinsic enhancement in acute GSIS. Compared with controls, IUGR lambs had higher body weight-specific glucose utilization rates and greater insulin sensitivity at fasting (1.6-fold) and hyperinsulinemic periods (2.4-fold). Improved insulin sensitivity for glucose utilization was not due to differences in skeletal muscle insulin receptor and glucose transporters 1 and 4 concentrations. Plasma lactate concentrations during HEC were elevated in IUGR lambs compared with controls, but no differences were found for glycogen content or citrate synthase activity in liver and muscle. Greater insulin sensitivity for glucose utilization and enhanced acute GSIS in young lambs are predicted from fetal studies but may promote conditions that exaggerate glucose disposal and lead to episodes of hypoglycemia in IUGR infants. Copyright © 2017 the American Physiological Society.

  10. Intracellular and extracellular adenosine triphosphate in regulation of insulin secretion from pancreatic β cells (β).

    Science.gov (United States)

    Wang, Chunjiong; Geng, Bin; Cui, Qinghua; Guan, Youfei; Yang, Jichun

    2014-03-01

    Adenosine triphosphate (ATP) synthesis and release in mitochondria play critical roles in regulating insulin secretion in pancreatic β cells. Mitochondrial dysfunction is mainly characterized by a decrease in ATP production, which is a central event in the progression of pancreatic β cell dysfunction and diabetes. ATP has been demonstrated to regulate insulin secretion via several pathways: (i) Intracellular ATP directly closes ATP-sensitive potassium channel to open L-type calcium channel, leading to an increase in free cytosolic calcium levels and exocytosis of insulin granules; (ii) A decrease in ATP production is always associated with an increase in production of reactive oxygen species, which exerts deleterious effects on pancreatic β cell survival and insulin secretion; and (iii) ATP can be co-secreted with insulin from pancreatic β cells, and the released ATP functions as an autocrine signal to modulate insulin secretory process via P2 receptors on the cell membrane. In this review, the recent findings regarding the role and mechanism of ATP synthesis and release in regulation of insulin secretion from pancreatic β cells will be summarized and discussed. © 2013 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.

  11. Ameliorative Effect of Allopurinol on Vascular Complications of Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Hany M. El-Bassossy

    2015-01-01

    Full Text Available The aim of the current study was to evaluate the possible protective effect of allopurinol (Allo on experimentally induced insulin resistance (IR and vascular complications. Rats were divided into four groups: control, IR, allopurinol-treated IR (IR-Allo, and allopurinol-treated control (Allo. IR was induced by adding fructose and high fat, high salt diet for 12 weeks. The results showed that Allo has alleviated the increased level of TNF-α and the systolic, diastolic, mean, and notch pressure observed in IR with no change in pulse pressure. In addition, Allo decreased the heart rate in the treated group compared to IR rats. On the other hand, it has no effect on increased levels of insulin, glucose, fructosamine, or body weight gain compared to IR group, while it increased significantly the insulin level and body weight without hyperglycemia in the control group. Moreover, Allo treatment ameliorated increased level of 4HNE, Ang II, and Ang R1. In conclusion, the results of the current study show that Allo has a protective effect on vascular complications of IR which may be attributed to the effect of Allo on decreasing the TNF-α, 4HNE, Ang II, and Ang R1 as well as increasing the level of insulin secretion.

  12. Effect of Dapagliflozin With and Without Acipimox on Insulin Sensitivity and Insulin Secretion in T2DM Males.

    Science.gov (United States)

    Merovci, Aurora; Abdul-Ghani, Muhammad; Mari, Andrea; Solis-Herrera, Carolina; Xiong, Juan; Daniele, Giuseppe; Tripathy, Devjit; DeFronzo, Ralph A

    2016-03-01

    To investigate the effect of lowering the plasma glucose and free fatty acid (FFA) concentrations with dapagliflozin and acipimox, respectively, on insulin sensitivity and insulin secretion in T2DM individuals. Fourteen male T2DM patients received an oral glucose tolerance test and euglycemic hyperinsulinemic clamp at baseline and were treated for 3 weeks with dapagliflozin (10 mg per day). During week 3, acipimox (250 mg four times per day) treatment was added to dapagliflozin. The oral glucose tolerance test and insulin clamp were repeated at the end of weeks 2 and 3. Dapagliflozin caused glucosuria and significantly lowered the plasma glucose concentration (by 35 mg/dL; P insulin-mediated glucose disposal increased significantly at week 2 (from 4.48 ± 0.50 to 5.30 ± 0.50 mg/kg · min; P insulin-mediated glucose disposal at week 3 (after the addition of acipimox) did not differ significantly from that at week 2. Glucose-stimulated insulin secretion at week 2 increased significantly compared to baseline, and it increased further and significantly at week 3 compared to week 2. Lowering the plasma glucose concentration with dapagliflozin improves both insulin sensitivity and β-cell function, whereas lowering plasma FFA concentration by addition of acipimox to dapagliflozin improves β-cell function without significantly affecting insulin sensitivity.

  13. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion : A DIRECT study

    NARCIS (Netherlands)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani; Brorsson, Caroline; van Leeuwen, Nienke; Banasik, Karina; Mahajan, Anubha; Groves, Christopher J; van de Bunt, Martijn; Dawed, Adem Y; Fritsche, Andreas; Staiger, Harald; Simonis-Bik, Annemarie M C; Deelen, Joris; Kramer, Mark H H; Dietrich, Axel; Hübschle, Thomas; Willemsen, Gonneke; Häring, Hans-Ulrich; de Geus, Eco J C; Boomsma, Dorret I; Eekhoff, Elisabeth M W; Ferrer, Jorge; McCarthy, Mark I; Pearson, Ewan R; Gupta, Ramneek; Brunak, Søren; 't Hart, Leen M

    2018-01-01

    Glucagon-like peptide 1 (GLP-1) stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS) of GLP-1 stimulated insulin

  14. Parasympathetic involvement in rapid meal-associated conditioned insulin secretion in the rat

    NARCIS (Netherlands)

    Strubbe, J.H.

    Blood glucose and plasma insulin concentrations were measured in blood sampled via a cardiac catheter in freely moving rats. To obtain a rapid conditioned cephalic phase of insulin secretion, rats were habituated to one of two feeding schedules. Clock-activated opening of doors in front of the food

  15. Circadian control of insulin secretion is independent of the temporal distribution of feeding

    NARCIS (Netherlands)

    Kalsbeek, Andries; Strubbe, JH

    1998-01-01

    To investigate whether there is a circadian regulation of insulin secretion, rats were adapted to a feeding regimen of six meals equally distributed over 24 h. Under these conditions basal glucose and insulin levels increased during the light phase and decreased during the dark phase. Maximal blood

  16. Pancreatic islet insulin secretion and metabolism in adult rats malnourished during neonatal life

    DEFF Research Database (Denmark)

    Barbosa, Francisco B; Capito, Kirsten; Kofod, Hans

    2002-01-01

    Pancreatic islets were isolated from rats that had been nursed by dams fed with a control or an 8.7% protein diet during the first 12 d of the lactation period. Glucose-induced insulin secretion from islets in the 8.7% protein group was reduced 50%. The islet insulin and DNA content were similar...

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

    DEFF Research Database (Denmark)

    Wewer Albrechtsen, Nicolai J.; Kuhre, Rune E.; Hornburg, Daniel

    2017-01-01

    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...

  18. Glucose intolerance and insulin resistance in cirrhosis are normalized after liver transplantation.

    Science.gov (United States)

    Merli, M; Leonetti, F; Riggio, O; Valeriano, V; Ribaudo, M C; Strati, F; Tisone, G; Casciani, C U; Capocaccia, L; Sprati, F

    1999-09-01

    Cirrhosis is often associated with insulin resistance and glucose intolerance. We evaluated if these alterations are restored by liver transplantation (LT). Glucose tolerance (oral glucose tolerance test [OGTT]), peripheral insulin sensitivity (euglycemic insulin clamp technique), glucose oxidation (indirect calorimetry), nonoxidative glucose disposal, and insulin secretion (hyperglycemic clamp technique) were measured in 6 patients (Group 1) before and 6 months after LT, in 12 patients (Group 2) who underwent LT 6 to 30 months previously, and in 6 healthy individuals (controls). In Group 1, glucose tolerance and insulin sensitivity (3.24 +/- 0.37 mg/kg/min) were normalized after LT (8.6 +/- 0.77 mg/kg/min; P <.0001; P = not significant vs. controls). The improved insulin-mediated glucose uptake was the result of a normalization of nonoxidative glucose disposal. Fasting insulin and C-peptide decreased from 24.6 +/- 3.3 microU/mL and 4.37 +/- 0.46 ng/dL, respectively, to 12.7 +/- 1.9 microU/mL and 2.46 +/- 0.5 ng/dL (controls: 10.0 +/- 3 microU/mL and 1.45 +/- 0.34 ng/dL). The glucose-induced increase of insulin concentration, which was higher before LT, showed a significant reduction, although the first phase of beta-cell secretion remained significantly higher compared with that of controls. All these findings were also confirmed in Group 2. The present data indicate that LT normalizes glucose tolerance and insulin sensitivity in cirrhotic patients through an improvement of both hepatic glucose clearance and the peripheral glucose disposal. The latter effect may be the result of the correction of chronic hyperinsulinemia. An increased first-phase beta-cell insulin secretion in response to high glucose levels persists, suggesting that a memory of previous insulin resistance is maintained.

  19. Tau hyperphosphorylation induces oligomeric insulin accumulation and insulin resistance in neurons.

    Science.gov (United States)

    Rodriguez-Rodriguez, Patricia; Sandebring-Matton, Anna; Merino-Serrais, Paula; Parrado-Fernandez, Cristina; Rabano, Alberto; Winblad, Bengt; Ávila, Jesús; Ferrer, Isidre; Cedazo-Minguez, Angel

    2017-12-01

    Insulin signalling deficiencies and insulin resistance have been directly linked to the progression of neurodegenerative disorders like Alzheimer's disease. However, to date little is known about the underlying molecular mechanisms or insulin state and distribution in the brain under pathological conditions. Here, we report that insulin is accumulated and retained as oligomers in hyperphosphorylated tau-bearing neurons in Alzheimer's disease and in several of the most prevalent human tauopathies. The intraneuronal accumulation of insulin is directly dependent on tau hyperphosphorylation, and follows the tauopathy progression. Furthermore, cells accumulating insulin show signs of insulin resistance and decreased insulin receptor levels. These results suggest that insulin retention in hyperphosphorylated tau-bearing neurons is a causative factor for the insulin resistance observed in tauopathies, and describe a novel neuropathological concept with important therapeutic implications. © The Author (2017). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  20. Monomeric tartrate resistant acid phosphatase induces insulin sensitive obesity.

    Directory of Open Access Journals (Sweden)

    Pernilla Lång

    2008-03-01

    Full Text Available Obesity is associated with macrophage infiltration of adipose tissue, which may link adipose inflammation to insulin resistance. However, the impact of inflammatory cells in the pathophysiology of obesity remains unclear. Tartrate resistant acid phosphatase (TRAP is an enzyme expressed by subsets of macrophages and osteoclasts that exists either as an enzymatically inactive monomer or as an active, proteolytically processed dimer.Using mice over expressing TRAP, we show that over-expression of monomeric, but not the dimeric form in adipose tissue leads to early onset spontaneous hyperplastic obesity i.e. many small fat cells. In vitro, recombinant monomeric, but not proteolytically processed TRAP induced proliferation and differentiation of mouse and human adipocyte precursor cells. In humans, monomeric TRAP was highly expressed in the adipose tissue of obese individuals. In both the mouse model and in the obese humans the source of TRAP in adipose tissue was macrophages. In addition, the obese TRAP over expressing mice exhibited signs of a low-grade inflammatory reaction in adipose tissue without evidence of abnormal adipocyte lipolysis, lipogenesis or insulin sensitivity.Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

  1. Blueberries? Impact on Insulin Resistance and Glucose Intolerance

    OpenAIRE

    Stull, April J.

    2016-01-01

    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 hom...

  2. Successful Treatment of Type B Insulin Resistance With Rituximab

    OpenAIRE

    Manikas, Emmanouil-Dimitrios; Isaac, Iona; Semple, Robert K.; Malek, Rana; F?hrer, Dagmar; Moeller, Lars C.

    2015-01-01

    Context: Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone. Case Description: A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose...

  3. Ablation of very long acyl chain sphingolipids causes hepatic insulin resistance in mice due to altered detergent-resistant membranes.

    Science.gov (United States)

    Park, Joo-Won; Park, Woo-Jae; Kuperman, Yael; Boura-Halfon, Sigalit; Pewzner-Jung, Yael; Futerman, Anthony H

    2013-02-01

    Sphingolipids are important structural components of cell membranes and act as critical regulators of cell function by modulating intracellular signaling pathways. Specific sphingolipids, such as ceramide, glucosylceramide, and ganglioside GM3, have been implicated in various aspects of insulin resistance, because they have been shown to modify several steps in the insulin signaling pathway, such as phosphorylation of either protein kinase B (Akt) or of the insulin receptor. We now explore the role of the ceramide acyl chain length in insulin signaling by using a ceramide synthase 2 (CerS2) null mouse, which is unable to synthesize very long acyl chain (C22-C24) ceramides. CerS2 null mice exhibited glucose intolerance despite normal insulin secretion from the pancreas. Both insulin receptor and Akt phosphorylation were abrogated in liver, but not in adipose tissue or in skeletal muscle. The lack of insulin receptor phosphorylation in liver correlated with its inability to translocate into detergent-resistant membranes (DRMs). Moreover, DRMs in CerS2 null mice displayed properties significantly different from those in wild-type mice, suggesting that the altered sphingolipid acyl chain length directly affects insulin receptor translocation and subsequent signaling. We conclude that the sphingolipid acyl chain composition of liver regulates insulin signaling by modifying insulin receptor translocation into membrane microdomains. Copyright © 2012 American Association for the Study of Liver Diseases.

  4. Insulin-induced cytokine production in macrophages causes insulin resistance in hepatocytes.

    Science.gov (United States)

    Manowsky, Julia; Camargo, Rodolfo Gonzalez; Kipp, Anna P; Henkel, Janin; Püschel, Gerhard P

    2016-06-01

    Overweight and obesity are associated with hyperinsulinemia, insulin resistance, and a low-grade inflammation. Although hyperinsulinemia is generally thought to result from an attempt of the β-cell to compensate for insulin resistance, there is evidence that hyperinsulinaemia itself may contribute to the development of insulin resistance and possibly the low-grade inflammation. To test this hypothesis, U937 macrophages were exposed to insulin. In these cells, insulin induced expression of the proinflammatory cytokines IL-1β, IL-8, CCL2, and OSM. The insulin-elicited induction of IL-1β was independent of the presence of endotoxin and most likely mediated by an insulin-dependent activation of NF-κB. Supernatants of the insulin-treated U937 macrophages rendered primary cultures of rat hepatocytes insulin resistant; they attenuated the insulin-dependent induction of glucokinase by 50%. The cytokines contained in the supernatants of insulin-treated U937 macrophages activated ERK1/2 and IKKβ, resulting in an inhibitory serine phosphorylation of the insulin receptor substrate. In addition, STAT3 was activated and SOCS3 induced, further contributing to the interruption of the insulin receptor signal chain in hepatocytes. These results indicate that hyperinsulinemia per se might contribute to the low-grade inflammation prevailing in overweight and obese patients and thereby promote the development of insulin resistance particularly in the liver, because the insulin concentration in the portal circulation is much higher than in all other tissues. Copyright © 2016 the American Physiological Society.

  5. Dietary glycemic load, insulin load, and weight loss in obese, insulin resistant adolescents: RESIST study.

    Science.gov (United States)

    Joslowski, Gesa; Halim, Jocelyn; Goletzke, Janina; Gow, Megan; Ho, Mandy; Louie, Jimmy C-Y; Buyken, Anette E; Cowell, Chris T; Garnett, Sarah P

    2015-02-01

    The optimal dietary approach for weight loss and improving insulin sensitivity in adolescents is unknown. This study aimed to explore the association between the estimated insulin demand of the diet, as measured by glycemic and insulin load, weight loss, percentage body fat and insulin sensitivity index (ISI) in obese adolescents with clinical features of insulin resistance and/or prediabetes after a 3 month lifestyle and metformin intervention. Secondary data analysis of 91 adolescents (median age 12.7 years (range 10.1-17.4) participating in a randomized controlled trial, known as RESIST; ACTRN12608000416392. Weight change between baseline and 3 months was measured by BMI expressed as percentage of the 95th centile (BMI %95). Body composition was measured by dual energy X-ray absorptiometry and ISI was determined by an oral glucose tolerance test. Higher dietary glycemic load and insulin load were associated with less weight loss (BMI %95), adjusted for sex and pubertal stage, β = 0.0466, P = 0.007 and β = 0.0124, P = 0.040, respectively. Inclusion of total energy intake in the model explained observed associations between dietary glycemic load and insulin load and change in BMI %95. Neither dietary glycemic load nor insulin load were associated with changes in percentage body fat or ISI. Dietary glycemic index and macronutrient content (% of total energy) were not associated to changes in BMI %95, percentage body fat or ISI. Reduced energy diet contributes to weight loss in obese, insulin resistant adolescents. Diets with a lower insulin demand were associated with a lower energy intake and may hence assist with weight loss. Copyright © 2014 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.

  6. Macrophage mTORC1 disruption reduces inflammation and insulin resistance in obese mice

    NARCIS (Netherlands)

    Jiang, Hongfeng; Westerterp, Marit; Wang, Chunjiong; Zhu, Yi; Ai, Ding

    2014-01-01

    Inflammatory factors secreted by macrophages play an important role in obesity-related insulin resistance. Being at the crossroads of a nutrient-hormonal signalling network, the mammalian target of rapamycin complex 1 (mTORC1) controls important functions in the regulation of energy balance and

  7. Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

    Energy Technology Data Exchange (ETDEWEB)

    Wu, C-W.; Biggar, K.K.; Storey, K.B. [Carleton University, Department of Biology, Institute of Biochemistry, Ottawa, ON (Canada)

    2013-01-28

    An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans.

  8. Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

    International Nuclear Information System (INIS)

    Wu, C-W.; Biggar, K.K.; Storey, K.B.

    2013-01-01

    An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans

  9. Biochemical adaptations of mammalian hibernation: exploring squirrels as a perspective model for naturally induced reversible insulin resistance

    Science.gov (United States)

    Wu, C-W.; Biggar, K.K.; Storey, K.B.

    2013-01-01

    An important disease among human metabolic disorders is type 2 diabetes mellitus. This disorder involves multiple physiological defects that result from high blood glucose content and eventually lead to the onset of insulin resistance. The combination of insulin resistance, increased glucose production, and decreased insulin secretion creates a diabetic metabolic environment that leads to a lifetime of management. Appropriate models are critical for the success of research. As such, a unique model providing insight into the mechanisms of reversible insulin resistance is mammalian hibernation. Hibernators, such as ground squirrels and bats, are excellent examples of animals exhibiting reversible insulin resistance, for which a rapid increase in body weight is required prior to entry into dormancy. Hibernator studies have shown differential regulation of specific molecular pathways involved in reversible resistance to insulin. The present review focuses on this growing area of research and the molecular mechanisms that regulate glucose homeostasis, and explores the roles of the Akt signaling pathway during hibernation. Here, we propose a link between hibernation, a well-documented response to periods of environmental stress, and reversible insulin resistance, potentially facilitated by key alterations in the Akt signaling network, PPAR-γ/PGC-1α regulation, and non-coding RNA expression. Coincidentally, many of the same pathways are frequently found to be dysregulated during insulin resistance in human type 2 diabetes. Hence, the molecular networks that may regulate reversible insulin resistance in hibernating mammals represent a novel approach by providing insight into medical treatment of insulin resistance in humans. PMID:23314346

  10. Metabolism and insulin signaling in common metabolic disorders and inherited insulin resistance

    DEFF Research Database (Denmark)

    Højlund, Kurt

    2014-01-01

    . These metabolic disorders are all characterized by reduced plasma adiponectin and insulin resistance in peripheral tissues. Quantitatively skeletal muscle is the major site of insulin resistance. Both low plasma adiponectin and insulin resistance contribute to an increased risk of type 2 diabetes...... and cardiovascular disease. In several studies, we have investigated insulin action on glucose and lipid metabolism, and at the molecular level, insulin signaling to glucose transport and glycogen synthesis in skeletal muscle from healthy individuals and in obesity, PCOS and type 2 diabetes. Moreover, we have...... described a novel syndrome characterized by postprandial hyperinsulinemic hypoglycemia and insulin resistance. This syndrome is caused by a mutation in the tyrosine kinase domain of the insulin receptor gene (INSR). We have studied individuals with this mutation as a model of inherited insulin resistance...

  11. Insulin receptor internalization defect in an insulin-resistant mouse melanoma cell line

    International Nuclear Information System (INIS)

    Androlewicz, M.J.; Straus, D.S.; Brandenburg, D.F.

    1989-01-01

    Previous studies from this laboratory demonstrated that the PG19 mouse melanoma cell line does not exhibit a biological response to insulin, whereas melanoma x mouse embryo fibroblast hybrids do respond to insulin. To investigate the molecular basis of the insulin resistance of the PG19 melanoma cells, insulin receptors from the insulin-resistant melanoma cells and insulin-sensitive fibroblast x melanoma hybrid cells were analyzed by the technique of photoaffinity labeling using the photoprobe 125 I-NAPA-DP-insulin. Photolabeled insulin receptors from the two cell types have identical molecular weights as determined by SDS gel electrophoresis under reducing and nonreducing conditions, indicating that the receptors on the two cell lines are structurally similar. Insulin receptor internalization studies revealed that the hybrid cells internalize receptors to a high degree at 37 degree C, whereas the melanoma cells internalize receptors to a very low degree or not at all. The correlation between ability to internalize insulin receptors and sensitivity to insulin action in this system suggests that uptake of the insulin-receptor complex may be required for insulin action in these cells. Insulin receptors from the two cell lines autophosphorylate in a similar insulin-dependent manner both in vitro and in intact cells, indicating that insulin receptors on the melanoma and hybrid cells have functional tyrosine protein kinase activity. Therefore, the block in insulin action in the PG19 melanoma cells appears to reside at a step beyond insulin-stimulated receptor autophosphorylation

  12. IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas transplant recipients

    DEFF Research Database (Denmark)

    Bouzakri, Karim; Karlsson, Håkan K R; Vestergaard, Henrik

    2006-01-01

    Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied...... by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal...... insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal...

  13. IRS-1 serine phosphorylation and insulin resistance in skeletal muscle from pancreas tranplant recipient

    DEFF Research Database (Denmark)

    Bouzakri, K; Karlsson, HRK; Vestergaard, Henrik

    2006-01-01

    Insulin-dependent diabetic recipients of successful pancreas allografts achieve self-regulatory insulin secretion and discontinue exogenous insulin therapy; however, chronic hyperinsulinemia and impaired insulin sensitivity generally develop. To determine whether insulin resistance is accompanied...... by altered signal transduction, skeletal muscle biopsies were obtained from pancreas-kidney transplant recipients (n = 4), nondiabetic kidney transplant recipients (receiving the same immunosuppressive drugs; n = 5), and healthy subjects (n = 6) before and during a euglycemic-hyperinsulinemic clamp. Basal...... insulin receptor substrate (IRS)-1 Ser (312) and Ser (616) phosphorylation, IRS-1-associated phosphatidylinositol 3-kinase activity, and extracellular signal-regulated kinase (ERK)-1/2 phosphorylation were elevated in pancreas-kidney transplant recipients, coincident with fasting hyperinsulinemia. Basal...

  14. Molecular Events Linking Oxidative Stress and Inflammation to Insulin Resistance and β-Cell Dysfunction

    Directory of Open Access Journals (Sweden)

    Kevin Noel Keane

    2015-01-01

    Full Text Available The prevalence of diabetes mellitus (DM is increasing worldwide, a consequence of the alarming rise in obesity and metabolic syndrome (MetS. Oxidative stress and inflammation are key physiological and pathological events linking obesity, insulin resistance, and the progression of type 2 DM (T2DM. Unresolved inflammation alongside a “glucolipotoxic” environment of the pancreatic islets, in insulin resistant pathologies, enhances the infiltration of immune cells which through secretory activity cause dysfunction of insulin-secreting β-cells and ultimately cell death. Recent molecular investigations have revealed that mechanisms responsible for insulin resistance associated with T2DM are detected in conditions such as obesity and MetS, including impaired insulin receptor (IR signalling in insulin responsive tissues, oxidative stress, and endoplasmic reticulum (ER stress. The aim of the present review is to describe the evidence linking oxidative stress and inflammation with impairment of insulin secretion and action, which result in the progression of T2DM and other conditions associated with metabolic dysregulation.

  15. 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

    The intestinally derived hormone glucagon-like peptide 1 (GLP-1) (7-36 amide) has potent effects on glucose-mediated insulin secretion, insulin gene expression, and beta-cell growth and differentiation. It is, therefore, considered a potential therapeutic agent for the treatment of type 2 diabetes....... 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...... that of the control subjects without GLP-1. Our results show that GLP-1 increases insulin secretion in patients with type 2 diabetes and control subjects in a dose-dependent manner and that the beta-cell responsiveness to glucose may be increased to normal levels with a low dose of GLP-1 infusion. Nevertheless...

  16. Regulation of adiponectin secretion by insulin and amino acids in 3T3-L1 adipocytes

    NARCIS (Netherlands)

    Blümer, Regje M. E.; van Roomen, Cindy P.; Meijer, Alfred J.; Houben-Weerts, Judith H. P. M.; Sauerwein, Hans P.; Dubbelhuis, Peter F.

    2008-01-01

    Adiponectin is a fat cell-derived hormone with insulin-sensitizing properties. Low plasma adiponectin levels are associated with insulin resistance as found in obesity. One of the mechanisms for this finding is hampered insulin signaling via phosphatidylinositol 3-kinase (PI3K) with concomitant

  17. Fetal adaptations in insulin secretion result from high catecholamines during placental insufficiency.

    Science.gov (United States)

    Limesand, Sean W; Rozance, Paul J

    2017-08-01

    Placental insufficiency and intrauterine growth restriction (IUGR) of the fetus affects approximately 8% of all pregnancies and is associated with short- and long-term disturbances in metabolism. In pregnant sheep, experimental models with a small, defective placenta that restricts delivery of nutrients and oxygen to the fetus result in IUGR. Low blood oxygen concentrations increase fetal plasma catecholamine concentrations, which lower fetal insulin concentrations. All of these observations in sheep models with placental insufficiency are consistent with cases of human IUGR. We propose that sustained high catecholamine concentrations observed in the IUGR fetus produce developmental adaptations in pancreatic β-cells that impair fetal insulin secretion. Experimental evidence supporting this hypothesis shows that chronic elevation in circulating catecholamines in IUGR fetuses persistently inhibits insulin concentrations and secretion. Elevated catecholamines also allow for maintenance of a normal fetal basal metabolic rate despite low fetal insulin and glucose concentrations while suppressing fetal growth. Importantly, a compensatory augmentation in insulin secretion occurs following inhibition or cessation of catecholamine signalling in IUGR fetuses. This finding has been replicated in normally grown sheep fetuses following a 7-day noradrenaline (norepinephrine) infusion. Together, these programmed effects will potentially create an imbalance between insulin secretion and insulin-stimulated glucose utilization in the neonate which probably explains the transient hyperinsulinism and hypoglycaemia in some IUGR infants. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  18. Beta-cell function is associated with carotid intima-media thickness independently of insulin resistance in healthy individuals

    DEFF Research Database (Denmark)

    Roussel, Ronan; Natali, Andrea; Balkau, Beverley

    2016-01-01

    Objective: It is a common belief that early atherosclerosis in prediabetes is causally linked to endothelial insulin resistance. Another condition, a low insulin secretion, may be associated with insufficient insulin action on the vascular wall and consequently favor atherosclerosis. Our aim...... was to test this hypothesis in people without diabetes, taking into account the gold-standard measurement of insulin sensitivity, a major confounder in the relationship between insulin secretion and atherosclerosis. Methods: We studied the European Relationship between Insulin Sensitivity and Cardiovascular...... Risk cohort of 451 men and 593 women (44±8 years, mean±SD) who were free of diabetes, hypertension, dyslipidemia, and other known chronic or acute conditions. All underwent an oral glucose tolerance test, a euglycemic-hyperinsulinemic clamp (M/I measured insulin sensitivity), and B-mode carotid...

  19. Metabolic endotoxemia initiates obesity and insulin resistance.

    Science.gov (United States)

    Cani, Patrice D; Amar, Jacques; Iglesias, Miguel Angel; Poggi, Marjorie; Knauf, Claude; Bastelica, Delphine; Neyrinck, Audrey M; Fava, Francesca; Tuohy, Kieran M; Chabo, Chantal; Waget, Aurélie; Delmée, Evelyne; Cousin, Béatrice; Sulpice, Thierry; Chamontin, Bernard; Ferrières, Jean; Tanti, Jean-François; Gibson, Glenn R; Casteilla, Louis; Delzenne, Nathalie M; Alessi, Marie Christine; Burcelin, Rémy

    2007-07-01

    Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.

  20. The Relationship between 25-hydroxyvitamin D Levels, Insulin Sensitivity and Insulin Secretion in Women 3 Years after Delivery.

    Science.gov (United States)

    Tänczer, Tímea; Magenheim, Rita; Fürst, Ágnes; Domján, Beatrix; Janicsek, Zsófia; Szabó, Eszter; Ferencz, Viktória; Tabák, Ádám G

    2017-12-01

    There is a direct correlation between 25-hydroxyvitamin D (25[OH]D) levels and insulin sensitivity. Furthermore, women with gestational diabetes (GDM) may have lower levels of 25(OH)D compared to controls. The present study intended to investigate 25(OH)D levels and their association with insulin sensitivity and insulin secretion in women with prior GDM and in controls 3.2 years after delivery. A total of 87 patients with prior GDM and 45 randomly selected controls (age range, 22 to 44 years) with normal glucose tolerance during pregnancy nested within a cohort of all deliveries at Saint Margit Hospital, Budapest, between January 1 2005, and December 31 2006, were examined. Their 25(OH) D levels were measured by radioimmunoassay. Insulin sensitivity and fasting insulin secretion were estimated using the homeostasis model asssessment (HOMA) calculator and early insulin secretion by the insulinogenic index based on a 75 g oral glucose tolerance test. There was no significant difference in 25(OH)D levels between cases and controls (27.2±13.1 [±SD] vs. 26.9±9.8 ng/L). There was a positive association between HOMA insulin sensitivity and 25(OH)D levels (beta = 0.017; 95% CI 0.001 to 0.034/1 ng/mL) that was robust to adjustment for age and body mass index. There was a nonsignificant association between HOMA insulin secretion and 25(OH)D (p=0.099), while no association was found with the insulinogenic index. Prior GDM status was not associated with 25(OH)D levels; however, 25(OH) D levels were associated with HOMA insulin sensitivity. It is hypothesized that the association between HOMA insulin secretion and 25(OH)D levels is related to the autoregulation of fasting glucose levels because no association between 25(OH)D and insulinogenic index was found. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

  1. Insulin Resistance Induced by Short term Fructose Feeding may not ...

    African Journals Online (AJOL)

    Fructose feeding causes insulin resistance and invariably Non-Insulin Dependent Diabetes Mellitus (NIDDM) in rats and genetically predisposed humans. The effect of insulin resistance induced by short term fructose feeding on fertility in female rats was investigated using the following parameters: oestrous phase and ...

  2. 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.

  3. Sodium arsenite impairs insulin secretion and transcription in pancreatic β-cells

    International Nuclear Information System (INIS)

    Diaz-Villasenor, Andrea; Sanchez-Soto, M. Carmen; Cebrian, Mariano E.; Ostrosky-Wegman, Patricia; Hiriart, Marcia

    2006-01-01

    Human studies have shown that chronic inorganic arsenic (iAs) exposure is associated with a high prevalence and incidence of type 2 diabetes. However, the mechanism(s) underlying this effect are not well understood, and practically, there is no information available on the effects of arsenic on pancreatic β-cells functions. Thus, since insulin secreted by the pancreas plays a crucial role in maintaining glucose homeostasis, our aim was to determine if sodium arsenite impairs insulin secretion and mRNA expression in single adult rat pancreatic β-cells. Cells were treated with 0.5, 1, 2, 5 and 10 μM sodium arsenite and incubated for 72 and 144 h. The highest dose tested (10 μM) decreased β-cell viability, by 33% and 83%, respectively. Insulin secretion and mRNA expression were evaluated in the presence of 1 and 5 μM sodium arsenite. Basal insulin secretion, in 5.6 mM glucose, was not significantly affected by 1 or 5 μM treatment for 72 h, but basal secretion was reduced when cells were exposed to 5 μM sodium arsenite for 144 h. On the other hand, insulin secretion in response to 15.6 mM glucose decreased with sodium arsenite in a dose-dependent manner in such a way that cells were no longer able to distinguish between different glucose concentrations. We also showed a significant decrease in insulin mRNA expression of cells exposed to 5 μM sodium arsenite during 72 h. Our data suggest that arsenic may contribute to the development of diabetes mellitus by impairing pancreatic β-cell functions, particularly insulin synthesis and secretion

  4. Subjective sleep complaints are associated with insulin resistance in individuals without diabetes: the PPP-Botnia Study.

    Science.gov (United States)

    Pyykkönen, Antti-Jussi; Isomaa, Bo; Pesonen, Anu-Katriina; Eriksson, Johan G; Groop, Leif; Tuomi, Tiinamaija; Räikkönen, Katri

    2012-11-01

    Sleep disorders and subjective sleep complaints have been associated with increased risk of type 2 diabetes. The evidence with respect to insulin resistance (IR) and insulin secretion in individuals without type 2 diabetes has been scarce and elusive. We examined if subjective sleep complaints and their co-occurrence were associated with IR and insulin secretion in adult women and men without diabetes. Women (n = 442) and men (n = 354) 18-75 years of age without type 2 diabetes underwent an oral glucose tolerance test (OGTT), with insulin and glucose measured at fasting and at 30 and 120 min. Complaints related to sleep apnea, insomnia, and daytime sleepiness were self-rated with the Basic Nordic Sleep Questionnaire. In comparison with individuals with no or minor sleep complaints, those with more frequent complaints of sleep apnea, insomnia, and daytime sleepiness were more insulin resistant, as evidenced by higher fasting insulin concentrations and insulin and glucose responses to OGTT, and more frequently had high homeostasis model assessment of IR and low insulin sensitivity index values. The likelihood of being insulin resistant increased significantly and linearly according to the accumulation of co-occurring sleep complaints. These associations changed only a little when adjusted for mediating and confounding factors and for depressive symptoms. Sleep complaints were not associated with indices of deficiency in insulin secretion. Subjective sleep complaints were associated with IR. The likelihood of being insulin resistant increased according to accumulation of co-occurring sleep complaints. Sleep complaints were not associated with deficiency in insulin secretion.

  5. Early differential defects of insulin secretion and action in 19-year-old caucasian men who had low birth weight

    DEFF Research Database (Denmark)

    Jensen, Christine B; Storgaard, Heidi; Dela, Flemming

    2002-01-01

    were significantly lower in the LBW group. Insulin-stimulated glycolytic flux was significantly reduced, and suppression of endogenous glucose production was enhanced in the LBW group. Nevertheless, basal and insulin-stimulated rates of whole-body peripheral glucose disposal, glucose oxidation, lipid...... oxidation, exogenous glucose storage, and nonoxidative glucose metabolism were similar in the two groups. Insulin secretion was reduced by 30% in the LBW group, when expressed relative to insulin sensitivity (disposition index = insulin secretion x insulin action). We propose that reduced insulin-stimulated...

  6. PEDF-induced alteration of metabolism leading to insulin resistance.

    Science.gov (United States)

    Carnagarin, Revathy; Dharmarajan, Arunasalam M; Dass, Crispin R

    2015-02-05

    Pigment epithelium-derived factor (PEDF) is an anti-angiogenic, immunomodulatory, and neurotrophic serine protease inhibitor protein. PEDF is evolving as a novel metabolic regulatory protein that plays a causal role in insulin resistance. Insulin resistance is the central pathogenesis of metabolic disorders such as obesity, type 2 diabetes mellitus, polycystic ovarian disease, and metabolic syndrome, and PEDF is associated with them. The current evidence suggests that PEDF administration to animals induces insulin resistance, whereas neutralisation improves insulin sensitivity. Inflammation, lipolytic free fatty acid mobilisation, and mitochondrial dysfunction are the proposed mechanism of PEDF-mediated insulin resistance. This review summarises the probable mechanisms adopted by PEDF to induce insulin resistance, and identifies PEDF as a potential therapeutic target in ameliorating insulin resistance. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  7. Insulin sensitizers improve the GLP-1 secretion and the amount of intestinal L cells on high-fat-diet-induced catch-up growth.

    Science.gov (United States)

    Zheng, Juan; Xiao, Kang-Li; Chen, Lulu; Wu, Chaodong; Hu, Xiang; Zeng, Tianshu; Chen, Xiao-Qian; Li, Wen-Juan; Deng, Xiuling; Li, Huiqing; Li, Yu-Ming

    The aim of this study was to investigate whether insulin resistance can result in impaired glucagon-like peptide (GLP)-1 secretion and to determine whether insulin-sensitizing drugs could improve the secretion of GLP-1 in catch-up growth rats. Male Sprague Dawley rats were used to establish a catch-up growth model. At the end of weeks 6 and 14, these rats were euthanized to measure energy intake, body weight, plasma triacylglycerol, and nonesterified fatty acid. Fat mass percentage was analyzed by dual-energy x-ray absorptiometry scan. The GLP-1 concentrations were measured by enzyme-linked immunosorbent assay, the glucose infusion rates were measured by hyperinsulinemic-glucose clamp experiment. Quantification of the GLP-1 positive cells in distal ileum was done by immunohistochemical staining method. The L cell line NCI-H716 cells were treated in vitro with palmitate acid, the cells' viability, the carnitine palmitoyl transferase-1, and the insulin signaling pathway were detected. Rats fed a high-fat diet rats had rapidly developed insulin resistance, impaired incretin effect, and a reduction in the number of intestinal L cells. The insulin sensitizers, metformin and pioglitazone, improved insulin resistance and the concentration of circulating GLP-1, increased the relative number of intestinal L cells to a certain degree. In vitro, the NCI-H716 cell viability was decreased and impaired insulin signaling pathway with palmitate acid treatment, metformin treatment could reverse these effects, whereas pioglitazone could not. Insulin resistance caused by a high-fat diet could result in reduced GLP-1 secretion; the insulin sensitizing drugs were able to improve the incretin effect in catch-up growth rats. Copyright © 2017. Published by Elsevier Inc.

  8. Evaluation of insulin expression and secretion in genetically engineered gut K and L-cells

    Directory of Open Access Journals (Sweden)

    Ahmad Zalinah

    2012-09-01

    Full Text Available Abstract Background Gene therapy could provide an effective treatment of diabetes. Previous studies have investigated the potential for several cell and tissue types to produce mature and active insulin. Gut K and L-cells could be potential candidate hosts for gene therapy because of their special features. Results In this study, we isolated gut K and L-cells to compare the potential of both cell types to produce insulin when exposed to similar conditions. The isolated pure K and L-cells were transfected with recombinant plasmids encoding insulin and with specific promoters for K or L-cells. Insulin expression was studied in response to glucose or meat hydrolysate. We found that glucose and meat hydrolysate efficiently induced insulin secretion from K and L-cells. However, the effects of meat hydrolysate on insulin secretion were more potent in both cells compared with glucose. Results of enzyme-linked immunosorbent assays showed that L-cells secreted more insulin compared with K-cells regardless of the stimulator, although this difference was not statistically significant. Conclusion The responses of K and L-cells to stimulation with glucose or meat hydrolysate were generally comparable. Therefore, both K and L-cells show similar potential to be used as surrogate cells for insulin gene expression in vitro. The potential use of these cells for diabetic gene therapy warrants further investigation.

  9. Exogenous glucose administration impairs glucose tolerance and pancreatic insulin secretion during acute sepsis in non-diabetic mice.

    Directory of Open Access Journals (Sweden)

    Yoshio Watanabe

    Full Text Available OBJECTIVES: The development of hyperglycemia and the use of early parenteral feeding are associated with poor outcomes in critically ill patients. We therefore examined the impact of exogenous glucose administration on the integrated metabolic function of endotoxemic mice using our recently developed frequently sampled intravenous glucose tolerance test (FSIVGTT. We next extended our findings using a cecal ligation and puncture (CLP sepsis model administered early parenteral glucose support. METHODS: Male C57BL/6J mice, 8-12 weeks, were instrumented with chronic indwelling arterial and venous catheters. Endotoxemia was initiated with intra-arterial lipopolysaccharide (LPS; 1 mg/kg in the presence of saline or glucose infusion (100 µL/hr, and an FSIVGTT was performed after five hours. In a second experiment, catheterized mice underwent CLP and the impact of early parenteral glucose administration on glucose homeostasis and mortality was assessed over 24 hrs. MEASUREMENTS: AND MAIN RESULTS: Administration of LPS alone did not impair metabolic function, whereas glucose administration alone induced an insulin sensitive state. In contrast, LPS and glucose combined caused marked glucose intolerance and insulin resistance and significantly impaired pancreatic insulin secretion. Similarly, CLP mice receiving parenteral glucose developed fulminant hyperglycemia within 18 hrs (all > 600 mg/dl associated with increased systemic cytokine release and 40% mortality, whereas CLP alone (85 ± 2 mg/dL or sham mice receiving parenteral glucose (113 ± 3 mg/dL all survived and were not hyperglycemic. Despite profound hyperglycemia, plasma insulin in the CLP glucose-infused mice (3.7 ± 1.2 ng/ml was not higher than sham glucose infused mice (2.1 ± 0.3 ng/ml. CONCLUSIONS: The combination of parenteral glucose support and the systemic inflammatory response in the acute phase of sepsis induces profound insulin resistance and impairs compensatory pancreatic insulin

  10. INSULIN AND INSULIN RESISTANCE: NEW MOLECULE MARKERS AND TARGET MOLECULE FOR THE DIAGNOSIS AND THERAPY OF DISEASES OF THE CENTRAL NERVOUS SYSTEM

    Directory of Open Access Journals (Sweden)

    A. B. Salmina

    2013-01-01

    Full Text Available The review summarizes current data on the role of insulin in the regulation of t glucose metabolism in the central nervous system at physiologic and pathologic conditions. For many years, the brain has been considered as an insulin-independent organ which utilizes glucose without insulin activity. However, it is become clear now that insulin not only regulates glucose transport and metabolism, but also has modulatory efftects in impact on excitability, proliferation and differentiation of brain progenitor cells, synaptic plasticity and memory formation, secretion of neurotransmitters, apoptosis. We have critically reviewed literature information and our own data on the role of insulin and insulin resistance in neuron-glia metabolic coupling, regulation of NAD+ metabolism and action of NAdependent enzymes, neurogenesis, brain development in (pathophysiological conditions. The paper clarifies interrelations between alterations in glucose homeostasis, development of insulin resistance and development of neurodegeneration (Alzheimer's disease and Parkinson's disease, autism, stroke, and depression. We discuss the application of novel molecular markers of insulin resistance (adipokines, α-hydroxybutyrate, BDNF, insulin-regulated aminopeptidase, provasopressin and molecular targets for diagnostics and treatment of brain disorders associated with insulin resistance.

  11. The Effect of Eight Weeks Resistance Training on Leptin and Insulin Resistance in Obese Female

    Directory of Open Access Journals (Sweden)

    S. Khalili

    2013-04-01

    Full Text Available Introduction & Objective: Leptin , the main peptide secreted by adipose tissue, is considered an alarming factor in the regulation of body fat content . With regard to the physiological effect of exercise as one of the potential regulators of leptin secretion from adipose tissue , this study was performed to examine the effects of resistance exercise on leptin. Materials & Methods: Twenty inactive and obese female students (10 controls and 10 experi-mentals participated in this study. The subjects in the experimental group performed an 8 week resistance training program (chest press, leg press, lat pull down, leg curl, bicep curl, leg extension with 60 - 70 percent of 1RM. ELISA was used to measure leptin. Results: The results of this study showed that 8 weeks of resistance training significantly decreased BMI (31.32 kg/m2 versus 29.73 kg/m2 , P=0.0001, weight body (80.5kg versus 76.25kg, P=0.0001, WHR (0.93 ver-sus0.89, P=0.0001 and body fat percent (27.48 versus 24.85, P=0.0001 in EG. Statistically significant differ-ences were not seen in leptin (P=0.939, insulin (P=0.336, glucose (P=0.264 and insulin resistance (P=0.306 between CG and EG. Conclusion: The results of this study showed that , there was no significant difference in leptin levels and insulin resistance between the control and experimental groups, after 8 weeks of resistance training. (Sci J Hamadan Univ Med Sci 2013; 20 (1:59-65

  12. Tau deletion promotes brain insulin resistance.

    Science.gov (United States)

    Marciniak, Elodie; Leboucher, Antoine; Caron, Emilie; Ahmed, Tariq; Tailleux, Anne; Dumont, Julie; Issad, Tarik; Gerhardt, Ellen; Pagesy, Patrick; Vileno, Margaux; Bournonville, Clément; Hamdane, Malika; Bantubungi, Kadiombo; Lancel, Steve; Demeyer, Dominique; Eddarkaoui, Sabiha; Vallez, Emmanuelle; Vieau, Didier; Humez, Sandrine; Faivre, Emilie; Grenier-Boley, Benjamin; Outeiro, Tiago F; Staels, Bart; Amouyel, Philippe; Balschun, Detlef; Buee, Luc; Blum, David

    2017-08-07

    The molecular pathways underlying tau pathology-induced synaptic/cognitive deficits and neurodegeneration are poorly understood. One prevalent hypothesis is that hyperphosphorylation, misfolding, and fibrillization of tau impair synaptic plasticity and cause degeneration. However, tau pathology may also result in the loss of specific physiological tau functions, which are largely unknown but could contribute to neuronal dysfunction. In the present study, we uncovered a novel function of tau in its ability to regulate brain insulin signaling. We found that tau deletion leads to an impaired hippocampal response to insulin, caused by altered IRS-1 and PTEN (phosphatase and tensin homologue on chromosome 10) activities. Our data also demonstrate that tau knockout mice exhibit an impaired hypothalamic anorexigenic effect of insulin that is associated with energy metabolism alterations. Consistently, we found that tau haplotypes are associated with glycemic traits in humans. The present data have far-reaching clinical implications and raise the hypothesis that pathophysiological tau loss-of-function favors brain insulin resistance, which is instrumental for cognitive and metabolic impairments in Alzheimer's disease patients. © 2017 Marciniak et al.

  13. Lipid-induced insulin resistance does not impair insulin access to skeletal muscle

    Science.gov (United States)

    Richey, Joyce M.; Castro, Ana Valeria B.; Broussard, Josiane L.; Ionut, Viorica; Bergman, Richard N.

    2015-01-01

    Elevated plasma free fatty acids (FFA) induce insulin resistance in skeletal muscle. Previously, we have shown that experimental insulin resistance induced by lipid infusion prevents the dispersion of insulin through the muscle, and we hypothesized that this would lead to an impairment of insulin moving from the plasma to the muscle interstitium. Thus, we infused lipid into our anesthetized canine model and measured the appearance of insulin in the lymph as a means to sample muscle interstitium under hyperinsulinemic euglycemic clamp conditions. Although lipid infusion lowered the glucose infusion rate and induced both peripheral and hepatic insulin resistance, we were unable to detect an impairment of insulin access to the lymph. Interestingly, despite a significant, 10-fold increase in plasma FFA, we detected little to no increase in free fatty acids or triglycerides in the lymph after lipid infusion. Thus, we conclude that experimental insulin resistance induced by lipid infusion does not reduce insulin access to skeletal muscle under clamp conditions. This would suggest that the peripheral insulin resistance is likely due to reduced cellular sensitivity to insulin in this model, and yet we did not detect a change in the tissue microenvironment that could contribute to cellular insulin resistance. PMID:25852002

  14. 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.

  15. Effect of Magnesium Supplements on Insulin Secretion After Kidney Transplantation: A Randomized Controlled Trial.

    Science.gov (United States)

    Van Laecke, Steven; Caluwe, Rogier; Huybrechts, Inge; Nagler, Evi V; Vanholder, Raymond; Peeters, Patrick; Van Vlem, Bruno; Van Biesen, Wim

    2017-08-29

    BACKGROUND Hypomagnesemia is associated with a disturbed glucose metabolism. Insulin hypo-secretion predicts diabetes in the general population and in transplant recipients. We aimed to assess whether magnesium improves insulin secretion and glycemic control after transplantation in prevalent hypomagnesemic kidney transplant recipients. MATERIAL AND METHODS We conducted an open-label, randomized, parallel-group study. Eligible participants were adults more than 4 months after kidney transplantation on tacrolimus with persisting serum magnesium concentrations food-frequency questionnaire. All analyses were done on an intention-to-treat basis. RESULTS Magnesium with a mean daily dose of 688±237mg in the treatment group failed to lead to significant differences between the 2 groups in FPIR, fasting glucose, HbA1c, or HOMA-IR. Persisting hypomagnesemia was very common and associated with more insulin hypo-secretion, glucose intolerance, and lower dietary magnesium intake (142±56 versus 202±90 mg; p=0.015) as compared to patients with a rise in serum magnesium over 6 months. CONCLUSIONS Magnesium supplementation does not improve insulin secretion in stable hypomagnesemic kidney transplant recipients on tacrolimus. Persisting hypomagnesemia is associated with impaired glucose tolerance, insulin hypo-secretion, and dietary factors.

  16. GLP-1 stimulates insulin secretion by PKC-dependent TRPM4 and TRPM5 activation.

    Science.gov (United States)

    Shigeto, Makoto; Ramracheya, Reshma; Tarasov, Andrei I; Cha, Chae Young; Chibalina, Margarita V; Hastoy, Benoit; Philippaert, Koenraad; Reinbothe, Thomas; Rorsman, Nils; Salehi, Albert; Sones, William R; Vergari, Elisa; Weston, Cathryn; Gorelik, Julia; Katsura, Masashi; Nikolaev, Viacheslav O; Vennekens, Rudi; Zaccolo, Manuela; Galione, Antony; Johnson, Paul R V; Kaku, Kohei; Ladds, Graham; Rorsman, Patrik

    2015-12-01

    Strategies aimed at mimicking or enhancing the action of the incretin hormone glucagon-like peptide 1 (GLP-1) therapeutically improve glucose-stimulated insulin secretion (GSIS); however, it is not clear whether GLP-1 directly drives insulin secretion in pancreatic islets. Here, we examined the mechanisms by which GLP-1 stimulates insulin secretion in mouse and human islets. We found that GLP-1 enhances GSIS at a half-maximal effective concentration of 0.4 pM. Moreover, we determined that GLP-1 activates PLC, which increases submembrane diacylglycerol and thereby activates PKC, resulting in membrane depolarization and increased action potential firing and subsequent stimulation of insulin secretion. The depolarizing effect of GLP-1 on electrical activity was mimicked by the PKC activator PMA, occurred without activation of PKA, and persisted in the presence of PKA inhibitors, the KATP channel blocker tolbutamide, and the L-type Ca(2+) channel blocker isradipine; however, depolarization was abolished by lowering extracellular Na(+). The PKC-dependent effect of GLP-1 on membrane potential and electrical activity was mediated by activation of Na(+)-permeable TRPM4 and TRPM5 channels by mobilization of intracellular Ca(2+) from thapsigargin-sensitive Ca(2+) stores. Concordantly, GLP-1 effects were negligible in Trpm4 or Trpm5 KO islets. These data provide important insight into the therapeutic action of GLP-1 and suggest that circulating levels of this hormone directly stimulate insulin secretion by β cells.

  17. Similar weight-adjusted insulin secretion and insulin sensitivity in short-duration late autoimmune diabetes of adulthood (LADA) and Type 2 diabetes

    DEFF Research Database (Denmark)

    Juhl, C B; Bradley, U; Holst, Jens Juul

    2014-01-01

    AIMS: To explore insulin sensitivity and insulin secretion in people with latent autoimmune diabetes in adulthood (LADA) compared with that in people with Type 2 diabetes. METHODS: A total of 12 people with LADA, defined as glutamic acid decarboxylase (GAD) antibody positivity and > 1 year...... of insulin independency (group A) were age-matched pairwise to people with Type 2 diabetes (group B) and to six people with Type 2 diabetes of similar age and BMI (group C). β-cell function (first-phase insulin secretion and assessment of insulin pulsatility), insulin sensitivity (hyperinsulinemic......-euglycemic clamp) and metabolic response during a mixed meal were studied. RESULTS: Both first-phase insulin secretion and insulin release during the meal were greater (P = 0.05 and P = 0.009, respectively) in Type 2 diabetes as compared with LADA; these differences were lost on adjustment for BMI (group C...

  18. Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations

    Directory of Open Access Journals (Sweden)

    Jana Vrbikova

    2016-12-01

    Full Text Available Objective: To compare the effects of biliopancreatic diversion (BPD and laparoscopic gastric banding (LAGB on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P. Methods: A total of 52 obese women (age 30-66 years suffering from type 2 diabetes mellitus (T2DM were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Results: Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. Conclusion: We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion, but without increasing the beta cell glucose sensitivity.

  19. Insulin Sensitivity and Secretion in Obese Type 2 Diabetic Women after Various Bariatric Operations.

    Science.gov (United States)

    Vrbikova, Jana; Kunesova, Marie; Kyrou, Ioannis; Tura, Andrea; Hill, Martin; Grimmichova, Tereza; Dvorakova, Katerina; Sramkova, Petra; Dolezalova, Karin; Lischkova, Olga; Vcelak, Josef; Hainer, Vojtech; Bendlova, Bela; Kumar, Sudhesh; Fried, Martin

    2016-01-01

    To compare the effects of biliopancreatic diversion (BPD) and laparoscopic gastric banding (LAGB) on insulin sensitivity and secretion with the effects of laparoscopic gastric plication (P). A total of 52 obese women (age 30-66 years) suffering from type 2 diabetes mellitus (T2DM) were prospectively recruited into three study groups: 16 BPD; 16 LAGB, and 20 P. Euglycemic clamps and mixed meal tolerance tests were performed before, at 1 month and at 6 months after bariatric surgery. Beta cell function derived from the meal test parameters was evaluated using mathematical modeling. Glucose disposal per kilogram of fat free mass (a marker of peripheral insulin sensitivity) increased significantly in all groups, especially after 1 month. Basal insulin secretion decreased significantly after all three types of operations, with the most marked decrease after BPD compared with P and LAGB. Total insulin secretion decreased significantly only following the BPD. Beta cell glucose sensitivity did not change significantly post-surgery in any of the study groups. We documented similar improvement in insulin sensitivity in obese T2DM women after all three study operations during the 6-month postoperative follow-up. Notably, only BPD led to decreased demand on beta cells (decreased integrated insulin secretion), but without increasing the beta cell glucose sensitivity. © 2016 The Author(s) Published by S. Karger GmbH, Freiburg.

  20. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses.

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-09-01

    Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle microvascular recruitment. We demonstrated that a high-fat diet induces vascular adiponectin and insulin resistance but globular adiponectin administration can restore vascular insulin responses and improve insulin's metabolic action via an AMPK- and nitric oxide-dependent mechanism. This suggests that globular adiponectin might have a therapeutic potential for improving insulin resistance and preventing cardiovascular complications in patients with diabetes via modulation of microvascular insulin responses. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague-Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by

  1. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance

    Science.gov (United States)

    Aroor, Annayya R.; McKarns, Susan; DeMarco, Vincent G.; Guanghong, Jia; Sowers, James R.

    2013-01-01

    Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance are associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contribute to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. PMID:23932846

  2. Maladaptive immune and inflammatory pathways lead to cardiovascular insulin resistance.

    Science.gov (United States)

    Aroor, Annayya R; McKarns, Susan; Demarco, Vincent G; Jia, Guanghong; Sowers, James R

    2013-11-01

    Insulin resistance is a hallmark of obesity, the cardiorenal metabolic syndrome and type 2 diabetes mellitus (T2DM). The progression of insulin resistance increases the risk for cardiovascular disease (CVD). The significance of insulin resistance is underscored by the alarming rise in the prevalence of obesity and its associated comorbidities in the Unites States and worldwide over the last 40-50 years. The incidence of obesity is also on the rise in adolescents. Furthermore, premenopausal women have lower CVD risk compared to men, but this protection is lost in the setting of obesity and insulin resistance. Although systemic and cardiovascular insulin resistance is associated with impaired insulin metabolic signaling and cardiovascular dysfunction, the mechanisms underlying insulin resistance and cardiovascular dysfunction remain poorly understood. Recent studies show that insulin resistance in obesity and diabetes is linked to a metabolic inflammatory response, a state of systemic and tissue specific chronic low grade inflammation. Evidence is also emerging that there is polarization of macrophages and lymphocytes towards a pro-inflammatory phenotype that contributes to progression of insulin resistance in obesity, cardiorenal metabolic syndrome and diabetes. In this review, we provide new insights into factors, such as, the renin-angiotensin-aldosterone system, sympathetic activation and incretin modulators (e.g., DPP-4) and immune responses that mediate this inflammatory state in obesity and other conditions characterized by insulin resistance. © 2013.

  3. 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.

  4. AMPK, insulin resistance, and the metabolic syndrome.

    Science.gov (United States)

    Ruderman, Neil B; Carling, David; Prentki, Marc; Cacicedo, José M

    2013-07-01

    Insulin resistance (IR) and hyperinsulinemia are hallmarks of the metabolic syndrome, as are central adiposity, dyslipidemia, and a predisposition to type 2 diabetes, atherosclerotic cardiovascular disease, hypertension, and certain cancers. Regular exercise and calorie restriction have long been known to increase insulin sensitivity and decrease the prevalence of these disorders. The subsequent identification of AMP-activated protein kinase (AMPK) and its activation by exercise and fuel deprivation have led to studies of the effects of AMPK on both IR and metabolic syndrome-related diseases. In this review, we evaluate this body of literature, with special emphasis on the hypothesis that dysregulation of AMPK is both a pathogenic factor for these disorders in humans and a target for their prevention and therapy.

  5. Insulin resistance in three dogs with hypothyroidism and diabetes mellitus.

    Science.gov (United States)

    Ford, S L; Nelson, R W; Feldman, E C; Niwa, D

    1993-05-01

    Insulin resistance resolved in 3 dogs with hypothyroidism and diabetes mellitus after treatment with sodium levothyroxine. A thorough diagnostic evaluation failed to identify any other cause of insulin resistance in these dogs. Hypothyroidism was diagnosed in each dog on the basis of clinical signs, physical findings, hyperlipidemia, and results of thyrotropin or thyrotropin-releasing hormone stimulation test. Hypoglycemia was documented in each dog within 2 weeks of starting sodium levothyroxine administration. The insulin dosage was decreased by 60 to 62% during the ensuing months and good glycemic control was obtained at these lower insulin dosages in all dogs. These findings would suggest hypothyroidism-induced insulin resistance in these dogs.

  6. Peripheral IV Insulin Infusion Infiltration Presenting as "Insulin Resistance".

    Science.gov (United States)

    Kim, Tiffany Y; Woeber, Kenneth A; MacMaster, Heidimarie Windham; Rushakoff, Robert J

    2016-11-01

    We present the case of a 66-year-old woman who developed hypoglycemia following the prolonged infiltration of a high dose continuous peripheral IV insulin infusion. Case report. PubMed was searched for relevant literature on exogenous hyperinsulinemic hypoglycemia. The patient was postlung transplantation and was receiving high doses of glucocorticoids. Despite increasing the peripheral IV insulin rate, hyperglycemia persisted. We discovered that the IV insulin infusion line infiltrated, resulting in a large subcutaneous insulin depot, estimated to be 450 units of regular insulin. She subsequently experienced prolonged hypoglycemia that was managed with concentrated dextrose containing fluids. In our literature search, there were no similar case reports. The literature on insulin overdose, usually from suicide attempts, can help guide the management of iatrogenic hyperinsulinemic hypoglycemia. Important management considerations include anticipated duration of hypoglycemia, supplemental glucose, fluid management, and electrolyte monitoring. Peripheral IV insulin infusion infiltration should be considered when patients do not respond to increasing rates of insulin infusion.

  7. DPP4 gene variation affects GLP-1 secretion, insulin secretion, and glucose tolerance in humans with high body adiposity

    DEFF Research Database (Denmark)

    Böhm, Anja; Wagner, Robert; Machicao, Fausto

    2017-01-01

    , inter-individual variance in the responsiveness to DPP-4 inhibitors was reported. Thus, we asked whether genetic variation in the DPP4 gene affects incretin levels, insulin secretion, and glucose tolerance in participants of the TÜbingen Family study for type-2 diabetes (TÜF). RESEARCH DESIGN...... determined. RESULTS: We identified a variant, i.e., SNP rs6741949, in intron 2 of the DPP4 gene that, after correction for multiple comparisons and appropriate adjustment, revealed a significant genotype-body fat interaction effect on glucose-stimulated plasma GLP-1 levels (p = 0.0021). Notably, no genotype......-BMI interaction effects were detected (p = 0.8). After stratification for body fat content, the SNP negatively affected glucose-stimulated GLP-1 levels (p = 0.0229), insulin secretion (p = 0.0061), and glucose tolerance (p = 0.0208) in subjects with high body fat content only. CONCLUSIONS: A common variant, i...

  8. Glucotoxicity induces abnormal glucagon secretion through impaired insulin signaling in InR1G cells.

    Directory of Open Access Journals (Sweden)

    Takashi Katsura

    Full Text Available The significance of glucagon in the pathophysiology of diabetes mellitus is widely recognized, but the mechanisms underlying dysregulated glucagon secretion are still unclear. Here, we explored the molecular mechanisms of glucagon dysregulation, using an in vitro model. Hamster-derived glucagon-secreting InR1G cells were exposed to high glucose (25 mM levels for 12 h before analyzing glucagon secretion and the activity of components involved in insulin signaling. High-glucose treatment induced increased glucagon secretion in InR1G cells, which represents a hallmark of diabetes mellitus. This treatment reduced the phosphorylation of Akt, indicating the deterioration of insulin signaling. Simultaneously, oxidative stress and JNK activity were shown to be increased. The inhibition of JNK signaling resulted in the amelioration of high-glucose level-induced glucagon secretion. Abnormally elevated glucagon secretion in diabetes can be reproduced by high-glucose treatment of InR1G cells, and the involvement of high glucose-oxidative stress-JNK-insulin signaling pathway axis has been demonstrated. These data elucidate, at least partly, the previously unclear mechanism of abnormal glucagon secretion, providing insights into a potential novel approach to diabetes treatment, targeting glucagon.

  9. Physical inactivity, insulin resistance, and the oxidative-inflammatory loop.

    Science.gov (United States)

    Gratas-Delamarche, A; Derbré, F; Vincent, S; Cillard, J

    2014-01-01

    Epidemiological data indicate that physical inactivity, a main factor of global energetic imbalance, is involved in the worldwide epidemic of obesity and metabolic disorders such as insulin resistance. Although the complex pathogenesis of insulin resistance is not fully understood, literature data accumulated during the past decades clearly indicate that the activation of the oxidative-inflammatory loop plays a major role. By activating the oxidative-inflammatory loop in insulin-sensitive tissues, fat gain and adipose tissue dysfunction likely contribute to induce insulin resistance during chronic and prolonged physical inactivity. However, in the past years, evidence has emerged showing that early insulin resistance also occurs after very short-term exposure to physical inactivity (1-7 days) without any fat gain or energetic imbalance. The possible role of liver disturbances or endothelial dysfunction is suggested, but further studies are necessary to really conclude. Inactive skeletal muscle probably constitutes the primary triggering tissue for the development of early insulin resistance. In the present review, we discuss on the current knowledge about the effect of physical inactivity on whole-body and peripheral insulin sensitivity, and how local inflammation and oxidative stress arising with physical inactivity could potentially induce insulin resistance. We assume that early muscle insulin resistance allows the excess nutrients to shift in the storage tissues to withstand starvation through energy storage. We also consider when chronic and prolonged, physical inactivity over an extended period of time is an underestimated contributor to pathological insulin resistance and hence indirectly to numerous chronic diseases.

  10. [Spontaneous changes in carbohydrate tolerance and insulin secretion in persons with indications of disturbed carbohydrate tolerance. Preliminary results and follow-up observations for 7 years].

    Science.gov (United States)

    Ratzmann, K P; Schulz, B; Witt, S; Heinke, P; Michaelis, D

    1980-03-15

    115 patients with normal weight and 15 adipose persons with suspicion of a disturbance of the carbohydrate metabolism were characterized by means of a glucose infusion test lasting two hours concerning the carbohydrate tolerance and insulin secretion. Longitudinal analyses of the spontaneous behaviour of the carbohydrate tolerance and insulin secretion depending on the degree of the carbohydrate tolerance up to duration of the observation of 7 years. A deterioration of the carbohydrate tolerance was to be proved in 21% of 87 persons with normal carbohydrate tolerance within two years. With normal carbohydrate tolerance within two years. With an increase of the duration of the observation up to 7 years the frequency of disturbances of the carbohydrate tolerance increases to 30%. This development cannot be coordinated to a certain type of insulin secretion. In the individual case a deterioration of the carbohydrate tolerance may be associated with an increase or reduction of the glucose stimulated insuline secretion. An improvement of the carbohydrate tolerance was observed in 15 (54%) of 28 patients with disturbed carbohydrate tolerance within 2 years. In a group with pathological carbohydrate tolerance this development was associated with a significant reduction of the basic and glucose stimulated insulin secretion. In all patients with improved carbohydrate tolerance on the side of the insulin secretion primarily the type of "normal response" was present. The lacking relation between changes of the B-cell function and the carbohydrate tolerance emphasizes the importance of other factors, such as a peripheral insulin resistance, for the development of disturbances in the carbohydrate metabolism.

  11. Depressive symptoms, antidepressant medication use, and insulin resistance: the PPP-Botnia Study.

    Science.gov (United States)

    Pyykkönen, Antti-Jussi; Räikkönen, Katri; Tuomi, Tiinamaija; Eriksson, Johan G; Groop, Leif; Isomaa, Bo

    2011-12-01

    Although insulin resistance (IR) may underlie associations between depressive symptoms and diabetes, previous findings have been contradictory. We examined whether depressive symptoms associate with IR and insulin secretion, and, additionally, whether antidepressant medication use may modulate such associations. A total of 4,419 individuals underwent an oral glucose tolerance test (OGTT). Participants with previously or newly diagnosed diabetes are excluded from this sample. The homeostasis model assessment of IR (HOMA-IR) and corrected insulin response (CIR) were calculated. Depressive symptoms and antidepressant medication use were self-reported. After controlling for confounding factors, depressive symptoms were associated with higher fasting and 30-min insulin during the OGTT and higher HOMA-IR but not CIR. Antidepressant medication use failed to modify these associations. Depressive symptoms are associated with IR but not with changes in insulin response when corrected for IR in individuals without previously or newly diagnosed diabetes.

  12. Insulin resistance in vascular endothelial cells promotes intestinal tumour formation

    DEFF Research Database (Denmark)

    Wang, X; Häring, M-F; Rathjen, Thomas

    2017-01-01

    The risk of several cancers, including colorectal cancer, is increased in patients with obesity and type 2 diabetes, conditions characterised by hyperinsulinaemia and insulin resistance. Because hyperinsulinaemia itself is an independent risk factor for cancer development, we examined tissue...... did not change intestinal tumour number or size distribution on either a low or high-fat diet. We therefore asked whether cells in the tumour stroma might explain the association between tumour formation and insulin resistance. To this end, we generated Apc(Min/+) mice with loss of insulin receptors...... and increased the frequency of neutrophils in tumours. We conclude that although insulin is mitogenic for intestinal tumour cells in vitro, impaired insulin action in the tumour microenvironment may be more important in conditions where hyperinsulinaemia is secondary to insulin resistance. Insulin resistance...

  13. GLP-1 Restores Altered Insulin and Glucagon Secretion in Posttransplantation Diabetes

    DEFF Research Database (Denmark)

    Halden, Thea A S; Egeland, Erlend J; Åsberg, Anders

    2016-01-01

    OBJECTIVE: Development of posttransplantation diabetes (PTDM) is characterized by reduced insulin secretion and sensitivity. We aimed to investigate whether hyperglucagonemia could play a role in PTDM and to examine the insulinotropic and glucagonostatic effects of the incretin hormone glucagon...... h of infusion, a 2-h hyperglycemic clamp (fasting plasma glucose + 5 mmol/L) was established. Five grams of arginine was given as an intravenous bolus 10 min before termination of the clamp. RESULTS: Fasting concentrations of glucagon (P = 0.92) and insulin (P = 0.23) were similar between the groups....... In PTDM patients, glucose-induced glucagon suppression was significantly less pronounced (maximal suppression from baseline: 43 ± 12 vs. 65 ± 12%, P insulin secretion were significantly lower. The PTDM group also exhibited a significantly lower insulin response...

  14. Zip4 mediated zinc influx stimulates insulin secretion in pancreatic beta cells.

    Directory of Open Access Journals (Sweden)

    Alexandre B Hardy

    Full Text Available Zinc has an important role in normal pancreatic beta cell physiology as it regulates gene transcription, insulin crystallization and secretion, and cell survival. Nevertheless, little is known about how zinc is transported through the plasma membrane of beta cells and which of the class of zinc influx transporters (Zip is involved. Zip4 was previously shown to be expressed in human and mouse beta cells; however, its function there is still unknown. Therefore, the aim of this study was to define the zinc transport role of Zip4 in beta cells. To investigate this, Zip4 was over-expressed in MIN6 beta cells using a pCMV6-Zip4GFP plasmid. Organelle staining combined with confocal microscopy showed that Zip4 exhibits a widespread localization in MIN6 cells. Time-lapse zinc imaging experiments showed that Zip4 increases cytoplasmic zinc levels. This resulted in increased granular zinc content and glucose-stimulated insulin secretion. Interestingly, it is unlikely that the increased glucose stimulated insulin secretion was triggered by a modulation of mitochondrial function, as mitochondrial membrane potential remained unchanged. To define the role of Zip4 in-vivo, we generated a beta cell-specific knockout mouse model (Zip4BKO. Deletion of the Zip4 gene was confirmed in Zip4BKO islets by PCR, RT-PCR, and immuno-histochemistry. Zip4BKO mice showed slightly improved glucose homeostasis but no change in insulin secretion during an oral glucose tolerance test. While Zip4 was not found to be essential for proper glucose homeostasis and insulin secretion in vivo in mice, this study also found that Zip4 mediates increases in cytoplasmic and granular zinc pools and stimulates glucose dependant insulin secretion in-vitro.

  15. Fasting insulin has a stronger association with an adverse cardiometabolic risk profile than insulin resistance: the RISC study

    DEFF Research Database (Denmark)

    de Rooij, Susanne R; Dekker, Jacqueline M; Kozakova, Michaela

    2009-01-01

    OBJECTIVE: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis. DESIGN AND METHODS: The Relationship between Insulin...... insulin, a simple and practical measure, may be a stronger and independent contributor to cardiometabolic risk and atherosclerosis in a healthy population than hyperinsulinemic euglycemic clamp-derived insulin sensitivity.......OBJECTIVE: Fasting insulin concentrations are often used as a surrogate measure of insulin resistance. We investigated the relative contributions of fasting insulin and insulin resistance to cardiometabolic risk and preclinical atherosclerosis. DESIGN AND METHODS: The Relationship between Insulin...... of the metabolic syndrome in 1177 participants. Carotid artery intima media thickness (IMT) was measured by ultrasound to assess preclinical atherosclerosis. RESULTS: Fasting insulin was correlated with all elements of the metabolic syndrome. Insulin sensitivity (M/I) was correlated with most elements. The odds...

  16. Conditioned insulin secretion and meal feeding in rats.

    Science.gov (United States)

    Woods, S C; Vasselli, J R; Kaestner, E; Szakmary, G A; Milburn, P; Vitiello, M V

    1977-02-01

    Previous researchers have reported that rats placed upon a feeding regimen such that they receive only 2 hr of food per day (meal-fed rats) develop hyperinsulinemia at the time of the day associated with feeding, even in the absence of food. Controls fed ad lib had no such response. In a series of several experiments, meal-fed rats had elevated insulin levels at only the specific time of the day associated with feeding, and the increment of insulin at that time could be eliminated with atropine. Free-feeding controls, on the other hand, always had higher insulin levels than the meal-fed rats, did not have an elevation of insulin at the time of the day that the meal-fed rats normally ate, and had insulin values that were unaffected by atropine. Further experimentation showed that hyperinsulinemia could become associated with arbitrary stimuli always associated with eating for meal-fed rats. It is concluded that the hyperinsulinemia of meal-fed rats associated with their feeding time is a learned response.

  17. Perilipin 5 regulates islet lipid metabolism and insulin secretion in a cAMP-dependent manner: implication of its role in the postprandial insulin secretion.

    Science.gov (United States)

    Trevino, Michelle B; Machida, Yui; Hallinger, Daniel R; Garcia, Eden; Christensen, Aaron; Dutta, Sucharita; Peake, David A; Ikeda, Yasuhiro; Imai, Yumi

    2015-04-01

    Elevation of circulating fatty acids (FA) during fasting supports postprandial (PP) insulin secretion that is critical for glucose homeostasis and is impaired in diabetes. We tested our hypothesis that lipid droplet (LD) protein perilipin 5 (PLIN5) in β-cells aids PP insulin secretion by regulating intracellular lipid metabolism. We demonstrated that PLIN5 serves as an LD protein in human islets. In vivo, Plin5 and triglycerides were increased by fasting in mouse islets. MIN6 cells expressing PLIN5 (adenovirus [Ad]-PLIN5) and those expressing perilipin 2 (PLIN2) (Ad-PLIN2) had higher [(3)H]FA incorporation into triglycerides than Ad-GFP control, which support their roles as LD proteins. However, Ad-PLIN5 cells had higher lipolysis than Ad-PLIN2 cells, which increased further by 8-Br-cAMP, indicating that PLIN5 facilitates FA mobilization upon cAMP stimulation as seen postprandially. Ad-PLIN5 in islets enhanced the augmentation of glucose-stimulated insulin secretion by FA and 8-Br-cAMP in G-protein-coupled receptor 40 (GPR40)- and cAMP-activated protein kinase-dependent manners, respectively. When PLIN5 was increased in mouse β-cells in vivo, glucose tolerance after an acute exenatide challenge was improved. Therefore, the elevation of islet PLIN5 during fasting allows partitioning of FA into LD that is released upon refeeding to support PP insulin secretion in cAMP- and GPR40-dependent manners. © 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.

  18. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro

    Science.gov (United States)

    Keller, Amy C.; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B.; Kennelly, Edward J.

    2012-01-01

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p=0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p≤0.007, and p= 0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. PMID:22133295

  19. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro.

    Science.gov (United States)

    Keller, Amy C; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B; Kennelly, Edward J

    2011-12-15

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(E)-dien-19-al (1), momordicine I (2), momordicine II (3), 3-hydroxycucurbita-5,24-dien-19-al-7,23-di-O-β-glucopyranoside (4), and kuguaglycoside G (5). Treatments were compared to incubation with high glucose (27 mM) and the insulin secretagogue, glipizide (50 μM). At 125 μg/ml, an LC-ToF-MS characterized saponin-rich fraction stimulated insulin secretion significantly more than the DMSO vehicle, p=0.02. At concentrations 10 and 25 μg/ml, compounds 3 and 5 also significantly stimulated insulin secretion as compared to the vehicle, p≤0.007, and p=0.002, respectively. This is the first report of a saponin-rich fraction, and isolated compounds from M. charantia, stimulating insulin secretion in an in vitro, static incubation assay. Copyright © 2011 Elsevier GmbH. All rights reserved.

  20. Role of sialic acid in insulin action and the insulin resistance of diabetes mellitus

    International Nuclear Information System (INIS)

    Salhanick, A.I.; Amatruda, J.M.

    1988-01-01

    Adipocytes treated with neuraminidase show markedly reduced responsiveness to insulin without any alteration in insulin binding. In addition, several studies have separately demonstrated both insulin resistance and decreases in membrane sialic acid content and associated biosynthetic enzymes in diabetes mellitus. In the present study, the authors investigated the role that sialic acid residues may play in insulin action and in the hepatic insulin resistance associated with nonketotic diabetes. Primary cultures of hepatocytes from normal rats treated with neuraminidase demonstrated a dose-dependent decrease in insulin-stimulated lipogenesis. At a concentration of neuraminidase that decreases insulin action by 50%, 23% of total cellular sialic acid content was released. Neuraminidase-releasable sialic acid was significantly decreased in hepatocytes from diabetic rats and this was associated with significant insulin resistance. Treatment of hepatocytes from diabetic rats with cytidine 5'-monophospho-N-acetylneuraminic acid (CMP-NANA) enhanced insulin responsiveness 39%. The enhanced insulin responsiveness induced by CMP-NANA was blocked by cytidine 5'-monophosphate (CMP) suggesting that the CMP-NANA effect was catalyzed by a cell surface sialyl-transferase. CMP reduced neuraminidase-releasable [ 14 C]sialic acid incorporation into hepatocytes by 43%. The data demonstrate a role for cell surface sialic acid residues in hepatic insulin action and support a role for decreased cell surface sialic acid residues in the insulin resistance of diabetes mellitus

  1. Acceptance of insulin therapy: a long shot? Psychological insulin resistance in primary care

    NARCIS (Netherlands)

    Woudenberg, Y. J. C.; Lucas, C.; Latour, C.; Scholte Op Reimer, W. J. M.

    2012-01-01

    Diabet. Med. 29, 796802 (2012) Abstract Aim To explore which factors are associated with psychological insulin resistance in insulin-naive patients with Type 2 diabetes in primary care. Methods A sample of 101 insulin-naive patients with Type 2 diabetes completed self-administered questionnaires

  2. High Serum Advanced Glycation End Products Are Associated with Decreased Insulin Secretion in Patients with Type 2 Diabetes: A Brief Report

    Directory of Open Access Journals (Sweden)

    Tsuyoshi Okura

    2017-01-01

    Full Text Available Objective. Advanced glycation end products (AGEs are important in the pathophysiology of type 2 diabetes mellitus (T2DM. They directly cause insulin secretory defects in animal and cell culture models and may promote insulin resistance in nondiabetic subjects. We have developed a highly sensitive liquid chromatography-tandem mass spectrometry method for measuring AGEs in human serum. Here, we use this method to investigate the relationship between AGEs and insulin secretion and resistance in patients with T2DM. Methods. Our study involved 15 participants with T2DM not on medication and 20 nondiabetic healthy participants. We measured the AGE carboxyethyllysine (CEL, carboxymethyllysine (CML, and methyl-glyoxal-hydro-imidazolone (MG-H1. Plasma glucose and insulin were measured in these participants during a meal tolerance test, and the glucose disposal rate was measured during a euglycemic-hyperinsulinemic clamp. Results. CML and CEL levels were significantly higher in T2DM than non-DM participants. CML showed a significant negative correlation with insulin secretion, HOMA-%B, and a significant positive correlation with the insulin sensitivity index in T2DM participants. There was no correlation between any of the AGEs measured and glucose disposal rate. Conclusions. These results suggest that AGE might play a role in the development or prediction of insulin secretory defects in type 2 diabetes.

  3. Potent humanin analog increases glucose-stimulated insulin secretion through enhanced metabolism in the β cell.

    Science.gov (United States)

    Kuliawat, Regina; Klein, Laura; Gong, Zhenwei; Nicoletta-Gentile, Marianna; Nemkal, Anjana; Cui, Lingguang; Bastie, Claire; Su, Kai; Huffman, Derek; Surana, Manju; Barzilai, Nir; Fleischer, Norman; Muzumdar, Radhika

    2013-12-01

    Humanin (HN) is a 24-aa polypeptide that offers protection from Alzheimer's disease and myocardial infarction, increases insulin sensitivity, improves survival of β cells, and delays onset of diabetes. Here we examined the acute effects of HN on insulin secretion and potential mechanisms through which they are mediated. Effects of a potent HN analog, HNGF6A, on glucose-stimulated insulin secretion (GSIS) were assessed in vivo and in isolated pancreatic islets and cultured murine β cell line (βTC3) in vitro. Sprague-Dawley rats (3 mo old) that received HNGF6A required a significantly higher glucose infusion rate and demonstrated higher insulin levels during hyperglycemic clamps compared to saline controls. In vitro, compared to scrambled peptide controls, HNGF6A increased GSIS in isolated islets from both normal and diabetic mice as well as in βTC3 cells. Effects of HNGF6A on GSIS were dose dependent, K-ATP channel independent, and associated with enhanced glucose metabolism. These findings demonstrate that HNGF6A increases GSIS in whole animals, from isolated islets and from cells in culture, which suggests a direct effect on the β cell. The glucose-dependent effects on insulin secretion along with the established effects on insulin action suggest potential for HN and its analogs in the treatment of diabetes.

  4. Mitochondrial malic enzyme 3 is important for insulin secretion in pancreatic β-cells.

    Science.gov (United States)

    Hasan, Noaman M; Longacre, Melissa J; Stoker, Scott W; Kendrick, Mindy A; MacDonald, Michael J

    2015-03-01

    Pancreatic β-cells with severely knocked down cytosolic malic enzyme (ME1) and mitochondrial NAD(P) malic enzyme (ME2) show normal insulin secretion. The mitochondrial NADP malic enzyme (ME3) is very low in pancreatic β-cells, and ME3 was previously thought unimportant for insulin secretion. Using short hairpin RNAs that targeted one or more malic enzyme mRNAs in the same cell, we generated more than 25 stable INS-1 832/13-derived insulin cell lines expressing extremely low levels of ME1, ME2, and ME3 alone or low levels of two of these enzymes in the same cell line. We also used double targeting of the same Me gene to achieve even more severe reduction in Me1 and Me2 mRNAs and enzyme activities than we reported previously. Knockdown of ME3, but not ME1 or ME2 alone or together, inhibited insulin release stimulated by glucose, pyruvate or 2-aminobicyclo [2,2,1]heptane-2-carboxylic acid-plus-glutamine. The data suggest that ME3, far more than ME1 or ME2, is necessary for insulin release. Because ME3 enzyme activity is low in β-cells, its role in insulin secretion may involve a function other than its ME catalytic activity.

  5. Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

    OpenAIRE

    Catalano, Karyn J.; Maddux, Betty A.; Szary, Jaroslaw; Youngren, Jack F.; Goldfine, Ira D.; Schaufele, Fred

    2014-01-01

    Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further...

  6. Molecular Mechanisms of Chromium in Alleviating Insulin Resistance

    Science.gov (United States)

    Hua, Yinan; Clark, Suzanne; Ren, Jun; Sreejayan, Nair

    2011-01-01

    Type 2 diabetes is often associated with obesity, dyslipidemia, and cardiovascular anomalies and is a major health problem approaching global epidemic proportions. Insulin resistance, a prediabetic condition, precedes the onset of frank type 2 diabetes and offers potential avenues for early intervention to treat the disease. Although lifestyle modifications and exercise can reduce the incidence of diabetes, compliance has proved to be difficult, warranting pharmacological interventions. However, most of the currently available drugs that improve insulin sensitivity have adverse effects. Therefore, attractive strategies to alleviate insulin resistance include dietary supplements. One such supplement is chromium, which has been shown reduce insulin resistance in some, but not all, studies. Furthermore, the molecular mechanisms of chromium in alleviating insulin resistance remain elusive. This review examines emerging reports on the effect of chromium, as well as molecular and cellular mechanisms by which chromium may provide beneficial effects in alleviating insulin resistance. PMID:22423897

  7. Peripheral nervous system insulin resistance in ob/ob mice.

    Science.gov (United States)

    Grote, Caleb W; Groover, Anna L; Ryals, Janelle M; Geiger, Paige C; Feldman, Eva L; Wright, Douglas E

    2013-05-10

    A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. The results indicate that insulin signaling abnormalities documented in other "insulin sensitive" tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy.

  8. Peripheral nervous system insulin resistance in ob/ob mice

    Science.gov (United States)

    2013-01-01

    Background A reduction in peripheral nervous system (PNS) insulin signaling is a proposed mechanism that may contribute to sensory neuron dysfunction and diabetic neuropathy. Neuronal insulin resistance is associated with several neurological disorders and recent evidence has indicated that dorsal root ganglion (DRG) neurons in primary culture display altered insulin signaling, yet in vivo results are lacking. Here, experiments were performed to test the hypothesis that the PNS of insulin-resistant mice displays altered insulin signal transduction in vivo. For these studies, nondiabetic control and type 2 diabetic ob/ob mice were challenged with an intrathecal injection of insulin or insulin-like growth factor 1 (IGF-1) and downstream signaling was evaluated in the DRG and sciatic nerve using Western blot analysis. Results The results indicate that insulin signaling abnormalities documented in other “insulin sensitive” tissues (i.e. muscle, fat, liver) of ob/ob mice are also present in the PNS. A robust increase in Akt activation was observed with insulin and IGF-1 stimulation in nondiabetic mice in both the sciatic nerve and DRG; however this response was blunted in both tissues from ob/ob mice. The results also suggest that upregulated JNK activation and reduced insulin receptor expression could be contributory mechanisms of PNS insulin resistance within sensory neurons. Conclusions These findings contribute to the growing body of evidence that alterations in insulin signaling occur in the PNS and may be a key factor in the pathogenesis of diabetic neuropathy. PMID:24252636

  9. 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.

  10. Globular adiponectin ameliorates metabolic insulin resistance via AMPK-mediated restoration of microvascular insulin responses

    Science.gov (United States)

    Zhao, Lina; Fu, Zhuo; Wu, Jing; Aylor, Kevin W; Barrett, Eugene J; Cao, Wenhong; Liu, Zhenqi

    2015-01-01

    Abstract Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance, and microvasculature plays a critical role in the regulation of insulin action in muscle. Here we tested whether adiponectin replenishment could improve metabolic insulin sensitivity in male rats fed a high-fat diet (HFD) via the modulation of microvascular insulin responses. Male Sprague–Dawley rats were fed either a HFD or low-fat diet (LFD) for 4 weeks. Small resistance artery myograph changes in tension, muscle microvascular recruitment and metabolic response to insulin were determined. Compared with rats fed a LFD, HFD feeding abolished the vasodilatory actions of globular adiponectin (gAd) and insulin on pre-constricted distal saphenous arteries. Pretreatment with gAd improved insulin responses in arterioles isolated from HFD rats, which was blocked by AMP-activated protein kinase (AMPK) inhibition. Similarly, HFD abolished microvascular responses to either gAd or insulin and decreased insulin-stimulated glucose disposal by ∼60%. However, supplementing gAd fully rescued insulin’s microvascular action and significantly improved the metabolic responses to insulin in HFD male rats and these actions were abolished by inhibition of either AMPK or nitric oxide production. We conclude that HFD induces vascular adiponectin and insulin resistance but gAd administration can restore vascular insulin responses and improve insulin’s metabolic action via an AMPK- and nitric oxide-dependent mechanism in male rats. Key points Adiponectin is an adipokine with anti-inflammatory and anti-diabetic properties. Hypoadiponectinaemia is closely associated with endothelial dysfunction and insulin resistance in obesity and diabetes. Insulin resistance is present in muscle microvasculature and this may contribute to decreased insulin delivery to, and action in, muscle. In this study we examined whether adiponectin ameliorates metabolic insulin resistance by affecting muscle

  11. Combined contributions of over-secreted glucagon-like peptide 1 and suppressed insulin secretion to hyperglycemia induced by gatifloxacin in rats

    Energy Technology Data Exchange (ETDEWEB)

    Yu, Yunli, E-mail: chrisyu1255@yahoo.com.cn [Department of Pharmaceutics, The Second Affiliated Hospital of Soochow University, Suzhou 215004 (China); Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Wang, Xinting, E-mail: wxinting1986@yahoo.com.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Can, E-mail: ltsan@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Yao, Dan, E-mail: erinyao@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Shanghai Institute of Materia Medica, Shanghai 201203 (China); Hu, Mengyue, E-mail: juliahmy@126.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Li, Jia, E-mail: ljbzd@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Hu, Nan, E-mail: hn_324@163.com [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Li, E-mail: liulee@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China); Liu, Xiaodong, E-mail: xdliu@cpu.edu.cn [Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing 210009 (China)

    2013-02-01

    Accumulating evidences have showed that gatifloxacin causes dysglycemia in both diabetic and non-diabetic patients. Our preliminary study demonstrated that gatifloxacin stimulated glucagon-like peptide 1 (GLP-1) secretion from intestinal cells. The aim of the study was to investigate the association between gatifloxacin-stimulated GLP-1 release and dysglycemia in both normal and streptozotocin-induced diabetic rats and explore the possible mechanisms. Oral administration of gatifloxacin (100 mg/kg/day and 200 mg/kg/day) for 3 and 12 days led to marked elevation of GLP-1 levels, accompanied by significant decrease in insulin levels and increase in plasma glucose. Similar results were found in normal rats treated with 3-day gatifloxacin. Gatifloxacin-stimulated GLP-1 release was further confirmed in NCI-H716 cells, which was abolished by diazoxide, a K{sub ATP} channel opener. QT-PCR analysis showed that gatifloxacin also upregulated expression of proglucagon and prohormone convertase 3 mRNA. To clarify the contradiction on elevated GLP-1 without insulinotropic effect, effects of GLP-1 and gatifloxacin on insulin release were investigated using INS-1 cells. We found that short exposure (2 h) to GLP-1 stimulated insulin secretion and biosynthesis, whereas long exposure (24 h and 48 h) to high level of GLP-1 inhibited insulin secretion and biosynthesis. Moreover, we also confirmed gatifloxacin acutely stimulated insulin secretion while chronically inhibited insulin biosynthesis. All the results gave an inference that gatifloxacin stimulated over-secretion of GLP-1, in turn, high levels of GLP-1 and gatifloxacin synergistically impaired insulin release, worsening hyperglycemia. -- Highlights: ► Gatifloxacin induced hyperglycemia both in diabetic rats and normal rats. ► Gatifloxacin enhanced GLP-1 secretion but inhibited insulin secretion in rats. ► Long-term exposure to high GLP-1 inhibited insulin secretion and biosynthesis. ► GLP-1 over-secretion may be

  12. 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.......Skeletal muscle is the largest tissues in the human body and is considered the primary target for insulin-stimulated glucose disposal. In skeletal muscle, binding of the insulin to insulin receptor (IR) initiates a signaling cascade that results in the translocation of the insulin-sensitive glucose...

  13. Insulin Secretion in Bantu with Siderosis or Hepatoma*

    African Journals Online (AJOL)

    1971-08-14

    Aug 14, 1971 ... Similar glucose and insulin studies were carried out on a group of 11 Bantu males from H. F. Verwoerd Hospital,. "Date received: 8 April 1971. in whom a diagnosis of hepatoma was made after liver biopsy. Tbeir ages ranged from 37 to 65 years. Control Group. A group of 25 Bantu males served as controls.

  14. Relationship among resistance to the insulin and obesity in Zacatecas population

    International Nuclear Information System (INIS)

    Zapata R, P. G.; Badillo A, V.

    2012-10-01

    The Zacatecas State (Mexico) occupies the second national place in obesity, although the adults have a bigger incidence every time exist more minors that present this problem which can facilitate other illnesses like diabetes and hypertension. The first resistance references to the insulin were made by Himsworth in 1936, when he referred to insulin-resistant and insulin-sensitive diabetics. The resistance to the insulin, as event pathogen primary in the diabetes mellitus type 2 is derived of the obesity, what implies a subnormal biological response to the actions of the hormone in the carbohydrates, proteins and lipids metabolism. In this work was carried out a study of insulin levels for the Radioimmunoassay method in 40 patients with evident obesity and 8 patients with normal weight in order to evaluate these levels according to their age and abdominal circumference. Three correlations were made for both groups (obese and normal), the first correlation indicates the size of the waist with the insulin quantity, according to the arrangements that shows the correlation is bigger in all; what means that there is a great dependence among the size of the waist and the insulin quantity that contain. The second correlation is the age with the insulin that although is small, indicates that the age does not important for the insulin quantity that is secreted. The third and last realized correlation was of the age with the waist, and according to the results correlation also exists, but this is not significant as the first correlation. Therefore is considered existent the relationship between obesity and resistance to the insulin. (Author)

  15. Early phase glucagon and insulin secretory abnormalities, but not incretin secretion, are similarly responsible for hyperglycemia after ingestion of nutrients

    DEFF Research Database (Denmark)

    Yabe, Daisuke; Kuroe, Akira; Watanabe, Koin

    2015-01-01

    AIMS: Hypersecretion of glucagon and reduced insulin secretion both contribute to hyperglycemia in type 2 diabetes (T2DM). However, the relative contributions of impaired glucagon and insulin secretions in glucose excursions at the various stages of T2DM development remain to be determined. METHO...

  16. Metabolic syndrome and insulin resistance in obese adolescents

    Directory of Open Access Journals (Sweden)

    Amanda Oliva Gobato

    2014-03-01

    Full Text Available Objective: To verify the prevalence of metabolic syndrome and insulin resistance in obese adolescents and its relationship with different body composition indicators. Methods: A cross-sectional study comprising 79 adolescents aged ten to 18 years old. The assessed body composition indicators were: body mass index (BMI, body fat percentage, abdominal circumference, and subcutaneous fat. The metabolic syndrome was diagnosed according to the criteria proposed by Cook et al. The insulin resistance was determined by the Homeostasis Model Assessment for Insulin Resistance (HOMA-IR index for values above 3.16. The analysis of ROC curves was used to assess the BMI and the abdominal circumference, aiming to identify the subjects with metabolic syndrome and insulin resistance. The cutoff point corresponded to the percentage above the reference value used to diagnose obesity. Results: The metabolic syndrome was diagnosed in 45.5% of the patients and insulin resistance, in 29.1%. Insulin resistance showed association with HDL-cholesterol (p=0.032 and with metabolic syndrome (p=0.006. All body composition indicators were correlated with insulin resistance (p<0.01. In relation to the cutoff point evaluation, the values of 23.5 and 36.3% above the BMI reference point allowed the identification of insulin resistance and metabolic syndrome. The best cutoff point for abdominal circumference to identify insulin resistance was 40%. Conclusions: All body composition indicators, HDL-cholesterol and metabolic syndrome showed correlation with insulin resistance. The BMI was the most effective anthropometric indicator to identify insulin resistance.

  17. Insulin resistance in drug naive patients with multiple sclerosis

    OpenAIRE

    Kostić Smiljana; Kolić Ivana; Raičević Ranko; Stojanović Zvezdana; Kostić Dejan; Dinčić Evica

    2017-01-01

    Background/Aim. Due to the fact that there is a relatively small number of data related to systemic insulin abnormalities in the multiple sclerosis (MS), the main objective of our study was to determine whether a dysbalance of glucose and insulin metabolism exist in patients with natural course of MS. Our hypothesis was that the metabolic disorder that characterizes state of the insulin resistance (IR) and reduced insulin sensitivity (IS) in untreated patie...

  18. Plasma kisspeptin levels are associated with insulin secretion in nondiabetic individuals.

    Directory of Open Access Journals (Sweden)

    Francesco Andreozzi

    Full Text Available To evaluate if plasma kisspeptin concentrations are associated with insulin secretion, as suggested by recent in vitro studies, independently of confounders. 261 nondiabetic subjects were stratified into tertiles according to kisspeptin values. Insulin secretion was assessed using indexes derived from oral glucose tolerance test (OGTT. After adjusting for age, gender, and BMI, subjects in the highest (tertile 3 kisspeptin group exhibited significantly lower values of insulinogenic index, corrected insulin response (CIR30, and Stumvoll indexes for first-phase and second-phase insulin release as compared with low (tertile 1 or intermediate (tertile 2 kisspeptin groups. Univariate correlations between kisspeptin concentration and metabolic variables showed that kisspeptin concentration was significantly and positively correlated with age, blood pressure, and 2-h post-load glucose, and inversely correlated with BMI, and waist circumference. There was an inverse relationship between kisspeptin levels and OGTT-derived indexes of glucose-stimulated insulin secretion. A multivariable regression analysis in a model including all the variables significantly correlated with kisspeptin concentration showed thar age (β = -0.338, P<0.0001, BMI (β = 0.272, P<0.0001, 2-h post-load glucose (β = -0.229, P<0.0001, and kisspeptin (β = -0.105, P = 0.03 remained associated with insulinogenic index. These factors explained 34.6% of the variance of the insulinogenic index. In conclusion, kisspeptin concentrations are associated with insulin secretion independently of important determinants of glucose homeostasis such as gender, age, adiposity, 2-h post-load glucose, and insulin sensitivity.

  19. Pigment epithelium-derived factor (PEDF) regulates metabolism and insulin secretion from a clonal rat pancreatic beta cell line BRIN-BD11 and mouse islets.

    Science.gov (United States)

    Chen, Younan; Carlessi, Rodrigo; Walz, Nikita; Cruzat, Vinicius Fernandes; Keane, Kevin; John, Abraham N; Jiang, Fang-Xu; Carnagarin, Revathy; Dass, Crispin R; Newsholme, Philip

    2016-05-05

    Pigment epithelium-derived factor (PEDF) is a multifunctional glycoprotein, associated with lipid catabolism and insulin resistance. In the present study, PEDF increased chronic and acute insulin secretion in a clonal rat β-cell line BRIN-BD11, without alteration of glucose consumption. PEDF also stimulated insulin secretion from primary mouse islets. Seahorse flux analysis demonstrated that PEDF did not change mitochondrial respiration and glycolytic function. The cytosolic presence of the putative PEDF receptor - adipose triglyceride lipase (ATGL) - was identified, and ATGL associated stimulation of glycerol release was robustly enhanced by PEDF, while intracellular ATP levels increased. Addition of palmitate or ex vivo stimulation with inflammatory mediators induced β-cell dysfunction, effects not altered by the addition of PEDF. In conclusion, PEDF increased insulin secretion in BRIN-BD11 and islet cells, but had no impact on glucose metabolism. Thus elevated lipolysis and enhanced fatty acid availability may impact insulin secretion following PEDF receptor (ATGL) stimulation. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  20. Insulin-degrading enzyme is exported via an unconventional protein secretion pathway

    Directory of Open Access Journals (Sweden)

    Leissring Malcolm A

    2009-01-01

    Full Text Available Abstract Insulin-degrading enzyme (IDE is a ubiquitously expressed zinc-metalloprotease that degrades several pathophysiologically significant extracellular substrates, including insulin and the amyloid β-protein (Aβ, and accumulating evidence suggests that IDE dysfunction may be operative in both type 2 diabetes mellitus and Alzheimer disease (AD. Although IDE is well known to be secreted by a variety of cell types, the underlying trafficking pathway(s remain poorly understood. To address this topic, we investigated the effects of known inhibitors or stimulators of protein secretion on the secretion of IDE from murine hepatocytes and HeLa cells. IDE secretion was found to be unaffected by the classical secretion inhibitors brefeldin A (BFA, monensin, or nocodazole, treatments that readily inhibited the secretion of α1-antitrypsin (AAT overexpressed in the same cells. Using a novel cell-based Aβ-degradation assay, we show further that IDE secretion was similarly unaffected by multiple stimulators of protein secretion, including glyburide and 3'-O-(4-benzoylbenzoyl-ATP (Bz-ATP. The calcium ionophore, A23187, increased extracellular IDE activity, but only under conditions that also elicited cytotoxicity. Our results provide the first biochemical evidence that IDE export is not dependent upon the classical secretion pathway, thereby identifying IDE as a novel member of the select class of unconventionally secreted proteins. Further elucidation of the mechanisms underlying IDE secretion, which would be facilitated by the assays described herein, promises to uncover processes that might be defective in disease or manipulated for therapeutic benefit.

  1. High Glucose Predisposes Gene Expression and ERK Phosphorylation to Apoptosis and Impaired Glucose-Stimulated Insulin Secretion via the Cytoskeleton

    Science.gov (United States)

    Yeo, Ronne Wee Yeh; Yang, Kaiyuan; Li, GuoDong; Lim, Sai Kiang

    2012-01-01

    Chronic high glucose (HG) inflicts glucotoxicity on vulnerable cell types such as pancreatic β cells and contributes to insulin resistance and impaired insulin secretion in diabetic patients. To identify HG-induced cellular aberrations that are candidate mediators of glucotoxicity in pancreatic β cells, we analyzed gene expression in ERoSHK6, a mouse insulin-secreting cell line after chronic HG exposure (six-day exposure to 33.3 mM glucose). Chronic HG exposure which reduced glucose-stimulated insulin secretion (GSIS) increased transcript levels of 185 genes that clustered primarily in 5 processes namely cellular growth and proliferation; cell death; cellular assembly and organization; cell morphology; and cell-to-cell signaling and interaction. The former two were validated by increased apoptosis of ERoSHK6 cells after chronic HG exposure and reaffirmed the vulnerability of β cells to glucotoxicity. The three remaining processes were partially substantiated by changes in cellular morphology and structure, and instigated an investigation of the cytoskeleton and cell-cell adhesion. These studies revealed a depolymerized actin cytoskeleton that lacked actin stress fibers anchored at vinculin-containing focal adhesion sites as well as loss of E-cadherin-mediated cell-cell adherence after exposure to chronic HG, and were concomitant with constitutive ERK1/2 phosphorylation that was refractory to serum and glucose deprivation. Although inhibition of ERK phosphorylation by PD98059 promoted actin polymerization, it increased apoptosis and GSIS impairment. These findings suggest that ERK phosphorylation is a proximate regulator of cellular processes targeted by chronic HG-induced gene expression and that dynamic actin polymerization and depolymerization is important in β cell survival and function. Therefore, chronic HG alters gene expression and signal transduction to predispose the cytoskeleton towards apoptosis and GSIS impairment. PMID:23024780

  2. Insulin Secretion in Bantu with Siderosis or Hepatoma | De Bruin ...

    African Journals Online (AJOL)

    The IR and concomitant GTC was evaluated in 10 siderotic Bantu patients and in 11 Bantu patients suffering from hepatoma. A normal IR was found in the siderotic Bantu, occurring, however, at much higher blood glucose levels than those of the control Bantu group. This relatively low IR is ascribed to impaired secretion of ...

  3. 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.

  4. Determinants of High Fasting Insulin and Insulin Resistance Among Overweight/Obese Adolescents

    OpenAIRE

    Jerri Chiu Yun Ling; Mohd Nahar Azmi Mohamed; Muhammad Yazid Jalaludin; Sanjay Rampal; Nur Lisa Zaharan; Zahurin Mohamed

    2016-01-01

    Hyperinsulinaemia is the earliest subclinical metabolic abnormality, which precedes insulin resistance in obese children. An investigation was conducted on the potential predictors of fasting insulin and insulin resistance among overweight/obese adolescents in a developing Asian country. A total of 173 overweight/obese (BMI?>?85th percentile) multi-ethnic Malaysian adolescents aged 13 were recruited from 23 randomly selected schools in this cross-sectional study. Waist circumference (WC), bod...

  5. Integrating Mechanisms for Insulin Resistance: Common Threads and Missing Links

    Science.gov (United States)

    Samuel, Varman T.; Shulman, Gerald I.

    2012-01-01

    Insulin resistance is a complex metabolic disorder that defies a single etiological pathway. Accumulation of ectopic lipid metabolites, activation of the unfolded protein response (UPR) pathway and innate immune pathways have all been implicated in the pathogenesis of insulin resistance. However, these pathways are also closely linked to changes in fatty acid uptake, lipogenesis, and energy expenditure that can impact ectopic lipid deposition. Ultimately, accumulation of specific lipid metabolites (diacylglycerols and/or ceramides) in liver and skeletal muscle, may be a common pathway leading to impaired insulin signaling and insulin resistance. PMID:22385956

  6. Direct Substrate Delivery Into Mitochondrial Fission-Deficient Pancreatic Islets Rescues Insulin Secretion.

    Science.gov (United States)

    Kabra, Uma D; Pfuhlmann, Katrin; Migliorini, Adriana; Keipert, Susanne; Lamp, Daniel; Korsgren, Olle; Gegg, Moritz; Woods, Stephen C; Pfluger, Paul T; Lickert, Heiko; Affourtit, Charles; Tschöp, Matthias H; Jastroch, Martin

    2017-05-01

    In pancreatic β-cells, mitochondrial bioenergetics control glucose-stimulated insulin secretion. Mitochondrial dynamics are generally associated with quality control, maintaining the functionality of bioenergetics. By acute pharmacological inhibition of mitochondrial fission protein Drp1 , we demonstrate in this study that mitochondrial fission is necessary for glucose-stimulated insulin secretion in mouse and human islets. We confirm that genetic silencing of Drp1 increases mitochondrial proton leak in MIN6 cells. However, our comprehensive analysis of pancreatic islet bioenergetics reveals that Drp1 does not control insulin secretion via its effect on proton leak but instead via modulation of glucose-fueled respiration. Notably, pyruvate fully rescues the impaired insulin secretion of fission-deficient β-cells, demonstrating that defective mitochondrial dynamics solely affect substrate supply upstream of oxidative phosphorylation. The present findings provide novel insights into how mitochondrial dysfunction may cause pancreatic β-cell failure. In addition, the results will stimulate new thinking in the intersecting fields of mitochondrial dynamics and bioenergetics, as treatment of defective dynamics in mitochondrial diseases appears to be possible by improving metabolism upstream of mitochondria. © 2017 by the American Diabetes Association.

  7. Involvement of nitric oxide in neuroglycopenia-induced insulin and glucagon secretion in the mouse

    NARCIS (Netherlands)

    Ahrén, Bo; Karlsson, Sven; Scheurink, Anton J.W.; Steffens, Anton B.

    1995-01-01

    Neuroglycopenia induced by administration of 2-deoxy-D-glucose is known to stimulate the secretion of both insulin and glucagon in mice by a mechanism that is dependent on neural activity. In the present study, we examined whether the neurotransmitter nitric oxide (NO) is involved in this process.

  8. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study

    DEFF Research Database (Denmark)

    Gudmundsdottir, Valborg; Pedersen, Helle Krogh; Allebrandt, Karla Viviani

    2018-01-01

    cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one...

  9. Physical activity, eating patterns, and insulin resistance in obesity

    OpenAIRE

    Emy Huriyati; Perdana Samekto Nugroho; Rina Susilowaty; Madarina Julia

    2014-01-01

    Background Unhealthy eating patterns and physical inactivity are associated with obesity. Insulin resistance, an early sign of type 2 diabetes mellitus, is common in obese individuals. Objective To assess for an association between physical activity and eating patterns to insulin resistance in obese female adolescents. Methods Subjects were 77 obese female adolescents aged 13-15 years. Peripheral blood specimens were obtained for measurements of fasting blood glucose, insulin, and the...

  10. [Effect of mazindol on insulin and glucagon secretion in ventromedial hypothalamic obese rats].

    Science.gov (United States)

    Usami, M; Seino, Y; Nishi, S; Nakahara, H; Ikeda, M; Matsukura, S; Imura, H

    1985-04-01

    The effect of mazindol on insulin and glucagon secretion was studied in ventromedial hypothalamic lesioned (VMH) obese rats with hyperinsulinemia and VMH sham rats. Three weeks after the VMH or sham operation, VMH and sham rats were divided into two groups: one was fed diet containing mazindol (50 mg/kg) and the other was fed diet without mazindol. They were housed three more weeks before the experiment. Mazindol reduced significantly body weight increase and calorie intake in VMH rats, but not in sham rats. In addition, the fasting plasma insulin level and the arginine-induced insulin secretion in VMH rats treated with mazindol were significantly lower than those in the VMH rats without treatment of mazindol. On the other hand, in both in vivo and in vitro experiments, mazindol produced no significant change in the insulin secretion of sham-operated rats. These results suggest that mazindol suppresses hypersecretion of insulin in VMH rats probably through an anorectic effect and/or suppression of vagal hyperactivity.

  11. Whole-Body and Hepatic Insulin Resistance in Obese Children

    Science.gov (United States)

    Ibarra-Reynoso, Lorena del Rocío; Pisarchyk, Liudmila; Pérez-Luque, Elva Leticia; Garay-Sevilla, Ma. Eugenia; Malacara, Juan Manuel

    2014-01-01

    Background Insulin resistance may be assessed as whole body or hepatic. Objective To study factors associated with both types of insulin resistance. Methods Cross-sectional study of 182 obese children. Somatometric measurements were registered, and the following three adiposity indexes were compared: BMI, waist-to-height ratio and visceral adiposity. Whole-body insulin resistance was evaluated using HOMA-IR, with 2.5 as the cut-off point. Hepatic insulin resistance was considered for IGFBP-1 level quartiles 1 to 3 (HOMA-IR was negatively associated with IGFBP-1 and positively associated with BMI, triglycerides, leptin and mother's BMI. Girls had increased HOMA-IR. IGFBP-1 was negatively associated with waist-to-height ratio, age, leptin, HOMA-IR and IGF-I. We did not find HOMA-IR or IGFBP-1 associated with fatty liver. Conclusion In school-aged children, BMI is the best metric to predict whole-body insulin resistance, and waist-to-height ratio is the best predictor of hepatic insulin resistance, indicating that central obesity is important for hepatic insulin resistance. The reciprocal negative association of IGFBP-1 and HOMA-IR may represent a strong interaction of the physiological processes of both whole-body and hepatic insulin resistance. PMID:25411786

  12. Natural killer T cells in adipose tissue prevent insulin resistance

    NARCIS (Netherlands)

    Schipper, H.S.; Rakhshandehroo, M.; Graaf, van de S.F.J.; Venken, K.; Koppen, A.; Stienstra, R.; Prop, S.; Meerding, J.; Hamers, N.; Besra, G.S.; Boon, den L.; Nieuwenhuis, E.E.S.; Elewaut, D.; Prakken, B.; Kersten, A.H.; Boes, M.; Kalkhoven, E.

    2012-01-01

    Lipid overload and adipocyte dysfunction are key to the development of insulin resistance and can be induced by a high-fat diet. CD1d-restricted invariant natural killer T (iNKT) cells have been proposed as mediators between lipid overload and insulin resistance, but recent studies found decreased

  13. C16:0-Ceramide Signals Insulin Resistance

    OpenAIRE

    Hla, Timothy; Kolesnick, Richard

    2014-01-01

    A substantive literature has accumulated implicating sphingolipids, in particular ceramides, as mediators of insulin resistance in metabolic syndrome. Thanks to recent technical advances in mouse genetics and lipidomics, two independent laboratories identify the same sphingolipid, C16:0-ceramide, as principal mediator of obesity-related insulin resistance.

  14. Determinants of insulin resistance in renal transplant recipients

    NARCIS (Netherlands)

    Oterdoom, Leendert H.; de Vries, Aiko P. J.; Gansevoort, Ron T.; van Son, Willem J.; van der Heide, Jaap J. Homan; Ploeg, Rutger J.; de Jong, Paul E.; Gans, Reinold O. B.; Bakker, Stephan J. L.

    2007-01-01

    Background. Insulin resistance is considered to play an important role in the development of cardiovascular disease, which limits long-term renal transplant survival. Renal transplant recipients are more insulin -resistant compared with healthy controls. It is not known to date which factors relate

  15. Insulin resistance : pathophysiology in South Asians & therapeutic strategies

    NARCIS (Netherlands)

    Sleddering, Maria Alexandra

    2014-01-01

    This thesis describes the pathophysiology of insulin resistance in the South Asian population and comprises studies on pharmacological and weight loss interventions in insulin resistant patients. Because of the increasing number of patients with obesity and T2DM, more research is needed to identify

  16. Method for preventing and/or treating insulin resistance

    NARCIS (Netherlands)

    Nieuwdorp, M.; Vos, de W.M.

    2013-01-01

    The present invention describes use of Eubacterium hallii et rel. and/or Alcaligenes faecalis et rel., as well as pharmaceutical, food, or feed compositions comprising these bacteria, as a medicament, in particular for preventing and/or treating insulin resistance and/or insulin resistance-related

  17. Insulin resistance and atherosclerosis : the role of visceral fat

    NARCIS (Netherlands)

    Gast, K.B.

    2016-01-01

    The main objective of this thesis was to unravel relationships between obesity, insulin resistance, hyperglycemia, and atherosclerosis. It is well-established that patients with type 2 diabetes have a 2- to 3-fold increased risk of cardiovascular disease. We investigated whether insulin resistance

  18. Diagnosis and treatment of obese children with insulin resistance

    NARCIS (Netherlands)

    Aa, van der M.P.

    2016-01-01

    Prevalence of childhood obesity is increasing. Insulin resistance is a consequence of childhood obesity, and it has a keyrole in the development of cardiometabolic complications, such as diabetes mellitus. In the first part of this thesis, the epidemiology of insulin resistance has been described.

  19. The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats

    Science.gov (United States)

    Godini, Aliashraf; Ghasemi, Asghar

    2015-01-01

    Although the insulin secretion deficit in hypothyroid male rats has been documented, the underling mechanisms of the effect of hypothyroidism on insulin secretion are not clear. Isolated islets of the PTU-induced hypothyroid and control rats were exposed to glibenclamide, acetylcholine, and nifedipine in the presence of glucose concentrations of 2.8 or 8.3 and 16.7 mmol/L. Glucokinase and hexokinase specific activity, glucokinase content, and glucose transporter 2 protein expression were also determined in the isolated islets. Isolated islets from the hypothyroid rats showed a defect in insulin secretion in response to high glucose. In the presence of glibenclamide or acetylcholine, the isolated islets from the hypothyroid and control rats stimulated by glucose concentration of 16.7 mmol/L secreted similar amounts of insulin. In the presence of glucose concentrations of 8.3 mmol/L and 16.7 mmol/L, nifedipine was able to diminish insulin secretion from isolated islets of both groups, indicating that probably the defect may not arise from L type calcium channels or the steps beyond depolarization or the elements involved in the acetylcoline signaling pathway. Glucokinase content and hexokinase specific activity were also the same in the control and hypothyroid groups. On the other hand, glucokinase specific activity and glucose transporter 2 protein expression were significantly (phypothyroid rats (6.50 ± 0.46 mU/min/mg protein and 0.55 ± 0.09 arbitrary unit) compared to the controls (10.93 ± 0.83 mU/min/mg protein and 0.98 ± 0.07 arbitrary unit) respectively. In conclusion, the results of this study indicated that hypothyroidism reduced insulin secretion from isolated pancreatic islets, which confirms the finding of the previous studies; in addition, the insulin secretion deficit observed in hypothyroid rats may arise from the abnormalities in some parts of the glucose sensor apparatus of the pancreatic islets including glucokinase activity and glucose

  20. The Possible Mechanisms of the Impaired Insulin Secretion in Hypothyroid Rats.

    Directory of Open Access Journals (Sweden)

    Aliashraf Godini

    Full Text Available Although the insulin secretion deficit in hypothyroid male rats has been documented, the underling mechanisms of the effect of hypothyroidism on insulin secretion are not clear. Isolated islets of the PTU-induced hypothyroid and control rats were exposed to glibenclamide, acetylcholine, and nifedipine in the presence of glucose concentrations of 2.8 or 8.3 and 16.7 mmol/L. Glucokinase and hexokinase specific activity, glucokinase content, and glucose transporter 2 protein expression were also determined in the isolated islets. Isolated islets from the hypothyroid rats showed a defect in insulin secretion in response to high glucose. In the presence of glibenclamide or acetylcholine, the isolated islets from the hypothyroid and control rats stimulated by glucose concentration of 16.7 mmol/L secreted similar amounts of insulin. In the presence of glucose concentrations of 8.3 mmol/L and 16.7 mmol/L, nifedipine was able to diminish insulin secretion from isolated islets of both groups, indicating that probably the defect may not arise from L type calcium channels or the steps beyond depolarization or the elements involved in the acetylcoline signaling pathway. Glucokinase content and hexokinase specific activity were also the same in the control and hypothyroid groups. On the other hand, glucokinase specific activity and glucose transporter 2 protein expression were significantly (p<0.001 and p<0.01 respectively lower in the islets isolated from the hypothyroid rats (6.50 ± 0.46 mU/min/mg protein and 0.55 ± 0.09 arbitrary unit compared to the controls (10.93 ± 0.83 mU/min/mg protein and 0.98 ± 0.07 arbitrary unit respectively. In conclusion, the results of this study indicated that hypothyroidism reduced insulin secretion from isolated pancreatic islets, which confirms the finding of the previous studies; in addition, the insulin secretion deficit observed in hypothyroid rats may arise from the abnormalities in some parts of the glucose sensor

  1. Factors influencing insulin and glucagon secretion in lean and genetically obese mice

    International Nuclear Information System (INIS)

    Beloff-Chain, A.; Newman, M.E.; Mansford, K.R.L.

    1977-01-01

    The control of 125 I-labelled insulin and glucagon secretion from isolated pancreatic islets of lean and genetically obese mice has been compared. The enlarged islets of obese mouse pancreas and islets of obese mice maintained on a restricted diet manifested a greater response to glucose stimulation of insulin secretion than the lean mice islets. The glucagon content of the islets, the secretion of glucagon in a medium containing 150 mg% glucose and the stimulation of glucagon secretion by arginine did not differ significantly in the two groups. Adrenaline stimulated glucagon secretion in vitro from obese mice but not from lean mice. Antiinsulin serum injections into obese mice increased the plasma glucagon levels about twofold and had no effect on glucagon levels in lean mice, although the level of hyperglycaemia was the same in both groups. It is suggested that the suppression of glucagon release by glucose requires a higher concentration of insulin in the obese mouse pancreas than in lean mice. (orig./AJ) [de

  2. Redifferentiation of insulin-secreting cells after in vitro expansion of adult human pancreatic islet tissue

    International Nuclear Information System (INIS)

    Lechner, Andreas; Nolan, Anna L.; Blacken, Robyn A.; Habener, Joel F.

    2005-01-01

    Cellular replacement therapy holds promise for the treatment of diabetes mellitus but donor tissue is severely limited. Therefore, we investigated whether insulin-secreting cells could be differentiated in vitro from a monolayer of cells expanded from human donor pancreatic islets. We describe a three-step culture protocol that allows for the efficient generation of insulin-producing cell clusters from in vitro expanded, hormone-negative cells. These clusters express insulin at levels of up to 34% that of average freshly isolated human islets and secrete C-peptide upon membrane depolarization. They also contain cells expressing the other major islet hormones (glucagon, somatostatin, and pancreatic polypeptide). The source of the newly differentiated endocrine cells could either be indigenous stem/progenitor cells or the proliferation-associated dedifferentiation and subsequent redifferentiation of mature endocrine cells. The in vitro generated cell clusters may be efficacious in providing islet-like tissue for transplantation into diabetic recipients

  3. Successful treatment of type B insulin resistance with rituximab.

    Science.gov (United States)

    Manikas, Emmanouil-Dimitrios; Isaac, Iona; Semple, Robert K; Malek, Rana; Führer, Dagmar; Moeller, Lars C

    2015-05-01

    Type B insulin resistance is a very rare disease caused by autoantibodies against the insulin receptor. The mortality of type B insulin resistance is high (>50%), and management of this disease is not yet standardized. We report the successful treatment of a patient with type B insulin resistance with rituximab, cyclophosphamide, and prednisone. A 45-year-old woman presented with unintended weight loss of 20 kg, unusually widespread acanthosis nigricans, and glucose levels > 500 mg/dL, which could not be controlled with up to 600 IU/d of insulin. Because of the severity of the insulin resistance combined with features of insulin deficiency, type B insulin resistance was suspected. Detection of high levels of insulin receptor autoantibodies confirmed the diagnosis. Neither immunosuppressive therapy with Ig iv nor plasmapheresis had an effect on glucose levels or insulin dose. Because the patient's condition was deteriorating, we started rituximab (750 mg/m(2) in two doses 2 wk apart) together with cyclophosphamide (100 mg/d orally) and dexamethasone 40 mg/d for 4 days. Two months after initiation of rituximab therapy, fasting glucose levels ranged from 80 to 110 mg/dL and could be controlled with very low insulin doses. Glycated hemoglobin decreased from 11.8 to 6.5%. Two months later, insulin therapy was stopped, and the patient showed normal blood glucose readings. In this patient with type B insulin resistance, Ig treatment and plasmapheresis failed to improve the condition. Finally, treatment with rituximab, cyclophosphamide, and steroids was successful in inducing a complete remission.

  4. Brain natriuretic peptide and insulin resistance in older adults.

    Science.gov (United States)

    Kim, F; Biggs, M L; Kizer, J R; Brutsaert, E F; de Filippi, C; Newman, A B; Kronmal, R A; Tracy, R P; Gottdiener, J S; Djoussé, L; de Boer, I H; Psaty, B M; Siscovick, D S; Mukamal, K J

    2017-02-01

    Higher levels of brain natriuretic peptide (BNP) have been associated with a decreased risk of diabetes in adults, but whether BNP is related to insulin resistance in older adults has not been established. N-terminal of the pro hormone brain natriuretic peptide (NT-pro BNP) was measured among Cardiovascular Health Study participants at the 1989-1990, 1992-1993 and 1996-1997 examinations. We calculated measures of insulin resistance [homeostatic model assessment of insulin resistance (HOMA-IR), quantitative insulin sensitivity check index (QUICKI), Gutt index, Matsuda index] from fasting and 2-h concentrations of glucose and insulin among 3318 individuals with at least one measure of NT-proBNP and free of heart failure, coronary heart disease and chronic kidney disease, and not taking diabetes medication. We used generalized estimating equations to assess the cross-sectional association of NT-proBNP with measures of insulin resistance. Instrumental variable analysis with an allele score derived from nine genetic variants (single nucleotide polymorphisms) within or near the NPPA and NPPB loci was used to estimate an un-confounded association of NT-proBNP levels on insulin resistance. Lower NT-proBNP levels were associated with higher insulin resistance even after adjustment for BMI, waist circumference and other risk factors (P insulin resistance (P = 0.38; P = 0.01 for comparison with the association of measured levels of NT-proBNP). In older adults, lower NT-proBNP is associated with higher insulin resistance, even after adjustment for traditional risk factors. Because related genetic variants were not associated with insulin resistance, the causal nature of this association will require future study. © 2016 Diabetes UK.

  5. Role of transient receptor potential melastatin-like subtype 5 channel in insulin secretion from rat β-cells.

    Science.gov (United States)

    Krishnan, Kalaiselvan; Ma, Zuheng; Björklund, Anneli; Islam, Md Shahidul

    2014-05-01

    Several studies have reported that the transient receptor potential melastatin-like subtype 5 (TRPM5) channel, a Ca(2+)-activated monovalent cation channel, is involved in the stimulus-secretion coupling in the mouse pancreatic β-cells. We have studied the role of the TRPM5 channel in regulating insulin secretion and cytoplasmic free Ca(2+) concentration ([Ca(2+)](i)) in the rat β-cells by using triphenylphosphine oxide, a selective inhibitor of the channel. Insulin secretion from islets from Sprague-Dawley rats was measured in batch incubations. Cytoplasmic free Ca(2+) concentration was measured from single β-cells by fura-2-based microfluorometry. Triphenylphosphine oxide did not alter insulin secretion and [Ca(2+)](i) response triggered by KCl or fructose. It inhibited insulin secretion in response to glucose, L-arginine, and glucagon-like peptide 1. It also inhibited glucose-induced insulin secretion by mechanisms that are independent of the adenosine triphosphate-sensitive potassium channels and [Ca(2+)](i) increase. Our results suggest that in the rat islets, TRPM5 is involved in mediating insulin secretion by glucose and l-arginine and in potentiating the glucose-induced insulin secretion by glucagon-like peptide 1.

  6. Effects of olive leaf polyphenols against H₂O₂ toxicity in insulin secreting β-cells.

    Science.gov (United States)

    Cumaoğlu, Ahmet; Rackova, Lucia; Stefek, Milan; Kartal, Murat; Maechler, Pierre; Karasu, Cimen

    2011-01-01

    In pancreatic β-cells, although H₂O₂ is a metabolic signal for glucose stimulated insulin secretion, it may induce injury in the presence of increased oxidative stress (OS) as in the case of diabetic chronic hyperglycemia. Olea europea L. (olive) leaves contain polyphenolic compounds that may protect insulin-secreting cells against OS. The major polyphenolic compound in ethanolic olive leaf extract (OLE) is oleuropein (about 20%), thus we compared the effects of OLE with the effects of standard oleuropein on INS-1 cells. The cells were incubated with increasing concentrations of OLE or oleuropein for 24 h followed by exposure to H₂O₂ (0.035 mM) for 45 min. H₂O₂ alone resulted in a significantly decreased viability (MTT assay), depressed glucose-stimulated insulin secretion, increased apoptotic and necrotic cell death (AO/EB staining), inhibited glutathione peroxidase activity (GPx) and stimulated catalase activity that were associated with increased intracellular generation of reactive oxygen species (ROS) (fluorescence DCF). OLE and oleuropein partly improved the viability, attenuated necrotic and apoptotic death, inhibited the ROS generation and improved insulin secretion in H₂O₂-exposed cells. The effects of oleuropein on insulin secretion were more pronounced than those of OLE, while OLE exerted a stronger anti-cytotoxic effect than oleuropein. Unlike OLE, oleuropein had no significant preserving effect on GPx; however, both compounds stimulated the activity of catalase in H₂O₂-exposed cells. These findings indicate different modulatory roles of polyphenolic constituents of olive leaves on redox homeostasis that may have a role in the maintenance of β-cell physiology against OS.

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

    Directory of Open Access Journals (Sweden)

    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

  8. No evidence for genetically determined alteration in insulin secretion or sensitivity predisposing to type 1 diabetes: a study of identical twins.

    Science.gov (United States)

    Hawa, Mohammed I; Bonfanti, Riccardo; Valeri, Christina; Delli Castelli, Michela; Beyan, Huriya; Leslie, R David G

    2005-06-01

    To determine whether inherited changes in insulin secretion or sensitivity could predispose to type 1 diabetes, we studied identical twins of type 1 diabetic patients. We studied prospectively a consecutive series of 27 identical twins of patients with type 1 diabetes who were initially nondiabetic, as well as 14 control subjects, over a period of 18 years. Of these 27 twins, 15 remain nondiabetic (now estimated at low disease risk) and 12 developed diabetes (pre-diabetic twins). Subjects were tested when not diabetic on at least two occasions with an intravenous glucose tolerance test (IVGTT), and we estimated insulin secretion as first-phase insulin response (FPIR), glucose clearance (K(g)), and insulin sensitivity both by homeostasis model assessment of insulin resistance (HOMA-IR) and relative to insulin response by the basal HOMA-IR-to-FPIR ratio. Twins now at low risk and control subjects had similar fasting blood glucose and insulin levels, FPIR, K(g), HOMA-IR, and HOMA-IR-to-FPIR ratio. In contrast, pre-diabetic twins compared with control twins had higher fasting insulin levels (10.3 +/- 6.0 vs. 4.6 +/- 4.0 mIU/ml), lower FPIR (245 +/- 129 vs. 796 +/- 622 mIU . ml(-1) . 10 min(-1)), lower K(g) (1.5 +/- 0.6 vs. 2.6 +/- 0.8% per min), and higher HOMA-IR-to-FPIR ratio (0.007 +/- 0.005 vs. 0.001 +/- 0.0009) (all P alteration in either insulin secretion or sensitivity predisposing to type 1 diabetes.

  9. 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)

  10. Differential hepatic distribution of insulin receptor substrates causes selective insulin resistance in diabetes and obesity.

    Science.gov (United States)

    Kubota, Naoto; Kubota, Tetsuya; Kajiwara, Eiji; Iwamura, Tomokatsu; Kumagai, Hiroki; Watanabe, Taku; Inoue, Mariko; Takamoto, Iseki; Sasako, Takayoshi; Kumagai, Katsuyoshi; Kohjima, Motoyuki; Nakamuta, Makoto; Moroi, Masao; Sugi, Kaoru; Noda, Tetsuo; Terauchi, Yasuo; Ueki, Kohjiro; Kadowaki, Takashi

    2016-10-06

    Hepatic insulin signalling involves insulin receptor substrates (Irs) 1/2, and is normally associated with the inhibition of gluconeogenesis and activation of lipogenesis. In diabetes and obesity, insulin no longer suppresses hepatic gluconeogenesis, while continuing to activate lipogenesis, a state referred to as 'selective insulin resistance'. Here, we show that 'selective insulin resistance' is caused by the differential expression of Irs1 and Irs2 in different zones of the liver. We demonstrate that hepatic Irs2-knockout mice develop 'selective insulin resistance', whereas mice lacking in Irs1, or both Irs1 and Irs2, develop 'total insulin resistance'. In obese diabetic mice, Irs1/2-mediated insulin signalling is impaired in the periportal zone, which is the primary site of gluconeogenesis, but enhanced in the perivenous zone, which is the primary site of lipogenesis. While hyperinsulinaemia reduces Irs2 expression in both the periportal and perivenous zones, Irs1 expression, which is predominantly in the perivenous zone, remains mostly unaffected. These data suggest that 'selective insulin resistance' is induced by the differential distribution, and alterations of hepatic Irs1 and Irs2 expression.

  11. Insulin Sensitivity Determines Effects of Insulin and Meal Ingestion on Systemic Vascular Resistance in Healthy Subjects.

    Science.gov (United States)

    Woerdeman, Jorn; Meijer, Rick I; Eringa, Etto C; Hoekstra, Trynke; Smulders, Yvo M; Serné, Erik H

    2016-01-01

    In addition to insulin's metabolic actions, insulin can dilate arterioles which increase blood flow to metabolically active tissues. This effect is blunted in insulin-resistant subjects. Insulin's effect on SVR, determined by resistance arterioles, has, however, rarely been examined directly. We determined the effects of both hyperinsulinemia and a mixed meal on SVR and its relationship with insulin sensitivity. Thirty-seven lean and obese women underwent a hyperinsulinemic-euglycemic clamp, and 24 obese volunteers underwent a mixed-meal test. SVR was assessed using CPP before and during hyperinsulinemia as well as before and 60 and 120 minutes after a meal. SVR decreased significantly during hyperinsulinemia (-13%; p Insulin decreased SVR more strongly in insulin-sensitive individuals (standardized β: -0.44; p = 0.01). In addition, SVR at 60 minutes after meal ingestion was inversely related to the Matsuda index (β: -0.39; p = 0.04) and the change in postprandial SVR was directly related to postprandial glycemia (β: 0.53; p insulin resistance. This suggests that resistance to insulin-induced vasodilatation contributes to regulation of vascular resistance. © 2015 John Wiley & Sons Ltd.

  12. [Probiotics improve obesity-associated dyslipidemia and insulin resistance in high-fat diet-fed rats].

    Science.gov (United States)

    Yu, Ren-Qiang; Yuan, Jin-Ling; Ma, Lu-Yi; Qin, Qing-Xu; Wu, Xiao-You

    2013-12-01

    To evaluate the effect of probiotics (bifidobacterium breve and lactobacillus acidophilus) on serum lipid, serum insulin and insulin resistance in high-fat diet (HFD)-induced obese rats. Fifty male Sprague-Dawley rats were randomly assigned to a control (n=10) and a high fat diet groups (n=40) and were fed with standard diet and HFD respectively. Four weeks later, thirty-six HFD-induced obese rats were randomly administered with normal saline (NS), bifidobacterium breve and lactobacillus acidophilus daily (n=12 each). Four weeks later, body lengths, body weights and abdomen circumference of rats were measured, blood lipid, glucose and insulin levels were measured, and Lee's index and insulin resistance index were calculated. Body weight, abdomen circumference, Lee's index, fasting glucose, triglyceride (TG), total cholesterol (TC), low density lipoprotein (LDL) in the NS-treated HFD group were significantly higher than the control group (Pfasting glucose, TC, TG and LDL than the NS-treated HFD group (Pfasting insulin, insulin resistance index and insulin secretion index between the bifidobacterium breve and lactobacillus acidophilus groups (P<0.05). Lactobacillus acidophilus and bifidobacterium breve can decrease serum levels of lipid and glucose and improve insulin resistance in obese rats. Bifidobacterium breve seems to be more effective on attenuating insulin resistance than lactobacillus acidophilus.

  13. [Alcohol, steatohepatitis, insulin resistance and hepatitis C].

    Science.gov (United States)

    Couzigou, P; Mathurin, P; Serfaty, L; Cacoub, P; Moussalli, J; Pialoux, G; Chossegros, P; Cattan, L; Pol, S

    2008-03-01

    Patients with chronic hepatitis C have frequently other morbidities, either because they are frequent in the general population (metabolic syndrome) and/or because the route of contamination (chronic alcohol consumption succeeding to drug abuse). These co-morbidities have a harmfull impact on fibrosis progression during the natural history of HCV infection and reduce the efficacy of antiviral treatments. Thus, it is crucial to diagnose early and treat these different diseases which may be combined. They are the metabolic syndrome and/or chronic alcohol consumption resulting in insuline resistance, infection by the human immune deficiency virus or by the hepatitis B virus as well as chronic tobacco use or excessive consumption of cannabis. An optimal is based on a multidisciplinary approach to reduce fibrosis progression and improve the efficiency of antiviral therapies. However, the hepatologist has to come back to a global care, which is mandatory at the individual level as well as for the public health.

  14. Natural history of insulin sensitivity and insulin secretion in the progression from normal glucose tolerance to impaired fasting glycemia and impaired glucose tolerance: the Inter99 study

    DEFF Research Database (Denmark)

    Faerch, Kristine; Vaag, Allan; Holst, Jens J

    2008-01-01

    of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated. RESULTS: Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than...... in individuals who maintained NGT. During the 5-year follow-up, individuals developing i-IFG experienced a significant decline only in HOMA-IS, whereas individuals developing i-IGT experienced significant declines in ISI, EPIR, and disposition index. Individuals with IFG/IGT exhibited pronounced declines in ISI......, HOMA-IS, EPIR, and disposition index during the 5-year follow-up. CONCLUSIONS: A stationary reduced insulin secretion followed by a decline in primarily hepatic insulin sensitivity characterizes the transition from NGT to i-IFG. In contrast, low whole-body insulin sensitivity with a secondary lack...

  15. Relationship between insulin resistance and plasma endothelin in hypertension patients

    International Nuclear Information System (INIS)

    Duan Yongqiang; Wang Zuobing; Yu Hui; Cao Wei; Wang Jing; Li Xiaoqin

    2011-01-01

    To explore the relationship between plasma endothelin and hypertension insulin resistance, and the improvement of insulin resistance in hypertension patients treated with captopril and l-amlodipine, 25 patients with primary hypertension and impaired glucose tolerance were selected and treated by captopril and l-amlodipine. Systolic pressure, diastolic pressure, fasting blood glucose, insulin and insulin antibody were measured before and after treatment and compared with healthy controls. The results showed that the plasma ET-1 level in hypertension group was significantly higher than that of healthy controls (P<0.01), and he plasma ET-1 level was positively correlated with FPG, FINS, Anti-INS, HOMA-IR. The systolic pressure, diastolic pressure, fasting blood glucose, insulin, insulin antibody and insulin resistance index in hypertension patients were decreased significantly after treatment (P<0.05). There is a good correlation between endothelin and insulin resistance index in hypertension patients. Captopril and l-amlodipine had obvious improvement effect on insulin resistance in hypertension patients. (authors)

  16. Postreceptor defects causing insulin resistance in normoinsulinemic non-insulin-dependent diabetes mellitus

    International Nuclear Information System (INIS)

    Bolinder, J.; Ostman, J.; Arner, P.

    1982-01-01

    The mechanisms of the diminished hypoglycemic response to insulin in non-insulin-dependent diabetes mellitus (NIDDM) with normal levels of circulating plasma insulin were investigated. Specific binding of mono- 125 I (Tyr A14)-insulin to isolated adipocytes and effects of insulin (5--10,000 microunits/ml) on glucose oxidation and lipolysis were determined simultaneously in subcutaneous adipose tissue of seven healthy subjects of normal weight and seven untreated NIDDM patients with normal plasma insulin levels. The two groups were matched for age, sex, and body weight. Insulin binding, measured in terms of receptor number and affinity, was normal in NIDDM, the total number of receptors averaging 350,000 per cell. Neither sensitivity nor the maximum antilipolytic effect of insulin was altered in NIDDM patients as compared with control subjects; the insulin concentration producing half the maximum effect (ED50) was 10 microunits/ml. As regards the effect of insulin on glucose oxidation, for the control subjects ED50 was 30 microunits/ml, whereas in NIDDM patients, insulin exerted no stimulatory effect. The results obtained suggest that the effect of insulin on glucose utilization in normoinsulinemic NIDDM may be diminished in spite of normal insulin binding to receptors. The resistance may be due solely to postreceptor defects, and does not involve antilipolysis

  17. Impact of Moderate Alcohol Discontinuation on Insulin Action and Secretion in Latinos With and Without Hepatitis C.

    Science.gov (United States)

    Uribe, Lindsay A; Bacchetti, Peter; Gelman, Nicholas; Burchard, Esteban; Fitch, Mark; Hellerstein, Marc; Khalili, Mandana

    2018-03-01

    Insulin resistance (IR) is associated with hepatitis C virus (HCV), and Latinos are both at risk of IR and are disproportionately affected by HCV. Moderate alcohol consumption improves insulin sensitivity and may modify HCV-associated IR. We investigated the impact of moderate alcohol discontinuation on insulin sensitivity and secretion in Latinos using direct measurements. Twenty-five nondiabetic, noncirrhotic Latino adults without (n = 17) or with (n = 8) HCV underwent 3-day metabolic assessment before and after prescription of 6 weeks of moderate alcohol discontinuation. Peripheral IR was measured via steady-state plasma glucose (SSPG) and hepatic IR using endogenous glucose production during a 2-step 240-minute insulin suppression test. Insulin secretion was measured using graded glucose infusion test. Baseline mean age was 46 ± 11 years, 63% male, 29% had HCV, and mean body mass index was 27 ± 4 kg/m 2 . Compared to non-HCV, HCV patients had a higher median SSPG (132 vs. 98.8 mg/dl, p = 1.0), hepatic IR (13.5 vs. 11.3, p = 0.24), and insulin secretion rate (ISR-AUC, 1,290 vs. 1,250 pmol/min, p = 0.98). After confirmed alcohol discontinuation, hepatic IR was the only parameter that changed significantly (increased, mean change 2.6 ± 4.8, p = 0.02). Higher baseline alanine aminotransferase (ALT) was also associated with a greater change in hepatic IR (average 4.0 points/ALT doubling, p = 0.004), and HCV was associated with a lesser change (average -7.3 points, p = 0.002), independent of ALT. Short-term moderate alcohol discontinuation adversely impacted hepatic IR in Latinos which was influenced by level of ALT at baseline independent of etiology. Although reduction in ALT through weight loss and HCV eradication remains a priority in improving IR, the observed nonharmful effect of moderate alcohol use represents a potentially confounding variable that warrants further study. Copyright © 2017 by the Research Society on Alcoholism.

  18. Altered insulin and glucagon secretion in treated genetic hyperlipemia: a mechanism of theraphy?

    Science.gov (United States)

    Eaton, R P; Oase, R; Schade, D S

    1976-03-01

    The influence of Halofenate therapy on insulin and glucagon secretion was examined in the Zucker rat with genetic endogenous hyperlipemia. Coincident with the lipid lowering effects of Halofenate, the net change in the basal bihormonal axis favored glucagon, with the I/G molar ratio (Insulin/Glucagon) decreasing from 2.72 +/- 0.53 to 0.96 +/- 0.20 during treatment with this drug. Following arginine stimulation the I/G ratio remained reduced at 0.87 +/- 0.13 in Halofenate treated animals, contrasting with the statistically greater ratio of 2.5 +/- 0.55 in control animals. The Halofenate induced state of reduced insulin:glucagon was associated with hypolipemia, postarginine hyperglycemia, and hyperketonemia,-three metabolic parameters characteristic of glucagon excess relative to insulin. It is suggested that the lipid-lowering action of Halofenate in genetic hyperlipemia may reflect the altered bihormonal axis induced by the drug.

  19. Effect of Chlorogenic Acid Administration on Glycemic Control, Insulin Secretion, and Insulin Sensitivity in Patients with Impaired Glucose Tolerance.

    Science.gov (United States)

    Zuñiga, Laura Y; Aceves-de la Mora, Martha C Aceves-de; González-Ortiz, Manuel; Ramos-Núñez, Julia L; Martínez-Abundis, Esperanza

    2017-12-20

    Chlorogenic acid has been described as a novel polyphenol with metabolic effects on glucose homeostasis. The aim of this study was to evaluate the effect of chlorogenic acid administration on glycemic control, insulin secretion, and insulin sensitivity in patients with impaired glucose tolerance (IGT). A randomized, double-blind, placebo-controlled clinical trial was performed in 30 patients with IGT; 15 patients randomly assigned to oral chlorogenic acid received 400 mg three times per day for 12 weeks, and the other 15 patients received placebo in the same way. Before and after the intervention, anthropometric and metabolic measurements, including fasting plasma glucose (FPG), glycated hemoglobin A1c, and a lipid profile, were performed. Area under the curve of glucose and insulin as well as the insulinogenic, Stumvoll, and Matsuda indices were calculated. Wilcoxon, Mann-Whitney U, and chi-square tests were performed, and P ≤ .05 was considered statistically significant. There were significant decreases in FPG (5.7 ± 0.4 vs. 5.5 ± 0.4 mmol/L, P = .002), insulinogenic index (0.71 ± 0.25 vs. 0.63 ± 0.25, P = .028), body weight, body mass index, waist circumference, triglycerides, total cholesterol, low-density lipoprotein cholesterol, and very low-density lipoprotein levels in the chlorogenic acid group, with an increment in the Matsuda index (1.98 ± 0.88 vs. 2.30 ± 1.23, P = .002). There were no significant differences in the placebo group. In conclusion, chlorogenic acid administration in patients with IGT decreased FPG and insulin secretion, while increasing insulin sensitivity and improving both anthropometric evaluations and the lipid profile.

  20. In nondiabetic, human immunodeficiency virus-infected patients with lipodystrophy, hepatic insulin extraction and posthepatic insulin clearance rate are decreased in proportion to insulin resistance

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Andersen, Ove; Hansen, Birgitte R

    2005-01-01

    In healthy, nondiabetic individuals with insulin resistance, fasting insulin is inversely correlated to the posthepatic insulin clearance rate (MCRi) and the hepatic insulin extraction (HEXi). We investigated whether similar early mechanisms to facilitate glucose homeostasis exist in nondiabetic...... > .1). Our data suggest that HEXi and MCRi are decreased in proportion to the degree of insulin resistance in nondiabetic HIV-infected patients with lipodystrophy....... insulin clearance rate was estimated as the ratio of posthepatic insulin appearance rate to steady-state plasma insulin concentration during a euglycemic hyperinsulinemic clamp (40 mU.m-2 .min-1). Posthepatic insulin appearance rate during the clamp was calculated, taking into account the remnant...

  1. Insulin is a key determinant of elevated retinal arteriolar flicker response in insulin-resistant individuals.

    Science.gov (United States)

    Reimann, Manja; Vilser, Walthard; Gruber, Matthias; Bornstein, Stefan R; Ziemssen, Tjalf

    2015-09-01

    Insulin may link metabolic disorders to retinal microvascular pathology. The aim of the present study was to investigate the impact of early insulin resistance on retinal microcirculation. Retinal diameter responses to flicker-light stimulation were investigated in 81 clinically healthy participants (32 ± 6 years [mean ± SD], 59% women) who were recruited according to their BMI. All participants underwent an OGTT and euglycaemic-hyperinsulinaemic clamp (40 mU/m(2) · min(-1) insulin dose). After stratification by low and high insulin sensitivity based on a clamp-derived glucose disposal rate of ≤ or >4.9 mg/kg body mass, respectively, baseline retinal diameters and their relative changes to flicker stimulation were compared while controlling for mean arterial pressure, BMI and sex. The arterial vasodilator response at the end of flicker stimulation (p = 0.044) and the area under the arterial reaction curve during flicker stimulation (p = 0.015) were significantly higher in individuals with low vs high insulin sensitivity. Vasodilatory responses of retinal veins to flicker stimulation and baseline retinal diameters did not differ between insulin-sensitive and insulin-resistant participants (p > 0.05). In a stepwise linear regression analysis, fasting insulin remained the only predictor of the arterial vasodilator response to flicker-light (p flicker response in insulin-resistant states is a result of higher circulating insulin levels.

  2. Testosterone deficiency, insulin-resistant obesity and cognitive function.

    Science.gov (United States)

    Pintana, Hiranya; Chattipakorn, Nipon; Chattipakorn, Siriporn

    2015-08-01

    Testosterone is an androgenic steroid hormone, which plays an important role in the regulation of male reproduction and behaviors, as well as in the maintenance of insulin sensitivity. Several studies showed that testosterone exerted beneficial effects in brain function, including preventing neuronal cell death, balancing brain oxidative stress and antioxidant activity, improving synaptic plasticity and involving cognitive formation. Although previous studies showed that testosterone deficiency is positively correlated with cognitive impairment and insulin-resistant obesity, several studies demonstrated contradictory findings. Thus, this review comprehensively summarizes the current evidence from in vitro, in vivo and clinical studies of the relationship between testosterone deficiency and insulin-resistant obesity as well as the correlation between either insulin-resistant obesity or testosterone deficiency and cognitive impairment. Controversial reports and the mechanistic insights regarding the roles of testosterone in insulin-resistant obesity and cognitive function are also presented and discussed.

  3. Insulin resistance and mitochondrial function in skeletal muscle

    DEFF Research Database (Denmark)

    Dela, Flemming; Helge, Jørn Wulff

    2013-01-01

    are used in the attempt to resolve the mechanisms of insulin resistance. In this context, a dysfunction of mitochondria in the skeletal muscle has been suggested to play a pivotal role. It has been postulated that a decrease in the content of mitochondria in the skeletal muscle can explain the insulin...... resistance. Complementary to this also specific defects of components in the respiratory chain in the mitochondria have been suggested to play a role in insulin resistance. A key element in these mechanistic suggestions is inability to handle substrate fluxes and subsequently an accumulation of ectopic...... intramyocellular lipids, interfering with insulin signaling. In this review we will present the prevailing view-points and argue for the unlikelihood of this scenario being instrumental in human insulin resistance. This article is part of a Directed Issue entitled: Bioenergetic dysfunction....

  4. Persistent Organic Pollutant Exposure Leads to Insulin Resistance Syndrome

    DEFF Research Database (Denmark)

    Ruzzin, Jérôme; Petersen, Rasmus; Meugnier, Emmanuelle

    2010-01-01

    BACKGROUND: The incidence of the insulin resistance syndrome has increased at an alarming rate worldwide creating a serious challenge to public health care in the 21st century. Recently, epidemiological studies have associated the prevalence of type 2 diabetes with elevated body burdens...... of persistent organic pollutants (POPs). However, experimental evidence demonstrating a causal link between POPs and the development of insulin resistance is lacking. OBJECTIVE: We investigated whether exposure to POPs contributes to insulin resistance and metabolic disorders. METHODS: Wistar rats were exposed...... salmon oil. We measured body weight, whole-body insulin sensitivity, POP accumulation, lipid and glucose homeostasis, gene expression and performed microarray analysis. RESULTS: Adult male rats exposed to crude, but not refined, salmon oil developed insulin resistance, abdominal obesity...

  5. Relationship among age, insulin resistance, and blood pressure.

    Science.gov (United States)

    Jung, Chan-Hee; Jung, Sang Hee; Lee, Bora; Rosenberg, Melanie; Reaven, Gerald M; Kim, Sun H

    2017-06-01

    The effect of age to modify the relationship between insulin resistance and hypertension is unclear. In this retrospective, cross-sectional study, median age was used to create two age groups (insulin suppression test to quantify insulin resistance. Individuals were stratified into SSPG tertiles and categorized as having normal blood pressure (BP), prehypertension, or hypertension. SSPG concentrations were similar in the two age groups (161 vs. 164 mg/dL). In the most insulin-resistant tertile, distribution of normal BP, prehypertension, and hypertension was equal in those aged insulin resistance on BP was accentuated in older individuals and may have a greater impact than further aging. Copyright © 2017 American Society of Hypertension. Published by Elsevier Inc. All rights reserved.

  6. Failure of Homeostatic Model Assessment of Insulin Resistance to Detect Marked Diet-Induced Insulin Resistance in Dogs

    Science.gov (United States)

    Ader, Marilyn; Stefanovski, Darko; Richey, Joyce M.; Kim, Stella P.; Kolka, Cathryn M.; Ionut, Viorica; Kabir, Morvarid; Bergman, Richard N.

    2014-01-01

    Accurate quantification of insulin resistance is essential for determining efficacy of treatments to reduce diabetes risk. Gold-standard methods to assess resistance are available (e.g., hyperinsulinemic clamp or minimal model), but surrogate indices based solely on fasting values have attractive simplicity. One such surrogate, the homeostatic model assessment of insulin resistance (HOMA-IR), is widely applied despite known inaccuracies in characterizing resistance across groups. Of greater significance is whether HOMA-IR can detect changes in insulin sensitivity induced by an intervention. We tested the ability of HOMA-IR to detect high-fat diet–induced insulin resistance in 36 healthy canines using clamp and minimal model analysis of the intravenous glucose tolerance test (IVGTT) to document progression of resistance. The influence of pancreatic function on HOMA-IR accuracy was assessed using the acute insulin response during the IVGTT (AIRG). Diet-induced resistance was confirmed by both clamp and minimal model (P HOMA-IR ([fasting insulin (μU/mL) × fasting glucose (mmol)]/22.5) did not detect reduced sensitivity induced by fat feeding (P = 0.22). In fact, 13 of 36 animals showed an artifactual decrease in HOMA-IR (i.e., increased sensitivity). The ability of HOMA-IR to detect diet-induced resistance was particularly limited under conditions when insulin secretory function (AIRG) is less than robust. In conclusion, HOMA-IR is of limited utility for detecting diet-induced deterioration of insulin sensitivity quantified by glucose clamp or minimal model. Caution should be exercised when using HOMA-IR to detect insulin resistance when pancreatic function is compromised. It is necessary to use other accurate indices to detect longitudinal changes in insulin resistance with any confidence. PMID:24353184

  7. Estimation of second-phase insulin secretion in the Zucker fatty rat.

    Science.gov (United States)

    Morettini, Micaela; Di Nardo, Francesco; Cogo, Carla E; Faelli, Emanuela; Fioretti, Sandro; Burattini, Laura; Ruggeri, Piero

    2016-08-01

    The purpose of the present study was to test the efficacy of the empiric index SPIR (Second-phase Insulin Release) in the quantification of second-phase insulin secretion in the Zucker Fatty Rat. SPIR index is defined as the area under the curve of insulin between 8 and 90 min after an Intravenous Glucose Tolerance Test (IVGTT). The validation of such index was performed against the second-phase β-cell responsiveness index (Φ 2 ) provided by C-peptide minimal model. To this aim, Φ 2 and SPIR were simultaneously computed from IVGTT data, measured in six Zucker fatty rats (ZFR), 7-to-9week-old, and seven age-matched Zucker lean rats (ZLR). SPIR index showed a significant linear correlation with Φ 2 (Pearson's correlation coefficient, r = 0.91, R-square = 0.82, Pinsulin secretion and of its alteration in Zucker Fatty Rats. Thus, the study proposes the SPIR, as a suitable index for a simple, reliable and low-cost quantification of the second-phase insulin secretion in ZFR.

  8. Mutations in UCP2 in congenital hyperinsulinism reveal a role for regulation of insulin secretion.

    Directory of Open Access Journals (Sweden)

    M Mar González-Barroso

    Full Text Available Although the most common mechanism underlying congenital hyperinsulinism is dysfunction of the pancreatic ATP-sensitive potassium channel, the pathogenesis and genetic origins of this disease remains largely unexplained in more than half of all patients. UCP2 knockout mice exhibit an hyperinsulinemic hypoglycemia, suggesting an involvement of UCP2 in insulin secretion. However, a possible pathogenic role for UCP2 protein in the development of human congenital hyperinsulinism or of any human disease has not yet been investigated. We studied ten children exhibiting congenital hyperinsulinism, without detectable mutations in the known congenital hyperinsulinism-causing genes. Parental-inherited heterozygous UCP2 variants encoding amino-acid changes were found in two unrelated children with congenital hyperinsulinism. Functional assays in yeast and in insulin-secreting cells revealed an impaired activity of UCP2 mutants. Therefore, we report the finding of UCP2 coding variants in human congenital hyperinsulinism, which reveals a role for this gene in the regulation of insulin secretion and glucose metabolism in humans. Our results show for the first time a direct association between UCP2 amino acid alteration and human disease and highlight a role for mitochondria in hormone secretion.

  9. Sox17 regulates insulin secretion in the normal and pathologic mouse β cell.

    Directory of Open Access Journals (Sweden)

    Diva Jonatan

    Full Text Available SOX17 is a key transcriptional regulator that can act by regulating other transcription factors including HNF1β and FOXA2, which are known to regulate postnatal β cell function. Given this, we investigated the role of SOX17 in the developing and postnatal pancreas and found a novel role for SOX17 in regulating insulin secretion. Deletion of the Sox17 gene in the pancreas (Sox17-paLOF had no observable impact on pancreas development. However, Sox17-paLOF mice had higher islet proinsulin protein content, abnormal trafficking of proinsulin, and dilated secretory organelles suggesting that Sox17-paLOF adult mice are prediabetic. Consistant with this, Sox17-paLOF mice were more susceptible to aged-related and high fat diet-induced hyperglycemia and diabetes. Overexpression of Sox17 in mature β cells using Ins2-rtTA driver mice resulted in precocious secretion of proinsulin. Transcriptionally, SOX17 appears to broadly regulate secretory networks since a 24-hour pulse of SOX17 expression resulted in global transcriptional changes in factors that regulate hormone transport and secretion. Lastly, transient SOX17 overexpression was able to reverse the insulin secretory defects observed in MODY4 animals and restored euglycemia. Together, these data demonstrate a critical new role for SOX17 in regulating insulin trafficking and secretion and that modulation of Sox17-regulated pathways might be used therapeutically to improve cell function in the context of diabetes.

  10. Environmental factors and dam characteristics associated with insulin sensitivity and insulin secretion in newborn Holstein calves

    International Nuclear Information System (INIS)

    Kamal, M.M.; Van Eetvelde, M.; Bogaert, H.; Hostens, M.; Vandaele, L.; Shamsuddin, M.; Opsomer, G.

    2015-01-01

    The objective of the present retrospective cohort study was to evaluate potential associations between environmental factors and dam characteristics, including level of milk production during gestation, and insulin traits in newborn Holstein calves

  11. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion

    DEFF Research Database (Denmark)

    Gustavsson, Natalia; Wang, Xiaorui; Wang, Yue

    2010-01-01

    neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium...... tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. CONCLUSIONS: Thus, synaptotagmin-9, although a major calcium sensor in the brain......BACKGROUND: Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define...

  12. Association Between Adiponectin and Insulin Resistance in Diabetic Urolithiasis

    Directory of Open Access Journals (Sweden)

    Kavitha Meiyappan

    2017-03-01

    Full Text Available Objectives: The prevalence of urolithiasis is increasing worldwide. Diabetes mellitus (DM is characterized by insulin resistance, which increases the risk of kidney stone formation. Adiponectin is an insulin-sensitizing and anti-inflammatory cytokine, which is known to improve glucose tolerance and insulin resistance in humans. The association of insulin and adiponectin with kidney stones is not clear. Hence, the present study aim to assess the serum levels of adiponectin and insulin resistance in DM patients with urolithiasis in comparison to those without. Methods: This study involved two groups, group A consisted of 30 patients with DM and urolithiasis, and group B consisted of 30 patients with DM but without urolithiasis (control group. Biochemical parameters studied were serum adiponectin, insulin, glucose, urea, creatinine, and 24 hours urinary calcium and phosphate. Results: The serum adiponectin level was significantly increased in the diabetic urolithiasis cases (group A compared to the control group (group B. The levels of 24 hours urine calcium and phosphorus were also significantly increased in group A. There was no significant difference in serum insulin and homeostasis model assessment of insulin resistance between the two groups. A negative correlation was seen between serum adiponectin and insulin among the cases (r = -0.368 and p = 0.045. Conclusions: We found that serum adiponectin levels are increased in patients with DM and urolithiasis.

  13. Impaired Sympathoadrenal Axis Function Contributes to Enhanced Insulin Secretion in Prediabetic Obese Rats

    Directory of Open Access Journals (Sweden)

    Ana Eliza Andreazzi

    2011-01-01

    Full Text Available The involvement of sympathoadrenal axis activity in obesity onset was investigated using the experimental model of treating neonatal rats with monosodium L-glutamate. To access general sympathetic nervous system activity, we recorded the firing rates of sympathetic superior cervical ganglion nerves in animals. Catecholamine content and secretion from isolated adrenal medulla were measured. Intravenous glucose tolerance test was performed, and isolated pancreatic islets were stimulated with glucose and adrenergic agonists. The nerve firing rate of obese rats was decreased compared to the rate for lean rats. Basal catecholamine secretion decreased whereas catecholamine secretion induced by carbachol, elevated extracellular potassium, and caffeine in the isolated adrenal medulla were all increased in obese rats compared to control. Both glucose intolerance and hyperinsulinaemia were observed in obese rats. Adrenaline strongly inhibited glucose-induced insulin secretion in obese animals. These findings suggest that low sympathoadrenal activity contributes to impaired glycaemic control in prediabetic obese rats.

  14. Complete loss of insulin secretion capacity in type 1A diabetes patients during long-term follow up.

    Science.gov (United States)

    Uno, Sae; Imagawa, Akihisa; Kozawa, Junji; Fukui, Kenji; Iwahashi, Hiromi; Shimomura, Iichiro

    2017-10-16

    Patients with type 1 diabetes are classified into three subtypes in Japan: acute onset, fulminant and slowly progressive. Acute-onset type 1 diabetes would be equivalent to type 1A diabetes, the typical type 1 diabetes in Western countries. The insulin secretion capacity in Japanese patients with long-standing type 1A diabetes is unclear. The aim of the present study was to clarify the course of endogenous insulin secretion during long-term follow up and the factors associated with residual insulin secretion in patients with acute-onset type 1 diabetes (autoimmune). We retrospectively investigated endogenous insulin secretion capacity in 71 patients who fulfilled the diagnostic criteria for acute-onset type 1 diabetes (autoimmune) in Japan. To assess the residual insulin secretion capacity, we evaluated randomly measured C-peptide levels and the results of glucagon stimulation test in 71 patients. In the first year of disease, the child- and adolescent-onset patients had significantly more in residual insulin secretion than the adult-onset patients (34 patients in total). C-peptide levels declined more rapidly in patients whose age of onset was ≤18 years than in patients whose age of onset was ≥19 years. Endogenous insulin secretion capacity stimulated by glucagon was completely lost in almost all patients at >15 years after onset (61 patients in total). Most patients with acute-onset type 1 diabetes (autoimmune) completely lose their endogenous insulin secretion capacity during the disease duration in Japan. Age of onset might affect the course of insulin secretion. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

  15. CFTR Influences Beta Cell Function and Insulin Secretion Through Non-Cell Autonomous Exocrine-Derived Factors.

    Science.gov (United States)

    Sun, Xingshen; Yi, Yaling; Xie, Weiliang; Liang, Bo; Winter, Michael C; He, Nan; Liu, Xiaoming; Luo, Meihui; Yang, Yu; Ode, Katie Larson; Uc, Aliye; Norris, Andrew W; Engelhardt, John F

    2017-10-01

    Although β-cell dysfunction in cystic fibrosis (CF) leads to diabetes, the mechanism by which the cystic fibrosis transmembrane conductance regulator (CFTR) channel influences islet insulin secretion remains debated. We investigated the CFTR-dependent islet-autonomous mechanisms affecting insulin secretion by using islets isolated from CFTR knockout ferrets. Total insulin content was lower in CF as compared with wild-type (WT) islets. Furthermore, glucose-stimulated insulin secretion (GSIS) was impaired in perifused neonatal CF islets, with reduced first, second, and amplifying phase secretion. Interestingly, CF islets compensated for reduced insulin content under static low-glucose conditions by secreting a larger fraction of islet insulin than WT islets, probably because of elevated SLC2A1 transcripts, increased basal inhibition of adenosine triphosphate-sensitive potassium channels (K-ATP), and elevated basal intracellular Ca2+. Interleukin (IL)-6 secretion by CF islets was higher relative to WT, and IL-6 treatment of WT ferret islets produced a CF-like phenotype with reduced islet insulin content and elevated percentage insulin secretion in low glucose. CF islets exhibited altered expression of INS, CELA3B, and several β-cell maturation and proliferation genes. Pharmacologic inhibition of CFTR reduced GSIS by WT ferret and human islets but similarly reduced insulin secretion and intracellular Ca2+ in CFTR knockout ferret islets, indicating that the mechanism of action is not through CFTR. Single-molecule fluorescent in situ hybridization, on isolated ferret and human islets and ferret pancreas, demonstrated that CFTR RNA colocalized within KRT7+ ductal cells but not endocrine cells. These results suggest that CFTR affects β-cell function via a paracrine mechanism involving proinflammatory factors secreted from islet-associated exocrine-derived cell types. Copyright © 2017 Endocrine Society.

  16. Effect of Low Salt Diet on Insulin Resistance in Salt Sensitive versus Salt Resistant Hypertension

    OpenAIRE

    Garg, Rajesh; Sun, Bei; Williams, Jonathan

    2014-01-01

    Accumulating evidence shows an increase in insulin resistance on salt restriction. We compared the effect of low salt diet on insulin resistance in salt sensitive versus salt resistant hypertensive subjects. We also evaluated the relationship between salt sensitivity of blood pressure and salt sensitivity of insulin resistance in a multivariate regression model. Studies were conducted after one week of high salt (200 mmol/day Na) and one week of low salt (10 mmol/day Na) diet. Salt sensitivit...

  17. Insulin resistance in Nigerians with essential hypertension

    African Journals Online (AJOL)

    EB

    2013-09-03

    Sep 3, 2013 ... parameters, blood pressure, fasting glucose and insulin were measured. Homeostasis model ... Results: The hypertensive subjects had significantly higher fasting insulin and HOMA-IR compared with normotensives. (p =0.02 and 0.04) ..... demonstrated the benefit of early interventions to improve insulin ...

  18. Soy Germed Protein Plus Zn as an Inducer Insulin Secretion on Type-2 Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    HERY WINARSI

    2010-09-01

    Full Text Available Hyperglicemic induces pancreatic cells to produce inadequate insulin. However, previous studies revealed that soy protein induce pancreatic cells to secrete insulin. Hence, this study was aimed to investigate effect of soy germed protein on the insulin and blood glucose level of type-2 diabetes mellitus with Zn enrichment. The research involved twenty four women that characterized with having more blood glucose level than normal, body mass index more than twenty three kg/m2, and age more than fourty years old. They were divided into three groups randomly, eight woman for each group. The first, second and third group were treated respectively with milk containing soy germed protein plus Zn, this product without Zn, and placebo, all for two months. Blood samples were taken at baseline, one and two months after observation. Results showed that two months after observation the insulin level increased from 194.79 to 519.82 pmol/ml (P = 0.033 in group consuming milk containing soy germed protein with or without Zn, supported by significantly reduced blood glucose level. This result might be correlated with the potency of isoflavones in soy germ protein to protect pancreatic beta cellsmembrane from free radicals attack. Therefore, this maintain the cells integrity and to secrete optimal insulin.

  19. Integrative network analysis highlights biological processes underlying GLP-1 stimulated insulin secretion: A DIRECT study.

    Directory of Open Access Journals (Sweden)

    Valborg Gudmundsdottir

    Full Text Available Glucagon-like peptide 1 (GLP-1 stimulated insulin secretion has a considerable heritable component as estimated from twin studies, yet few genetic variants influencing this phenotype have been identified. We performed the first genome-wide association study (GWAS of GLP-1 stimulated insulin secretion in non-diabetic individuals from the Netherlands Twin register (n = 126. This GWAS was enhanced using a tissue-specific protein-protein interaction network approach. We identified a beta-cell protein-protein interaction module that was significantly enriched for low gene scores based on the GWAS P-values and found support at the network level in an independent cohort from Tübingen, Germany (n = 100. Additionally, a polygenic risk score based on SNPs prioritized from the network was associated (P < 0.05 with glucose-stimulated insulin secretion phenotypes in up to 5,318 individuals in MAGIC cohorts. The network contains both known and novel genes in the context of insulin secretion and is enriched for members of the focal adhesion, extracellular-matrix receptor interaction, actin cytoskeleton regulation, Rap1 and PI3K-Akt signaling pathways. Adipose tissue is, like the beta-cell, one of the target tissues of GLP-1 and we thus hypothesized that similar networks might be functional in both tissues. In order to verify peripheral effects of GLP-1 stimulation, we compared the transcriptome profiling of ob/ob mice treated with liraglutide, a clinically used GLP-1 receptor agonist, versus baseline controls. Some of the upstream regulators of differentially expressed genes in the white adipose tissue of ob/ob mice were also detected in the human beta-cell network of genes associated with GLP-1 stimulated insulin secretion. The findings provide biological insight into the mechanisms through which the effects of GLP-1 may be modulated and highlight a potential role of the beta-cell expressed genes RYR2, GDI2, KIAA0232, COL4A1 and COL4A2 in GLP-1 stimulated

  20. Effect of neonatal hypothyroidism on carbohydrate metabolism, insulin secretion, and pancreatic islets morphology of adult male offspring in rats.

    Science.gov (United States)

    Farahani, H; Ghasemi, A; Roghani, M; Zahediasl, S

    2013-01-01

    Neonatal hypothyroidism has serious effects on growth, development, and metabolism. This study aims to investigate the effects of the neonatal hypothyroidism on carbohydrate metabolism, islet insulin secretion and morphology of the pancreatic islets in adult male offspring. Lactating mothers of Wistar rats consumed 0.02% solution of 6-propyl-2-thiouracil during the weaning period (neonatal hypothyroid group), while mothers of the control group drank merely tap water. Body weight and survival of pups were followed up. Intravenous glucose tolerance test was performed in adult male offspring and 5-6 weeks later, glucose-stimulated insulin secretion (GSIS) was evaluated. During the glucose tolerance test, plasma glucose level of the neonatal hypothyroid group (13.18 ± 0.59 mmol/l) was significantly higher at 5 min compared to the control group (11.54 ± 0.47 mmol/l), whereas plasma insulin concentrations and GSIS of the groups was not significantly different. Homeostasis model assessment of insulin resistance of adult male offspring of the hypothyroid group (9.1 ± 1.0) was significantly higher as compared to the control group (4.5 ± 0.6). Area (14,613.0 ± 2646.3 μm2) and the diameter of the islets (147 ± 3.0 μm) of the neonatal hypothyroid group were significantly lower, as compared to the control group (32,886.3 ± 4690.3 and 206.6 ± 5.9 μm2 and μm, respectively). Neonatal hypothyroidism can alter carbohydrate metabolism in euthyroid adult offspring, which may increase susceptibility to the development of glucose intolerance and occurrence of Type 2 diabetes later in life.

  1. The effect of a very low calorie diet on insulin sensitivity, beta cell function, insulin clearance, incretin hormone secretion, androgen levels and body composition in obese young women

    DEFF Research Database (Denmark)

    Svendsen, Pernille F; Jensen, Frank K; Holst, Jens Juul

    2012-01-01

    Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women.......Evaluation of the effect of an 8-week very low calorie diet (VLCD, 500-600 kcal daily) on weight, body fat distribution, glucose, insulin and lipid metabolism, androgen levels and incretin secretion in obese women....

  2. Exposure to static magnetic fields increases insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

    Science.gov (United States)

    Mao, Libin; Wang, Huiqin; Ma, Fenghui; Guo, Zhixia; He, Hongpeng; Zhou, Hao; Wang, Nan

    2017-08-01

    To evaluate the effect of static magnetic fields (SMFs) on insulin secretion and explore the mechanisms underlying exposure to SMF-induced insulin secretion in rat insulinoma INS-1 cells. INS-1 cells were exposed to a 400 mT SMF for 72 h, and the proliferation of INS-1 cells was detected by (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The secretion of insulin was measured with an enzyme linked immunosorbent assays (ELISA), the expression of genes was detected by real-time PCR, and the expression of proteins was measured by Western blotting. Exposure to an SMF increased the expression and secretion of insulin by INS-1 cells but did not affect cell proliferation. Moreover, SMF exposure up-regulated the expression of several pancreas-specific transcriptional factors. Specifically, the activity of the rat insulin promoter was enhanced in INS-1 cells exposed to an SMF, and the expression levels of synaptosomal-associated protein 25 (SNAP-25) and syntaxin-1A were up-regulated after exposure to an SMF. SMF exposure can promote insulin secretion in rat INS-1 cells by activating the transcription of the insulin gene and up-regulating the expression of vesicle-secreted proteins.

  3. Insulin resistance, role of metformin and other non-insulin therapies in pediatric type 1 diabetes.

    Science.gov (United States)

    Bacha, Fida; Klinepeter Bartz, Sara

    2016-12-01

    Type 1 diabetes mellitus (T1DM) in youth is a challenging chronic medical condition. Its management should address not only the glycemic control but also insulin resistance and cardiovascular disease risk factors which are increasingly recognized to be present in youth with TID. Current knowledge on the mechanisms of insulin resistance in T1DM is reviewed. The use of adjunctive therapies that are beneficial to achieve adequate glycemic control while mitigating the effects of insulin resistance are discussed with a focus on metformin therapy and an overview of other new pharmacologic agents. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Hypertension management and microvascular insulin resistance in diabetes.

    Science.gov (United States)

    Ko, Seung-Hyun; Cao, Wenhong; Liu, Zhenqi

    2010-08-01

    Type 2 diabetes is in essence a vascular disease and is frequently associated with hypertension, macrovascular events, and microvascular complications. Microvascular dysfunction, including impaired recruitment and capillary rarefaction, has been implicated in the pathogenesis of diabetic complications. Microvascular insulin resistance and renin-angiotensin system upregulation are present in diabetes, and each contributes to the development of hypertension and microvascular dysfunction. In the insulin-sensitive state, insulin increases microvascular perfusion by increasing endothelial nitric oxide production, but this effect is abolished by insulin resistance. Angiotensin II, acting via the type 1 receptors, induces inflammation and oxidative stress, leading to impaired insulin signaling, reduced nitric oxide availability, and vasoconstriction. Conversely, it acts on the type 2 receptors to cause vasodilatation. Because substrate and hormonal exchanges occur in the microvasculature, antihypertensive agents targeted to improve microvascular insulin sensitivity and function may have beneficial effects beyond their capacity to lower blood pressure in patients with diabetes.

  5. Assessing Psychological Insulin Resistance in Type 2 Diabetes

    DEFF Research Database (Denmark)

    Holmes-Truscott, Elizabeth; Pouwer, F; Speight, Jane

    2017-01-01

    PURPOSE OF REVIEW: This study aims to examine the operationalisation of 'psychological insulin resistance' (PIR) among people with type 2 diabetes and to identify and critique relevant measures. RECENT FINDINGS: PIR has been operationalised as (1) the assessment of attitudes or beliefs about...... insulin therapy and (2) hypothetical or actual resistance, or unwillingness, to use to insulin. Five validated PIR questionnaires were identified. None was fully comprehensive of all aspects of PIR, and the rigour and reporting of questionnaire development and psychometric validation varied considerably...... between measures. Assessment of PIR should focus on the identification of negative and positive attitudes towards insulin use. Actual or hypothetical insulin refusal may be better conceptualised as a potential consequence of PIR, as its assessment overlooks the attitudes that may prevent insulin use...

  6. A TRP channel contributes to insulin secretion by pancreatic β-cells.

    Science.gov (United States)

    Liman, Emily R

    2010-01-01

    The release of insulin by pancreatic beta cells involves a complex interplay of conductances that generate oscillations and drive secretion. A recent report identifies a new player in this process, the ion channel TRPM5. TRPM5 was originally identified in taste cells, where it forms a Ca(2+)-activated cation channel that is required for sensory responses to bitter and sweet tastes. New research now shows that TRPM5 is expressed within the pancreatic islets of Langerhans, where it regulates the frequency of Ca(2+) oscillations and contributes to insulin release by β-cells.

  7. Autophagy downregulation contributes to insulin resistance mediated injury in insulin receptor knockout podocytes in vitro

    Directory of Open Access Journals (Sweden)

    Ying Xu

    2016-04-01

    Full Text Available It is unknown whether autophagy activity is altered in insulin resistant podocytes and whether autophagy could be a therapeutic target for diabetic nephropathy (DN. Here we used shRNA transfection to knockdown the insulin receptor (IR gene in cultured human immortalized podocytes as an in vitro insulin resistant model. Autophagy related proteins LC3, Beclin, and p62 as well as nephrin, a podocyte injury marker, were assessed using western blot and immunofluorescence staining. Our results show that autophagy is suppressed when podocytes lose insulin sensitivity and that treatment of rapamycin, an mTOR specific inhibitor, could attenuate insulin resistance induced podocytes injury via autophagy activation. The present study deepens our understanding of the role of autophagy in the pathogenesis of DN.

  8. Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes

    DEFF Research Database (Denmark)

    Hulman, Adam; Simmons, Rebecca K; Brunner, Eric J

    2017-01-01

    (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI0,120) among 120 South Asian and 867 white participants who developed diabetes during.......03) and a higher FPG level at diagnosis (0.27 mmol/l; 95% CI 0.06, 0.48; p = 0.01). They also had higher FSI and 2hSI levels before and at diabetes diagnosis. South Asians had a faster decline and lower HOMA2-S (log e -transformed) at diagnosis compared with white individuals (0.33; 95% CI 0.21, 0.46; p ....001). HOMA2-B increased in both ethnic groups until 7 years before diagnosis and then declined; the initial increase was faster in white individuals. ISI0,120 declined steeply in both groups before diagnosis; levels were lower among South Asians before and at diagnosis. There were no ethnic differences in 2h...

  9. Insulin Secretion and Risk for Future Diabetes in Subjects with a Nonpositive Insulinogenic Index

    Directory of Open Access Journals (Sweden)

    Daisuke Aono

    2018-01-01

    Full Text Available Aim. To characterize subjects with a nonpositive insulinogenic index and longitudinally observe changes in their glucose tolerance. Subjects and Methods. A historical cohort study was conducted using data from the medical checkups of public school workers. Indices of insulin secretion and insulin sensitivity derived from oral glucose tolerance test (OGTT and the incidences of diabetes and impaired glucose tolerance (IGT were compared among subgroups of subjects with different insulinogenic index (change in insulin/change in glucose over the first 30 min on the OGTT. Results. Of the 1464 nondiabetic subjects at baseline, 72 (4.9% subjects had a nonpositive insulinogenic index: 42 of those subjects had a nonpositive glucose response (ΔGlu0–30 ≤ 0 and 30 had a nonpositive insulin response (ΔIns0–30 ≤ 0. Compared with subjects who had normal glucose tolerance (NGT with insulinogenic index ≥ 0.4, subjects with a nonpositive glucose response had a higher first-phase Stumvoll and lower incidences of diabetes and IGT based on a log-rank test (p<0.05, whereas subjects with a nonpositive insulin response had lower indices of insulin secretion and a higher incidence of diabetes (p<0.05. Conclusions. These results demonstrate that in the first 30 min on the OGTT, subjects with a nonpositive insulinogenic index due to a nonpositive glucose response (ΔGlu0–30 ≤ 0 had a lower risk for future diabetes and that subjects with nonpositive insulin response (ΔIns0–30 ≤ 0 had a higher risk for future one.

  10. Insulin Resistance and Risk of Cardiovascular Disease in Postmenopausal Women

    DEFF Research Database (Denmark)

    Schmiegelow, Michelle D; Hedlin, Haley; Stefanick, Marcia L

    2015-01-01

    BACKGROUND: Insulin resistance is associated with diabetes mellitus, but it is uncertain whether it improves cardiovascular disease (CVD) risk prediction beyond traditional cardiovascular risk factors. METHODS AND RESULTS: We identified 15,288 women from the Women's Health Initiative Biomarkers...... studies with no history of CVD, atrial fibrillation, or diabetes mellitus at baseline (1993-1998). We assessed the prognostic value of adding fasting serum insulin, HOMA-IR (homeostasis model assessment-insulin resistance), serum-triglyceride-to-serum-high-density lipoprotein-cholesterol ratio TG...... occurred in 894 (5.8%) women. Insulin resistance was associated with CVD risk after adjusting for age and race/ethnicity with hazard ratios (95% confidence interval [CI]) per doubling in insulin of 1.21 (CI, 1.12-1.31), in HOMA-IR of 1.19 (CI, 1.11-1.28), in TG/HDL-C of 1.35 (CI, 1...

  11. The Association Between IGF-I and Insulin Resistance

    DEFF Research Database (Denmark)

    Friedrich, Nele; Thuesen, Betina; Jørgensen, Torben

    2012-01-01

    the association between IGF-I level and insulin resistance in a Danish general population.RESEARCH DESIGN AND METHODSIncluded were 3,354 adults, aged 19-72 years, from the cross-sectional Health2006 study. The homeostasis model assessment of insulin resistance (HOMA-IR) was used as the index to estimate insulin...... with intermediate (Q3) IGF-I levels. These associations remained statistically significant after the exclusion of subjects with type 2 diabetes and by using the updated computer HOMA2-IR model.CONCLUSIONSLow- and high-normal IGF-I levels are both related to insulin resistance. The biological mechanism......OBJECTIVEIGF-I has an almost 50% amino acid sequence homology with insulin and elicits nearly the same hypoglycemic response. Studies showed that low and high IGF-I levels are related to impaired glucose tolerance and to a higher risk of type 2 diabetes. The aim of the current study was to evaluate...

  12. Unsaturated fatty acids and insulin resistance in childhood obesity.

    Science.gov (United States)

    Toledo, Karen; Aranda, Mario; Asenjo, Sylvia; Sáez, Katia; Bustos, Paulina

    2014-05-01

    Obesity is characterized by increased levels of plasma free fatty acids (FFAs) that interfere with insulin signaling. The aim of our study was to assess the FFA profile in obese children and adolescents and to determine their relation with different degrees of insulin resistance. A transversal study was conducted of 51 children and adolescents (mean age, 11.7±1.6 years; 47% males) with obesity (body mass index ≥95 percentile). Anthropometric, clinical, and biochemical parameters were assessed. Insulin resistance was determined using the homeostasis model assessment of insulin resistance (HOMA-IR) index. Plasma fatty acids were quantified by high-performance liquid chromatography with heptadecanoic acid as the internal standard. The mean concentration of myristic acid, linoleic acid, palmitic acid, oleic acid, stearic acid, and total fatty acids was 9.3±2.2, 86.5±38.3, 93.0±35.5, 177.0±83.6, 48.5±14.9, and 414.3±160.9 μmol/L, respectively. Total fatty acids and unsaturated fatty acids such as oleic acid and linoleic acid showed an inverse significant correlation with insulin resistance. Children with high insulin resistance (HOMA-IR >2.5) showed a decrease in unsaturated fatty acids compared with children having a HOMA-IR of fatty acid concentrations between those groups. A decrease in unsaturated fatty acids was correlated with insulin resistance in childhood obesity.

  13. Evidence That the Sympathetic Nervous System Elicits Rapid, Coordinated, and Reciprocal Adjustments of Insulin Secretion and Insulin Sensitivity During Cold Exposure.

    Science.gov (United States)

    Morton, Gregory J; Muta, Kenjiro; Kaiyala, Karl J; Rojas, Jennifer M; Scarlett, Jarrad M; Matsen, Miles E; Nelson, Jarrell T; Acharya, Nikhil K; Piccinini, Francesca; Stefanovski, Darko; Bergman, Richard N; Taborsky, Gerald J; Kahn, Steven E; Schwartz, Michael W

    2017-04-01

    Dynamic adjustment of insulin secretion to compensate for changes of insulin sensitivity that result from alteration of nutritional or metabolic status is a fundamental aspect of glucose homeostasis. To investigate the role of the brain in this coupling process, we used cold exposure as an experimental paradigm because the sympathetic nervous system (SNS) helps to coordinate the major shifts of tissue glucose utilization needed to ensure that increased thermogenic needs are met. We found that glucose-induced insulin secretion declined by 50% in rats housed at 5°C for 28 h, and yet, glucose tolerance did not change, owing to a doubling of insulin sensitivity. These potent effects on insulin secretion and sensitivity were fully reversed by returning animals to room temperature (22°C) for 4 h or by intravenous infusion of the α-adrenergic receptor antagonist phentolamine for only 30 min. By comparison, insulin clearance was not affected by cold exposure or phentolamine infusion. These findings offer direct evidence of a key role for the brain, acting via the SNS, in the rapid, highly coordinated, and reciprocal changes of insulin secretion and insulin sensitivity that preserve glucose homeostasis in the setting of cold exposure. © 2017 by the American Diabetes Association.

  14. Indices of insulin sensitivity and secretion from a standard liquid meal test in subjects with type 2 diabetes, impaired or normal fasting glucose

    Directory of Open Access Journals (Sweden)

    Farmer Mildred V

    2009-05-01

    Full Text Available Abstract Background To provide an initial evaluation of insulin sensitivity and secretion indices derived from a standard liquid meal tolerance test protocol in subjects with normal (NFG, impaired fasting glucose (IFG or type 2 diabetes mellitus. Methods Areas under the curve (AUC for glucose, insulin and C-peptide from pre-meal to 120 min after consumption of a liquid meal were calculated, as were homeostasis model assessments of insulin resistance (HOMA2-IR and the Matsuda index of insulin sensitivity. Results Subjects with NFG (n = 19, IFG (n = 19, and diabetes (n = 35 had mean ± SEM HOMA2-IR values of 1.0 ± 0.1, 1.6 ± 0.2 and 2.5 ± 0.3 and Matsuda insulin sensitivity index values of 15.6 ± 2.0, 8.8 ± 1.2 and 6.0 ± 0.6, respectively. The log-transformed values for these variables were highly correlated overall and within each fasting glucose category (r = -0.91 to -0.94, all p Conclusion These results provide initial evidence to support the usefulness of a standard liquid meal tolerance test for evaluation of insulin secretion and sensitivity in clinical and population studies.

  15. Cognitively impaired elderly exhibit insulin resistance and no memory improvement with infused insulin.

    Science.gov (United States)

    Morris, Jill K; Vidoni, Eric D; Mahnken, Jonathan D; Montgomery, Robert N; Johnson, David K; Thyfault, John P; Burns, Jeffrey M

    2016-03-01

    Insulin resistance is a risk factor for Alzheimer's disease (AD), although its role in AD etiology is unclear. We assessed insulin resistance using fasting and insulin-stimulated measures in 51 elderly subjects with no dementia (ND; n = 37) and with cognitive impairment (CI; n = 14). CI subjects exhibited either mild CI or AD. Fasting insulin resistance was measured using the homeostatic model assessment of insulin resistance (HOMA-IR). Insulin-stimulated glucose disposal was assessed using the hyperinsulinemic-euglycemic clamp to calculate glucose disposal rate into lean mass, the primary site of insulin-stimulated glucose disposal. Because insulin crosses the blood-brain barrier, we also assessed whether insulin infusion would improve verbal episodic memory compared to baseline. Different but equivalent versions of cognitive tests were administered in counterbalanced order in the basal and insulin-stimulated state. Groups did not differ in age or body mass index. Cognitively impaired subjects exhibited greater insulin resistance as measured at fasting (HOMA-IR; ND: 1.09 [1.1] vs. CI: 2.01 [2.3], p = 0.028) and during the hyperinsulinemic clamp (glucose disposal rate into lean mass; ND: 9.9 (4.5) vs. AD 7.2 (3.2), p = 0.040). Cognitively impaired subjects also exhibited higher fasting insulin compared to ND subjects, (CI: 8.7 [7.8] vs. ND: 4.2 [3.8] μU/mL; p = 0.023) and higher fasting amylin (CI: 24.1 [39.1] vs. 8.37 [14.2]; p = 0.050) with no difference in fasting glucose. Insulin infusion elicited a detrimental effect on one test of verbal episodic memory (Free and Cued Selective Reminding Test) in both groups (p insulin resistance was observed in cognitively impaired subjects compared to ND controls, insulin infusion did not improve memory. Furthermore, a significant correlation between HOMA-IR and glucose disposal rate was present only in ND (p = 0.0002) but not in cognitively impaired (p = 0.884) subjects, indicating potentially important

  16. Long-term antidiabetic activity of vanadyl after treatment withdrawal: restoration of insulin secretion?

    Science.gov (United States)

    Cros, G H; Cam, M C; Serrano, J J; Ribes, G; McNeill, J H

    In its vanadate (V5+) or vanadyl (V4+) forms, vanadium has been demonstrated to possess antidiabetic activity. Oral treatment of streptozotocin (STZ)-diabetic animals with either form is associated with correction of hyperglycemia, and prevention of diabetes-induced complications, although weight gain is unaffected. Vanadium treatment of non-diabetic animals lowers plasma insulin levels by reducing insulin demand, as these animals remain normoglycemic. These results suggest that vanadium has in vivo insulin-mimetic or insulin-enhancing effects, in agreement with several in vitro observations. Chronic treatment with vanadium has also been shown to result in sustained antidiabetic effects in STZ-diabetic animals long after treatment has ceased. Thus, at 13 weeks after withdrawal from treatment, corrected animals had normalized glucose and weight gain, and improved basal insulin levels. In addition, near-normal glucose tolerance was found despite an insignificant insulin response. Since vanadium accumulates in several tissue sites (e.g. bone, kidney) when pharmacological doses are administered, it is possible that stored vanadium may be important in maintaining near-normal glucose tolerance at least in the short-term following withdrawal from treatment. Recently, following withdrawal of vanadyl treatment up to 30 weeks, diabetic animals which had remained normoglycemic and had normalized glucose tolerance showed improvements in plasma insulin levels both in the basal state and in response to oral glucose, as compared to those which had reverted to hyperglycemia. The observed significant improvements in insulin capacity over the long-term ( > 3 months) suggests that a restored and/or preserved insulin secretion may be essential for maintained reversal of the diabetic state over a prolonged period after treatment is withdrawn.

  17. Related Factors of Insulin Resistance in Korean Children: Adiposity and Maternal Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Kang-Sook Lee

    2011-12-01

    Full Text Available Increased adiposity and unhealthy lifestyle augment the risk for type 2 diabetes in children with familial predisposition. Insulin resistance (IR is an excellent clinical marker for identifying children at high risk for type 2 diabetes. This study was conducted to investigate parental, physiological, behavioral and socio-economic factors related to IR in Korean children. This study is a cross-sectional study using data from 111 children aged 7 years and their parents. Homeostasis model assessment of insulin resistance (HOMA-IR was calculated using fasting glucose and insulin level as a marker of IR. All children’s adiposity indices (r = 0.309–0.318, all P-value = 0.001 and maternal levels of fasting insulin (r = 0.285, P-value = 0.003 and HOMA-IR (r = 0.290, P-value = 0.002 were positively correlated with children’s HOMA-IR level. There was no statistical difference of children’s HOMA-IR level according to children’s lifestyle habits and socioeconomic status of families. An increase of 1 percentage point in body fat was related to 2.7% increase in children’s HOMA-IR (P-value < 0.001 and an increase of 1% of maternal level of HOMA-IR was related to 0.2% increase in children’s HOMA-IR (P-value = 0.002. This study shows that children’s adiposity and maternal IR are positively associated with children’s IR.

  18. Chlorogenic acid alleviates autophagy and insulin resistance by ...

    Indian Academy of Sciences (India)

    49

    with hypertension, obesity, dyslipidemia and type 2 diabetes (Lim et al, 2015). A prevalent hypothesis for NAFLD development points out that insulin resistance, as the. “first-hit” to the liver, elicits the onset of second hits, such as oxidative stress, inflammation, apoptosis, and autophagy (Polyzos et al, 2012). Indeed, insulin.

  19. Insulin resistance in Nigerians with essential hypertension | Akande ...

    African Journals Online (AJOL)

    Homeostasis model assessment (HOMA) was used to determine insulin resistance (IR). Results: The hypertensive subjects had significantly higher fasting insulin and HOMA-IR compared with normotensives (p =0.02 and 0.04) respectively. There were significant correlations between HOMA-IR, BMI, waist and hip ...

  20. Binge Drinking Induces Whole-Body Insulin Resistance by Impairing Hypothalamic Insulin Action

    Science.gov (United States)

    Lindtner, Claudia; Scherer, Thomas; Zielinski, Elizabeth; Filatova, Nika; Fasshauer, Martin; Tonks, Nicholas K.; Puchowicz, Michelle; Buettner, Christoph

    2013-01-01

    Individuals with a history of binge drinking have an increased risk of developing the metabolic syndrome and type 2 diabetes. Whether binge drinking impairs glucose homeostasis and insulin action is unknown. To test this, we treated Sprague-Dawley rats daily with alcohol (3 g/kg) for three consecutive days to simulate human binge drinking and found that these rats developed and exhibited insulin resistance even after blood alcohol concentrations had become undetectable. The animals were resistant to insulin for up to 54 hours after the last dose of ethanol, chiefly a result of impaired hepatic and adipose tissue insulin action. Because insulin regulates hepatic glucose production and white adipose tissue lipolysis, in part through signaling in the central nervous system, we tested whether binge drinking impaired brain control of nutrient partitioning. Rats that had consumed alcohol exhibited impaired hypothalamic insulin action, defined as the ability of insulin infused into the mediobasal hypothalamus to suppress hepatic glucose production and white adipose tissue lipolysis. Insulin signaling in the hypothalamus, as assessed by insulin receptor and AKT phosphorylation, decreased after binge drinking. Quantitative polymerase chain reaction showed increased hypothalamic inflammation and expression of protein tyrosine phosphatase 1B (PTP1B), a negative regulator of insulin signaling. Intracerebroventricular infusion of CPT-157633, a small-molecule inhibitor of PTP1B, prevented binge drinking–induced glucose intolerance. These results show that, in rats, binge drinking induces systemic insulin resistance by impairing hypothalamic insulin action and that this effect can be prevented by inhibition of brain PTP1B. PMID:23363978

  1. Fasting insulin, insulin resistance and risk of hypertension in the general population: A meta-analysis.

    Science.gov (United States)

    Wang, Feng; Han, Lili; Hu, Dayi

    2017-01-01

    Studies on the association of fasting insulin concentrations or insulin resistance with subsequent risk of hypertension have yielded conflicting results. To quantitatively assess the association of fasting insulin concentrations or homeostasis model assessment insulin resistance (HOMA-IR) with incident hypertension in a general population by performing a meta-analysis. We searched the PubMed and Embase databases until August 31, 2016 for prospective observational studies investigating the elevated fasting insulin concentrations or HOMA-IR with subsequent risk of hypertension in the general population. Pooled risk ratio (RR) and 95% confidence interval (CI) of hypertension was calculated for the highest versus the lowest category of fasting insulin or HOMA-IR. Eleven studies involving 10,230 hypertension cases were identified from 55,059 participants. Meta-analysis showed that the pooled adjusted RR of hypertension was 1.54 (95% CI 1.34-1.76) for fasting insulin concentrations and 1.43 (95% CI 1.27-1.62) for HOMA-IR comparing the highest to the lowest category. Subgroup analysis results showed that the association of fasting insulin concentrations with subsequent risk of hypertension seemed more pronounced in women (RR 2.07; 95% CI 1.19-3.60) than in men (RR 1.48; 95% CI 1.17-1.88). This meta-analysis suggests that elevated fasting insulin concentrations or insulin resistance as estimated by homeostasis model assessment is independently associated with an exacerbated risk of hypertension in the general population. Early intervention of hyperinsulinemia or insulin resistance may help clinicians to identify the high risk of hypertensive population. Copyright © 2016 Elsevier B.V. All rights reserved.

  2. High dietary protein intake, reducing or eliciting insulin resistance?

    NARCIS (Netherlands)

    Rietman, A.; Schwarz, J.; Tome, D.; Kok, F.J.; Mensink, M.R.

    2014-01-01

    Dietary proteins have an insulinotropic effect and thus promote insulin secretion, which indeed leads to enhanced glucose clearance from the blood. In the long term, however, a high dietary protein intake is associated with an increased risk of type 2 diabetes. Moreover, branched-chain amino acids

  3. Low-Density Lipoprotein Receptor-Related Protein-1 Protects Against Hepatic Insulin Resistance and Hepatic Steatosis

    Directory of Open Access Journals (Sweden)

    Yinyuan Ding

    2016-05-01

    Full Text Available Low-density lipoprotein receptor-related protein-1 (LRP1 is a multifunctional uptake receptor for chylomicron remnants in the liver. In vascular smooth muscle cells LRP1 controls reverse cholesterol transport through platelet-derived growth factor receptor β (PDGFR-β trafficking and tyrosine kinase activity. Here we show that LRP1 regulates hepatic energy homeostasis by integrating insulin signaling with lipid uptake and secretion. Somatic inactivation of LRP1 in the liver (hLRP1KO predisposes to diet-induced insulin resistance with dyslipidemia and non-alcoholic hepatic steatosis. On a high-fat diet, hLRP1KO mice develop a severe Metabolic Syndrome secondary to hepatic insulin resistance, reduced expression of insulin receptors on the hepatocyte surface and decreased glucose transporter 2 (GLUT2 translocation. While LRP1 is also required for efficient cell surface insulin receptor expression in the absence of exogenous lipids, this latent state of insulin resistance is unmasked by exposure to fatty acids. This further impairs insulin receptor trafficking and results in increased hepatic lipogenesis, impaired fatty acid oxidation and reduced very low density lipoprotein (VLDL triglyceride secretion.

  4. 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

    (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....

  5. Superoxide generation is diminished during glucose-stimulated insulin secretion in INS-1E cells

    Czech Academy of Sciences Publication Activity Database

    Ježek, Petr; Hlavatá, Lydie; Špaček, Tomáš

    2008-01-01

    Roč. 275, Suppl.1 (2008), s. 310-310 ISSN 1742-464X. [FEBS Congress /33./ and IUBMB Conference /11./. 28.06.2008-03.07.2008, Athens] R&D Projects: GA MZd(CZ) NR7917; GA AV ČR(CZ) IAA500110701 Institutional research plan: CEZ:AV0Z50110509 Keywords : cpo1 * superoxide production * glucose-stimulated insulin secretion * INS-1E cells Subject RIV: ED - Physiology

  6. Dual role of proapoptotic BAD in insulin secretion and beta cell survival

    OpenAIRE

    Danial, Nika N.; Walensky, Loren D.; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K.; Molina, Anthony J. A.; Datta, Sandeep Robert; Pitter, Kenneth L.; Bird, Gregory H.; Wikstrom, Jakob D.; Deeney, Jude T.; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne

    2008-01-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeab...

  7. L-leucine methyl ester stimulates insulin secretion and islet glutamate dehydrogenase

    DEFF Research Database (Denmark)

    Knudsen, P; Kofod, Hans; Lernmark, A

    1983-01-01

    , a cloned rat islet tumor cell line. A twofold increase in islet glutamate dehydrogenase activity was induced by 5 mmol/liter L-leucine OMe, a larger effect than that of L-leucine (P less than 0.02), whereas L-arginine OMe had a small inhibitory effect. We conclude that L-leucine OMe is a potent stimulus...... of insulin secretion and that its effect on the beta-cells may be exerted by activating islet glutamate dehydrogenase....

  8. Saponins from the traditional medicinal plant Momordica charantia stimulate insulin secretion in vitro

    OpenAIRE

    Keller, Amy C.; Ma, Jun; Kavalier, Adam; He, Kan; Brillantes, Anne-Marie B.; Kennelly, Edward J.

    2011-01-01

    The antidiabetic activity of Momordica charantia (L.), Cucurbitaceae, a widely-used treatment for diabetes in a number of traditional medicine systems, was investigated in vitro. Antidiabetic activity has been reported for certain saponins isolated from M. charantia. In this study insulin secretion was measured in MIN6 β-cells incubated with an ethanol extract, saponin-rich fraction, and five purified saponins and cucurbitane triterpenoids from M. charantia, 3β,7β,25-trihydroxycucurbita-5,23(...

  9. The prolyl isomerase Pin1 increases β-cell proliferation and enhances insulin secretion.

    Science.gov (United States)

    Nakatsu, Yusuke; Mori, Keiichi; Matsunaga, Yasuka; Yamamotoya, Takeshi; Ueda, Koji; Inoue, Yuki; Mitsuzaki-Miyoshi, Keiko; Sakoda, Hideyuki; Fujishiro, Midori; Yamaguchi, Suguru; Kushiyama, Akifumi; Ono, Hiraku; Ishihara, Hisamitsu; Asano, Tomoichiro

    2017-07-14

    The prolyl isomerase Pin1 binds to the phosphorylated Ser/Thr-Pro motif of target proteins and enhances their cis-trans conversion. This report is the first to show that Pin1 expression in pancreatic β cells is markedly elevated by high-fat diet feeding and in ob/ob mice. To elucidate the role of Pin1 in pancreatic β cells, we generated β-cell-specific Pin1 KO (βPin1 KO) mice. These mutant mice showed exacerbation of glucose intolerance but had normal insulin sensitivity. We identified two independent factors underlying impaired insulin secretion in the βPin1 KO mice. Pin1 enhanced pancreatic β-cell proliferation, as indicated by a reduced β-cell mass in βPin1 KO mice compared with control mice. Moreover, a diet high in fat and sucrose failed to increase pancreatic β-cell growth in the βPin1 KO mice, an observation to which up-regulation of the cell cycle protein cyclin D appeared to contribute. The other role of Pin1 was to activate the insulin-secretory step: Pin1 KO β cells showed impairments in glucose- and KCl-induced elevation of the intracellular Ca 2+ concentration and insulin secretion. We also identified salt-inducible kinase 2 (SIK2) as a Pin1-binding protein that affected the regulation of Ca 2+ influx and found Pin1 to enhance SIK2 kinase activity, resulting in a decrease in p35 protein, a negative regulator of Ca 2+ influx. Taken together, our observations demonstrate critical roles of Pin1 in pancreatic β cells and that Pin1 both promotes β-cell proliferation and activates insulin secretion. © 2017 by The American Society for Biochemistry and Molecular Biology, Inc.

  10. Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk

    Science.gov (United States)

    Cornford, Andrea S.; Barkan, Ariel L.; Hinko, Alexander

    2012-01-01

    Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass−1·day−1; 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P overeating also blunted the increase in systemic proteolysis (P overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating. PMID:23011065

  11. Suppression in growth hormone during overeating ameliorates the increase in insulin resistance and cardiovascular disease risk.

    Science.gov (United States)

    Cornford, Andrea S; Barkan, Ariel L; Hinko, Alexander; Horowitz, Jeffrey F

    2012-11-15

    Previously, we reported that overeating for only a few days markedly suppressed the secretion of growth hormone (GH). The purpose of the present study was to determine the role of this reduction in GH concentration on key metabolic adaptations that occur during 2 wk of overeating. Nine nonobese, healthy adults were admitted to the hospital for 2 wk, during which time they ate ∼4,000 kcal/day (70 kcal·kg fat-free mass(-1)·day(-1); 50% carbohydrate, 35% fat, and 15% protein), and their plasma GH concentration was allowed to decline naturally (control). An additional eight subjects underwent the same overeating intervention and received exogenous GH treatment (GHT) administered in four daily injections to mimic physiological GH secretion throughout the 2-wk overeating period. We measured plasma insulin and glucose concentrations in the fasting and postprandial state as well as fasting lipolytic rate, proteolytic rate, and fractional synthetic rate (FSR) using stable-isotope tracer methods. GHT prevented the fall in plasma GH concentration, maintaining plasma GH concentration at baseline levels (1.2 ± 0.2 ng/ml), which increased fasting and postprandial assessments of insulin resistance (P overeating also blunted the increase in systemic proteolysis (P overeating. In conclusion, our main findings suggest that the suppression in GH secretion that naturally occurs during the early stages of overeating may help attenuate the insulin resistance and hyperlipidemia that typically accompany overeating.

  12. Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain.

    Science.gov (United States)

    Catalano, Karyn J; Maddux, Betty A; Szary, Jaroslaw; Youngren, Jack F; Goldfine, Ira D; Schaufele, Fred

    2014-01-01

    Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered 'insulin refractory' IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based 'memory' of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.

  13. Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain.

    Directory of Open Access Journals (Sweden)

    Karyn J Catalano

    Full Text Available Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered 'insulin refractory' IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based 'memory' of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.

  14. Insulin Resistance Induced by Hyperinsulinemia Coincides with a Persistent Alteration at the Insulin Receptor Tyrosine Kinase Domain

    Science.gov (United States)

    Catalano, Karyn J.; Maddux, Betty A.; Szary, Jaroslaw; Youngren, Jack F.; Goldfine, Ira D.; Schaufele, Fred

    2014-01-01

    Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered ‘insulin refractory’ IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based ‘memory’ of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states. PMID:25259572

  15. Xylitol prevents NEFA-induced insulin resistance in rats

    Science.gov (United States)

    Kishore, P.; Kehlenbrink, S.; Hu, M.; Zhang, K.; Gutierrez-Juarez, R.; Koppaka, S.; El-Maghrabi, M. R.

    2013-01-01

    Aims/hypothesis Increased NEFA levels, characteristic of type 2 diabetes mellitus, contribute to skeletal muscle insulin resistance. While NEFA-induced insulin resistance was formerly attributed to decreased glycolysis, it is likely that glucose transport is the rate-limiting defect. Recently, the plant-derived sugar alcohol xylitol has been shown to have favourable metabolic effects in various animal models. Furthermore, its derivative xylulose 5-phosphate may prevent NEFA-induced suppression of glycolysis. We therefore examined whether and how xylitol might prevent NEFA-induced insulin resistance. Methods We examined the ability of xylitol to prevent NEFA-induced insulin resistance. Sustained ~1.5-fold elevations in NEFA levels were induced with Intralipid/heparin infusions during 5 h euglycaemic–hyperinsulinaemic clamp studies in 24 conscious non-diabetic Sprague-Dawley rats, with or without infusion of xylitol. Results Intralipid infusion reduced peripheral glucose uptake by ~25%, predominantly through suppression of glycogen synthesis. Co-infusion of xylitol prevented the NEFA-induced decreases in both glucose uptake and glycogen synthesis. Although glycolysis was increased by xylitol infusion alone, there was minimal NEFA-induced suppression of glycolysis, which was not affected by co-infusion of xylitol. Conclusions/interpretation We conclude that xylitol prevented NEFA-induced insulin resistance, with favourable effects on glycogen synthesis accompanying the improved insulin-mediated glucose uptake. This suggests that this pentose sweetener has beneficial insulin-sensitising effects. PMID:22460760

  16. Cerebral blood flow links insulin resistance and baroreflex sensitivity.

    Science.gov (United States)

    Ryan, John P; Sheu, Lei K; Verstynen, Timothy D; Onyewuenyi, Ikechukwu C; Gianaros, Peter J

    2013-01-01

    Insulin resistance confers risk for diabetes mellitus and associates with a reduced capacity of the arterial baroreflex to regulate blood pressure. Importantly, several brain regions that comprise the central autonomic network, which controls the baroreflex, are also sensitive to the neuromodulatory effects of insulin. However, it is unknown whether peripheral insulin resistance relates to activity within central autonomic network regions, which may in turn relate to reduced baroreflex regulation. Accordingly, we tested whether resting cerebral blood flow within central autonomic regions statistically mediated the relationship between insulin resistance and an indirect indicator of baroreflex regulation; namely, baroreflex sensitivity. Subjects were 92 community-dwelling adults free of confounding medical illnesses (48 men, 30-50 years old) who completed protocols to assess fasting insulin and glucose levels, resting baroreflex sensitivity, and resting cerebral blood flow. Baroreflex sensitivity was quantified by measuring the magnitude of spontaneous and sequential associations between beat-by-beat systolic blood pressure and heart rate changes. Individuals with greater insulin resistance, as measured by the homeostatic model assessment, exhibited reduced baroreflex sensitivity (b = -0.16, p baroreflex sensitivity was statistically mediated by cerebral blood flow in central autonomic regions, including the insula and cingulate cortex (mediation coefficients baroreflex sensitivity. Our observations may help to characterize the neural pathways by which insulin resistance, and possibly diabetes mellitus, relates to adverse cardiovascular outcomes.

  17. [Reliability of HOMA-IR for evaluation of insulin resistance during perioperative period].

    Science.gov (United States)

    Fujino, Hiroko; Itoda, Shoko; Sako, Saori; Matsuo, Kazuki; Sakamoto, Eiji; Yokoyama, Takeshi

    2013-02-01

    Hyperglycemia due to increase in insulin resistance (IR) is often observed after surgery in spite of normal insulin secretion. To evaluate the degree of IR, the golden standard method is the normoglycemic hyperinsulinemic clamp technique (glucose clamp: GC). The GC using the artificial pancreas, STG-22 (Nikkiso, Tokyo, Japan), was established as a more reliable method, since it was evaluated during steady-state period under constant insulin infusion. Homeostasis model assessment insulin resistance (HOMA-IR), however, is frequently employed in daily practice because of its convenience. We, therefore, investigated the reliability of HOMA-IR in comparison with the glucose clamp using the STG-22. Eight healthy patients undergoing maxillofacial surgery were employed in this study after obtaining written informed consent. Their insulin resistance was evaluated by HOMA-IR and the GC using the STG-22 before and after surgery. HOMA-IR increased from 0.81 +/- 0.48 to 1.17 +/- 0.50, although there were no significant differences between before and after surgery. On the other hand, M-value by GC significantly decreased after surgery from 8.82 +/- 2.49 mg x kg(-1) x min(-1) to 3.84 +/- 0.79 mg x kg(-1) x min(-1) (P = 0.0003). In addition, no significant correlation was found between the values of HOMA-IR and the M-value by GC. HOMA-IR may not be reliable to evaluate IR for perioperative period.

  18. Effects of Bariatric Surgery on Adipokine-Induced Inflammation and Insulin Resistance

    Directory of Open Access Journals (Sweden)

    Zeynep eGoktas

    2013-06-01

    Full Text Available Over a third of the US population is obese and at high risk for developing type 2 diabetes, insulin resistance and other metabolic disorders. Obesity is considered a chronic low grade inflammatory condition that is primarily attributed to expansion and inflammation of adipose tissues. Indeed, adipocytes produce and secrete numerous proinflammatory and anti-inflammatory cytokines known as adipokines. When the balance of these adipokines is shifted towards higher production of proinflammatory factors, local inflammation within adipose tissues and subsequently systemic inflammation occur. These adipokines including leptin, visfatin, resistin, apelin, vaspin, and retinol binding protein-4 can regulate inflammatory responses and contribute to the pathogenesis of diabetes. These effects are mediated by key inflammatory signaling molecules including activated serine kinases such as c-Jun N-terminal kinase (JNK and serine kinases inhibitor κB kinase (IKK and insulin signaling molecules including insulin receptor substrates, protein kinase B (PKB, also known as Akt, and nuclear factor kappa B (NF-kB. Bariatric surgery can decrease body weight and improve insulin resistance in morbidly obese subjects. However, despite reports suggesting reduced inflammation and weight-independent effects of bariatric surgery on glucose metabolism, mechanisms behind such improvements are not yet well understood. This review article focuses on some of these novel adipokines and discusses their changes after bariatric surgery and their relationship to insulin resistance, fat mass, inflammation, and glucose homeostasis.

  19. 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.

  20. Diagnostic criteria for sarcopenia relate differently to insulin resistance

    NARCIS (Netherlands)

    Bijlsma, A.Y.; Meskers, C.G.M.; van Heemst, D.; Westendorp, R.G.J.; Craen, A.J.M.; Maier, A.B.

    2013-01-01

    Skeletal muscle is important in insulinstimulated glucose uptake. Sarcopenia is, therefore, a possible risk factor for insulin resistance. Currently, different diagnostic criteria for sarcopenia include low muscle mass, muscle strength, and walking speed. We assessed these muscle characteristics in

  1. The etiology of oxidative stress in insulin resistance

    Directory of Open Access Journals (Sweden)

    Samantha Hurrle

    2017-10-01

    Full Text Available Insulin resistance is a prevalent syndrome in developed as well as developing countries. It is the predisposing factor for type 2 diabetes mellitus, the most common end stage development of metabolic syndrome in the United States. Previously, studies investigating type 2 diabetes have focused on beta cell dysfunction in the pancreas and insulin resistance, and developing ways to correct these dysfunctions. However, in recent years, there has been a profound interest in the role that oxidative stress in the peripheral tissues plays to induce insulin resistance. The objective of this review is to focus on the mechanism of oxidative species generation and its direct correlation to insulin resistance, to discuss the role of obesity in the pathophysiology of this phenomenon, and to explore the potential of antioxidants as treatments for metabolic dysfunction.

  2. Changes In Insulin Resistance Risk Markers Among Oral ...

    African Journals Online (AJOL)

    However, observations at longer and abstinence periods should be made in order to generate sufficient data needed to establish convincing evidence among Nigerian users. Keywords: Insulin resistance, Oral contraceptives, Triacylglycerol, Lipids, Glucose. Egyptian Journal of Biochemistry and Molecular Biology Vol.

  3. Lipid-induced insulin resistance in cultured hepatoma cells is associated with a decreased insulin receptor tyrosine kinase activity.

    OpenAIRE

    Hubert, P; Bruneau-Wack, C; Cremel, G; Le Marchand-Brustel, Y; Staedel, C

    1991-01-01

    We have shown previously that experimental modifications of the cellular lipid composition of an insulin-sensitive rat hepatoma cell line (Zajdela Hepatoma Culture, ZHC) affect both binding and biological actions of insulin. Discrepancies between insulin binding and actions implied a postbinding defect, responsible for the observed insulin resistance in lipid-treated cells. To elucidate the mechanism for this defect, we have studied insulin binding and insulin receptor kinase activity in part...

  4. Effects of saxagliptin on β-cell stimulation and insulin secretion in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Henry, R R; Smith, Susanne; Schwartz, Saul

    2011-01-01

    Aim: To study the effect of dipeptidyl peptidase-4 (DPP-4) inhibition with saxagliptin on ß-cell function as reflected by the stimulated insulin secretion rate after an enteral glucose load in patients with type 2 diabetes. Methods: Patients in this randomized, parallel-group, double-blind, placebo......-oral hyperglycaemic clamp (180–480 min, postprandial state) following oral ingestion of 75 g glucose. Primary and secondary endpoints were percent changes from baseline in insulin secretion during postprandial and fasting states, respectively. Insulin secretion was calculated by C-peptide deconvolution. Results......: After 12 weeks, saxagliptin significantly increased insulin secretion percent change from baseline during the postprandial state by an 18.5% adjusted difference versus placebo (p = 0.04), an improvement associated with increased peak plasma concentrations of intact glucagon-like peptide-1 and glucose...

  5. Delta-like Ligand-4-Notch Signaling Inhibition Regulates Pancreatic Islet Function and Insulin Secretion

    Directory of Open Access Journals (Sweden)

    Fabienne Billiard

    2018-01-01

    Full Text Available Although Notch signaling has been proposed as a therapeutic target for type-2 diabetes, liver steatosis, and atherosclerosis, its direct effect on pancreatic islets remains unknown. Here, we demonstrated a function of Dll4-Notch signaling inhibition on the biology of insulin-producing cells. We confirmed enhanced expression of key Notch signaling genes in purified pancreatic islets from diabetic NOD mice and showed that treatment with anti-Dll4 antibody specifically abolished Notch signaling pathway activation. Furthermore, we showed that Notch inhibition could drive proliferation of β-islet cells and confer protection from the development of STZ-induced diabetes. Importantly, inhibition of the Dll4 pathway in WT mice increased insulin secretion by inducing the differentiation of pancreatic β-islet cell progenitors, as well as the proliferation of insulin-secreting cells. These findings reveal a direct effect of Dll4-blockade on pancreatic islets that, in conjunction with its immunomodulatory effects, could be used for unmet medical needs hallmarked by inefficient insulin action.

  6. Improvement of insulin secretion in rat models of diabetes after ACEI/ARB therapy

    International Nuclear Information System (INIS)

    Tian Jingyan; Li Fengying; Liu Yun; Long Hongmei; Li Weiyi; Wang Xiao; Zhang Hongli; Li Guo; Luo Min

    2009-01-01

    Objective To study the effect of ACEI/ARB therapy on the secretion of insulin and glucagon as well as serum lipid peroxidation marker 8-iso PGF-2α levels in streptozoticin (STZ) induced diabetic rat models.Methods Twenty-four rat models of STZ induced diabetes were prepared (random blood sugar>16.7 mmol/L). Of which, 8 models were fed enalaprial 5mg/kg/d, 8 models were fed losartan 10μg/kg/d and 8 models left unterated. Fasting serum insulin,glucagon (with RIA) and 8-iso PGF-2α (with ELISA) levels were measured in these models and 8 control rats three weeks later. Intravenous glucose tolerance test (IVGTT) were performed in 12 rats (3 animals in each group) six weeks later. Results: Serum levels of insulin in the treated models were higher than those in the non-treated models but without significance (P>0.05). Serum levels of glucagon and 8-iso PGF-2α levels in the treated models were significantly lower than those in the non-treated models (P 6 x ) in the treated models. Conclusion: ACEI/ARB treatment could improve the secretion of insulin in rat models of diabetes, which might be beneficial for controlling the progression of the disease. This phenomenon is consistent with the result of clinical study. (authors)

  7. Investigating the Roles of Mitochondrial and Cytosolic Malic Enzyme in Insulin Secretion

    Science.gov (United States)

    Pongratz, Rebecca L.; Kibbey, Richard G.; Cline, Gary W.

    2015-01-01

    Glucose homeostasis depends upon the appropriate release of insulin from pancreatic islet β-cells. Postpandrial changes in circulating nutrient concentrations are coupled with graded release of stored insulin pools by the proportional changes in mitochondrial metabolism. The corresponding increased synthesis rates of both ATP and of anaplerotic metabolites have been shown to be mediators for nutrient-stimulated insulin secretion. Anaplerosis leads to the export of malate or citrate from the mitochondria, both of which can be recycled through metabolic pathways to reenter the Kreb's cycle. These metabolic cycles have the net effect of either transferring mitochondrial reducing equivalents to the cytosol, or of efficiently providing pyruvate to facilitate responsive changes in the Kreb's cycle flux in proportion to increased availability of glutamate and anaplerotic flux through glutamate dehydrogenase. Here, we describe siRNA knock-down and isotopic labeling strategies to evaluate the role of cytosolic and mitochondrial isoforms of malic enzyme in facilitating malate–pyruvate cycling in the context of fuel-stimulated insulin secretion. PMID:19426882

  8. Psychological insulin resistance in type 2 diabetes patients regarding oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin.

    Science.gov (United States)

    Petrak, Frank; Herpertz, Stephan; Stridde, Elmar; Pfützner, Andreas

    2013-08-01

    "Psychological insulin resistance" (PIR) is an obstacle to insulin treatment in type 2 diabetes, and patients' expectations regarding alternative ways of insulin delivery are poorly understood. PIR and beliefs regarding treatment alternatives were analyzed in patients with type 2 diabetes (n=532; mean glycated hemoglobin, 68±12 mmol/mol [8.34±1.5%]) comparing oral antidiabetes treatment, subcutaneous insulin injections, or inhaled insulin. Questionnaires were used to assess barriers to insulin treatment (BIT), generic and diabetes-specific quality of life (Short Form 36 and Problem Areas in Diabetes, German version), diabetes knowledge, locus of control (Questionnaire for the Assessment of Diabetes-Specific Locus of Control, in German), coping styles (Freiburg Questionnaire of Illness Coping, 15-Items Short Form), self-esteem (Rosenberg Self-Esteem Scale, German version), and mental disorders (Patient Health Questionnaire, German version). Patients discussed treatment optimization options with a physician and were asked to make a choice about future diabetes therapy options in a two-step treatment choice scenario. Step 1 included oral antidiabetes drugs or subcutaneous insulin injection (SCI). Step 2 included an additional treatment alternative of inhaled insulin (INH). Subgroups were analyzed according to their treatment choice. Most patients perceived their own diabetes-related behavior as active, problem-focused, internally controlled, and oriented toward their doctors' recommendations, although their diabetes knowledge was limited. In Step 1, rejection of the recommended insulin was 82%, and in Step 2, it was 57%. Fear of hypoglycemia was the most important barrier to insulin treatment. Patients choosing INH (versus SCI) scored higher regarding fear of injection, expected hardship from insulin therapy, and BIT-Sumscore. The acceptance of insulin is very low in type 2 diabetes patients. The option to inhale insulin increases the acceptability for some but

  9. Insulin resistance and exercise tolerance in heart failure patients

    DEFF Research Database (Denmark)

    Snoer, Martin; Monk-Hansen, Tea; Olsen, Rasmus Huan

    2012-01-01

    Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage.......Insulin resistance has been linked to exercise intolerance in heart failure patients. The aim of this study was to assess the potential role of coronary flow reserve (CFR), endothelial function and arterial stiffness in explaining this linkage....

  10. DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet

    Directory of Open Access Journals (Sweden)

    Katherine Veras

    2014-01-01

    Full Text Available Dehydroepiandrosterone (DHEA and the dehydroepiandrosterone sulfate (DHEA-S are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX female rats fed a high-fat diet would maintain glucose-induced insulin secretion (GSIS and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period.

  11. Effects of acarbose on proinsulin and insulin secretion and their potential significance for the intermediary metabolism and cardiovascular system.

    Science.gov (United States)

    Rosak, Christoph; Mertes, Gabriele

    2009-08-01

    The alpha-glucosidase inhibitor acarbose is administered to control blood glucose levels in type 2 diabetic patients and, in several countries, in those with impaired glucose tolerance. The efficacy and safety of the drug has been well established in these patient populations. Acarbose shows no weakening of efficacy in long-term diabetes treatment, reduces the development of type 2 diabetes in those with impaired glucose tolerance, and also appears to reduce the risk of cardiovascular disease. The underlying mechanisms of its effect on the risk of developing macrovascular complications have still to be elucidated. The mode of action of acarbose, which precedes all other metabolic processes involved in blood glucose regulation, inhibits high increases in postprandial blood glucose. Due to this early mode of action, acarbose also modifies insulin and proinsulin secretion which are both involved in ss-cell dysfunction and insulin resistance and may be independent risk factors for cardiovascular mortality. Based on the literature available the present state of knowledge on insulin and proinsulin as risk factors for cardiovascular mortality is reviewed as well as the effect of acarbose on the regulation of the ss-cells as monotherapy and in combination regimens. Possible associated interactions with the cardiovascular system are identified.

  12. Evidence for altered transport of insulin across the blood-brain barrier in insulin-resistant humans.

    Science.gov (United States)

    Heni, Martin; Schöpfer, Patricia; Peter, Andreas; Sartorius, Tina; Fritsche, Andreas; Synofzik, Matthis; Häring, Hans-Ulrich; Maetzler, Walter; Hennige, Anita M

    2014-08-01

    Eating behavior, body weight regulation, peripheral glucose metabolism, and cognitive function depend on adequate insulin action in the brain, and recent studies in humans suggested that impaired insulin action in the brain emerges upon fat intake, obesity, and genetic variants. As insulin enters into the brain in a receptor-mediated fashion, we hypothesized that whole-body insulin sensitivity might affect the transport of insulin into the brain and contribute to the aversive effect of insulin resistance in the central nervous system. In this study, we aimed to determine the ratio of insulin in the cerebrospinal fluid and serum to whole-body insulin sensitivity. Healthy human subjects participated in an oral glucose tolerance test to determine whole-body insulin sensitivity and underwent lumbar puncture. Blood and CSF concentrations of insulin were significantly correlated. The CSF/serum ratio for insulin was significantly associated with whole body insulin sensitivity with reduced insulin transported into the CSF in insulin-resistant subjects. Together, our data suggest that transport of insulin into the CSF relates to peripheral insulin sensitivity and impairs insulin action in the brain. This underlines the need for sensitizing measures in insulin-resistant subjects.

  13. High serum resistin is associated with an increase in adiposity but not a worsening of insulin resistance in Pima Indians

    DEFF Research Database (Denmark)

    de Courten, Barbora; Degawa-Yamauchi, Mikako; Considine, Robert V

    2004-01-01

    Resistin is an adipokine with putative prodiabetogenic properties. Like other hormones secreted by adipose tissue, resistin is being investigated as a possible etiologic link between excessive adiposity and insulin resistance. Although there is growing evidence that circulating levels...... of this adipokine are proportional to the degree of adiposity, an effect on insulin resistance in humans remains unproven. To evaluate the relations among resistin, obesity, and insulin resistance, we measured fasting serum resistin levels in 113 nondiabetic (75-g oral glucose tolerance test) Pima Indians (ages 29...... +/- 7 years, body fat 31 +/- 8%, resistin 3.7 +/- 1.1 ng/ml [means +/- SD]), who were characterized for body composition (assessed by hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M; assessed by hyperinsulinemic clamp), basal hepatic glucose output (BHGO...

  14. Oxidative stress impairs insulin signal in skeletal muscle and causes insulin resistance in postinfarct heart failure.

    Science.gov (United States)

    Ohta, Yukihiro; Kinugawa, Shintaro; Matsushima, Shouji; Ono, Taisuke; Sobirin, Mochamad A; Inoue, Naoki; Yokota, Takashi; Hirabayashi, Kagami; Tsutsui, Hiroyuki

    2011-05-01

    Insulin resistance has been shown to occur as a consequence of heart failure. However, its exact mechanisms in this setting remain unknown. We have previously reported that oxidative stress is enhanced in the skeletal muscle from mice with heart failure after myocardial infarction (MI) (30). This study is aimed to investigate whether insulin resistance in postinfarct heart failure is due to the impairment of insulin signaling in the skeletal muscle caused by oxidative stress. Mice were divided into four groups: sham operated (sham); sham treated with apocynin, an inhibitor of NAD(P)H oxidase activation (10 mmol/l in drinking water); MI; and MI treated with apocynin. After 4 wk, intraperitoneal insulin tolerance tests were performed, and skeletal muscle samples were obtained for insulin signaling measurements. MI mice showed left ventricular dilation and dysfunction by echocardiography and increased left ventricular end-diastolic pressure and lung weight. The decrease in glucose level after insulin load significantly attenuated in MI compared with sham. Insulin-stimulated serine phosphorylation of Akt and glucose transporter-4 translocation were decreased in MI mice by 61 and 23%, respectively. Apocynin ameliorated the increase in oxidative stress and NAD(P)H oxidase activities measured by the lucigenin assay in the skeletal muscle after MI. It also improved insulin resistance and inhibited the decrease of Akt phosphorylation and glucose transporter-4 translocation. Insulin resistance was induced by the direct impairment of insulin signaling in the skeletal muscle from postinfarct heart failure, which was associated with the enhanced oxidative stress via NAD(P)H oxidase.

  15. Hormone-sensitive lipase null mice exhibit signs of impaired insulin sensitivity whereas insulin secretion is intact

    DEFF Research Database (Denmark)

    Mulder, Hindrik; Sörhede-Winzell, Maria; Contreras, Juan Antonio

    2003-01-01

    of the HSL gene for glucose homeostasis were examined. HSL null mice were slightly hyperglycemic in the fasted, but not fed state, which was accompanied by moderate hyperinsulinemia. During glucose challenges, however, disposal of the sugar was not affected in HSL null mice, presumably because of release......-stimulated glucose uptake into soleus muscle, and lipogenesis in adipocytes were moderately reduced, suggesting additional sites of insulin resistance. Morphometric analysis of pancreatic islets revealed a doubling of beta-cell mass in HSL null mice, which is consistent with an adaptation to insulin resistance......Lipid metabolism plays an important role in glucose homeostasis under normal and pathological conditions. In adipocytes, skeletal muscle, and pancreatic beta-cells, lipids are mobilized from acylglycerides by the hormone-sensitive lipase (HSL). Here, the consequences of a targeted disruption...

  16. [Evaluation of preserved insulin secretion in children and adolescents with type 1 diabetes].

    Science.gov (United States)

    Wegner, Olga; Wyka, Krystyna; Fendler, Wojciech; Zmysłowska, Agnieszka; Młynarski, Wojciech

    2010-01-01

    The pathogenesis of type 1 diabetes is connected with immune-mediated beta-cell destruction leading to insulin deficiency. The majority of patients will become completely incapable of insulin secretion within a few years, however, some individuals will have persistent beta-cell function years after the diagnosis of diabetes. Despite clinical symptoms of insulin deficiency, residual beta-cell secretion can modify the clinical course and can be an independent factor influencing the delay of development of chronic diabetic complications. The aim of the study was to compare a 10-year clinical course in children with type 1 diabetes with and without preserved beta-cell secretion. 72 children and adolescents with diabetes lasting for minimum 10 years and available biological material to c-peptide evaluation (3-4 years and 10 years from the onset of diabetes) were chosen from 768 children with type 1 diabetes. We assessed fasting c-peptide and recruited 23 out of 72 patients whose concentration of c-peptide was below or over 0.23 ng/ml at all time points (this cut point derives from the definition of preserved beta-cell function according to DCCT). Afterwards we divided children into two subgroups: A (n=13) - without insulin secretion and B (n=10) - with preserved beta-cell function during 10 years of observation. We assessed markers of beta-cell autoimmunity (ICA, GADA, IA2, IAA) in the examined groups. Insulin requirement and concentration of glycated hemoglobin (assessed as the year mean from four measurements in each year) were compared between group A and B. The age at onset of diabetes in children from both examined groups was similar. All children from group B and 12/13 from group A were positive for at least one type of the screened autoantibodies. There was no difference in insulin requirement between the groups (p=0.6). The level of glycated hemoglobin was significantly lower in group B during a 10-year observational period (p=0.04). Repeated measures of c

  17. Effect of daily consumption of probiotic yoghurt on insulin resistance in pregnant women: a randomized controlled trial.

    Science.gov (United States)

    Asemi, Z; Samimi, M; Tabassi, Z; Naghibi Rad, M; Rahimi Foroushani, A; Khorammian, H; Esmaillzadeh, A

    2013-01-01

    Owing to excess body weight and increased secretion of inflammatory cytokines primarily during the third trimester, pregnancy is associated with elevated insulin resistance. To our knowledge, no report is available indicating the effects of probiotic yoghurt consumption on serum insulin levels in pregnant women. This study was designed to determine the effects of daily consumption of probiotic yoghurt on insulin resistance and serum insulin levels of Iranian pregnant women. In this randomized controlled clinical trial, 70 primigravida pregnant women with singleton pregnancy at their third trimester were participated. We randomly assigned participants to consume 200 g per day of conventional (n=33) or the probiotic group (n=37) for 9 weeks. The probiotic yoghurt was a commercially available product prepared with the starter cultures of Streptococcus thermophilus and Lactobacillus bulgaricus, enriched with probiotic culture of two strains of lactobacilli (Lactobacillus acidophilus LA5) and bifidobacteria (Bifidobacterium animalis BB12) with a total of min 1 × 10⁷ colony-forming units. Fasting blood samples were taken at baseline and after 9-week intervention to measure fasting plasma glucose and serum insulin levels. Homeostatic model assessment of insulin resistance (HOMA-IR) was used to calculate insulin resistance score. Although consumption of probiotic yogurt for 9 weeks did not affect serum insulin levels and HOMA-IR score, significant differences were found comparing changes in these variables between probiotic and conventional yogurts (changes from baseline in serum insulin levels: +1.2±1.2 vs +5.0±1.1 μIU/ml, respectively, P=0.02; and in HOMA-IR score: -0.2±0.3 vs 0.7±0.2, respectively, P=0.01). It is concluded that in contrast to conventional yogurt, daily consumption of probiotic yogurt for 9 weeks maintains serum insulin levels and might help pregnant women prevent developing insulin resistance.

  18. Imeglimin lowers glucose primarily by amplifying glucose-stimulated insulin secretion in high-fat-fed rodents

    DEFF Research Database (Denmark)

    Perry, Rachel J; Cardone, Rebecca L; Petersen, Max C

    2016-01-01

    directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than trigger the β-cell mechanism that explains the acute, antidiabetic activity of imeglimin....

  19. The loss of Sirt1 in mouse pancreatic beta cells impairs insulin secretion by disrupting glucose sensing

    DEFF Research Database (Denmark)

    Luu, L; Dai, F F; Prentice, K J

    2013-01-01

    Sirtuin 1 (SIRT1) has emerged as a key metabolic regulator of glucose homeostasis and insulin secretion. Enhanced SIRT1 activity has been shown to be protective against diabetes, although the mechanisms remain largely unknown. The aim of this study was to determine how SIRT1 regulates insulin sec...

  20. Homeostatic Model Assessment for Insulin Resistance (HOMA-IR): A Better Marker for Evaluating Insulin Resistance Than Fasting Insulin in Women with Polycystic Ovarian Syndrome.

    Science.gov (United States)

    Majid, Hafsa; Masood, Qamar; Khan, Aysha Habib

    2017-03-01

    To assess the utility of HOMA-IR in assessing insulin resistance in patients with polycystic ovary syndrome (PCOS) and compare it with fasting insulin for assessing insulin resistance (IR). Observational study. Section of Clinical Chemistry, Department of Pathology and Laboratory Medicine, The Aga Khan University Hospital, Karachi, from January 2009 to September 2012. Medical chart review of all women diagnosed with PCOS was performed. Of the 400 PCOS women reviewed, 91 met the inclusion criteria. Insulin resistance was assessed by calculating HOMA-IR using the formula (fasting glucose x fasting insulin)/405, taking normal value insulin levels ≥12 µIU/ml. A total of 91 premenopausal women diagnosed with PCOS were included. Mean age was 30 ±5.5 years. Mean HOMA-IR of women was 3.1 ±1.7, respectively with IR in 69% (n=63) women, while hyperinsulinemia was present in 60% (n=55) women (fasting Insulin 18.5 ±5.8 µIU/ml). Hyperandrogenism was present in 53.8% (n=49), whereas 38.5% (n=35) women had primary infertility or subfertility, while 65.9% (n=60) had menstrual irregularities; and higher frequencies were observed in women with IR. Eight subjects with IR and endocrine abnormalities were missed by fasting insulin. Insulin resistance is common in PCOS and it is likely a pathogenic factor for development of PCOS. HOMAIR model performed better than hyperinsulinemia alone for diagnosing IR.

  1. Effect of cigarette smoking on insulin resistance risk.

    Science.gov (United States)

    Haj Mouhamed, D; Ezzaher, A; Neffati, F; Douki, W; Gaha, L; Najjar, M F

    2016-02-01

    Smoking is one of the main risk factors for cardiovascular disease (CVD). The mechanism(s) of the effects of smoking on CVD are not clearly understood; however, a number of atherogenic characteristics, such as insulin resistance have been reported. We aim to investigate the effects of cigarette smoking on insulin resistance and to determine the correlation between this parameter with smoking status characteristics. This study was conducted on 138 non-smokers and 162 smokers aged respectively 35.6±16.0 and 38.5±21.9 years. All subjects are not diabetic. Fasting glucose was determined by enzymatic methods and insulin by chemiluminescence method. Insulin resistance (IR) was estimated using the Homeostasis Model of Assessment equation: HOMA-IR=[fasting insulin (mU/L)×fasting glucose (mmol/L)]/22.5. IR was defined as the upper quartile of HOMA-IR. Values above 2.5 were taken as abnormal and reflect insulin resistance. Compared to non-smokers, smokers had significantly higher levels of fasting glucose, fasting insulin and HOMA-IR index. These associations remained significant after adjustment for confounding factors (age, gender, BMI and alcohol consumption). A statistically significant association was noted between the smoking status parameters, including both the number of cigarettes smoked/day and the duration of smoking, and fasting insulin levels as well for HOMA-IR index. Among smokers, we noted a positive correlation between HOMA-IR index and both plasma thiocyanates and urinary cotinine. Our results show that smokers have a high risk to developing an insulin resistance and hyperinsulinemia, compared with a matched group of non-smokers, and may help to explain the high risk of cardiovascular diseases in smokers. Copyright © 2015. Published by Elsevier SAS.

  2. Atrial Natriuretic Peptide in the high normal range is associated with lower prevalence of insulin resistance

    DEFF Research Database (Denmark)

    Jujić, Amra; Nilsson, Peter M; Persson, Margaretha

    2016-01-01

    plasma levels of mid-regional proANP (MR-proANP) are associated with insulin resistance and post challenge incretin secretion after long-term follow-up. Design/Setting/Patients MR-proANP was measured in 2243 non-diabetic individuals at baseline examination of Malmö Diet and Cancer Cardiovascular cohort...... was inversely associated with insulin resistance calculated as HOMA-IR (per 1 SD change β= -0.066, p-value 0.001) at follow-up. Logistic regression analysis showed that each 1 SD increment of baseline ANP levels resulted in lower risk of belonging to upper quartile of HOMA-IR at follow-up (OR 0.88; CI 95 % 0...... after 75g glucose intake at 16.5 years of follow up. CONCLUSION: Midlife exposure to ANP within the high normal range is associated with lower risk of insulin resistance. Further, midlife exposure to ANP within the high normal range is associated with greater post challenge GIP secretion at follow...

  3. High saturated fatty acid intake induces insulin secretion by elevating gastric inhibitory polypeptide levels in healthy individuals

    DEFF Research Database (Denmark)

    Itoh, Kazue; Moriguchi, Ririko; Yamada, Yuichiro

    2014-01-01

    insulin and gastric inhibitory polypeptide (GIP) secretion. To clarify the effect of ingested fatty acid composition on glucose levels, we conducted an intervention study to investigate the insulin and plasma GIP responses in 11 healthy women, including a dietary control. Subjects were provided daily...... and FB-30 or F-30. However, insulin levels were higher after the FB-30 than after the F-20 (P incremental GIP between FB-30 and F-30 correlated significantly and positively...

  4. Insulin Secretion and Incretin Hormone Concentration in Women with Previous Gestational Diabetes Mellitus

    Directory of Open Access Journals (Sweden)

    Sung Hoon Yu

    2011-02-01

    Full Text Available BackgroundWe examined the change in the levels of incretin hormone and effects of glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide 1 (GLP-1 on insulin secretion in women with previous gestational diabetes (pGDM.MethodsA 75-g oral glucose tolerance test (OGTT was conducted on 34 women with pGDM. In addition, 11 women with normal glucose tolerance, matched for age, height and weight, were also tested. The insulin, GIP, GLP-1, and glucagon concentrations were measured, and their anthropometric and biochemical markers were also measured.ResultsAmong 34 women with pGDM, 18 had normal glucose tolerance, 13 had impaired glucose tolerance (IGT and 1 had diabetes. No significant differences were found in GLP-1 concentration between the pGDM and control group. However, a significantly high level of glucagon was present in the pGDM group at 30 minutes into the OGTT. The GIP concentration was elevated at 30 minutes and 60 minutes in the pGDM group. With the exception of the 30-minute timepoint, women with IGT had significantly high blood glucose from 0 to 120 minutes. However, there was no significant difference in insulin or GLP-1 concentration. The GIP level was significantly high from 0 to 90 minutes in patients diagnosed with IGT.ConclusionGLP-1 secretion does not differ between pGDM patients and normal women. GIP was elevated, but that does not seem to induce in increase in insulin secretion. Therefore, we conclude that other factors such as heredity and environment play important roles in the development of type 2 diabetes.

  5. status and insulin resistance in diabetic peripheral neuropathy

    Directory of Open Access Journals (Sweden)

    Taslima Akter

    2016-12-01

    Full Text Available Background: Complication of diabetes mellitus includes peripheral neuropathy which causes ischemic foot ulceration. Hyperglycemia and insulin resistance may accelerate the development of diabetic peripheral neuropathy. Objective: To assess the glycaemic status and insulin resistance for development of peripheral neuropathy in type 2 diabetes mellitus. Methods: This control case control study was conducted in the Department of Physiology, Dhaka Medical College, Dhaka from July 2014 to June 2015. A total number of 150 Type 2 diabetic patients of both sexes were selected with age ranging 40 to 50 years. Among them, 75 patients with peripheral neuropathy were included in study group and 75 patients without peripheral neuropathy were control. For evaluation of glycaemic status, fasting serum glucose (FSG, Glycosylated hemoglobin (HbA1c and to calculate insulin resistance by homeostatic model assessment for insulin resistance (HOMA-IR, fasting serum insulin (FSI, were estimated. For statistical analysis, unpaired Student’s ‘t’ test was done. Results: In this study, significant increase in FSG, HbA1c, FSI, HOMA-IR were found in diabetic subjects with peripheral neuropathy in comparison to control group. Conclusion: From the study results, it is concluded that poor glycaemic control and greater insulin resistance may be associated with diabetic peripheral neuropathy.

  6. Genetic predisposition to obesity is associated with insulin secretion in Chinese adults: The Cardiometabolic Risk in Chinese (CRC) study.

    Science.gov (United States)

    Liang, Jun; Sun, Yuting; Liu, Xuekui; Zhu, Yan; Pei, Ying; Wang, Yu; Qiu, Qinqin; Yang, Manqing; Qi, Lu

    2016-01-01

    The etiological role of obesity in determining diabetes risk among Asians may be different from that among Caucasians. The current study aimed to investigate the association between genetic predisposition to obesity and measures of insulin secretion and resistance in a large Chinese cohort. Study samples were from a community-based health examination survey in central China. A total of 2058 subjects with available biomarkers levels were included in the present study. A genetic risk score (GRS) of obesity was derived on the basis of thirteen Asian-specific body mass index (BMI)-associated variants. High obesity GRS was significantly associated with increased homeostasis model assessment (HOMA)-B score (β=7.309; P=0.001) but not related to measures of insulin resistance. Adjustment for age, sex, BMI, and levels of lipids did not appreciably change the results. In addition, we found significant interactions between the obesity GRS and measures of body fat distribution including waist circumference (WC; P for interaction=0.004) and neck circumference (NC; P for interaction=0.014) on HOMA-B score. Our results suggest that genetic predisposition to obesity may affect beta cell function in Chinese; and body fat distribution may modify the genetic effects. Copyright © 2016 Elsevier Inc. All rights reserved.

  7. Third Exposure to a Reduced Carbohydrate Meal Lowers Evening Postprandial Insulin and GIP Responses and HOMA-IR Estimate of Insulin Resistance.

    Science.gov (United States)

    Lin, Po-Ju; Borer, Katarina T

    2016-01-01

    Postprandial hyperinsulinemia, hyperglycemia, and insulin resistance increase the risk of type 2 diabetes (T2D) and cardiovascular disease mortality. Postprandial hyperinsulinemia and hyperglycemia also occur in metabolically healthy subjects consuming high-carbohydrate diets particularly after evening meals and when carbohydrate loads follow acute exercise. We hypothesized the involvement of dietary carbohydrate load, especially when timed after exercise, and mediation by the glucose-dependent insulinotropic peptide (GIP) in this phenomenon, as this incretin promotes insulin secretion after carbohydrate intake in insulin-sensitive, but not in insulin-resistant states. Four groups of eight metabolically healthy weight-matched postmenopausal women were provided with three isocaloric meals (a pre-trial meal and two meals during the trial day) containing either 30% or 60% carbohydrate, with and without two-hours of moderate-intensity exercise before the last two meals. Plasma glucose, insulin, glucagon, GIP, glucagon-like peptide 1 (GLP-1), free fatty acids (FFAs), and D-3-hydroxybutyrate concentrations were measured during 4-h postprandial periods and 3-h exercise periods, and their areas under the curve (AUCs) were analyzed by mixed-model ANOVA, and insulin resistance during fasting and meal tolerance tests within each diet was estimated using homeostasis-model assessment (HOMA-IR). The third low-carbohydrate meal, but not the high-carbohydrate meal, reduced: (1) evening insulin AUC by 39% without exercise and by 31% after exercise; (2) GIP AUC by 48% without exercise and by 45% after exercise, and (3) evening insulin resistance by 37% without exercise and by 24% after exercise. Pre-meal exercise did not alter insulin-, GIP- and HOMA-IR- lowering effects of low-carbohydrate diet, but exacerbated evening hyperglycemia. Evening postprandial insulin and GIP responses and insulin resistance declined by over 30% after three meals that limited daily carbohydrate intake to

  8. Third Exposure to a Reduced Carbohydrate Meal Lowers Evening Postprandial Insulin and GIP Responses and HOMA-IR Estimate of Insulin Resistance

    Science.gov (United States)

    Lin, Po-Ju; Borer, Katarina T.

    2016-01-01

    Background Postprandial hyperinsulinemia, hyperglycemia, and insulin resistance increase the risk of type 2 diabetes (T2D) and cardiovascular disease mortality. Postprandial hyperinsulinemia and hyperglycemia also occur in metabolically healthy subjects consuming high-carbohydrate diets particularly after evening meals and when carbohydrate loads follow acute exercise. We hypothesized the involvement of dietary carbohydrate load, especially when timed after exercise, and mediation by the glucose-dependent insulinotropic peptide (GIP) in this phenomenon, as this incretin promotes insulin secretion after carbohydrate intake in insulin-sensitive, but not in insulin-resistant states. Methods Four groups of eight metabolically healthy weight-matched postmenopausal women were provided with three isocaloric meals (a pre-trial meal and two meals during the trial day) containing either 30% or 60% carbohydrate, with and without two-hours of moderate-intensity exercise before the last two meals. Plasma glucose, insulin, glucagon, GIP, glucagon-like peptide 1 (GLP-1), free fatty acids (FFAs), and D-3-hydroxybutyrate concentrations were measured during 4-h postprandial periods and 3-h exercise periods, and their areas under the curve (AUCs) were analyzed by mixed-model ANOVA, and insulin resistance during fasting and meal tolerance tests within each diet was estimated using homeostasis-model assessment (HOMA-IR). Results The third low-carbohydrate meal, but not the high-carbohydrate meal, reduced: (1) evening insulin AUC by 39% without exercise and by 31% after exercise; (2) GIP AUC by 48% without exercise and by 45% after exercise, and (3) evening insulin resistance by 37% without exercise and by 24% after exercise. Pre-meal exercise did not alter insulin-, GIP- and HOMA-IR- lowering effects of low-carbohydrate diet, but exacerbated evening hyperglycemia. Conclusions Evening postprandial insulin and GIP responses and insulin resistance declined by over 30% after three meals

  9. C-Peptide, Baseline and Postprandial Insulin Resistance after a Carbohydrate-Rich Test Meal - Evidence for an Increased Insulin Clearance in PCOS Patients?

    Science.gov (United States)

    Stassek, J; Erdmann, J; Ohnolz, F; Berg, F D; Kiechle, M; Seifert-Klauss, V

    2017-01-01

    Introduction Known characteristics of patients with PCOS include infertility, menstrual disorders, hirsutism and also often insulin resistance. These symptoms increase with increasing body weight. In the LIPCOS study ( L ifestyle I ntervention for Patients with Polycystic Ovary Syndrome [ PCOS ]) long-term changes of the PCOS in dependence on pregnancy and parenthood were systematically assessed. In the framework of the LIPCOS study, PCOS patients were given a standardised carbohydrate-rich test meal in order to examine glucose homeostasis and insulin secretion. The results were compared with those of a eumenorrhoeic control group who all had corresponding BMI values and corresponding ages. Methods and Patients 41 PCOS patients (without diabetes) and 68 controls received a standardised carbohydrate-rich test meal (260 kcal, 62 % carbohydrates, 32 % fat, 6 % proteins) in order to generate a submaximal insulin and glucose stimulation. The values were determined at baseline and postprandial after 60, 120 and 180 minutes. In addition, the corresponding C-peptide levels were recorded. Results In the PCOS patients (n = 41), the insulin secretion test after a standardised test meal showed almost identical baseline and postprandial insulin levels when compared with those of the age- and BMI-matched eumenorrhoeic controls (n = 68). In the PCOS patients, the baseline and postprandial glucose levels were significantly elevated (92.88 ± 10.28 [PCOS] vs. 85.07 ± 9.42 mg/dL [controls]; p PCOS patients formally exhibit a higher fasting insulin resistance than controls. In spite of the higher stimulated C-peptide levels, the insulin levels did not increase more strongly with increasing glucose levels than in controls which may be indicative of a higher insulin clearance in PCOS patients.

  10. Glucagon-Like Peptide 1 Recruits Muscle Microvasculature and Improves Insulin’s Metabolic Action in the Presence of Insulin Resistance

    Science.gov (United States)

    Chai, Weidong; Zhang, Xingxing; Barrett, Eugene J.

    2014-01-01

    Glucagon-like peptide 1 (GLP-1) acutely recruits muscle microvasculature, increases muscle delivery of insulin, and enhances muscle use of glucose, independent of its effect on insulin secretion. To examine whether GLP-1 modulates muscle microvascular and metabolic insulin responses in the setting of insulin resistance, we assessed muscle microvascular blood volume (MBV), flow velocity, and blood flow in control insulin-sensitive rats and rats made insulin-resistant acutely (systemic lipid infusion) or chronically (high-fat diet [HFD]) before and after a euglycemic-hyperinsulinemic clamp (3 mU/kg/min) with or without superimposed systemic GLP-1 infusion. Insulin significantly recruited muscle microvasculature and addition of GLP-1 further expanded muscle MBV and increased insulin-mediated glucose disposal. GLP-1 infusion potently recruited muscle microvasculature in the presence of either acute or chronic insulin resistance by increasing muscle MBV. This was associated with an increased muscle delivery of insulin and muscle interstitial oxygen saturation. Muscle insulin sensitivity was completely restored in the presence of systemic lipid infusion and significantly improved in rats fed an HFD. We conclude that GLP-1 infusion potently expands muscle microvascular surface area and improves insulin’s metabolic action in the insulin-resistant states. This may contribute to improved glycemic control seen in diabetic patients receiving incretin-based therapy. PMID:24658303

  11. Neuronal calcium sensor synaptotagmin-9 is not involved in the regulation of glucose homeostasis or insulin secretion.

    Directory of Open Access Journals (Sweden)

    Natalia Gustavsson

    Full Text Available BACKGROUND: Insulin secretion is a complex and highly regulated process. It is well established that cytoplasmic calcium is a key regulator of insulin secretion, but how elevated intracellular calcium triggers insulin granule exocytosis remains unclear, and we have only begun to define the identities of proteins that are responsible for sensing calcium changes and for transmitting the calcium signal to release machineries. Synaptotagmins are primarily expressed in brain and endocrine cells and exhibit diverse calcium binding properties. Synaptotagmin-1, -2 and -9 are calcium sensors for fast neurotransmitter release in respective brain regions, while synaptotagmin-7 is a positive regulator of calcium-dependent insulin release. Unlike the three neuronal calcium sensors, whose deletion abolished fast neurotransmitter release, synaptotagmin-7 deletion resulted in only partial loss of calcium-dependent insulin secretion, thus suggesting that other calcium-sensors must participate in the regulation of insulin secretion. Of the other synaptotagmin isoforms that are present in pancreatic islets, the neuronal calcium sensor synaptotagmin-9 is expressed at the highest level after synaptotagmin-7. METHODOLOGY/PRINCIPAL FINDINGS: In this study we tested whether synaptotagmin-9 participates in the regulation of glucose-stimulated insulin release by using pancreas-specific synaptotagmin-9 knockout (p-S9X mice. Deletion of synaptotagmin-9 in the pancreas resulted in no changes in glucose homeostasis or body weight. Glucose tolerance, and insulin secretion in vivo and from isolated islets were not affected in the p-S9X mice. Single-cell capacitance measurements showed no difference in insulin granule exocytosis between p-S9X and control mice. CONCLUSIONS: Thus, synaptotagmin-9, although a major calcium sensor in the brain, is not involved in the regulation of glucose-stimulated insulin release from pancreatic β-cells.

  12. Impact of acute psychological stress on cardiovascular risk factors in face of insulin resistance.

    Science.gov (United States)

    Jones, Kristian T; Shelton, Richard C; Wan, Jun; Li, Li

    2016-11-01

    Individuals with insulin resistance (IR) are at greater risk for cardiovascular disease (CVD). Psychological stress may contribute to develop CVD in IR, although mechanisms are poorly understood. Our aim was to test the hypothesis that individuals with IR have enhanced emotional and physiological responses to acute psychological stress, leading to increased CVD risk. Sixty participants were enrolled into the study, and classified into IR group (n = 31) and insulin sensitive group (n = 29) according to the Quantitative insulin sensitivity check index, which was calculated based on an oral glucose tolerance test. The Trier social stress test, a standardized experimental stress paradigm, was performed on each participant, and emotional and physiological responses were examined. Blood was collected from each subject for insulin, cytokines, and cortisol measurements. Compared with the insulin-sensitive group, individuals with IR had significantly lower ratings of energy and calm, but higher fatigue levels in response to acute stressors. Individuals with IR also showed blunted heart rate reactivity following stress. In addition, the IR status was worsened by acute psychological stress as demonstrated by further increased insulin secretion. Furthermore, individuals with IR showed significantly increased levels of leptin and interleukin-6, but decreased levels of adiponectin, at baseline, stress test, and post-stress period. Our findings in individuals with IR under acute stress would allow a better understanding of the risks for developing CVD and to tailor the interventions for better outcomes.

  13. The molecular mechanism linking muscle fat accumulation to insulin resistance.

    Science.gov (United States)

    Hulver, Matthew W; Dohm, G Lynis

    2004-05-01

    Skeletal muscle insulin resistance is a co-morbidity of obesity and a risk factor for the development of type 2 diabetes mellitus. Insulin resistance is associated with the accumulation of intramyocellular lipids. Intramyocellular triacylglycerols do not appear to be the cause of insulin resistance but are more likely to be a marker of other lipid intermediates such as fatty acyl-CoA, ceramides or diacylglycerols. Fatty acyl-CoA, ceramides and diacylglycerols are known to directly alter various aspects of the insulin signalling cascade. Insulin signalling is inhibited by the phosphorylation of serine and threonine residues at the levels of the insulin receptor and insulin receptor substrate 1. Protein kinase C is responsible for the phosphorylation of the serine and threonine residues. Fatty acyl-CoA and diacylglycerols are known to activate protein kinase C. The cause of the intramyocellular accumulation of fatty acyl-CoA and diacylglycerols is unclear at this time. Reduced fatty acid oxidation does not appear to be responsible, as fatty acyl-CoA accumulates in skeletal muscle with a normal fatty acid oxidative capacity. Other potential mechanisms include oversupply of lipids to muscle and/or up regulated fatty acid transport.

  14. 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

    UNLABELLED: Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. He...

  15. Chronic intermittent hypoxia disturbs insulin secretion and causes pancreatic injury via the MAPK signaling pathway.

    Science.gov (United States)

    Wang, Yeying; Hai, Bing; Niu, Xiaoqun; Ai, Li; Cao, Yu; Li, Ran; Li, Yongxia

    2017-06-01

    Obstructive sleep apnea (OSA) is a breathing disorder during sleep, with a most prominent character of chronic intermittent hypoxia (CIH), which induces the generation of reactive oxygen species (ROS) that damages multiple tissues and causes metabolic disorders. In this study, we established a rat model of varying OSA with different grades of CIH (12.5% O 2 , 10% O 2 , 7.5% O 2 , and 5% O 2 ) for 12 weeks, and found that CIH stimulated insulin secretion, reduced the insulin:proinsulin ratio in pancreatic tissue, and caused pancreatic tissue lesions and cell apoptosis in a dose-dependent manner. Moreover, CIH promoted the production of tumor necrosis factor (TNF)-α, interleukin (IL)-1β and IL-6, and activated mitogen-activated protein kinase (MAPK) family members, extracellular regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), and P38, depending on the O 2 concentration. In summary, CIH disturbed insulin secretion, and caused inflammation, lesions, and cell apoptosis in pancreatic tissue via the MAPK signaling pathway, which may be of great significance for clinical treatment of OSA and type 2 diabetes mellitus (T2DM).

  16. Dual role of proapoptotic BAD in insulin secretion and beta cell survival.

    Science.gov (United States)

    Danial, Nika N; Walensky, Loren D; Zhang, Chen-Yu; Choi, Cheol Soo; Fisher, Jill K; Molina, Anthony J A; Datta, Sandeep Robert; Pitter, Kenneth L; Bird, Gregory H; Wikstrom, Jakob D; Deeney, Jude T; Robertson, Kirsten; Morash, Joel; Kulkarni, Ameya; Neschen, Susanne; Kim, Sheene; Greenberg, Michael E; Corkey, Barbara E; Shirihai, Orian S; Shulman, Gerald I; Lowell, Bradford B; Korsmeyer, Stanley J

    2008-02-01

    The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose-stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose-driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.

  17. OXIDATIVE STRESS: ITS ROLE IN INSULIN SECRETION, HORMONE RECEPTION BY ADIPOCYTES AND LIPOLYSIS IN ADIPOSE TISSUE

    Directory of Open Access Journals (Sweden)

    V. V. Ivanov

    2014-01-01

    Full Text Available Oxidative stress is one of the pathogenetic components of many diseases during which generation of reactive oxigen species increases and the capacity of the antioxidant protection system diminishes. In the research of the last decades special attention has been given to adipose tissue, production of adipokines by it and their role in development of immunoresistance associated with formation of the metabolic syndrome and diabetes.Search for methods of therapeutic correction of adipokine secretion disorders, their influence on metabolism of separate cells and the organism on the whole as well as development of new approaches to correction of disorders in cell sensitivity to insulin are extremely topical nowadays. Systematization and consolidation of accumulated data allow to determine the strategies of further research more accurately; as a result, we have attempted to summarize and analyze the accumulated data on the role of adipose tissue in oxidative stress development.On the basis of literature data and the results of the personal investigations, the role of adipose tissue in forming oxidative stress in diabetes has been analyzed in the article. Brief description of adipose tissue was given as a secretory organ regulating metabolic processes in adipocytes and influencing functions of various organs and systems of the body. Mechanisms of disorder in insulin secretion as well as development of insulin sesistance in type I diabetes were described along with the contribution of lipolysis in adipose tissue to these processes.

  18. Block of Kv1.7 potassium currents increases glucose-stimulated insulin secretion.

    Science.gov (United States)

    Finol-Urdaneta, Rocio K; Remedi, Maria S; Raasch, Walter; Becker, Stefan; Clark, Robert B; Strüver, Nina; Pavlov, Evgeny; Nichols, Colin G; French, Robert J; Terlau, Heinrich

    2012-05-01

    Glucose-stimulated insulin secretion (GSIS) relies on repetitive, electrical spiking activity of the beta cell membrane. Cyclic activation of voltage-gated potassium channels (K(v) ) generates an outward, 'delayed rectifier' potassium current, which drives the repolarizing phase of each spike and modulates insulin release. Although several K(v) channels are expressed in pancreatic islets, their individual contributions to GSIS remain incompletely understood. We take advantage of a naturally occurring cone-snail peptide toxin, Conkunitzin-S1 (Conk-S1), which selectively blocks K(v) 1.7 channels to provide an intrinsically limited, finely graded control of total beta cell delayed rectifier current and hence of GSIS. Conk-S1 increases GSIS in isolated rat islets, likely by reducing K(v) 1.7-mediated delayed rectifier currents in beta cells, which yields increases in action potential firing and cytoplasmic free calcium. In rats, Conk-S1 increases glucose-dependent insulin secretion without decreasing basal glucose. Thus, we conclude that K(v) 1.7 contributes to the membrane-repolarizing current of beta cells during GSIS and that block of this specific component of beta cell K(v) current offers a potential strategy for enhancing GSIS with minimal risk of hypoglycaemia during metabolic disorders such as Type 2 diabetes. Copyright © 2012 EMBO Molecular Medicine.

  19. Protein malnutrition after weaning disrupts peripheral clock and daily insulin secretion in mice.

    Science.gov (United States)

    Borck, Patricia Cristine; Batista, Thiago Martins; Vettorazzi, Jean Franciesco; Camargo, Rafael Ludemann; Boschero, Antonio Carlos; Vieira, Elaine; Carneiro, Everardo Magalhães

    2017-12-01

    Changes in nutritional state may alter circadian rhythms through alterations in expression of clock genes. Protein deficiency has a profound effect on body metabolism, but the effect of this nutrient restriction after weaning on biological clock has not been explored. Thus, this study aims to investigate whether the protein restriction affects the daily oscillation in the behavior and metabolic rhythms, as well as expression of clock genes in peripheral tissues. Male C57BL/6 J mice, after weaning, were fed a normal-protein (NP) diet or a low-protein (LP) diet for 8 weeks. Mice fed an LP diet did not show difference in locomotor activity and energy expenditure, but the food intake was increased, with parallel increased expression of the orexigenic neuropeptide Npy and disruption of the anorexigenic Pomc oscillatory pattern in the hypothalamus. LP mice showed disruption in the daily rhythmic patterns of plasma glucose, triglycerides and insulin. Also, the rhythmic expression of clock genes in peripheral tissues and pancreatic islets was altered in LP mice. In pancreatic islets, the disruption of clock genes was followed by impairment of daily glucose-stimulated insulin secretion and the expression of genes involved in exocytosis. Pharmacological activation of REV-ERBα could not restore the insulin secretion in LP mice. The present study demonstrates that protein restriction, leading to development of malnutrition, alters the peripheral clock and metabolic outputs, suggesting that this nutrient provides important entraining cues to regulate the daily fluctuation of biological clock. Copyright © 2017 Elsevier Inc. All rights reserved.

  20. Integrative analysis of a cross-loci regulation network identifies App as a gene regulating insulin secretion from pancreatic islets.

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    Zhidong Tu

    Full Text Available Complex diseases result from molecular changes induced by multiple genetic factors and the environment. To derive a systems view of how genetic loci interact in the context of tissue-specific molecular networks, we constructed an F2 intercross comprised of >500 mice from diabetes-resistant (B6 and diabetes-susceptible (BTBR mouse strains made genetically obese by the Leptin(ob/ob mutation (Lep(ob. High-density genotypes, diabetes-related clinical traits, and whole-transcriptome expression profiling in five tissues (white adipose, liver, pancreatic islets, hypothalamus, and gastrocnemius muscle were determined for all mice. We performed an integrative analysis to investigate the inter-relationship among genetic factors, expression traits, and plasma insulin, a hallmark diabetes trait. Among five tissues under study, there are extensive protein-protein interactions between genes responding to different loci in adipose and pancreatic islets that potentially jointly participated in the regulation of plasma insulin. We developed a novel ranking scheme based on cross-loci protein-protein network topology and gene expression to assess each gene's potential to regulate plasma insulin. Unique candidate genes were identified in adipose tissue and islets. In islets, the Alzheimer's gene App was identified as a top candidate regulator. Islets from 17-week-old, but not 10-week-old, App knockout mice showed increased insulin secretion in response to glucose or a membrane-permeant cAMP analog, in agreement with the predictions of the network model. Our result provides a novel hypothesis on the mechanism for the connection between two aging-related diseases: Alzheimer's disease and type 2 diabetes.

  1. Association of insulin resistance with obesity in children

    International Nuclear Information System (INIS)

    Siddiqui, S.A.; Bashir, S.; Shabbir, I.; Sherwani, M.K.; Aasim, M.

    2011-01-01

    Background: Insulin resistance is the primary metabolic disorder associated with obesity. Little is known about its role as a determinant of the metabolic syndrome in obese children. Objectives: To assess the association of insulin resistance with metabolic syndrome in obese and non obese children. Study type and settings: Cross sectional analytical study conducted among children of ten Municipal Corporation high schools of Data Ganj Buksh Town Lahore. Subjects and Methods: A total of 46 obese and 49 non obese children with consent were recruited for the study. Fasting blood glucose, serum insulin, high density lipoprotein in cholesterol, triglycerides, cholesterol, non HDL-cholesterol LDL-cholesterol were measured using standard methods. Data were analyzed by using statistical software SPSS-Version 15. Results: A total of 95 children 49 obese and 46 non obese were recruited for the study. A significant association of serum triglyceride(p<0.001), high density lipoprotein cholesterol(p<0.001), fasting blood glucose(p<0.001), and insulin levels (p<0.001) , was seen between the two groups. For each component of metabolic syndrome, when insulin resistance increased so did odds ratios for cardio metabolic risk factors. Conclusions: Insulin resistance was seen in 34.7% children. Metabolic syndrome was found in 31.6% children reflecting that obese children are at high risk for metabolic syndrome and have low HDL-cholesterol and high triglycerides levels. (author)

  2. Explaining psychological insulin resistance in adults with non-insulin-treated type 2 diabetes

    DEFF Research Database (Denmark)

    Holmes-Truscott, E.; Skinner, T. C.; Pouwer, F.

    2016-01-01

    significantly to the model. Conclusions Psychological insulin resistance may reflect broader distress about diabetes and concerns about its treatment but not general beliefs about medicines, depression or anxiety. Reducing diabetes distress and current treatment concerns may improve attitudes towards insulin......Aims To investigate the contribution of general and diabetes-specific emotional wellbeing and beliefs about medicines in the prediction of insulin therapy appraisals in adults with non-insulin-treated type 2 diabetes. Methods The sample included Diabetes MILES-Australia cross-sectional survey......' of current diabetes medications (BMQ Specific); negative insulin therapy appraisals (ITAS); depression (PHQ-9); anxiety (GAD-7), and diabetes distress (DDS-17). Factors associated with ITAS Negative scores were examined using hierarchical multiple regressions. Results Twenty-two percent of the variance...

  3. Cardiac Development and Transcription Factors: Insulin Signalling, Insulin Resistance, and Intrauterine Nutritional Programming of Cardiovascular Disease

    Science.gov (United States)

    Govindsamy, Annelene; Naidoo, Strinivasen

    2018-01-01

    Programming with an insult or stimulus during critical developmental life stages shapes metabolic disease through divergent mechanisms. Cardiovascular disease increasingly contributes to global morbidity and mortality, and the heart as an insulin-sensitive organ may become insulin resistant, which manifests as micro- and/or macrovascular complications due to diabetic complications. Cardiogenesis is a sequential process during which the heart develops into a mature organ and is regulated by several cardiac-specific transcription factors. Disrupted cardiac insulin signalling contributes to cardiac insulin resistance. Intrauterine under- or overnutrition alters offspring cardiac structure and function, notably cardiac hypertrophy, systolic and diastolic dysfunction, and hypertension that precede the onset of cardiovascular disease. Optimal intrauterine nutrition and oxygen saturation are required for normal cardiac development in offspring and the maintenance of their cardiovascular physiology. PMID:29484207

  4. Glycated albumin suppresses glucose-induced insulin secretion by impairing glucose metabolism in rat pancreatic β-cells

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    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.

  5. The GLP-1 mimetic exenatide potentiates insulin secretion in healthy cats.

    Science.gov (United States)

    Gilor, C; Graves, T K; Gilor, S; Ridge, T K; Rick, M

    2011-07-01

    The glucagon-like peptide-1 mimetic exenatide has a glucose-dependent insulinotropic effect, and it is effective in controlling blood glucose (BG) with minimal side effects in people with type 2 diabetes. Exenatide also delays gastric emptying, increases satiety, and improves β-cell function. We studied the effect of exenatide on insulin secretion during euglycemia and hyperglycemia in cats. Nine young, healthy, neutered, purpose-bred cats were used in a randomized, cross-over design. BG concentrations during an oral glucose tolerance test were determined in these cats previously. Two isoglycemic glucose clamps (mimicking the BG concentration during the oral glucose tolerance test) were performed in each cat on separate days, one without prior treatment (IGC) and the second with exenatide (1 μg/kg) injected subcutaneously 2 h before (ExIGC). BG, insulin, and exenatide concentrations were measured, and glucose infusion rates were recorded and compared in paired tests between the two experiments. After exenatide injection, insulin serum concentrations increased significantly (2.4-fold; range 1.0- to 9.2-fold; P = 0.004) within 15 min. This was followed by a mild decrease in BG concentration and a return of insulin concentration to baseline despite a continuous increase in serum exenatide concentrations. Insulin area under the curve (AUC) during ExIGC was significantly higher than insulin AUC during IGC (AUC ratio, 2.0 ± 0.4; P = 0.03). Total glucose infused was not significantly different between IGC and ExIGC. Exenatide was detectable in plasma at 15 min after injection. The mean exenatide concentration peaked at 45 min and then returned to baseline by 75 min. Exenatide was still detectable in the serum of three of five cats 8 h after injection. No adverse reactions to exenatide were observed. In conclusion, exenatide affects insulin secretion in cats in a glucose-dependent manner, similar to its effect in other species. Although this effect was not accompanied

  6. Insulin Modulates Cytokine Release, Collagen and Mucus Secretion in Lung Remodeling of Allergic Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Sabrina S. Ferreira

    2017-06-01

    cytokines, and collagen deposition and mucus secretion into the lungs.ConclusionThe results suggest that insulin modulates the production/release of cytokines, cell migration, deposition of collagen, and mucus secretion in lung remodeling of a mouse model of asthma.

  7. Imeglimin increases glucose-dependent insulin secretion and improves β-cell function in patients with type 2 diabetes.

    Science.gov (United States)

    Pacini, G; Mari, A; Fouqueray, P; Bolze, S; Roden, M

    2015-06-01

    To assess the glucose-stimulated insulin secretion effect of imeglimin in patients with type 2 diabetes. We conducted a double-blind, randomized, placebo-controlled study in 33 patients with type 2 diabetes [glycated haemoglobin 6.8 ± 0.1% (51 mmol/mol)], who were drug-naïve or withdrawn from their previous metformin monotherapy for 2 weeks and received imeglimin 1500 mg twice daily or placebo for 1 week. Glucose-stimulated insulin secretion was assessed using a hyperglycaemic clamp. The primary endpoint was insulin secretion as defined by total insulin response [incremental area under the curve (iAUC)0-45 min ] and insulin secretion rate (ISR) calculated from C-peptide deconvolution. β-cell glucose sensitivity at steady state (second phase: 25-45 min), hepatic insulin extraction and insulin clearance were also calculated. Imeglimin treatment for 7 days raised the insulin secretory response to glucose by +112% (iAUC0-45 , p = 0.035), first-phase ISR by +110% (p = 0.034) and second-phase ISR by +29% (p = 0.031). Imeglimin improved β-cell glucose sensitivity by +36% (p = 0.034) and tended to decrease hepatic insulin extraction (-13%; p = 0.056). Imeglimin did not affect glucagon secretion. In patients with type 2 diabetes, imeglimin improves β-cell function, which may contribute to the glucose-lowering effect observed with imeglimin in clinical trials. © 2015 John Wiley & Sons Ltd.

  8. Acanthosis nigricans and insulin resistance in obese children

    Directory of Open Access Journals (Sweden)

    Kristellina Sangirta Tirtamulia

    2010-10-01

    Full Text Available Background Acanthosis nigricans (AN is a skin condition characterized by darkening and thickening of skin. AN has been reported to be linked to insulin resistance (IR, that associated with type 2 diabetes, in obese children in many country. Objective To determine the relation between acanthosis nigricans and insulin resistance in obese children. Methods We conducted a cross sectional study in Wenang District, Manado, from October 2009 until January 2010. We examined 54 obese children aged 10-14  years for insulin resistance using Homeostasis Model Assessment of Insulin Resistance Index (HOMA-IR. We analyzed the results byT-test and phi coefficient correlation. The value of PInsulin resistance was found in 34 from 54 subjects, 28 of them has AN and 6has no AN. Obese children with AN had higher HOMA-IR than children without AN. Presence of AN was associated with IR (P

  9. Activation of PPARd and RXRa stimulates fatty acid oxidatin and insulin secretion inpancreatic beta-cells

    DEFF Research Database (Denmark)

    Børgesen, Michael; Ravnskjær, Kim; Frigerio, Francesca

    , in animal models of obesity PPARd agonists display a modest insulin sensitizing action and a marked improvement of the plasma lipid profile by reducing circulating free fatty acids and triglycerides and raising HDL-cholesterol. The lipid-lowering effect of PPARd-activation correlates with increased......ACTIVATION OF PPARd AND RXRa STIMULATES FATTY ACID OXIDATION AND INSULIN SECRETION IN PANCREATIC b-CELLS Michael Boergesen1, Kim Ravnskjaer2, Francesca Frigerio3, Allan E. Karlsen4, Pierre Maechler3 and Susanne Mandrup1 1 Department of Biochemistry and Molecular Biology, University of Southern...... Denmark, DK-5230 Odense M, Denmark; 2 Peptide Biology Laboratories, Salk Institute for Biological Studies, La Jolla, CA 92037, USA; 3 Department of Cell Physiology and Metabolism, University Medical Centre, CH-1211 Geneva 4, Switzerland; 4 Novo Nordisk, Denmark Synthetic agonists of the peroxisome...

  10. Zinc Status Affects Glucose Homeostasis and Insulin Secretion in Patients with Thalassemia

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    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.

  11. Branched-chain amino acid-enriched diet: effects on insulin secretion and cellular immune aggression.

    Science.gov (United States)

    Karabatas, L M; De Bruno, L F; Pastorale, C; Lombardo, Y B; Basabe, J C

    2000-07-01

    Several reports have demonstrated that high-protein diets may have beneficial effects on experimental models of diabetes and have raised the possibility that branched-chain amino acids could play a role in these protective effects. We investigated the effect of a normoproteic, branched-chain amino acid-enriched diet (experimental diet) on insulin secretion from C57BL/6N mice transferred with splenocytes from diabetic syngeneic donors. Mice previously fed with the experimental or control diet received three intraperitoneal injections, every other day, of 5 x 107 viable mononuclear splenocytes obtained from control or diabetic donors. Results showed that mice fed with the experimental diet and transferred with "diabetic" splenocytes presented: i) normoglycemia, and (ii) significantly higher levels in both phases of glucose-induced insulin secretion and normal values of arginine-glucose-induced insulin secretion. To evaluate the in vitro cellular immune aggression, dispersed mouse islet cells were co-cultured with splenocytes from syngeneic diabetic mice. First, dispersed islet cells from mice on the experimental or control diet were co-cultured with splenocytes from control or diabetic mice on a commercial diet. In the presence of "diabetic splenocytes, dispersed islet cells from mice on the experimental diet presented a significantly lower in vitro cellular immune aggression. On the other hand, "diabetic" splenocytes from mice fed with the experimental diet produced a significantly reduced cellular immune aggression on dispersed islet cells. Our results showed that feeding branched-chain amino acids increased the capacity of beta cells to withstand a functional assault and diminished the extent of in vitro cellular immune aggression.

  12. Insulin resistance in uremia: Insulin receptor kinase activity in liver and muscle from chronic uremic rats

    International Nuclear Information System (INIS)

    Cecchin, F.; Ittoop, O.; Sinha, M.K.; Caro, J.F.

    1988-01-01

    The authors have studied the structure and function of the partially purified insulin receptors from liver and skeletal muscle in a rat model of severe chronic uremia. 125 I-insulin binding was higher in the liver from uremic rats when compared with ad libitum- and pair-fed controls. Furthermore, the ability of insulin to stimulate the autophosphorylation of the β-subunit and insulin receptor kinase activity using Glu 80 , Tyr 20 as exogenous phosphoacceptor was increased in the liver of the uremic animals. The structural characteristics of the receptors, as determined by electrophoretic mobilities of affinity labeled α-subunit and the phosphorylated β-subunit, were normal in uremia. 125 I-insulin binding and insulin receptor kinase activity were similar in the skeletal muscle from uremic and pair- and ad libitum-fed animals. Thus the data are supportive of the hypothesis that in liver and muscle of chronic uremic rats, insulin resistance is due to a defect(s) distal to the insulin receptor kinase

  13. Insulin resistance as a physiological defense against metabolic stress

    DEFF Research Database (Denmark)

    Nolan, Christopher J; Ruderman, Neil B; Kahn, Steven E

    2015-01-01

    challenging subgroup of patients with T2D who are overweight or obese with insulin resistance (IR) and the most refractory hyperglycemia due to an inability to change lifestyle to reverse positive energy balance. For this subgroup of patients with T2D, we question the dogma that IR is primarily harmful...... with intensive insulin therapy, could therefore be harmful. Treatments that nutrient off-load to lower glucose are more likely to be beneficial. The concepts of "IR as an adaptive defense mechanism" and "insulin-induced metabolic stress" may provide explanation for some of the unexpected outcomes of recent major...

  14. Major Pathophysiology in Prediabetes and Type 2 Diabetes: Decreased Insulin in Lean and Insulin Resistance in Obese.

    Science.gov (United States)

    Kabadi, Udaya M

    2017-06-01

    Lowering of body mass index (BMI) to ≥25 kg/m 2 as obesity by ADA suggests insulin resistance as a major mechanism of impaired glucose metabolism (IGM) in Asians. However, glimepiride, an insulin secretagogue, delayed onset of type 2 diabetes (DM2) from prediabetes (PreDM), indicating decreased insulin secretion (IS) as a major factor in lean (L; BMI DM2. Seventy-five men and 45 women ages 36 to 75 years were divided into six groups: LN, LPreDM, LDM2, ObN, ObPreDM, and ObDM2. Determination of IS by insulinogenic indices (I/G) at fasting (FI/FG), first phase (∆I/∆G), and cumulative responses over 2 hours of OGTT (CRI/CRG), and IR by FIXFG, ∆IX∆G, and CRIXCRG. Changes in IS and IR for PreDM and DM2 were calculated as % fall and % rise, respectively, from levels in N. All indices of IS and IR were lower ( P DM2 ( P < 0.05) in both groups. However, the declines in IS were greater ( P < 0.05) than rises in IR in LPreDM and LDM2. Whereas, the rises in IR were higher ( P < 0.05) than declines in IS in ObPreDM and ObDM2. In L, major mechanism of IGM is declining IS and not rising IR documented among Ob.

  15. Genetic Markers of Insulin Sensitivity and Insulin Secretion Are Associated With Spontaneous Postnatal Growth and Response to Growth Hormone Treatment in Short SGA Children

    DEFF Research Database (Denmark)

    Jensen, Rikke Beck; Thankamony, Ajay; Day, Felix

    2015-01-01

    PURPOSE: The wide heterogeneity in the early growth and metabolism of children born small for gestational age (SGA), both before and during GH therapy, may reflect common genetic variations related to insulin secretion or sensitivity. METHOD: Combined multiallele single nucleotide polymorphism...... scores with known associations with insulin sensitivity or insulin secretion were analyzed for their relationships with spontaneous postnatal growth and first-year responses to GH therapy in 96 short SGA children. RESULTS: The insulin sensitivity allele score (GS-InSens) was positively associated...... with spontaneous postnatal weight gain (regression coefficient [B]: 0.12 SD scores per allele; 95% confidence interval [CI], 0.01-0.23; P = .03) and also in response to GH therapy with first-year height velocity (B: 0.18 cm/y per allele; 95% CI, 0.02-0.35; P = .03) and change in IGF-1 (B: 0.17 SD scores per allele...

  16. Evaluation of immunoisolated insulin-secreting beta TC6-F7 cells as a bioartificial pancreas.

    Science.gov (United States)

    Mamujee, S N; Zhou, D; Wheeler, M B; Vacek, I; Sun, A M

    1997-01-01

    To evaluate the growth and insulin secretion from microencapsulated beta TC6-F7 cells in vitro and to assess the in vivo function of microencapsulated cells transplanted in rats with steptozotocin (STZ)-induced diabetes. Alginate-poly-L-lysine encapsulated beta TC6-F7 cells were exposed to glucose, isobutylmethylxanthine (IBMX) and glucagon-like peptide I (7-36 amide) in a static in vitro challenge. In vivo, 2.5-3.5 x 10(7) encapsulated cells were implanted into diabetic rats. Graft function was evaluated by monitoring blood glucose concentrations and by an intraperitoneal glucose tolerance test. The cell density (number of cells per capsule) of cultured microencapsulated beta TC6-F7 cells increased almost 35-fold over a 55 day observation period to reach a plateau of approximately 3500 cells/capsule. While insulin secretion per capsule remained unchanged over the first 21 days of culture, a 7-fold increase was observed during the last 14 days of the 55 day observation period. Intraperitoneal transplantation of 3.5 x 10(7) encapsulated cells into diabetic rats resulted, within 24 hours, in reversal of hyperglycemia for up to 60 days. Post-transplantation blood glucose concentrations varied between 2 and 4 mM. Glucose clearance rates evaluated by an intraperitoneal glucose tolerance test at 30 days post-transplantation resulted in a markedly flat glucose clearance curve with blood glucose never rising above 4 mM. The glucose challenge of microencapsulated cells recovered 30 days post-transplantation resulted in a 2-fold increase in insulin response at glucose concentrations greater than 5.5 mM as compared to glucose-free media. In addition, immunostaining of recovered grafted tissue for insulin, reveals a strong presence of the peptide within the cell population. These data demonstrate the potential use of an immunoisolated beta-cell line for the treatment of diabetes.

  17. Differential patterns of insulin secretion and sensitivity in patients with type 2 diabetes mellitus and nonalcoholic fatty liver disease versus patients with type 2 diabetes mellitus alone.

    Science.gov (United States)

    Chai, Shang-Yu; Pan, Xiao-Yu; Song, Ke-Xiu; Huang, Yue-Ye; Li, Fei; Cheng, Xiao-Yun; Qu, Shen

    2014-01-07

    Nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes mellitus (T2DM) often coexist and have adverse outcomes. The aim of our study was to elucidate metabolic abnormalities in patients with DM-NAFLD versus those with T2DM alone. Patients were divided into two groups: 26 T2DM patients with NAFLD and 26 gender-, age-, and body mass index-matched patients with T2DM alone. Patients took a 75-g oral glucose tolerance test (OGTT), which measured serum insulin and C-peptide (C-p) levels at baseline (0 min), 30 min, 60 min, and 120 min after glucose challenge. Patients with DM-NAFLD or T2DM alone had similar blood glucose levels. β-cell hypersecretion was more obvious in patients with DM-NAFLD. In addition, fasting, early-phase, and late-phase C-peptide levels were significantly increased in patients with DM-NAFLD (ΔC-p 0-30 min, P insulin resistance during the OGTT did not differ significantly between groups. Hepatic insulin sensitivity independently contributed to the early phase (0-30 min) of the OGTT in patients with T2DM and NAFLD, whereas a significant deficit in late insulin secretion independently contributed to the 30-120 min glucose status in patients with T2DM only. In patients with similar levels of insulin resistance and hyperglycemia, DM-NAFLD was associated with higher serum insulin levels than T2DM alone. Hyperinsulinemia is caused mainly by β-cell hypersecretion. The present study demonstrates pathophysiological differences in mechanisms of insulin resistance in patients with DM-NAFLD versus T2DM alone.

  18. Reconstructing the insulin secretion rate by Bayesian deconvolution of phase-type densities

    DEFF Research Database (Denmark)

    Andersen, Kim Emil; Højbjerre, Malene

    2005-01-01

    of the insulin secretion rate (ISR) can be done by solving a highly ill-posed deconvolution problem. We represent the ISR, the C-peptide concentration and the convolution kernel as scaled phase-type densities and develop a Bayesian methodology for estimating such densities via Markov chain Monte Carlo techniques....... Hereby closed form evaluation of ISR is possible. We demonstrate the methodology on experimental data from healthy subjects and obtain results which are more realistic than recently reported conclusions based upon methods where the ISR is considered as piecewise constant....

  19. Mathematical Beta Cell Model for Insulin Secretion following IVGTT and OGTT

    DEFF Research Database (Denmark)

    Madsen, Henrik; Henriksen, Jan Erik; Karlsson, Mats

    2006-01-01

    Evaluation of beta cell function is conducted by a variety of glucose tolerance tests and evaluated by a number of different models with less than perfect consistency among results obtained from different tests. We formulated a new approximation of the distributed threshold model for insulin...... secretion in order to approach a model for quantifying beta cell function, not only for one, but for several different experiments. Data was obtained from 40 subjects that had both an oral glucose tolerance test (OGTT) and an intravenous tolerance test (IVGTT) performed. Parameter estimates from the two...

  20. Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat.

    Science.gov (United States)

    Lasram, Mohamed Montassar; Bouzid, Kahena; Douib, Ines Bini; Annabi, Alya; El Elj, Naziha; El Fazaa, Saloua; Abdelmoula, Jaouida; Gharbi, Najoua

    2015-04-01

    Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

  1. Validation of insulin resistance indexes in a stable renal transplant population

    NARCIS (Netherlands)

    Oterdoom, LH; De Vries, APJ; Van Son, WJ; Van Der Heide, JJH; Ploeg, RJ; Gansevoort, RT; De Jong, PE; Gans, ROB; Bakker, SJL

    2005-01-01

    OBJECTIVE - The purpose of this study was to investigate the validity of established insulin resistance indexes, based on fasting blood parameters, in a stable renal transplant population. RESEARCH DESIGN AND METHODS - Fasting insulin, homeostasis model assessment (HOMA), the quantitative insulin

  2. Validation of insulin resistance indexes in a stable renal transplant population

    NARCIS (Netherlands)

    Oterdoom, Leendert H.; de Vries, Aiko P. J.; van Son, Willem J.; Homan van der Heide, Jaap J.; Ploeg, Rutger J.; Gansevoort, Ron T.; de Jong, Paul E.; Gans, Rijk O. B.; Bakker, Stephan J. L.

    2005-01-01

    The purpose of this study was to investigate the validity of established insulin resistance indexes, based on fasting blood parameters, in a stable renal transplant population. Fasting insulin, homeostasis model assessment (HOMA), the quantitative insulin sensitivity check index (QUICKI), and

  3. 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.

  4. Insulin resistance and glucose levels in subjects with subclinical hypothyroidism

    International Nuclear Information System (INIS)

    Kahn, S.H.; Fazal, N.; Yasir, M.; Asif, N.; Rafi, T.

    2017-01-01

    To compare insulin resistance and glycemic indicators among subjects with euthyroidism and subclinical hypothyroidism. Study Design: Comparative cross-sectional study. Place and Duration of Study: Department of Pathology and Medicine, PNS Hafeez, Islamabad, in collaboration with the Department of Chemical Pathology and Endocrinology at the Armed Forces Institute of Pathology (AFIP), Rawalpindi, from December 2015 to September 2016. Methodology: Subjects referred for executive screening of apparently healthy population (without any known history of diabetes, hypertension, heart disease or other chronic ailments), were included. Subjects were grouped as euthyroidism and subclinical hypothyroidism. Results: Median (IQR) insulin resistance indices including fasting insulin and Homeostasis Model Assessment for Insulin Resistance in subjects with group-1 (n=176, 87%, Thyroid Stimulating Hormone: 0.5 - 3.5 mIU/L) and group-2 (n=26, 13%, Thyroid Stimulating Hormone: 3.51 - 15 mIU/L) were 7.6 (6.70) vs. 11.4 (13.72, p=0.040) and 1.77 (1.79) vs. 2.8 (3.07, p=0.071). The median differences for fasting plasma glucose were 5.0 (1.0) in group-1 vs. 5.0 (1.47) for Group-2 [p=0.618], and glycated hemoglobin was 5.60 (1.1) vs. 5.60 (1.7, p=0.824). Homeostasis Model Assessment for beta sensitivity index in paradox showed slightly higher values for group-2 [median (IQR) 86.67 (92.94)] than group-1 [111.6 (189.64, p= 0.040)]. Conclusion: Measures of insulin resistance including Homeostasis Model Assessment for Insulin Resistance and fasting insulin levels were significantly different between subjects with euthyroidism and having subclinical hypothyroidism. (author)

  5. Phenolic Substances from Ocimum Species Enhance Glucose- Stimulated Insulin Secretion and Modulate the Expression of Key Insulin Regulatory Genes in Mice Pancreatic Islets

    DEFF Research Database (Denmark)

    Casanova, Livia Marques; Gu, Wenqian; Costa, Sônia Soares

    2017-01-01

    cinnamic acid derivatives (caftaric, caffeic, chicoric, and rosmarinic acids) or a C-glucosylated flavonoid (vicenin-2). All substances acutely enhanced glucose-stimulated insulin secretion (GSIS) from islets at concentrations from 10−10 to 10−6 M. They also increased GSIS after chronic incubation (10−8 M...... islets. Thus, they may play an important role in diabetes treatment. This is the first report on the insulin-secretory activity of caftaric acid, rosmarinic acid, and vicenin-2....

  6. Neu5Gc and α1-3 GAL Xenoantigen Knockout Does Not Affect Glycemia Homeostasis and Insulin Secretion in Pigs.

    Science.gov (United States)

    Salama, Apolline; Mosser, Mathilde; Lévêque, Xavier; Perota, Andrea; Judor, Jean-Paul; Danna, Corentin; Pogu, Sylvie; Mouré, Anne; Jégou, Dominique; Gaide, Nicolas; Abadie, Jérôme; Gauthier, Olivier; Concordet, Jean-Paul; Le Bas-Bernardet, Stéphanie; Riochet, David; Le Berre, Ludmilla; Hervouet, Jérémy; Minault, David; Weiss, Pierre; Guicheux, Jérôme; Brouard, Sophie; Bosch, Steffi; Lagutina, Irina; Duchi, Roberto; Lazzari, Giovanna; Cozzi, Emanuele; Blancho, Gilles; Conchon, Sophie; Galli, Cesare; Soulillou, Jean-Paul; Bach, Jean-Marie

    2017-04-01

    Xenocell therapy from neonate or adult pig pancreatic islets is one of the most promising alternatives to allograft in type 1 diabetes for addressing organ shortage. In humans, however, natural and elicited antibodies specific for pig xenoantigens, α-(1,3)-galactose (GAL) and N -glycolylneuraminic acid (Neu5Gc), are likely to significantly contribute to xenoislet rejection. We obtained double-knockout (DKO) pigs lacking GAL and Neu5Gc. Because Neu5Gc -/- mice exhibit glycemic dysregulations and pancreatic β-cell dysfunctions, we evaluated islet function and glucose metabolism regulation in DKO pigs. Isolation of islets from neonate piglets yielded identical islet equivalent quantities to quantities obtained from control wild-type pigs. In contrast to wild-type islets, DKO islets did not induce anti-Neu5Gc antibody when grafted in cytidine monophosphate- N -acetylneuraminic acid hydroxylase KO mice and exhibited in vitro normal insulin secretion stimulated by glucose and theophylline. Adult DKO pancreata showed no histological abnormalities, and immunostaining of insulin and glucagon was similar to that from wild-type pancreata. Blood glucose, insulin, C-peptide, the insulin-to-glucagon ratio, and HOMA-insulin resistance in fasted adult DKO pigs and blood glucose and C-peptide changes after intravenous glucose or insulin administration were similar to wild-type pigs. This first evaluation of glucose homeostasis in DKO pigs for two major xenoantigens paves the way to their use in (pre)clinical studies. © 2017 by the American Diabetes Association.

  7. Bioactives in Blueberries Improve Insulin Sensitivity in Obese, Insulin-Resistant Men and Women1234

    Science.gov (United States)

    Stull, April J.; Cash, Katherine C.; Johnson, William D.; Champagne, Catherine M.; Cefalu, William T.

    2010-01-01

    Dietary supplementation with whole blueberries in a preclinical study resulted in a reduction in glucose concentrations over time. We sought to evaluate the effect of daily dietary supplementation with bioactives from blueberries on whole-body insulin sensitivity in men and women. A double-blinded, randomized, and placebo-controlled clinical study design was used. After screening to resolve study eligibility, baseline (wk 0) insulin sensitivity was measured on 32 obese, nondiabetic, and insulin-resistant subjects using a high-dose hyperinsulinemic-euglycemic clamp (insulin infusion of 120 mU(861 pmol)⋅m−2⋅min−1). Serum inflammatory biomarkers and adiposity were measured at baseline. At the end of the study, insulin sensitivity, inflammatory biomarkers, and adiposity were reassessed. Participants were randomized to consume either a smoothie containing 22.5 g blueberry bioactives (blueberry group, n = 15) or a smoothie of equal nutritional value without added blueberry bioactives (placebo group, n = 17) twice daily for 6 wk. Both groups were instructed to maintain their body weight by reducing ad libitum intake by an amount equal to the energy intake of the smoothies. Participants’ body weights were evaluated weekly and 3-d food records were collected at baseline, the middle, and end of the study. The mean change in insulin sensitivity improved more in the blueberry group (1.7 ± 0.5 mg⋅kg FFM−1⋅min−1) than in the placebo group (0.4 ± 0.4 mg⋅kg FFM−1⋅min−1) (P = 0.04). Insulin sensitivity was enhanced in the blueberry group at the end of the study without significant changes in adiposity, energy intake, and inflammatory biomarkers. In conclusion, daily dietary supplementation with bioactives from whole blueberries improved insulin sensitivity in obese, nondiabetic, and insulin-resistant participants. PMID:20724487

  8. Acanthosis nigricans: a flag for insulin resistance

    African Journals Online (AJOL)

    2013-11-04

    Nov 4, 2013 ... Outcome measures: OGTT, fasting serum insulin and HOMA IR were the outcome measures studied. Results: This cross-sectional study revealed that 94 subjects with acanthosis nigricans (31.34%) had IR. Grades III and IV, and textures II and III, were more predictive of IR. Acanthosis nigricans grading was ...

  9. Visceral adiposity, insulin resistance and cancer risk

    LENUS (Irish Health Repository)

    Donohoe, Claire L

    2011-06-22

    Abstract Background There is a well established link between obesity and cancer. Emerging research is characterising this relationship further and delineating the specific role of excess visceral adiposity, as opposed to simple obesity, in promoting tumorigenesis. This review summarises the evidence from an epidemiological and pathophysiological perspective. Methods Relevant medical literature was identified from searches of PubMed and references cited in appropriate articles identified. Selection of articles was based on peer review, journal and relevance. Results Numerous epidemiological studies consistently identify increased risk of developing carcinoma in the obese. Adipose tissue, particularly viscerally located fat, is metabolically active and exerts systemic endocrine effects. Putative pathophysiological mechanisms linking obesity and carcinogenesis include the paracrine effects of adipose tissue and systemic alterations associated with obesity. Systemic changes in the obese state include chronic inflammation and alterations in adipokines and sex steroids. Insulin and the insulin-like growth factor axis influence tumorigenesis and also have a complex relationship with adiposity. There is evidence to suggest that insulin and the IGF axis play an important role in mediating obesity associated malignancy. Conclusions There is much evidence to support a role for obesity in cancer progression, however further research is warranted to determine the specific effect of excess visceral adipose tissue on tumorigenesis. Investigation of the potential mechanisms underpinning the association, including the role of insulin and the IGF axis, will improve understanding of the obesity and cancer link and may uncover targets for intervention.

  10. Acute pain induces insulin resistance in humans

    DEFF Research Database (Denmark)

    Greisen, J.; Juhl, C.B.; Grøfte, Thorbjørn

    2001-01-01

    Background: Painful trauma results in a disturbed metabolic state with impaired insulin sensitivity, which is related to the magnitude of the trauma. The authors explored whether pain per se influences hepatic and extrahepatic actions of insulin. Methods: Ten healthy male volunteers underwent two...... randomly sequenced hyperinsulinemic–euglycemic (insulin infusion rate, 0.6 mU · kg-1 · min-1 for 180 min) clamp studies 4 weeks apart. Self-controlled painful electrical stimulation was applied to the abdominal skin for 30 min, to a pain intensity of 8 on a visual analog scale of 0–10, just before...... the clamp procedure (study P). In the other study, no pain was inflicted (study C). Results: Pain reduced whole-body insulin-stimulated glucose uptake from 6.37 ± 1.87 mg · kg-1 · min-1 (mean ± SD) in study C to 4.97 ± 1.38 mg · kg-1 · min-1 in study P (P

  11. Meal composition affects insulin secretion in women with type 2 diabetes: a comparison with healthy controls. The Hoorn prandial study.

    Science.gov (United States)

    Alssema, M; Schindhelm, R K; Rijkelijkhuizen, J M; Kostense, P J; Teerlink, T; Nijpels, G; Heine, R J; Dekker, J M

    2009-03-01

    Early insulin secretion following a meal is representative for normal physiology and may depend on meal composition. To compare the effects of a fat-rich and a carbohydrate-rich mixed meal on insulinogenic index as a measure of early insulin secretion in normoglycemic women (NGM) and in women with type 2 diabetes mellitus (DM2), and to assess the relationship of anthropometric and metabolic factors with insulinogenic index. Postmenopausal women, 76 with NGM and 64 with DM2, received a fat-rich meal and a carbohydrate-rich meal on separate occasions. Early insulin response was estimated as insulinogenic index ( big up tri, Deltainsulin(0-30 min)/ big up tri, Deltaglucose(0-30 min)) for each meal. Associations of fasting and postprandial triglycerides, body mass index, waist and hip circumference and alanine aminotransferase with insulinogenic indices were determined. Women with NGM present with higher insulinogenic index than women with DM2. The insulinogenic index following the fat-rich meal ( big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat)) was higher than the index following the carbohydrate-rich meal (big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH)) (Pwomen with DM2, and not significant in women with NGM). In women with DM2, homeostasis model assessment for insulin resistance was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH). In women with NGM, waist circumference was independently and inversely associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat) and with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (CH); hip circumference was positively associated with big up tri, DeltaI(30)/ big up tri, DeltaG(30) (fat). The insulinogenic index following the fat-rich meal was higher than following the isocaloric carbohydrate-rich meal, which might favorably affect postprandial glucose excursions, especially in women with DM2. The association between a larger waist circumference and a lower meal-induced insulinogenic

  12. Ablation of TSC2 enhances insulin secretion by increasing the number of mitochondria through activation of mTORC1.

    Directory of Open Access Journals (Sweden)

    Maki Koyanagi

    Full Text Available AIM: We previously found that chronic tuberous sclerosis protein 2 (TSC2 deletion induces activation of mammalian target of rapamycin Complex 1 (mTORC1 and leads to hypertrophy of pancreatic beta cells from pancreatic beta cell-specific TSC2 knockout (βTSC2(-/- mice. The present study examines the effects of TSC2 ablation on insulin secretion from pancreatic beta cells. METHODS: Isolated islets from βTSC2(-/- mice and TSC2 knockdown insulin 1 (INS-1 insulinoma cells treated with small interfering ribonucleic acid were used to investigate insulin secretion, ATP content and the expression of mitochondrial genes. RESULTS: Activation of mTORC1 increased mitochondrial DNA expression, mitochondrial density and ATP production in pancreatic beta cells of βTSC2(-/- mice. In TSC2 knockdown INS-1 cells, mitochondrial DNA expression, mitochondrial density and ATP production were increased compared with those in control INS-1 cells, consistent with the phenotype of βTSC2(-/- mice. TSC2 knockdown INS-1 cells also exhibited augmented insulin secretory response to glucose. Rapamycin inhibited mitochondrial DNA expression and ATP production as well as insulin secretion in response to glucose. Thus, βTSC2(-/- mice exhibit hyperinsulinemia due to an increase in the number of mitochondria as well as enlargement of individual beta cells via activation of mTORC1. CONCLUSION: Activation of mTORC1 by TSC2 ablation increases mitochondrial biogenesis and enhances insulin secretion from pancreatic beta cells.

  13. Parathyroidectomy Decreases Insulin Resistance Index in Patients with Primary Hyperparathyroidism.

    Science.gov (United States)

    Duran, Cevdet; Sevinc, Barıs; Kutlu, Orkide; Karahan, Omer

    2017-04-01

    Primary hyperparathyroidism (PHPT) has been considered a cause of insulin resistance (IR) and impaired glucose metabolism. However, there are conflicting results related with the recovery of insulin resistance in patients with PHPT following curative parathyroidectomy. Our aim is to evaluate the effects of curative parathyroidectomy on IR in patients with PHPT. This is a prospective interventional study. Twenty-one consecutive patients with symptomatic PHPT were included into the study. All patients underwent parathyroidectomy. Fasting serum glucose, calcium, phosphorous, parathormone, plasma insulin, and vitamin D levels were measured both at baseline and 2 months after parathyroidectomy. Insulin resistance was calculated by homeostasis of model assessment-insulin resistance (HOMA-IR). Two months after curative parathyroidectomy, serum levels of calcium ( p  = 0.001), PTH ( p  HOMA-IR ( p  = 0.003) decreased, while phosphorous levels increased ( p  = 0.001). During this period, no changes were observed at vitamin D and glucose levels. We concluded that curative parathyroidectomy decreases HOMA-IR index in patients with PHPT. Studies with larger population and longer follow-up period are required to confirm our results.

  14. Relationship between insulin resistance and inflamation markers in hemodialysis patients.

    Science.gov (United States)

    Borazan, Ali; Binici, Dogan Nasir

    2010-01-01

    The prevalence and risk factors of cardiovascular disease (CVD) are increasing in end stage renal disease (ESRD) patients. In this study, we sought to research the relationship between the insulin resistance, which is one of the risk factors for CVD, and the inflammation markers, especially C-reactive protein, fibrinogen, uric acid, and homocysteine levels in our patients who were recently diagnosed with ESRD and started hemodialysis. 64 HOMA-IR-positive and 114 HOMA-IR-negative patients were enrolled in this study. Blood samples were obtained from the patients for fasting plasma glucose, insulin, CRP, fibrinogen, uric acid, total homocysteine, urea, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglyceride, total protein, and albumin analysis after physical examinations and anamnesis were completed. Fibrinogen and CRP levels of HOMA-IR-positive HD patients were significantly increased compared to non-insulin resistants. Furthermore, there is significant positive relationship between insulin resistance and serum CRP and fibrinogen levels in these HOMA-IR-positive HD patients (r = 0.258, p < 0.001). We found out that the fibrinogen and CRP levels are significantly high in HOMA-IR positive HD patients, according to determine the risk ratio for coronary artery disease in HD patients, and think that an assessment of insulin resistance is necessary.

  15. Exercise and obesity-induced insulin resistance in skeletal muscle

    Directory of Open Access Journals (Sweden)

    Hyo-Bum Kwak

    2013-12-01

    Full Text Available The skeletal muscle in our body is a major site for bioenergetics and metabolism during exercise. Carbohydrates and fats are the primary nutrients that provide the necessary energy required to maintain cellular activities during exercise. The metabolic responses to exercise in glucose and lipid regulation depend on the intensity and duration of exercise. Because of the increasing prevalence of obesity, recent studies have focused on the cellular and molecular mechanisms of obesity-induced insulin resistance in skeletal muscle. Accumulation of intramyocellular lipid may lead to insulin resistance in skeletal muscle. In addition, lipid intermediates (e.g., fatty acyl-coenzyme A, diacylglycerol, and ceramide impair insulin signaling in skeletal muscle. Recently, emerging evidence linking obesity-induced insulin resistance to excessive lipid oxidation, mitochondrial overload, and mitochondrial oxidative stress have been provided with mitochondrial function. This review will provide a brief comprehensive summary on exercise and skeletal muscle metabolism, and discuss the potential mechanisms of obesity-induced insulin resistance in skeletal muscle.

  16. PPARγ agonists diminish serum VEGF elevation in diet-induced insulin resistant SD rats and ZDF rats

    International Nuclear Information System (INIS)

    Yang Baichun; Lin Peiyuan; Carrick, Kevin M.; McNulty, Judi A.; Clifton, Lisa G.; Winegar, Deborah A.; Strum, Jay C.; Stimpson, Stephen A.; Pahel, Greg L.

    2005-01-01

    We investigated the effect of peroxisome proliferator-activated receptor gamma (PPARγ) agonists on serum vascular endothelial growth factor (VEGF) in diet-induced insulin resistant SD rats and ZDF rats. SD rats fed a high fat/sucrose diet showed increases in serum insulin and VEGF (both p < 0.01). Treatment with a PPARγ agonist GI262570 normalized the diet-elevated insulin and VEGF (both p < 0.01). There was a positive correlation between serum insulin and VEGF (p < 0.05) in SD rats. ZDF rats had higher serum glucose, insulin, and VEGF than Zucker lean rats (all p < 0.01). Treatment of ZDF rats with PPARγ agonist pioglitazone decreased serum glucose and VEGF (both p < 0.01). There was a positive correlation between glucose and VEGF in ZDF rats (p < 0.05). In 3T3-L1 adipocytes, GI262570 did not affect insulin-stimulated VEGF secretion. These studies demonstrated that hyperinsulinemia in SD rats and hyperglycemia in ZDF rats were associated with increased serum VEGF; PPARγ agonists normalized serum insulin, glucose, and VEGF, but did not affect VEGF secretion in vitro

  17. Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.

    Science.gov (United States)

    Vazirani, Reema P; Verma, Akanksha; Sadacca, L Amanda; Buckman, Melanie S; Picatoste, Belen; Beg, Muheeb; Torsitano, Christopher; Bruno, Joanne H; Patel, Rajesh T; Simonyte, Kotryna; Camporez, Joao P; Moreira, Gabriela; Falcone, Domenick J; Accili, Domenico; Elemento, Olivier; Shulman, Gerald I; Kahn, Barbara B; McGraw, Timothy E

    2016-06-01

    Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes. © 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.

  18. Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion.

    Science.gov (United States)

    Wollam, Joshua; Mahata, Sumana; Riopel, Matthew; Hernandez-Carretero, Angelina; Biswas, Angshuman; Bandyopadhyay, Gautam K; Chi, Nai-Wen; Eiden, Lee E; Mahapatra, Nitish R; Corti, Angelo; Webster, Nicholas J G; Mahata, Sushil K

    2017-06-01

    Chromogranin A (CgA) is a prohormone and a granulogenic factor that regulates secretory pathways in neuroendocrine tissues. In β-cells of the endocrine pancreas, CgA is a major cargo in insulin secretory vesicles. The impact of CgA deficiency on the formation and exocytosis of insulin vesicles is yet to be investigated. In addition, no literature exists on the impact of CgA on mitochondrial function in β-cells. Using three different antibodies, we demonstrate that CgA is processed to vasostatin- and catestatin-containing fragments in pancreatic islet cells. CgA deficiency in Chga-KO islets leads to compensatory overexpression of chromogranin B, secretogranin II, SNARE proteins and insulin genes, as well as increased insulin protein content. Ultrastructural studies of pancreatic islets revealed that Chga-KO β-cells contain fewer immature secretory granules than wild-type (WT) control but increased numbers of mature secretory granules and plasma membrane-docked vesicles. Compared to WT control, CgA-deficient β-cells exhibited increases in mitochondrial volume, numerical densities and fusion, as well as increased expression of nuclear encoded genes (Ndufa9, Ndufs8, Cyc1 and Atp5o). These changes in secretory vesicles and the mitochondria likely contribute to the increased glucose-stimulated insulin secretion observed in Chga-KO mice. We conclude that CgA is an important regulator for coordination of mitochondrial dynamics, secretory vesicular quanta and GSIS for optimal secretory functioning of β-cells, suggesting a strong, CgA-dependent positive link between mitochondrial fusion and GSIS.

  19. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases...

  20. Alteration in insulin action

    DEFF Research Database (Denmark)

    Tanti, J F; Gual, P; Grémeaux, T

    2004-01-01

    Insulin resistance, when combined with impaired insulin secretion, contributes to the development of type 2 diabetes. Insulin resistance is characterised by a decrease in insulin effect on glucose transport in muscle and adipose tIssue. Tyrosine phosphorylation of insulin receptor substrate 1 (IRS...... to phosphorylate these serine residues have been identified. These exciting results suggest that serine phosphorylation of IRS-1 is a possible hallmark of insulin resistance in biologically insulin responsive cells or tIssues. Identifying the pathways by which "diabetogenic" factors activate IRS-1 kinases......-1) and its binding to phosphatidylinositol 3-kinase (PI 3-kinase) are critical events in the insulin signalling cascade leading to insulin-stimulated glucose transport. Modification of IRS-1 by serine phosphorylation could be one of the mechanisms leading to a decrease in IRS-1 tyrosine...