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Sample records for cellular insulin sensitivity

  1. The assembly of lipid droplets and its relation to cellular insulin sensitivity

    DEFF Research Database (Denmark)

    Boström, Pontus; Andersson, Linda; Li, Lu;

    2009-01-01

    and VAMP-4 (vesicle-associated protein 4). SNAP-23 is also involved in the insulin-dependent translocation of the glucose transporter GLUT4 to the plasma membrane. Fatty acids induce a missorting of SNAP-23, from the plasma membrane to the interior of the cell, resulting in cellular insulin resistance...

  2. Insulin sensitivity and albuminuria

    DEFF Research Database (Denmark)

    Pilz, Stefan; Rutters, Femke; Nijpels, Giel;

    2014-01-01

    was assessed by hyperinsulinemic-euglycemic clamps, expressed as the M/I value. Oral glucose tolerance test-based insulin sensitivity (OGIS), homeostasis model assessment of insulin resistance (HOMA-IR), and urinary albumin-to-creatinine ratio (UACR) were determined at baseline and follow-up. RESULTS...... AND METHODS: We investigated 1,415 healthy, nondiabetic participants (mean age 43.9 ± 8.3 years; 54.3% women) from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study, of whom 852 participated in a follow-up examination after 3 years. At baseline, insulin sensitivity...

  3. Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion.

    Science.gov (United States)

    Salunkhe, Vishal A; Mollet, Inês G; Ofori, Jones K; Malm, Helena A; Esguerra, Jonathan L S; Reinbothe, Thomas M; Stenkula, Karin G; Wendt, Anna; Eliasson, Lena; Vikman, Jenny

    2016-08-01

    Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired.

  4. Quantification of adipose tissue insulin sensitivity.

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    Søndergaard, Esben; Jensen, Michael D

    2016-06-01

    In metabolically healthy humans, adipose tissue is exquisitely sensitive to insulin. Similar to muscle and liver, adipose tissue lipolysis is insulin resistant in adults with central obesity and type 2 diabetes. Perhaps uniquely, however, insulin resistance in adipose tissue may directly contribute to development of insulin resistance in muscle and liver because of the increased delivery of free fatty acids to those tissues. It has been hypothesized that insulin adipose tissue resistance may precede other metabolic defects in obesity and type 2 diabetes. Therefore, precise and reproducible quantification of adipose tissue insulin sensitivity, in vivo, in humans, is an important measure. Unfortunately, no consensus exists on how to determine adipose tissue insulin sensitivity. We review the methods available to quantitate adipose tissue insulin sensitivity and will discuss their strengths and weaknesses.

  5. Increased skeletal muscle capillarization enhances insulin sensitivity

    DEFF Research Database (Denmark)

    Åkerström, Thorbjörn; Laub, Lasse; Vedel, Kenneth;

    2014-01-01

    Increased skeletal muscle capillarization is associated with improved glucose tolerance and insulin sensitivity. However, a possible causal relationship has not previously been identified. We therefore investigated whether increased skeletal muscle capillarization increases insulin sensitivity....... Skeletal muscle specific angiogenesis was induced by adding the α1-adrenergic receptor antagonist Prazosin to the drinking water of Sprague Dawley rats (n=33) while 34 rats served as controls. Insulin sensitivity was measured ≥40 h after termination of the 3-week Prazosin treatment, which ensured......-body insulin sensitivity increased by ~24% and insulin-stimulated skeletal muscle 2-deoxy-[(3)H]-Glucose disposal increased by ~30% concomitant with a ~20% increase in skeletal muscle capillarization. Adipose tissue insulin sensitivity was not affected by the treatment. Insulin-stimulated muscle glucose uptake...

  6. Insulin sensitivity : modulation by the brain

    NARCIS (Netherlands)

    Coomans, Claudia Pascalle

    2012-01-01

    The studies in this thesis contribute to the understanding of the role of the brain in insulin sensitivity. We demonstrate that disturbances in circadian rhythm resulting in alterations in SCN output, can contribute to the development of insulin resistance. We also shown that insulin-stimulated gluc

  7. Salt sensitivity correlates positively with insulin sensitivity in healthy volunteers

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    ter Maaten, JC; Voordouw, JJ; Bakker, SJL; Gans, ROB

    1999-01-01

    Background The aim of the study was to assess the relationship between insulin sensitivity and salt sensitivity in healthy subjects who display a wide range of insulin sensitivity. As a secondary objective, we assessed the relationship between salt sensitivity and the other characteristics of the in

  8. Insulin resistance, insulin sensitization and inflammation in polycystic ovarian syndrome

    Directory of Open Access Journals (Sweden)

    Dhindsa G

    2004-04-01

    Full Text Available It is estimated that 5-10% of women of reproductive age have polycystic ovarian syndrome (PCOS. While insulin resistance is not part of the diagnostic criteria for PCOS, its importance in the pathogenesis of PCOS cannot be denied. PCOS is associated with insulin resistance independent of total or fat-free body mass. Post-receptor defects in the action of insulin have been described in PCOS which are similar to those found in obesity and type 2 diabetes. Treatment with insulin sensitizers, metformin and thiazolidinediones, improve both metabolic and hormonal patterns and also improve ovulation in PCOS. Recent studies have shown that PCOS women have higher circulating levels of inflammatory mediators like C-reactive protein, tumour necrosis factor- , tissue plasminogen activator and plasminogen activator inhibitor-1 (PAI-1 . It is possible that the beneficial effect of insulin sensitizers in PCOS may be partly due to a decrease in inflammation.

  9. Diclofenac derivatives with insulin-sensitizing activity

    Institute of Scientific and Technical Information of China (English)

    Jian Ta Wang; Ying Wang; Ji Quan Zhang; Xing Cui; Yi Zhang; Gao Feng Zhu; Lei Tang

    2011-01-01

    A series of diclofenac derivatives were synthesized. The insulin-sensitizing activity of 28 new compounds was evaluated in 3T3-L1 cells. The compounds 10a and 10f exhibited similar insulin-sensitizing activity with positive drag rosiglitazone.

  10. Insulin and Insulin-Sensitizing Drugs in Neurodegeneration: Mitochondria as Therapeutic Targets

    Directory of Open Access Journals (Sweden)

    Paula I. Moreira

    2009-12-01

    Full Text Available Insulin, besides its glucose lowering effects, is involved in the modulation of lifespan, aging and memory and learning processes. As the population ages, neurodegenerative disorders become epidemic and a connection between insulin signaling dysregulation, cognitive decline and dementia has been established. Mitochondria are intracellular organelles that despite playing a critical role in cellular metabolism are also one of the major sources of reactive oxygen species. Mitochondrial dysfunction, oxidative stress and neuroinflammation, hallmarks of neurodegeneration, can result from impaired insulin signaling. Insulin-sensitizing drugs such as the thiazolidinediones are a new class of synthetic compounds that potentiate insulin action in the target tissues and act as specific agonists of the peroxisome proliferator-activated receptor gamma (PPAR-γ. Recently, several PPAR agonists have been proposed as novel and possible therapeutic agents for neurodegenerative disorders. Indeed, the literature shows that these agents are able to protect against mitochondrial dysfunction, oxidative damage, inflammation and apoptosis. This review discusses the role of mitochondria and insulin signaling in normal brain function and in neurodegeneration. Furthermore, the potential protective role of insulin and insulin sensitizers in Alzheimer´s, Parkinson´s and Huntington´s diseases and amyotrophic lateral sclerosis will be also discussed.

  11. Chromium picolinate enhances skeletal muscle cellular insulin signaling in vivo in obese, insulin-resistant JCR:LA-cp rats.

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    Wang, Zhong Q; Zhang, Xian H; Russell, James C; Hulver, Matthew; Cefalu, William T

    2006-02-01

    Chromium is one of the few trace minerals for which a specific cellular mechanism of action has not been identified. Recent in vitro studies suggest that chromium supplementation may improve insulin sensitivity by enhancing insulin receptor signaling, but this has not been demonstrated in vivo. We investigated the effect of chromium supplementation on insulin receptor signaling in an insulin-resistant rat model, the JCR:LA-corpulent rat. Male JCR:LA-cp rats (4 mo of age) were randomly assigned to receive chromium picolinate (CrPic) (obese n=6, lean n=5) or vehicle (obese n=5, lean n=5) for 3 mo. The CrPic was provided in the water, and based on calculated water intake, rats randomized to CrPic received 80 microg/(kg.d). At the end of the study, skeletal muscle (vastus lateralis) biopsies were obtained at baseline and at 5, 15, and 30 min postinsulin stimulation to assess insulin signaling. Obese rats treated with CrPic had significantly improved glucose disposal rates and demonstrated a significant increase in insulin-stimulated phosphorylation of insulin receptor substrate (IRS)-1 and phosphatidylinositol (PI)-3 kinase activity in skeletal muscle compared with obese controls. The increase in cellular signaling was not associated with increased protein levels of the IRS proteins, PI-3 kinase or Akt. However, protein tyrosine phosphatase 1B (PTP1B) levels were significantly lower in obese rats administered CrPic than obese controls. When corrected for protein content, PTP1B activity was also significantly lower in obese rats administered CrPic than obese controls. Our data suggest that chromium supplementation of obese, insulin-resistant rats may improve insulin action by enhancing intracellular signaling.

  12. MAPK/ERK signaling regulates insulin sensitivity to control glucose metabolism in Drosophila.

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    Wei Zhang

    2011-12-01

    Full Text Available The insulin/IGF-activated AKT signaling pathway plays a crucial role in regulating tissue growth and metabolism in multicellular animals. Although core components of the pathway are well defined, less is known about mechanisms that adjust the sensitivity of the pathway to extracellular stimuli. In humans, disturbance in insulin sensitivity leads to impaired clearance of glucose from the blood stream, which is a hallmark of diabetes. Here we present the results of a genetic screen in Drosophila designed to identify regulators of insulin sensitivity in vivo. Components of the MAPK/ERK pathway were identified as modifiers of cellular insulin responsiveness. Insulin resistance was due to downregulation of insulin-like receptor gene expression following persistent MAPK/ERK inhibition. The MAPK/ERK pathway acts via the ETS-1 transcription factor Pointed. This mechanism permits physiological adjustment of insulin sensitivity and subsequent maintenance of circulating glucose at appropriate levels.

  13. Modulation of the cellular content of metabolites in adipocytes by insulin.

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    Qiao, Yuhang; Tomonaga, Shozo; Matsui, Tohru; Funaba, Masayuki

    2016-03-15

    Although the insulin-mediated cell signaling pathway has been extensively examined, changes in the cellular content of metabolites currently remain unclear. We herein examined metabolite contents in 3T3-L1 adipocytes treated with insulin using a metabolomic analysis. Fifty-four compounds were detected, and the contents of metabolites from the citric acid cycle increased in response to the insulin treatment for 4 h, which was sensitive to U0126 and LY294002, inhibitors for mitogen-activated protein kinase kinase-1 and phosphoinositide 3-kinase, respectively. The cellular contents of fumaric acid and malic acid were increased more by insulin than those of citric acid and succinic acid. Time-course changes in metabolites from the citric acid cycle exhibited oscillations with a 2-h cycle. A metabolic pathway analysis also indicated that insulin affected the metabolism of alanine, aspartate and glutamate, as well as that of arginine and proline. The contents of free amino acids were slightly decreased by the insulin treatment, while the co-treatment with U0126 and LY294002 abrogated these insulin-mediated decreases. The present study revealed the unexpected accumulation of citric acid cycle metabolites in adipocytes by insulin. Our results indicate the usefulness of metabolomic analyses for obtaining a more comprehensive understanding of the regulation of metabolic pathways in cell-culture systems.

  14. Role of Vitamin D in Insulin Secretion and Insulin Sensitivity for Glucose Homeostasis

    OpenAIRE

    Alvarez, Jessica A.; Ambika Ashraf

    2010-01-01

    Vitamin D functions are not limited to skeletal health benefits and may extend to preservation of insulin secretion and insulin sensitivity. This review summarizes the literature related to potential vitamin D influences on glucose homeostasis and insulin sensitivity. Cross-sectional data provide some evidence that circulating 25-hydroxyvitamin D (25(OH)D) is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Report...

  15. Insulin sensitivity in post-obese women

    DEFF Research Database (Denmark)

    Toubro, S; Western, P; Bülow, J

    1994-01-01

    1. Both increased and decreased sensitivity to insulin has been proposed to precede the development of obesity. Therefore, insulin sensitivity was measured during a 2 h hyperinsulinaemia (100 m-units min-1 m-2) euglycaemic (4.5 mmol/l) glucose clamp combined with indirect calorimetry in nine weight...... metabolism is unaltered in the post-obese state. The study, however, points to an increased antilipolytic insulin action in post-obese subjects, which may favour fat storage and lower lipid oxidation rate postprandially.(ABSTRACT TRUNCATED AT 250 WORDS)......-stable post-obese women and in nine matched control women preceded by 12 h fasting after 48 h on a standardized diet. 2. Both glucose disposal rate (post-obese women, 9.5 +/- 2.2 mg min-1 kg-1, control women, 11.2 +/- 1.4 mg min-1 kg-1, not significant) and glucose oxidation (3.6 +/- 0.5 mg min-1 kg-1 versus...

  16. A novel insulin sensitizer (S15511) enhances insulin-stimulated glucose uptake in rat skeletal muscles.

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    Jessen, N; Selmer Buhl, E; Pold, R; Schmitz, O; Lund, S

    2008-04-01

    Type 2 diabetes is preceded by the presence of skeletal muscle insulin resistance, and drugs that increase insulin sensitivity in skeletal muscle prevent the disease. S15511 is an original compound with demonstrated effects on insulin sensitivity in animal models of insulin resistance. However, the mechanisms behind the insulin-sensitizing effect of S15511 are unknown. The aim of our study was to explore whether S15511 improves insulin sensitivity in skeletal muscles. Insulin sensitivity was assessed in skeletal muscles from S15511-treated rats by measuring intracellular insulin-signaling activity and insulin-stimulated glucose transport in isolated muscles. In addition, GLUT4 expression and glycogen levels were assessed after treatment. S15511 treatment was associated with an increase in insulin-stimulated glucose transport in type IIb fibers, while type I fibers were unaffected. The enhanced glucose transport was mirrored by a fiber type-specific increase in GLUT4 expression, while no improvement in insulin-signaling activity was observed. S15511 is a novel insulin sensitizer that is capable of improving glucose homeostasis in nondiabetic rats. The compound enhances skeletal muscle insulin sensitivity and specifically targets type IIb muscle fibers by increasing GLUT4 expression. Together these data show S15511 to be a potentially promising new drug in the treatment and prevention of type 2 diabetes.

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

    NARCIS (Netherlands)

    Bot, M.; Pouwer, F.; De Jonge, P.; Nolan, J. J.; Mari, A.; Hojlund, K.; Golay, A.; Balkau, B.; Dekker, J. M.

    2013-01-01

    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

  18. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes

    DEFF Research Database (Denmark)

    Malin, Steven K; Haus, Jacob M; Solomon, Thomas P J;

    2013-01-01

    Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization...

  19. Euglycemic clamp insulin sensitivity and longitudinal systolic blood pressure

    DEFF Research Database (Denmark)

    Petrie, John R; Malik, Muhammad Omar; Balkau, Beverley;

    2013-01-01

    and Cardiovascular disease (RISC) study, we measured insulin sensitivity (M/I) using the euglycemic clamp technique in 1073 healthy European adults (587 women, 486 men) aged 30 to 60 years followed up 3 years later. Systolic BP (SBP) at baseline was higher in insulin-resistant women (ie, those in the low sex......Insulin resistance may be an independent risk factor for the development of hypertension, but change in blood pressure (BP) over time has not been adequately studied in healthy individuals fully characterized for insulin sensitivity. In the Relationship between Insulin Sensitivity...

  20. The Insulin-Sensitive Side of SHIP2

    Directory of Open Access Journals (Sweden)

    Stephane Schurmans

    2001-01-01

    Full Text Available A substantial and increasing proportion of death and disability in the EU (and elsewhere is attributable to diseases associated with insulin resistance (i.e., decreased insulin sensitivity. Beside type II diabetes, other diseases like obesity, hypertension, atherosclerosis, hyperlipidaemia, polycystic ovarian syndrome, and acromegaly are indeed associated with insulin resistance [1].

  1. Improved insulin sensitivity after exercise: focus on insulin signaling

    DEFF Research Database (Denmark)

    Frøsig, Christian; Richter, Erik

    2009-01-01

    of the mechanism relates to an improved ability of insulin to stimulate translocation of glucose transporters (GLUT4) to the muscle membrane after exercise. How this is accomplished is still unclear; however, an obvious possibility is that exercise interacts with the insulin signaling pathway to GLUT4...

  2. A Modified Sensitive Driving Cellular Automaton Model

    Institute of Scientific and Technical Information of China (English)

    GE Hong-Xia; DAI Shi-Qiang; DONG Li-Yun; LEI Li

    2005-01-01

    A modified cellular automaton model for traffic flow on highway is proposed with a novel concept about the variable security gap. The concept is first introduced into the original Nagel-Schreckenberg model, which is called the non-sensitive driving cellular automaton model. And then it is incorporated with a sensitive driving NaSch model,in which the randomization brake is arranged before the deterministic deceleration. A parameter related to the variable security gap is determined through simulation. Comparison of the simulation results indicates that the variable security gap has different influence on the two models. The fundamental diagram obtained by simulation with the modified sensitive driving NaSch model shows that the maximumflow are in good agreement with the observed data, indicating that the presented model is more reasonable and realistic.

  3. Insulin sensitivity in clinically healthy individuals with microalbuminuria

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    Jensen, J S; Borch-Johnsen, K; Jensen, G;

    1996-01-01

    In epidemiologic studies microalbuminuria is associated with increased atherosclerotic risk profile, morbidity, and mortality. In order to examine whether such association could be explained by impaired insulin sensitivity, 23 clinically healthy subjects with microalbuminuria (urinary albumin...... glucose, tobacco and alcohol consumption, physical activity, and age and sex, fasting serum insulin concentration was the only variable independently associated with insulin sensitivity (r = -0.55; P = 0.0001). It is concluded that microalbuminuria is not associated with impaired insulin sensitivity...... in clinically healthy individuals. The effect of microalbuminuria as predictor of atherosclerotic vascular disease may be mediated through other factors....

  4. Current understanding of increased insulin sensitivity after exercise - emerging candidates

    DEFF Research Database (Denmark)

    Maarbjerg, Stine Just; Sylow, Lykke; Richter, Erik

    2011-01-01

    insulin sensitivity. It is believed that increased sarcolemmal content of the glucose transporter GLUT4 can explain the phenomenon to some extent. Surprisingly no improvement in the proximal insulin signaling pathway is observed at the level of the insulin receptor, IRS1, PI3K or Akt. Recently more distal...... signaling component in the insulin signaling pathway such as aPKC, Rac1, TBC1D4 and TBC1D1 have been described. These are all affected by both insulin and exercise which means that they are likely converging points in promoting GLUT4 translocation and therefore possible candidates for regulating insulin...... in signaling to GLUT4 translocation, factors influencing the trans-sarcolemmal glucose concentration gradient might also be important. With regard to the interstitial glucose concentration microvascular perfusion is particular relevant as correlative evidence supports a connection between insulin sensitivity...

  5. Exercise rescues obese mothers’ insulin sensitivity, placental hypoxia and male offspring insulin sensitivity

    Science.gov (United States)

    Fernandez-Twinn, Denise S.; Gascoin, Geraldine; Musial, Barbara; Carr, Sarah; Duque-Guimaraes, Daniella; Blackmore, Heather L.; Alfaradhi, Maria Z.; Loche, Elena; Sferruzzi-Perri, Amanda N.; Fowden, Abigail L.; Ozanne, Susan E.

    2017-01-01

    The prevalence of obesity during pregnancy continues to increase at alarming rates. This is concerning as in addition to immediate impacts on maternal wellbeing, obesity during pregnancy has detrimental effects on the long-term health of the offspring through non-genetic mechanisms. A major knowledge gap limiting our capacity to develop intervention strategies is the lack of understanding of the factors in the obese mother that mediate these epigenetic effects on the offspring. We used a mouse model of maternal-diet induced obesity to define predictive correlations between maternal factors and offspring insulin resistance. Maternal hyperinsulinemia (independent of maternal body weight and composition) strongly associated with offspring insulin resistance. To test causality, we implemented an exercise intervention that improved maternal insulin sensitivity without changing maternal body weight or composition. This maternal intervention prevented excess placental lipid deposition and hypoxia (independent of sex) and insulin resistance in male offspring. We conclude that hyperinsulinemia is a key programming factor and therefore an important interventional target during obese pregnancy, and propose moderate exercise as a promising strategy to improve metabolic outcome in both the obese mother and her offspring. PMID:28291256

  6. Role of AMPK in Regulating Muscle Insulin Sensitivity

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus

    exercise in healthy and insulin resistant skeletal muscle. This has been addressed in three studies that consist of various experimental procedures ranging from in vivo experiments in healthy obese and type 2 diabetic subjects to in situ and ex vivo experiments in AMPK-deficient mouse models. Results...... signaling in skeletal muscle of type 2 diabetic patients in response to exercise. Interestingly, we observe that AMPK activity and phosphorylation of TBC1D4 Ser318, Ser341 and Ser704 are increased 3 hours into exercise recovery - a time point when post-exercise improvements in muscle insulin sensitivity......The ability of insulin to stimulate skeletal muscle glucose uptake is instrumental for controlling whole-body glucose homeostasis. Decreased peripheral sensitivity to insulin increases the risk of developing type 2 diabetes. Insulin sensitivity can be defined as the concentration of insulin...

  7. Insulin sensitivity and hemodynamic responses to insulin in Wistar-Kyoto and spontaneously hypertensive rats.

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    Pître, M; Nadeau, A; Bachelard, H

    1996-10-01

    The insulin-mediated vasodilator effect has been proposed as an important physiological determinant of insulin action on glucose disposal in normotensive humans. The present study was designed to further examine the acute regional hemodynamic effects of insulin in different vascular beds and to explore the relationships between insulin vascular effects and insulin sensitivity during euglycemic hyperinsulinemic clamps in conscious normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and regional blood flows. In WKY rats, the euglycemic infusion of insulin (4 and 16 mU.kg-1.min-1) causes vasodilations in renal and hindquarter vascular beds but no changes in mean blood pressure, heart rate, or superior mesenteric vascular conductance. In contrast, in SHR, the same doses of insulin produce vasoconstrictions in superior mesenteric and hindquarter vascular beds and, at high doses, increase blood pressure. Moreover, at the lower dose of insulin tested, we found a reduction in the insulin sensitivity index in the SHR compared with the WKY rats. The present findings provide further evidence for an association between insulin sensitivity and insulin-mediated hemodynamic responses.

  8. 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

    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 Sensitiv......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....... 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...

  9. Insulin sensitizing and insulinotropic action of berberine from Cortidis rhizoma.

    Science.gov (United States)

    Ko, Byoung-Seob; Choi, Soo Bong; Park, Seong Kyu; Jang, Jin Sun; Kim, Yeong Eun; Park, Sunmin

    2005-08-01

    Our preliminary study demonstrated that 70% ethanol Cortidis Rhizoma extracts (CR) had a hypoglycemic action in diabetic animal models. We determined whether CR fractions acted as anti-diabetic agent, and a subsequent investigation of the action mechanism of the major compound, berberine ([C(20)H(18)NO(4)](+)), was carried out in vitro. The 20, 40 and 60% methanol fractions from the XAD-4 column contained the most insulin sensitizing activities in 3T3-L1 adipocytes. The common major peak in these fractions was berberine. Treatment with 50 microM berberine plus differentiation inducers significantly reduced triglyceride accumulation by decreased differentiation of 3T3-L1 fibroblasts to adipocytes and triglyceride synthesis. Significant insulin sensitizing activity was observed in 3T3-L1 adipocytes which were given 50 microM berberine plus 0.2 nM insulin to reach a glucose uptake level increased by 10 nM of insulin alone. This was associated with increased glucose transporter-4 translocation into the plasma membrane via enhancing insulin signaling pathways and the insulin receptor substrate-1-phosphoinositide 3 Kinase-Akt. Berberine also increased glucose-stimulated insulin secretion and proliferation in Min6 cells via an enhanced insulin/insulin-like growth factor-1 signaling cascade. Data suggested that berberine can act as an effective insulin sensitizing and insulinotropic agent. Therefore, berberine can be used as anti-diabetic agent for obese diabetic patients.

  10. Low ethanol consumption increases insulin sensitivity in Wistar rats

    Directory of Open Access Journals (Sweden)

    D.T. Furuya

    2003-01-01

    Full Text Available Several human studies suggest that light-to-moderate alcohol consumption is associated with enhanced insulin sensitivity, but these studies are not free of conflicting results. To determine if ethanol-enhanced insulin sensitivity could be demonstrated in an animal model, male Wistar rats were fed a standard chow diet and received drinking water without (control or with different ethanol concentrations (0.5, 1.5, 3, 4.5 and 7%, v/v for 4 weeks ad libitum. Then, an intravenous insulin tolerance test (IVITT was performed to determine insulin sensitivity. Among the ethanol groups, only the 3% ethanol group showed an increase in insulin sensitivity based on the increase of the plasma glucose disappearance rate in the IVITT (30%, P<0.05. In addition, an intravenous glucose tolerance test (IVGTT was performed in control and 3% ethanol animals. Insulin sensitivity was confirmed in 3% ethanol rats based on the reduction of insulin secretion in the IVGTT (35%, P<0.05, despite the same glucose profile. Additionally, the 3% ethanol treatment did not impair body weight gain or plasma aspartate aminotransferase and alanine aminotransferase activities. Thus, the present study established that 3% ethanol in the drinking water for 4 weeks in normal rats is a model of increased insulin sensitivity, which can be used for further investigations of the mechanisms involved.

  11. Attenuated insulin response and normal insulin sensitivity in lean patients with ankylosing spondylitis.

    Science.gov (United States)

    Penesova, A; Rovensky, J; Zlnay, M; Dedik, L; Radikova, Z; Koska, J; Vigas, M; Imrich, R

    2005-01-01

    Chronic low-grade inflammation is associated with insulin resistance. The aim of this study was to determine insulin response to intravenous glucose load and insulin sensitivity in patients with ankylosing spondylitis (AS). Fourteen nonobese male patients with AS and 14 matched healthy controls underwent frequent-sampling intravenous glucose tolerance test (FSIVGTT). Insulin secretion and insulin sensitivity were calculated using the computer-minimal and homeostasis-model assessment 2 (HOMA2) models. Fasting glucose, insulin, cholesterol, high-density lipoprotein and low-density lipoprotein cholesterol, triglyceride levels, HOMA2, glucose effectiveness, insulin sensitivity and insulin response to FSIVGTT did not differ between patients and controls. Tumor necrosis factor-alpha and interleukin (IL)-6 concentrations tended to be higher in AS patients than in controls. Second-phase beta-cell responsiveness was 37% lower (p = 0.05) in AS patients than in controls. A negative correlation was found between the percentage of beta-cell secretion and IL-6 in all subjects (r = -0.54, p = 0.006). We found normal insulin sensitivity but attenuated glucose utilization in the second phase of FSIVGTT in AS patients. Our results indicate that elevated IL-6 levels may play a pathophysiological role in attenuating beta-cell responsiveness, which may explain the association between elevated IL-6 levels and increased risk for type 2 diabetes.

  12. Exercise, pregnancy, and insulin sensitivity--what is new?

    DEFF Research Database (Denmark)

    Damm, Peter; Breitowicz, Bettina; Hegaard, Hanne Kristine

    2007-01-01

    Pregnancy is characterized by a marked physiological insulin resistance. Overweight and obesity or lack of physical activity can aggravate this reduced insulin sensitivity further. Increased insulin resistance has been associated with serious pregnancy complications, such as gestational diabetes ...... mellitus (GDM) and pre-eclampsia. Recent studies clearly indicate that physical activity before and during pregnancy can reduce the risk of GDM and pre-eclampsia....

  13. Exercise, pregnancy, and insulin sensitivity--what is new?

    DEFF Research Database (Denmark)

    Damm, Peter; Breitowicz, Bettina; Hegaard, Hanne

    2007-01-01

    Pregnancy is characterized by a marked physiological insulin resistance. Overweight and obesity or lack of physical activity can aggravate this reduced insulin sensitivity further. Increased insulin resistance has been associated with serious pregnancy complications, such as gestational diabetes...... mellitus (GDM) and pre-eclampsia. Recent studies clearly indicate that physical activity before and during pregnancy can reduce the risk of GDM and pre-eclampsia....

  14. The Adipose Transcriptional Response to Insulin Is Determined by Obesity, Not Insulin Sensitivity

    DEFF Research Database (Denmark)

    Rydén, Mikael; Hrydziuszko, Olga; Mileti, Enrichetta;

    2016-01-01

    Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 healthy...... non-obese (NO), 21 insulin-sensitive severely obese (ISO), and 30 insulin-resistant severely obese (IRO) subjects, before and 2 hr into a hyperinsulinemic euglycemic clamp. ISO and IRO subjects displayed a clear but globally similar transcriptional response to insulin, which differed from the small...... that differences in the acute transcriptional response to insulin are primarily driven by obesity per se, challenging the notion of healthy obese adipose tissue, at least in severe obesity....

  15. Skeletal Muscle Angiogenesis and Its Relation to Insulin Sensitivity

    DEFF Research Database (Denmark)

    Lindqvist, Anna Maria Charlotte K

    in skeletal muscle capillarization (17.0±2.0%; EDL and 20.1±2.4%; soleus muscle) and whole-body insulin sensitivity increased by 24.0±5.0%. In study II obese Zucker rats were transfected with a VEGF-A overexpression vector. The rats were then subjected to 30 days of swim training (over a period of 6 weeks...... mediator of angiogenesis) are reduced in insulin resistant individuals. Exercise training can improve skeletal muscle capillarization and the angiogenic potential and physical activity has also been proven to enhance muscle insulin sensitivity. Increased skeletal muscle capillarization is associated......). After the intervention period, insulin sensitivity was measured as in study I. VEGF-A transfection caused a normalization of the VEGF levels in the muscle. VEGF transfection in combination with training resulted in an increased capillarization (20.7±4.3%) and insulin-stimulated glucose uptake (124...

  16. The adipose transcriptional response to insulin is determined by obesity, not insulin sensitivity

    DEFF Research Database (Denmark)

    Rydén, Mikael; Hrydziuszko, Olga; Mileti, Enrichetta;

    2016-01-01

    Metabolically healthy obese subjects display preserved insulin sensitivity and a beneficial white adipose tissue gene expression pattern. However, this observation stems from fasting studies when insulin levels are low. We investigated adipose gene expression by 5'Cap-mRNA sequencing in 17 health...

  17. On the topological sensitivity of cellular automata

    Science.gov (United States)

    Baetens, Jan M.; De Baets, Bernard

    2011-06-01

    Ever since the conceptualization of cellular automata (CA), much attention has been paid to the dynamical properties of these discrete dynamical systems, and, more in particular, to their sensitivity to the initial condition from which they are evolved. Yet, the sensitivity of CA to the topology upon which they are based has received only minor attention, such that a clear insight in this dependence is still lacking and, furthermore, a quantification of this so-called topological sensitivity has not yet been proposed. The lack of attention for this issue is rather surprising since CA are spatially explicit, which means that their dynamics is directly affected by their topology. To overcome these shortcomings, we propose topological Lyapunov exponents that measure the divergence of two close trajectories in phase space originating from a topological perturbation, and we relate them to a measure grasping the sensitivity of CA to their topology that relies on the concept of topological derivatives, which is introduced in this paper. The validity of the proposed methodology is illustrated for the 256 elementary CA and for a family of two-state irregular totalistic CA.

  18. Lipid-anthropometric index optimization for insulin sensitivity estimation

    Science.gov (United States)

    Velásquez, J.; Wong, S.; Encalada, L.; Herrera, H.; Severeyn, E.

    2015-12-01

    Insulin sensitivity (IS) is the ability of cells to react due to insulińs presence; when this ability is diminished, low insulin sensitivity or insulin resistance (IR) is considered. IR had been related to other metabolic disorders as metabolic syndrome (MS), obesity, dyslipidemia and diabetes. IS can be determined using direct or indirect methods. The indirect methods are less accurate and invasive than direct and they use glucose and insulin values from oral glucose tolerance test (OGTT). The accuracy is established by comparison using spearman rank correlation coefficient between direct and indirect method. This paper aims to propose a lipid-anthropometric index which offers acceptable correlation to insulin sensitivity index for different populations (DB1=MS subjects, DB2=sedentary without MS subjects and DB3=marathoners subjects) without to use OGTT glucose and insulin values. The proposed method is parametrically optimized through a random cross-validation, using the spearman rank correlation as comparator with CAUMO method. CAUMO is an indirect method designed from a simplification of the minimal model intravenous glucose tolerance test direct method (MINMOD-IGTT) and with acceptable correlation (0.89). The results show that the proposed optimized method got a better correlation with CAUMO in all populations compared to non-optimized. On the other hand, it was observed that the optimized method has better correlation with CAUMO in DB2 and DB3 groups than HOMA-IR method, which is the most widely used for diagnosing insulin resistance. The optimized propose method could detect incipient insulin resistance, when classify as insulin resistant subjects that present impaired postprandial insulin and glucose values.

  19. Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production.

    Science.gov (United States)

    Merovci, Aurora; Solis-Herrera, Carolina; Daniele, Giuseppe; Eldor, Roy; Fiorentino, Teresa Vanessa; Tripathy, Devjit; Xiong, Juan; Perez, Zandra; Norton, Luke; Abdul-Ghani, Muhammad A; DeFronzo, Ralph A

    2014-02-01

    Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.

  20. Insulin sensitivity and metabolic flexibility following exercise training among different obese insulin-resistant phenotypes.

    Science.gov (United States)

    Malin, Steven K; Haus, Jacob M; Solomon, Thomas P J; Blaszczak, Alecia; Kashyap, Sangeeta R; Kirwan, John P

    2013-11-15

    Impaired fasting glucose (IFG) blunts the reversal of impaired glucose tolerance (IGT) after exercise training. Metabolic inflexibility has been implicated in the etiology of insulin resistance; however, the efficacy of exercise on peripheral and hepatic insulin sensitivity or substrate utilization in adults with IFG, IGT, or IFG + IGT is unknown. Twenty-four older (66.7 ± 0.8 yr) obese (34.2 ± 0.9 kg/m(2)) adults were categorized as IFG (n = 8), IGT (n = 8), or IFG + IGT (n = 8) according to a 75-g oral glucose tolerance test (OGTT). Subjects underwent 12-wk of exercise (60 min/day for 5 days/wk at ∼85% HRmax) and were instructed to maintain a eucaloric diet. A euglycemic hyperinsulinemic clamp (40 mU·m(2)·min(-1)) with [6,6-(2)H]glucose was used to determine peripheral and hepatic insulin sensitivity. Nonoxidative glucose disposal and metabolic flexibility [insulin-stimulated respiratory quotient (RQ) minus fasting RQ] were also assessed. Glucose incremental area under the curve (iAUCOGTT) was calculated from the OGTT. Exercise increased clamp-derived peripheral and hepatic insulin sensitivity more in adults with IFG or IGT alone than with IFG + IGT (P flexibility, reduced fasting RQ, and higher nonoxidative glucose disposal (P flexibility, which was related to blunted improvements in postprandial glucose. Additional work is required to assess the molecular mechanism(s) by which chronic hyperglycemia modifies insulin sensitivity following exercise training.

  1. Circulating docosahexaenoic acid levels are associated with fetal insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Jin-Ping Zhao

    Full Text Available BACKGROUND: Arachidonic acid (AA; C20∶4 n-6 and docosahexaenoic acid (DHA; C22∶6 n-3 are important long-chain polyunsaturated fatty acids (LC-PUFA in maintaining pancreatic beta-cell structure and function. Newborns of gestational diabetic mothers are more susceptible to the development of type 2 diabetes in adulthood. It is not known whether low circulating AA or DHA is involved in perinatally "programming" this susceptibility. This study aimed to assess whether circulating concentrations of AA, DHA and other fatty acids are associated with fetal insulin sensitivity or beta-cell function, and whether low circulating concentrations of AA or DHA are involved in compromised fetal insulin sensitivity in gestational diabetic pregnancies. METHODS AND PRINCIPAL FINDINGS: In a prospective singleton pregnancy cohort, maternal (32-35 weeks gestation and cord plasma fatty acids were assessed in relation to surrogate indicators of fetal insulin sensitivity (cord plasma glucose-to-insulin ratio, proinsulin concentration and beta-cell function (proinsulin-to-insulin ratio in 108 mother-newborn pairs. Cord plasma DHA levels (in percentage of total fatty acids were lower comparing newborns of gestational diabetic (n = 24 vs. non-diabetic pregnancies (2.9% vs. 3.5%, P = 0.01. Adjusting for gestational age at blood sampling, lower cord plasma DHA levels were associated with lower fetal insulin sensitivity (lower glucose-to-insulin ratio, r = 0.20, P = 0.036; higher proinsulin concentration, r = -0.37, P <0.0001. The associations remained after adjustment for maternal and newborn characteristics. Cord plasma saturated fatty acids C18∶0 and C20∶0 were negatively correlated with fetal insulin sensitivity, but their levels were not different between gestational diabetic and non-diabetic pregnancies. Cord plasma AA levels were not correlated with fetal insulin sensitivity. CONCLUSION: Low circulating DHA levels are associated with

  2. Fast track surgery accelerates the recovery of postoperative insulin sensitivity

    Institute of Scientific and Technical Information of China (English)

    YANG Dong-jie; ZHANG Chang-hua; HE Yu-long; ZHANG Sheng; HE Wei-ling; CHEN Hua-yun; CAI Shi-rong; CHEN Chuang-qi; SONG Xin-ming; CUI Ji; MA Jin-ping

    2012-01-01

    Background Few clinical studies or randomized clinical trial results have reported the impact of fast track surgery on postoperative insulin sensitivity.This study aimed to investigate the effects of fast track surgery on postoperative insulin sensitivity in patients undergoing elective open colorectal resection.Methods Controlled,randomized clinical trial was conducted from November 2008 to January 2009 with one-month post-discharge follow-up.Seventy patients with colorectal carcinoma requiring colorectal resection were randomized into two groups:a fast track group (35 cases) and a conventional care group (35 cases).All included patients received elective open colorectal resection with combined tracheal intubation and general anesthesia.Clinical parameters (complication rates,return of gastrointestinal function and postoperative length of stay),stress index and insulin sensitivity were evaluated in both groups perioperatively.Reaults Sixty-two patients finally completed the study,32 cases in the fast-track group and 30 cases in the conventional care group.Our findings revealed a significantly faster recovery of postoperative insulin sensitivity on postoperative day 7 in the fast-track group than that in the conventional care group.We also found a significantly shorter length of postoperative stay and a significantly faster return of gastrointestinal function in patients undergoing fast-track rehabilitation.Conclusion Fast track surgery accelerates the recovery of postoperative insulin sensitivity in elective surgery for colorectal carcinoma with a shorter length of postoperative hospital stay.

  3. Grizzly bears exhibit augmented insulin sensitivity while obese prior to a reversible insulin resistance during hibernation.

    Science.gov (United States)

    Nelson, O Lynne; Jansen, Heiko T; Galbreath, Elizabeth; Morgenstern, Kurt; Gehring, Jamie Lauren; Rigano, Kimberly Scott; Lee, Jae; Gong, Jianhua; Shaywitz, Adam J; Vella, Chantal A; Robbins, Charles T; Corbit, Kevin C

    2014-08-01

    The confluence of obesity and diabetes as a worldwide epidemic necessitates the discovery of new therapies. Success in this endeavor requires translatable preclinical studies, which traditionally employ rodent models. As an alternative approach, we explored hibernation where obesity is a natural adaptation to survive months of fasting. Here we report that grizzly bears exhibit seasonal tripartite insulin responsiveness such that obese animals augment insulin sensitivity but only weeks later enter hibernation-specific insulin resistance (IR) and subsequently reinitiate responsiveness upon awakening. Preparation for hibernation is characterized by adiposity coupled to increased insulin sensitivity via modified PTEN/AKT signaling specifically in adipose tissue, suggesting a state of "healthy" obesity analogous to humans with PTEN haploinsufficiency. Collectively, we show that bears reversibly cope with homeostatic perturbations considered detrimental to humans and describe a mechanism whereby IR functions not as a late-stage metabolic adaptation to obesity, but rather a gatekeeper of the fed-fasting transition.

  4. Insulin-Dependent Activation of MCH Neurons Impairs Locomotor Activity and Insulin Sensitivity in Obesity.

    Science.gov (United States)

    Hausen, A Christine; Ruud, Johan; Jiang, Hong; Hess, Simon; Varbanov, Hristo; Kloppenburg, Peter; Brüning, Jens C

    2016-12-06

    Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR(ΔMCH)) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR(ΔMCH) mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

  5. Spectroscopic study of the interaction of insulin and its aptamer – sensitive optical detection of insulin

    Energy Technology Data Exchange (ETDEWEB)

    Verdian-Doghaei, A.; Housaindokht, M.R., E-mail: housain@um.ac.ir

    2015-03-15

    The binding of insulin to the insulin binding aptamer (IBA) was investigated with different spectroscopy techniques (UV/vis absorption, fluorescence, resonance light-scattering spectra (RLS), synchronous fluorescence, and three-dimensional fluorescence). The thermodynamic parameters (K{sub b}, ΔH, ΔG, and ΔS) of the insulin–IBA complex were further investigated by temperature-dependent fluorescence measurement over the range of 25–37 °C. The results of synchronous fluorescence, resonance light scattering (RLS) and three-dimensional fluorescence spectra showed that IBA would alter the structure of insulin. Folding of the dual-labeled insulin binding aptamer, FL-IBA, carrying 6-carboxyfluorescein (FAM) and 6-carboxytetramethylrhodamine (TAMRA) labels at termini of the insulin binding aptamer (IBA), into G-quadruplex leading to the contact quenching occurs as a result of the formation of a nonfluorescent complex between donor and acceptor. Significant fluorescent signal change when FL-IBA was bound to insulin is attributed to a conformational change in FL-IBA from a loose random coil to a compact G-quadruplex. Based on fluorescence quenching of IBA folding, a simple and sensitive insulin aptamer-based biosensor in the range of 2–70 nM was proposed. - Highlights: • The binding parameters were gotten from contact quenching data. • The binding of IBA induced some microenvironment and conformational changes in insulin. • The van der Waals interactions or hydrogen bonds play a major role on this binding. • A simple and sensitive insulin aptamer-based biosensor was proposed.

  6. Chromogranin A Regulation of Obesity and Peripheral Insulin Sensitivity

    Science.gov (United States)

    Bandyopadhyay, Gautam K.; Mahata, Sushil K.

    2017-01-01

    Chromogranin A (CgA) is a prohormone and granulogenic factor in endocrine and neuroendocrine tissues, as well as in neurons, and has a regulated secretory pathway. The intracellular functions of CgA include the initiation and regulation of dense-core granule biogenesis and sequestration of hormones in neuroendocrine cells. This protein is co-stored and co-released with secreted hormones. The extracellular functions of CgA include the generation of bioactive peptides, such as pancreastatin (PST), vasostatin, WE14, catestatin (CST), and serpinin. CgA knockout mice (Chga-KO) display: (i) hypertension with increased plasma catecholamines, (ii) obesity, (iii) improved hepatic insulin sensitivity, and (iv) muscle insulin resistance. These findings suggest that individual CgA-derived peptides may regulate different physiological functions. Indeed, additional studies have revealed that the pro-inflammatory PST influences insulin sensitivity and glucose tolerance, whereas CST alleviates adiposity and hypertension. This review will focus on the different metabolic roles of PST and CST peptides in insulin-sensitive and insulin-resistant models, and their potential use as therapeutic targets. PMID:28228748

  7. Prediction of the insulin sensitivity index using Bayesian networks

    DEFF Research Database (Denmark)

    Bøttcher, Susanne Gammelgaard; Dethlefsen, Claus

    . In this paper we learn the parameters and structure of several Bayesian networks relating measurements from an oral glucose tolerance test to the insulin sensitivity index determined from an intravenous study on the same individuals. The networks can then be used in prediction of from an oral glucose tolerance...

  8. Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk

    Directory of Open Access Journals (Sweden)

    Rosa Lauretta

    2016-01-01

    Full Text Available Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold. Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis.

  9. Insulin-Sensitizers, Polycystic Ovary Syndrome and Gynaecological Cancer Risk

    Science.gov (United States)

    Lauretta, Rosa; Lanzolla, Giulia; Vici, Patrizia; Mariani, Luciano; Moretti, Costanzo

    2016-01-01

    Preclinical, early phase clinical trials and epidemiological evidence support the potential role of insulin-sensitizers in cancer prevention and treatment. Insulin-sensitizers improve the metabolic and hormonal profile in PCOS patients and may also act as anticancer agents, especially in cancers associated with hyperinsulinemia and oestrogen dependent cancers. Several lines of evidence support the protection against cancer exerted by dietary inositol, in particular inositol hexaphosphate. Metformin, thiazolidinediones, and myoinositol postreceptor signaling may exhibit direct inhibitory effects on cancer cell growth. AMPK, the main molecular target of metformin, is emerging as a target for cancer prevention and treatment. PCOS may be correlated to an increased risk for developing ovarian and endometrial cancer (up to threefold). Several studies have demonstrated an increase in mortality rate from ovarian cancer among overweight/obese PCOS women compared with normal weight women. Long-term use of metformin has been associated with lower rates of ovarian cancer. Considering the evidence supporting a higher risk of gynaecological cancer in PCOS women, we discuss the potential use of insulin-sensitizers as a potential tool for chemoprevention, hypothesizing a possible rationale through which insulin-sensitizers may inhibit tumourigenesis. PMID:27725832

  10. The effect of dietary phytosphingosine on cholesterol levels and insulin sensitivity in subjects with the metabolic syndrome

    NARCIS (Netherlands)

    Snel, M.; Sleddering, M.A.; Pijl, H.; Nieuwenhuizen, W.F.; Frölich, M.; Havekes, L.M.; Romijn, J.A.; Jazet, I.M.

    2010-01-01

    Background: Sphingolipids, like phytosphingosine (PS) are part of cellular membranes of yeasts, vegetables and fruits. Addition of PS to the diet decreases serum cholesterol and free fatty acid (FFA) levels in rodents and improves insulin sensitivity.Objective:To study the effect of dietary suppleme

  11. Effect of vanadium on insulin sensitivity and appetite.

    Science.gov (United States)

    Wang, J; Yuen, V G; McNeill, J H

    2001-06-01

    Vanadium, a potent nonselective inhibitor of protein tyrosine phosphatases, has been shown to mimic many of the metabolic actions of insulin both in vivo and in vitro. The mechanism(s) of the effect of vanadium on the decrease in appetite and body weight in Zucker fa/fa rats, an insulin-resistant model, is still unclear. Because insulin may inhibit hypothalamic neuropeptide Y (NPY), which is known to be related to appetite, and increase leptin secretion in adipose tissue, we studied the possibility that the changes in appetite produced by vanadium may be linked to altered NPY levels in the hypothalamus. We also examined effects of vanadium on leptin. Zucker lean and fatty rats were chronically treated with bis(maltolato)oxovanadium(IV) (BMOV), an organic vanadium compound, in the drinking water. Plasma and adipose tissue leptin levels were measured by radioimmunoassay and immunoblotting, respectively. Hypothalamic NPY mRNA and peptide levels were measured using in situ hybridization and immunocytochemistry, respectively. BMOV treatment significantly reduced food intake, body fat, body weight, plasma insulin levels, and glucose levels in fatty Zucker rats. Fifteen minutes after insulin injection (5 U/kg, intravenous [IV]), circulating leptin levels (+100%) and adipose leptin levels (+60%) were elevated in BMOV-treated fatty rats, although these effects were not observed in untreated fatty rats. NPY mRNA levels in the arcuate nucleus (ARC) (-29%), NPY peptide levels in ARC (-31%), as well as in the paraventricular nucleus (PVN) (-37%) were decreased with BMOV treatment in these fatty rats. These data indicate that BMOV may increase insulin sensitivity in adipose tissue and decrease appetite and body fat by decreasing NPY levels in the hypothalamus. BMOV-induced reduction in appetite and weight gain along with normalized insulin levels in models of obesity, suggest its possible use as a therapeutic agent in obesity.

  12. [Insulin sensitizer--anti-diabetic drugs, metformin and pioglitazone that can improve insulin resistance].

    Science.gov (United States)

    Korenaga, Masaaki; Kawaguchi, Koutaro; Korenaga, Keiko; Uchida, Kouichi; Sakaida, Iso

    2006-06-01

    Nonalcoholic steatohepatitis (NASH), which is considered the hepatic manifestation of the metabolic syndrome is an increasingly cause of chronic liver disease in Japan. NASH is finally lead to liver cirrhosis and hepatocellular carcinoma as viral hepatitis, therefore, medical treatment should be considered, when NASH occurs. Treatment of patients with metabolic syndrome has been focused on the management of associated conditions such as obesity, hyperlipidemia, hypertension and hyperinsulinemia. Insulin resistance, that could accelerate liver inflammation and fibrosis by up-regulation of TNFa seems to be most important factor in many cases of NASH. The insulin-sensitizing drugs, which were biguanides (metformin) and thiazolidinediones (pioglitazone) have been shown to correct not only insulin resistance but also steatosis and inflammation in the liver. Metformin and pioglitazone might be useful drugs against NASH, however further investigations were needed.

  13. Insulin requirement in non-insulin-dependent diabetes mellitus: relation to simple tests of islet B-cell function and insulin sensitivity

    DEFF Research Database (Denmark)

    Gjessing, H J; Matzen, L E; Pedersen, P C

    1988-01-01

    Evaluation of simple tests of islet B-cell function and insulin sensitivity as predictors of metabolic control was performed during 3 months of insulin withdrawal in 25 insulin-treated diabetic subjects. All patients had a glucagon stimulated plasma C-peptide concentration above 0.33 nmol/l and a...

  14. Insulin sensitivity in chronic pancreatitis and features of insulin resistance syndrome

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    Agnieszka B. Niebisz-Cieślak

    2010-07-01

    Full Text Available INTRODUCTION: Chronic pancreatitis predisposes to diabetes. Loss of endocrine function by β-cells in the Langerhans islets is considered to be the main causative factor, although several studies have also suggested insulin resistance as a possible additional mechanism. OBJECTIVES: The aim of the study was to estimate insulin sensitivity in chronic pancreatitis in view of the coexisting meta bolic syndrome components. PATIENTS AND METHODS: The study involved 30 patients (mean age 50.83 ±6.61 years; 23.33% women, 76.66% men diagnosed with chronic pancreatitis (using imaging tests. Insulin sensitivitywith regard to the coexistent obesity, dyslipidemia, and arterial hypertension was measured using the euglycemic clamp method. RESULTS: Diabetes was present in 22 patients, impaired glucose tolerance in 4, and no carbohydrate metabolism disturbances in 4. Insulin resistance was present in 22 patients (73.33%, in whom a higher prevalence of diabetes (77.27% vs. 62.5% and prediabetes (13.63% vs. 12.5% was observed. The analysis of anthropometric para meters revealed that individuals with a high index of central obesity had a statistically significantly lower tissue glucose utilization (TGU (3.23 vs. 4.89 mg/kg/min; P = 0.02, although there were no obese patients in the study group according to the body mass index. No statistically significant differences in TGU were observed in relation to lipid disorders (total cholesterol, low- and high-density lipoprotein cholesterol, triglycerides and arterial hypertension. CONCLUSIONS: In patients with chronic pancreatitis, lack of correlation between insulin sensitivity and metabolic syndrome components may indicate that insulin resistance is related to primary disease or that an additional mechanism underlying pancreatic diabetes operates.

  15. Zinc in Pancreatic Islet Biology, Insulin Sensitivity, and Diabetes

    Science.gov (United States)

    Maret, Wolfgang

    2017-01-01

    About 20 chemical elements are nutritionally essential for humans with defined molecular functions. Several essential and nonessential biometals are either functional nutrients with antidiabetic actions or can be diabetogenic. A key question remains whether changes in the metabolism of biometals and biominerals are a consequence of diabetes or are involved in its etiology. Exploration of the roles of zinc (Zn) in this regard is most revealing because 80 years of scientific discoveries link zinc and diabetes. In pancreatic β- and α-cells, zinc has specific functions in the biochemistry of insulin and glucagon. When zinc ions are secreted during vesicular exocytosis, they have autocrine, paracrine, and endocrine roles. The membrane protein ZnT8 transports zinc ions into the insulin and glucagon granules. ZnT8 has a risk allele that predisposes the majority of humans to developing diabetes. In target tissues, increased availability of zinc enhances the insulin response by inhibiting protein tyrosine phosphatase 1B, which controls the phosphorylation state of the insulin receptor and hence downstream signalling. Inherited diseases of zinc metabolism, environmental exposures that interfere with the control of cellular zinc homeostasis, and nutritional or conditioned zinc deficiency influence the patho-biochemistry of diabetes. Accepting the view that zinc is one of the many factors in multiple gene-environment interactions that cause the functional demise of β-cells generates an immense potential for treating and perhaps preventing diabetes. Personalized nutrition, bioactive food, and pharmaceuticals targeting the control of cellular zinc in precision medicine are among the possible interventions.

  16. Enhancement of insulin sensitivity in adipocytes by ginger.

    Science.gov (United States)

    Sekiya, Keizo; Ohtani, Atsuko; Kusano, Shuichi

    2004-01-01

    Antidiabetic and hypoglycemic drugs have been reported to enhance adipocyte differentiation of 3T3-L1 preadipocytes. We previously reported that ginseng (active constituents: ginsenosides) enhanced the differentiation [1]. In this experiment, effect of some ginger group food extracts on the adipocyte differentiation was investigated using cultured mouse 3T3-L1 preadipocytes. 3T3-L1 cells were grown as monolayer cultures at 37 degrees C in DMEM supplemented by 10% FBS under the atmosphere of 5% CO(2)-95% air. Ginger extracts were found to enhance the adipocyte differentiation. Active constituent was purified and identified as gingerol. In the gingerol-treated cells, insulin-sensitive glucose uptake was increased. It is expected that ginger enhance the insulin-sensitivity, and improve chronic disease, such as diabetes.

  17. Effect of Candesartan Cilexetil as a Sensitive and Effective Inhibitor of SHP-1 on Insulin Signaling Pathway

    Institute of Scientific and Technical Information of China (English)

    ZHANG Lei; ZHANG Shi-tao; ZHANG Xiao-ping; SUN Jing; WANG Yong-sen; LIU Yue-long; XUE Miao-miao

    2013-01-01

    The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues.Among them,SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases.Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway.In this study,we found the role of Candesartan cilexetil targeting at SHP-1.The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC50=85.6 μmol/L and Ki=24 μmol/L).We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs.Through the consequence of Western blotting,it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR),insulin receptor substrate(IRS) and ERK] in insulin signaling pathway in HepG2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1.These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.

  18. Diabetes mellitus and insulin in an aspirin sensitive asthmatic.

    Science.gov (United States)

    Caplin, I

    1976-03-01

    The infrequency of diabetes mellitus and asthma in the same individual is re-examined. The antagonism between epinephrine and insulin, as suggested by Konig in 1935, is indeed accurate. The assays done by the Eli Lilly Research Department revealed no in vitro effect of insulin on the CAMP and GMP level of mast cells as occurs in liver cells. It is felt that this effect is probably an in vivo effect produced via the vagus nerve and alpha-adrenergic receptor system stimulation. This would explain the mechanism of aggravation of asthma by excess insulin. Dr. Petersen's studies, the negative intradermal skin tests to insulin and the absence of change on either beef or pork insulin usage by our patient all point to a nonatopic factor in the aggravation of the asthma of this patient. In the uncommon occurrence of asthma and diabetes in the same patient, insulin dosage should be considered as a factor in all such asthmatics who do not respond well to conventional therapy. Two additional asthmatics who also have diabetes did improve with cessation of nocturnal asthma by a reduction of their evening dose of insulin. A high fat, low carbohydrate diet, as suggested by Abrahamson to avoid dietary hyperinsulinism, is certainly worth considering in patients with nocturnal asthma. If patients cannot be made to follow a diet requiring frequent feedings high in protein and fats and low in carbohydrates, another approach suggests itself. Abrahamson was able to relieve the patients who developed nocturnal asthma with hypoglycemia by having them drink a glass of milk. Assuming other causes have been eliminated and a patient awakens each day at 3:00 a.m., an alarm clock could be set at 2:00 a.m. Milk or a milk substitute in milk sensitive patients could be taken at 2:00 a.m. to raise the blood sugar and hopefully prevent the asthma associated with hypoglycemia. Also to be noted is the ubiquitous use of tartrazine in so many drugs, including those used to relieve asthmatic symptoms

  19. Heart Rate Variability, Insulin Resistance, and Insulin Sensitivity in Japanese Adults: The Toon Health Study

    Directory of Open Access Journals (Sweden)

    Isao Saito

    2015-09-01

    Full Text Available Background: Although impaired cardiac autonomic function is associated with an increased risk of type 2 diabetes in Caucasians, evidence in Asian populations with a lower body mass index is limited. Methods: Between 2009–2012, the Toon Health Study recruited 1899 individuals aged 30–79 years who were not taking medication for diabetes. A 75-g oral glucose tolerance test was used to diagnose type 2 diabetes, and fasting and 2-h-postload glucose and insulin concentrations were measured. We assessed the homeostasis model assessment index for insulin resistance (HOMA-IR and Gutt’s insulin sensitivity index (ISI. Pulse was recorded for 5 min, and time-domain heart rate variability (HRV indices were calculated: the standard deviation of normal-to-normal intervals (SDNN and the root mean square of successive difference (RMSSD. Power spectral analysis provided frequency domain measures of HRV: high frequency (HF power, low frequency (LF power, and the LF:HF ratio. Results: Multivariate-adjusted logistic regression models showed decreased SDNN, RMSSD, and HF, and increased LF:HF ratio were associated significantly with increased HOMA-IR and decreased ISI. When stratified by overweight status, the association of RMSSD, HF, and LF:HF ratio with decreased ISI was also apparent in non-overweight individuals. The interaction between LF:HF ratio and decreased ISI in overweight individuals was significant, with the odds ratio for decreased ISI in the highest quartile of LF:HF ratio in non-overweight individuals being 2.09 (95% confidence interval, 1.41–3.10. Conclusions: Reduced HRV was associated with insulin resistance and lower insulin sensitivity. Decreased ISI was linked with parasympathetic dysfunction, primarily in non-overweight individuals.

  20. New measure of insulin sensitivity predicts cardiovascular disease better than HOMA estimated insulin resistance.

    Directory of Open Access Journals (Sweden)

    Kavita Venkataraman

    Full Text Available CONTEXT: Accurate assessment of insulin sensitivity may better identify individuals at increased risk of cardio-metabolic diseases. OBJECTIVES: To examine whether a combination of anthropometric, biochemical and imaging measures can better estimate insulin sensitivity index (ISI and provide improved prediction of cardio-metabolic risk, in comparison to HOMA-IR. DESIGN AND PARTICIPANTS: Healthy male volunteers (96 Chinese, 80 Malay, 77 Indian, 21 to 40 years, body mass index 18-30 kg/m(2. Predicted ISI (ISI-cal was generated using 45 randomly selected Chinese through stepwise multiple linear regression, and validated in the rest using non-parametric correlation (Kendall's tau τ. In an independent longitudinal cohort, ISI-cal and HOMA-IR were compared for prediction of diabetes and cardiovascular disease (CVD, using ROC curves. SETTING: The study was conducted in a university academic medical centre. OUTCOME MEASURES: ISI measured by hyperinsulinemic euglycemic glucose clamp, along with anthropometric measurements, biochemical assessment and imaging; incident diabetes and CVD. RESULTS: A combination of fasting insulin, serum triglycerides and waist-to-hip ratio (WHR provided the best estimate of clamp-derived ISI (adjusted R(2 0.58 versus 0.32 HOMA-IR. In an independent cohort, ROC areas under the curve were 0.77±0.02 ISI-cal versus 0.76±0.02 HOMA-IR (p>0.05 for incident diabetes, and 0.74±0.03 ISI-cal versus 0.61±0.03 HOMA-IR (p<0.001 for incident CVD. ISI-cal also had greater sensitivity than defined metabolic syndrome in predicting CVD, with a four-fold increase in the risk of CVD independent of metabolic syndrome. CONCLUSIONS: Triglycerides and WHR, combined with fasting insulin levels, provide a better estimate of current insulin resistance state and improved identification of individuals with future risk of CVD, compared to HOMA-IR. This may be useful for estimating insulin sensitivity and cardio-metabolic risk in clinical and

  1. APPL1 potentiates insulin sensitivity by facilitating the binding of IRS1/2 to the insulin receptor.

    Science.gov (United States)

    Ryu, Jiyoon; Galan, Amanda K; Xin, Xiaoban; Dong, Feng; Abdul-Ghani, Muhammad A; Zhou, Lijun; Wang, Changhua; Li, Cuiling; Holmes, Bekke M; Sloane, Lauren B; Austad, Steven N; Guo, Shaodong; Musi, Nicolas; DeFronzo, Ralph A; Deng, Chuxia; White, Morris F; Liu, Feng; Dong, Lily Q

    2014-05-22

    Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2) to the insulin receptor (IR) is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways.

  2. APPL1 Potentiates Insulin Sensitivity by Facilitating the Binding of IRS1/2 to the Insulin Receptor

    Directory of Open Access Journals (Sweden)

    Jiyoon Ryu

    2014-05-01

    Full Text Available Binding of insulin receptor substrate proteins 1 and 2 (IRS1/2 to the insulin receptor (IR is essential for the regulation of insulin sensitivity and energy homeostasis. However, the mechanism of IRS1/2 recruitment to the IR remains elusive. Here, we identify adaptor protein APPL1 as a critical molecule that promotes IRS1/2-IR interaction. APPL1 forms a complex with IRS1/2 under basal conditions, and this complex is then recruited to the IR in response to insulin or adiponectin stimulation. The interaction between APPL1 and IR depends on insulin- or adiponectin-stimulated APPL1 phosphorylation, which is greatly reduced in insulin target tissues in obese mice. appl1 deletion in mice consistently leads to systemic insulin resistance and a significant reduction in insulin-stimulated IRS1/2, but not IR, tyrosine phosphorylation, indicating that APPL1 sensitizes insulin signaling by acting at a site downstream of the IR. Our study uncovers a mechanism regulating insulin signaling and crosstalk between the insulin and adiponectin pathways.

  3. Fructose, but not glucose, impairs insulin signaling in the three major insulin-sensitive tissues.

    Science.gov (United States)

    Baena, Miguel; Sangüesa, Gemma; Dávalos, Alberto; Latasa, María-Jesús; Sala-Vila, Aleix; Sánchez, Rosa María; Roglans, Núria; Laguna, Juan Carlos; Alegret, Marta

    2016-05-19

    Human studies support the relationship between high intake of fructose-sweetened beverages and type 2 diabetes, but there is a debate on whether this effect is fructose-specific or it is merely associated to an excessive caloric intake. Here we investigate the effects of 2 months' supplementation to female rats of equicaloric 10% w/v fructose or glucose solutions on insulin sensitivity in target tissues. Fructose supplementation caused hepatic deposition of triglycerides and changed the fatty acid profile of this fraction, with an increase in monounsaturated and a decrease in polyunsaturated species, but did not cause inflammation and oxidative stress. Fructose but not glucose-supplemented rats displayed an abnormal glucose tolerance test, and did not show increased phosphorylation of V-akt murine thymoma viral oncogene homolog-2 (Akt) in white adipose tissue and liver after insulin administration. In skeletal muscle, phosphorylation of Akt and of Akt substrate of 160 kDA (AS160) was not impaired but the expression of the glucose transporter type 4 (GLUT4) in the plasma membrane was reduced only in fructose-fed rats. In conclusion, fructose but not glucose supplementation causes fatty liver without inflammation and oxidative stress and impairs insulin signaling in the three major insulin-responsive tissues independently from the increase in energy intake.

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

    Directory of Open Access Journals (Sweden)

    Pernilla Lång

    Full Text Available BACKGROUND: 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. PRINCIPAL FINDINGS: 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. CONCLUSION: Monomeric TRAP, most likely secreted from adipose tissue macrophages, induces hyperplastic obesity with normal adipocyte lipid metabolism and insulin sensitivity.

  5. Antidiabetogenic Effects of Chromium Mitigate Hyperinsulinemia-Induced Cellular Insulin Resistance via Correction of Plasma Membrane Cholesterol Imbalance

    OpenAIRE

    Horvath, Emily M.; Tackett, Lixuan; McCarthy, Alicia M.; Raman, Priya; Brozinick, Joseph T.; Elmendorf, Jeffrey S.

    2007-01-01

    Previously, we found that a loss of plasma membrane (PM) phosphatidylinositol 4,5-bisphosphate (PIP2)-regulated filamentous actin (F-actin) structure contributes to insulin-induced insulin resistance. Interestingly, we also demonstrated that chromium picolinate (CrPic), a dietary supplement thought to improve glycemic status in insulin-resistant individuals, augments insulin-regulated glucose transport in insulin-sensitive 3T3-L1 adipocytes by lowering PM cholesterol. Here, to gain mechanisti...

  6. Sustained Self-Regulation of Energy Intake: Initial Hunger Improves Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Mario Ciampolini

    2010-01-01

    Results. In trained subjects, significant decreases were found in insulin sensitivity index, insulin and BG peaks, glycated haemoglobin, mean pre-meal BG, standard deviation of diary BG (BG as recorded by subjects' 7-day diary, energy intake, BMI, and body weight when compared to control subjects. Conclusion. The IHMP improved insulin sensitivity and other cardiovascular risk factors over a 5-month period.

  7. 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

    and tacrolimus has been attributed to both beta cell dysfunction and impaired insulin sensitivity. WHAT THIS STUDY ADDS: This is the first trial to investigate beta cell function and insulin sensitivity using gold standard methodology in healthy human volunteers treated with clinically relevant doses...... 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...... observed in circulating glucagon, FFA or adiponectin concentrations. Mean blood concentrations of CNIs were 486.9 ± 23.5 µg l(-1) for CsA and 12.8 ± 0.5 µg l(-1) for Tac. CONCLUSIONS: Acute effects of i.v. CsA, and to a lesser degree Tac infusions, in healthy volunteers include increased insulin...

  8. Genome-wide association study of the modified Stumvoll Insulin Sensitivity Index identifies BCL2 and FAM19A2 as novel insulin sensitivity loci

    DEFF Research Database (Denmark)

    Walford, Geoffrey A; Gustafsson, Stefan; Rybin, Denis;

    2016-01-01

    Genome-wide association studies (GWAS) have found few common variants that influence fasting measures of insulin sensitivity. We hypothesized that a GWAS of an integrated assessment of fasting and dynamic measures of insulin sensitivity would detect novel common variants. We performed GWAS of the...

  9. Insulin sensitivity as a key mediator of growth hormone actions on longevity.

    Science.gov (United States)

    Masternak, Michal M; Panici, Jacob A; Bonkowski, Michael S; Hughes, Larry F; Bartke, Andrzej

    2009-05-01

    Reduced insulin sensitivity and glucose intolerance have been long suspected of having important involvement in aging. Here we report that in studies of calorie restriction (CR) effects in mutant (Prop1(df) and growth hormone receptor knockout [GHRKO]) and normal mice, insulin sensitivity was strongly associated with longevity. Of particular interest was enhancement of the already increased insulin sensitivity in CR df/df mice in which longevity was also further extended and the lack of changes in insulin sensitivity in calorically restricted GHRKO mice in which there was no further increase in average life span. We suggest that enhanced insulin sensitivity, in conjunction with reduced insulin levels, may represent an important (although almost certainly not exclusive) mechanism of increased longevity in hypopituitary, growth hormone (GH)-resistant, and calorie-restricted animals. We also report that the effects of GH treatment on insulin sensitivity may be limited to the period of GH administration.

  10. Anthropometric measurements for assessing insulin sensitivity on patients with metabolic syndrome, sedentaries and marathoners.

    Science.gov (United States)

    Severeyn, Erika; Wong, Sara; Herrera, Hector; Altuve, Miguel

    2015-08-01

    The diagnosis of low insulin sensitivity is commonly done through the HOMA-IR index, in which fasting insulin and glucose blood levels are evaluated. Insulin and blood glucose levels are used for insulin sensitivity assessment by surrogate methods (HOMA-IR, Matsuda, etc), but anthropometric measurements like body weight, height and waist circumference are not considered, even if these variables also are related to low insulin sensitivity and metabolic syndrome. In this study we evaluate the impact of anthropometric measurements on the HOMA-IR, Matsuda and Caumo indexes to estimate insulin sensitivity. Specifically, we compare insulin sensitivity indexes with and without the anthropometric measurements in their equations on three different groups: patients with metabolic syndrome, sedentaries and marathoners. Results show relationships between anthropometric variables and insulin sensitivity indexes. On the other hand, subjects are mapped differently for insulin sensitivity assessment when anthropometric variables are taken into account. In addition, subjects diagnosed with normal insulin sensitivity could be considered as having low insulin sensitivity when anthropometric variables are considered.

  11. Pharmacologic inhibition of ghrelin receptor signaling is insulin sparing and promotes insulin sensitivity.

    Science.gov (United States)

    Longo, Kenneth A; Govek, Elizabeth K; Nolan, Anna; McDonagh, Thomas; Charoenthongtrakul, Soratree; Giuliana, Derek J; Morgan, Kristen; Hixon, Jeffrey; Zhou, Chaoseng; Kelder, Bruce; Kopchick, John J; Saunders, Jeffrey O; Navia, Manuel A; Curtis, Rory; DiStefano, Peter S; Geddes, Brad J

    2011-10-01

    Ghrelin influences a variety of metabolic functions through a direct action at its receptor, the GhrR (GhrR-1a). Ghrelin knockout (KO) and GhrR KO mice are resistant to the negative effects of high-fat diet (HFD) feeding. We have generated several classes of small-molecule GhrR antagonists and evaluated whether pharmacologic blockade of ghrelin signaling can recapitulate the phenotype of ghrelin/GhrR KO mice. Antagonist treatment blocked ghrelin-induced and spontaneous food intake; however, the effects on spontaneous feeding were absent in GhrR KO mice, suggesting target-specific effects of the antagonists. Oral administration of antagonists to HFD-fed mice improved insulin sensitivity in both glucose tolerance and glycemic clamp tests. The insulin sensitivity observed was characterized by improved glucose disposal with dramatically decreased insulin secretion. It is noteworthy that these results mimic those obtained in similar tests of HFD-fed GhrR KO mice. HFD-fed mice treated for 56 days with antagonist experienced a transient decrease in food intake but a sustained body weight decrease resulting from decreased white adipose, but not lean tissue. They also had improved glucose disposal and a striking reduction in the amount of insulin needed to achieve this. These mice had reduced hepatic steatosis, improved liver function, and no evidence of systemic toxicity relative to controls. Furthermore, GhrR KO mice placed on low- or high-fat diets had lifespans similar to the wild type, emphasizing the long-term safety of ghrelin receptor blockade. We have therefore demonstrated that chronic pharmacologic blockade of the GhrR is an effective and safe strategy for treating metabolic syndrome.

  12. Intralipid decreases apolipoprotein M levels and insulin sensitivity in rats.

    Directory of Open Access Journals (Sweden)

    Lu Zheng

    Full Text Available BACKGROUND: Apolipoprotein M (ApoM is a constituent of high-density lipoproteins (HDL. It plays a crucial role in HDL-mediated reverse cholesterol transport. Insulin resistance is associated with decreased ApoM levels. AIMS: To assess the effects of increased free fatty acids (FFAs levels after short-term Intralipid infusion on insulin sensitivity and hepatic ApoM gene expression. METHODS: Adult male Sprague-Dawley (SD rats infused with 20% Intralipid solution for 6 h. Glucose infusion rates (GIR were determined by hyperinsulinemic-euglycemic clamp during Intralipid infusion and plasma FFA levels were measured by colorimetry. Rats were sacrificed after Intralipid treatment and livers were sampled. Human embryonic kidney 293T cells were transfected with a lentivirus mediated human apoM overexpression system. Goto-Kakizaki (GK rats were injected with the lentiviral vector and insulin tolerance was assessed. Gene expression was assessed by real-time RT-PCR and PCR array. RESULTS: Intralipid increased FFAs by 17.6 folds and GIR was decreased by 27.1% compared to the control group. ApoM gene expression was decreased by 40.4% after Intralipid infusion. PPARβ/δ expression was not changed by Intralipid. Whereas the mRNA levels of Acaca, Acox1, Akt1, V-raf murine sarcoma 3611 viral oncogene homolog, G6pc, Irs2, Ldlr, Map2k1, pyruvate kinase and RBC were significantly increased in rat liver after Intralipid infusion. The Mitogen-activated protein kinase 8 (MAPK8 was significantly down-regulated in 293T cells overexpressing ApoM. Overexpression of human ApoM in GK rats could enhance the glucose-lowering effect of exogenous insulin. CONCLUSION: These results suggest that Intralipid could decrease hepatic ApoM levels. ApoM overexpression may have a potential role in improving insulin resistance in vivo and modulating apoM expression might be a future therapeutic strategy against insulin resistance in type 2 diabetes.

  13. The impact of kidney transplantation on insulin sensitivity

    DEFF Research Database (Denmark)

    Jørgensen, Morten B; Hornum, Mads; van Hall, Gerrit

    2017-01-01

    OBJECTIVE: To investigate the impact of kidney transplantation (KTx) on insulin sensitivity affecting glucose metabolism. METHODS: Nine non-diabetic patients awaiting living donor KTx were examined prior to transplantation with an oral glucose tolerance test and a 3h hyperinsulinaemic euglycaemic...... as mean [range]. RESULTS: Two patients had pre-transplant prediabetes whereas all others had normal glucose tolerance. After KTx, average glucose infusion rate to maintain euglycaemia during clamp declined significantly from 15.1 [9.1 - 23.7] to 9.8 [2.8 - 14.6] μmol kg(-1) min(-1) (P

  14. Cinnamon improves insulin sensitivity and alters body composition in an animal model of the metabolic syndrome

    Science.gov (United States)

    Polyphenols from cinnamon (CN) have been described recently as insulin sensitizers and antioxidants, but their effects on the glucose/insulin system in vivo have not been totally investigated. The aim of this study was to determine the effects of CN on insulin resistance and body composition, using ...

  15. Determining pancreatic β-cell compensation for changing insulin sensitivity using an oral glucose tolerance test

    DEFF Research Database (Denmark)

    Solomon, Thomas; Malin, Steven K; Karstoft, Kristian

    2014-01-01

    Plasma glucose, insulin, and C-peptide responses during an OGTT are informative for both research and clinical practice in type 2 diabetes. The aim of this study was to use such information to determine insulin sensitivity and insulin secretion so as to calculate an oral glucose disposition index...

  16. Resistance training, insulin sensitivity and muscle function in the elderly

    DEFF Research Database (Denmark)

    Dela, Flemming; Kjaer, Michael

    2006-01-01

    are associated with an age-related decrease in the physical activity level and can be counteracted by increased physical activity of a resistive nature. Strength training has been shown to improve insulin-stimulated glucose uptake in both healthy elderly individuals and patients with manifest diabetes......, and likewise to improve muscle strength in both elderly healthy individuals and in elderly individuals with chronic disease. The increased strength is coupled to improved function and a decreased risk for fall injuries and fractures. Elderly individuals have preserved the capacity to improve muscle strength...... and mass with training, but seem to display a reduced sensitivity towards stimulating protein synthesis from nutritional intake, rather than by any reduced response in protein turnover to exercise....

  17. Low fish oil intake improves insulin sensitivity, lipid profile and muscle metabolism on insulin resistant MSG-obese rats

    Directory of Open Access Journals (Sweden)

    Iagher Fabiola

    2011-04-01

    Full Text Available Abstract Background Obesity is commonly associated with diabetes, cardiovascular diseases and cancer. The purpose of this study was to determinate the effect of a lower dose of fish oil supplementation on insulin sensitivity, lipid profile, and muscle metabolism in obese rats. Methods Monosodium glutamate (MSG (4 mg/g body weight was injected in neonatal Wistar male rats. Three-month-old rats were divided in normal-weight control group (C, coconut fat-treated normal weight group (CO, fish oil-treated normal weight group (FO, obese control group (Ob, coconut fat-treated obese group (ObCO and fish oil-treated obese group (ObFO. Obese insulin-resistant rats were supplemented with fish oil or coconut fat (1 g/kg/day for 4 weeks. Insulin sensitivity, fasting blood biochemicals parameters, and skeletal muscle glucose metabolism were analyzed. Results Obese animals (Ob presented higher Index Lee and 2.5 fold epididymal and retroperitoneal adipose tissue than C. Insulin sensitivity test (Kitt showed that fish oil supplementation was able to maintain insulin sensitivity of obese rats (ObFO similar to C. There were no changes in glucose and HDL-cholesterol levels amongst groups. Yet, ObFO revealed lower levels of total cholesterol (TC; 30% and triacylglycerol (TG; 33% compared to Ob. Finally, since exposed to insulin, ObFO skeletal muscle revealed an increase of 10% in lactate production, 38% in glycogen synthesis and 39% in oxidation of glucose compared to Ob. Conclusions Low dose of fish oil supplementation (1 g/kg/day was able to reduce TC and TG levels, in addition to improved systemic and muscle insulin sensitivity. These results lend credence to the benefits of n-3 fatty acids upon the deleterious effects of insulin resistance mechanisms.

  18. Insulin's acute effects on glomerular filtration rate correlate with insulin sensitivity whereas insulin's acute effects on proximal tubular sodium reabsorption correlate with salt sensitivity in normal subjects

    NARCIS (Netherlands)

    ter Maaten, JC; Bakker, SJL; Serne, EH; ter Wee, PM; Gans, ROB

    1999-01-01

    Background. Insulin induces increasing distal tubular sodium reabsorption. Opposite effects of insulin to offset insulin-induced sodium retention are supposedly increases in glomerular filtration rate (GFR) and decreases in proximal tubular sodium reabsorption. Defects in these opposing effects coul

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

    Institute of Scientific and Technical Information of China (English)

    Takumi; Kawaguchi; Michio; Sata

    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.Mounting evidence indic...

  20. Does bicarbonated mineral water rich in sodium change insulin sensitivity of postmenopausal women?

    Directory of Open Access Journals (Sweden)

    S. Schoppen

    Full Text Available Aim: To study the effects of drinking 0.5 L of two sodium-rich bicarbonated mineral waters (BMW-1 and 2, with a standard meal, on postprandial insulin and glucose changes. And to determine, if the effects vary depending on insulin resistance, measured by homeostasis model assessment (HOMA. Methods: In a 3-way randomized crossover study, 18 healthy postmenopausal women consumed two sodiumrich BMWs and a low-mineral water (LMW with a standard fat-rich meal. Fasting and postprandial blood samples were taken at 30, 60 and 120 min. Serum glucose, insulin, cholesterol and triacylglycerols were determined. Insulin resistance was estimated by HOMA and insulin sensitivity was calculated by quantitative insulin sensitivity check index (QUICKY. Results: Glucose levels did not change. HOMA and QUICKY values were highly inversely correlated (r = -1,000; p < 0.0001. Insulin concentrations showed a significant time effect (p < 0.0001 and a significant water x time interaction (p < 0.021. At 120 min insulin levels with BMW-1 were significantly lower than with LMW (p = 0.022. Postprandial insulin concentrations showed significantly different patterns of mineral water intake depending on HOMA n-tiles (p = 0.016. Conclusion: Results suggests an increase in insulin sensitivity after BMWs consumption. This effect is more marked in the women, who have higher HOMA values. These waters should be considered part of a healthy diet in order to prevent insulin resistance and cardiovascular disease.

  1. Insulin sensitivity and related cytokines, chemokines, and adipokines in polymyalgia rheumatica

    DEFF Research Database (Denmark)

    Kreiner, F; Galbo, H

    2010-01-01

    To evaluate the insulin sensitivity (IS) and levels of peptides with impact on IS in polymyalgia rheumatica (PMR) before and after prednisolone treatment.......To evaluate the insulin sensitivity (IS) and levels of peptides with impact on IS in polymyalgia rheumatica (PMR) before and after prednisolone treatment....

  2. Influence of apolipoproteins on the association between lipids and insulin sensitivity

    DEFF Research Database (Denmark)

    Baldi, Simona; Bonnet, Fabrice; Laville, Martine;

    2013-01-01

    We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence.......We evaluated whether the association of insulin sensitivity with HDL cholesterol (HDL) and triglycerides is influenced by major plasma apolipoproteins, as suggested by recent experimental evidence....

  3. Microvascular function relates to insulin sensitivity and blood pressure in normal subjects

    NARCIS (Netherlands)

    Serne, EH; Stehouwer, CDA; ter Maaten, JC; ter Wee, PM; Rauwerda, JA; Gans, ROB

    1999-01-01

    Background-A strong but presently unexplained inverse association between blood pressure and insulin sensitivity has been reported. Microvascular vasodilator capacity may be a common antecedent linking insulin sensitivity to blood pressure. To test this hypothesis, we studied LX normotensive and glu

  4. Insulin sensitivity indices: a proposal of cut-off points for simple identification of insulin-resistant subjects.

    Science.gov (United States)

    Radikova, Z; Koska, J; Huckova, M; Ksinantova, L; Imrich, R; Vigas, M; Trnovec, T; Langer, P; Sebokova, E; Klimes, I

    2006-05-01

    Demanding measurement of insulin sensitivity using clamp methods does not simplify the identification of insulin resistant subjects in the general population. Other approaches such as fasting- or oral glucose tolerance test-derived insulin sensitivity indices were proposed and validated with the euglycemic clamp. Nevertheless, a lack of reference values for these indices prevents their wider use in epidemiological studies and clinical practice. The aim of our study was therefore to define the cut-off points of insulin resistance indices as well as the ranges of the most frequently obtained values for selected indices. A standard 75 g oral glucose tolerance test was carried out in 1156 subjects from a Caucasian rural population with no previous evidence of diabetes or other dysglycemias. Insulin resistance/sensitivity indices (HOMA-IR, HOMA-IR2, ISI Cederholm, and ISI Matsuda) were calculated. The 75th percentile value as the cut-off point to define IR corresponded with a HOMA-IR of 2.29, a HOMA-IR2 of 1.21, a 25th percentile for ISI Cederholm, and ISI Matsuda of 57 and 5.0, respectively. For the first time, the cut-off points for selected indices and their most frequently obtained values were established for groups of subjects as defined by glucose homeostasis and BMI. Thus, insulin-resistant subjects can be identified using this simple approach.

  5. Association of obesity and insulin resistance with asthma and aeroallergen sensitization

    DEFF Research Database (Denmark)

    Husemoen, L L N; Glümer, C; Lau, C

    2008-01-01

    BACKGROUND: It has been hypothesized that obesity and insulin resistance may play a role in the development of asthma and allergy. The aim of the study was to examine the association of obesity and insulin resistance with asthma and aeroallergen sensitization. METHODS: Cross-sectional population...... and aeroallergen sensitization. The homeostasis model assessment of insulin resistance was used to estimate the degree of insulin resistance. Body mass index, waist-to-hip ratio, and waist circumference were used as measures of obesity. Data were analyzed by multiple logistic regression analyses. RESULTS: Obesity...... was associated with increased risk of aeroallergen sensitization as well as allergic and nonallergic asthma. Insulin resistance was asssociated with aeroallergen sensitization and allergic asthma, but not nonallergic asthma. The associations of obesity with aeroallegen sensitization and allergic asthma became...

  6. Effect of Sodium Fluoride on Bone Biomechanical and Histomorphometric Parameters and on Insulin Signaling and Insulin Sensitivity in Ovariectomized Rats.

    Science.gov (United States)

    de Cássia Alves Nunes, Rita; Chiba, Fernando Yamamoto; Pereira, Amanda Gomes; Pereira, Renato Felipe; de Lima Coutinho Mattera, Maria Sara; Ervolino, Edilson; Louzada, Mário Jefferson Quirino; Buzalaf, Marília Afonso Rabelo; Silva, Cristina Antoniali; Sumida, Doris Hissako

    2016-09-01

    Osteoporosis is a systemic disease characterized by bone degradation and decreased bone mass that promotes increased bone fragility and eventual fracture risk. Studies have investigated the use of sodium fluoride (NaF) for the treatment of osteoporosis. However, fluoride can alter glucose homeostasis. The aim of this study was to evaluate the effects of NaF intake (50 mg/L) from water on the following parameters of ovariectomized (OVX) rats: (1) tyrosine phosphorylation status of insulin receptor substrate (pp185 (IRS-1/IRS-2)) in white adipose tissue; (2) insulin sensitivity; (3) plasma concentrations of glucose, insulin, total cholesterol, triglyceride, TNF-α, IL-6, osteocalcin, calcium, and fluoride; (4) bone density and biomechanical properties in the tibia; and (5) tibia histomorphometric analysis. Fifty-two Wistar rats (2 months old) were ovariectomized and distributed into two groups: control group (OVX-C) and NaF group (OVX-F), which was subjected to treatment with NaF (50 mg/L) administered in drinking water for 42 days. The chronic treatment with NaF promoted (1) a decrease in pp185 (IRS-1/IRS-2) tyrosine phosphorylation status after insulin infusion in white adipose tissue and in insulin sensitivity; (2) an increase in the plasma concentration of insulin, fluoride, osteocalcin, calcium, triglyceride, VLDL-cholesterol, TNF-α, and IL-6; (3) a reduction in the trabecular width, bone area, stiffness, maximum strength, and tenacity; (4) no changes in body weight, food and water intake, plasma glucose, total cholesterol, HDL-cholesterol, LDL-cholesterol, bone mineral content, and bone mineral density. It was concluded that chronic treatment with NaF (50 mg/L) in OVX rats causes a decrease in insulin sensitivity, insulin signaling transduction, and biochemical, biomechanical, and histomorphometric bone parameters.

  7. Common genetic variation in the human CTF1 locus, encoding cardiotrophin-1, determines insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Stefan Z Lutz

    Full Text Available AIMS/HYPOTHESIS: Recently, cardiotrophin-1, a member of the interleukin-6 family of cytokines was described to protect beta-cells from apoptosis, to improve glucose-stimulated insulin secretion and insulin resistance, and to prevent streptozotocin-induced diabetes in mice. Here, we studied whether common single nucleotide polymorphisms (SNPs in the CTF1 locus, encoding cardiotrophin-1, influence insulin secretion and insulin sensitivity in humans. METHODS: We genotyped 1,771 German subjects for three CTF1 tagging SNPs (rs1046276, rs1458201, and rs8046707. The subjects were metabolically characterized by an oral glucose tolerance test. Subgroups underwent magnetic resonance (MR imaging/spectroscopy and hyperinsulinaemic-euglycaemic clamps. RESULTS: After appropriate adjustment, the minor allele of CTF1 SNP rs8046707 was significantly associated with decreased in vivo measures of insulin sensitivity. The other tested SNPs were not associated with OGTT-derived sensitivity parameters, nor did the three tested SNPs show any association with OGTT-derived parameters of insulin release. In the MR subgroup, SNP rs8046707 was nominally associated with lower visceral adipose tissue. Furthermore, the SNP rs1458201 showed a nominal association with increased VLDL levels. CONCLUSIONS: In conclusion, this study, even though preliminary and awaiting further confirmation by independent replication, provides first evidence that common genetic variation in CTF1 could contribute to insulin sensitivity in humans. Our SNP data indicate an insulin-desensitizing effect of cardiotrophin-1 and underline that cardiotrophin-1 represents an interesting target to influence insulin sensitivity.

  8. Activin B regulates islet composition and islet mass but not whole body glucose homeostasis or insulin sensitivity

    Science.gov (United States)

    Bonomi, Lara; Brown, Melissa; Ungerleider, Nathan; Muse, Meghan; Matzuk, Martin M.

    2012-01-01

    Based on the phenotype of the activin-like kinase-7 (ALK7)-null mouse, activins A and B have been proposed to play distinct roles in regulating pancreatic islet function and glucose homeostasis, with activin A acting to enhance islet function and insulin release while activin B antagonizes these actions. We therefore hypothesized that islets from activin B-null (BBKO) mice would have enhanced glucose-stimulated insulin secretion. In addition, we hypothesized that this enhanced islet function would translate into increased whole body glucose tolerance. We tested these hypotheses by analyzing glucose homeostasis, insulin secretion, and islet function in BBKO mice. No differences were observed in fasting glucose or insulin levels, glucose tolerance, or insulin sensitivity compared with weight-matched young or older males. Similarly, there were no significant differences in insulin secretion comparing islets from WT or BBKO males at either age. However, BBKO islets were more sensitive to activin A, myostatin (MSTN), and follistatin (FST) treatments, so that activin A and FST inhibited and MSTN enhanced glucose stimulated insulin secretion. While mean islet area and the distribution of islet areas were not different between the genotypes, islet mass, islet number, and the proportion of α-cells/islet were significantly reduced in BBKO islets. These results indicate that activin B does not antagonize activin A to influence whole body glucose homeostasis or β-cell function but does influence islet mass and proportion of α-cells/islet. Therefore, loss of activin B signaling alone does not account for the ALK7-null phenotype, but activin B may have important roles in modulating islet mass, islet number, and the cellular composition of islets. PMID:22739106

  9. Human gut microbes impact host serum metabolome and insulin sensitivity

    DEFF Research Database (Denmark)

    Pedersen, Helle Krogh; Gudmundsdottir, Valborg; Nielsen, Henrik Bjørn

    2016-01-01

    Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin-resistant individ......Insulin resistance is a forerunner state of ischaemic cardiovascular disease and type 2 diabetes. Here we show how the human gut microbiome impacts the serum metabolome and associates with insulin resistance in 277 non-diabetic Danish individuals. The serum metabolome of insulin......-resistant individuals is characterized by increased levels of branched-chain amino acids (BCAAs), which correlate with a gut microbiome that has an enriched biosynthetic potential for BCAAs and is deprived of genes encoding bacterial inward transporters for these amino acids. Prevotella copri and Bacteroides vulgatus...

  10. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans

    DEFF Research Database (Denmark)

    Stefan, Norbert; Vozarova, Barbora; Funahashi, Tohru;

    2002-01-01

    -induced tyrosine phosphorylation of the insulin receptor (IR) and also increase whole-body insulin sensitivity. To further characterize the relationship between plasma adiponectin concentration and insulin sensitivity in humans, we examined 1) the cross-sectional association between plasma adiponectin......Adiponectin, the most abundant adipose-specific protein, has been found to be negatively associated with degree of adiposity and positively associated with insulin sensitivity in Pima Indians and other populations. Moreover, adiponectin administration to rodents has been shown to increase insulin...... concentration and skeletal muscle IR tyrosine phosphorylation and 2) the prospective effect of plasma adiponectin concentration at baseline on change in insulin sensitivity. Fasting plasma adiponectin concentration, body composition (hydrodensitometry or dual energy X-ray absorptiometry), insulin sensitivity...

  11. mTORC2 Regulation of Muscle Metabolism and Insulin Sensitivity

    DEFF Research Database (Denmark)

    Kleinert, Maximilian

    why organs can become insulin insensitive and b) the need to identify and study insulin sensitizing effects. Blood glucose entry into skeletal muscle is largely regulated by the glucose transporter (GLUT) 4. GLUT4 acts as a channel in the impenetrable plasma membrane through which glucose can enter....... In the absence of insulin, the majority of GLUT4 resides within the muscle. Conversely, insulin stimulation increases the muscle’s permeability to glucose, by triggering GLUT4 translocation to the plasma membrane. The effect of insulin on GLUT4 translocation is mediated by a chain of molecular signaling events...... that are initiated by insulin binding to its receptor on the muscle’s plasma membrane. The recently discovered mammalian target of rapamycin complex 2 (mTORC2) has been implicated as an integral member of this signaling chain and therefore might be necessary for insulin stimulated GLUT4 translocation and therefore...

  12. Assessment of the Role of Metabolic Determinants on the Relationship between Insulin Sensitivity and Secretion

    Science.gov (United States)

    Galgani, Jose E.; Gómez, Carmen; Mizgier, Maria L.; Gutierrez, Juan; Santos, Jose L.; Olmos, Pablo; Mari, Andrea

    2016-01-01

    Background Insulin secretion correlates inversely with insulin sensitivity, which may suggest the existence of a crosstalk between peripheral organs and pancreas. Such interaction might be mediated through glucose oxidation that may drive the release of circulating factors with action on insulin secretion. Aim To evaluate the association between whole-body carbohydrate oxidation and circulating factors with insulin secretion to consecutive oral glucose loading in non-diabetic individuals. Methods Carbohydrate oxidation was measured after an overnight fast and for 6 hours after two 3-h apart 75-g oral glucose tolerance tests (OGTT) in 53 participants (24/29 males/females; 34±9 y; 27±4 kg/m2). Insulin secretion was estimated by deconvolution of serum C-peptide concentration, β cell function by mathematical modelling and insulin sensitivity from an OGTT. Circulating lactate, free-fatty acids (FFA) and candidate chemokines were assessed before and after OGTT. The effect of recombinant RANTES (regulated on activation, normal T cell expressed and secreted) and IL8 (interleukin 8) on insulin secretion from isolated mice islets was also measured. Results Carbohydrate oxidation assessed over the 6-h period did not relate with insulin secretion (r = -0.11; p = 0.45) or β cell function indexes. Circulating lactate and FFA showed no association with 6-h insulin secretion. Circulating chemokines concentration increased upon oral glucose stimulation. Insulin secretion associated with plasma IL6 (r = 0.35; p<0.05), RANTES (r = 0.30; p<0.05) and IL8 (r = 0.41; p<0.05) determined at 60 min OGTT. IL8 was independently associated with in vivo insulin secretion; however, it did not affect in vitro insulin secretion. Conclusion Whole-body carbohydrate oxidation appears to have no influence on insulin secretion or putative circulating mediators. IL8 may be a potential factor influencing insulin secretion. PMID:28002466

  13. Enhanced muscle insulin sensitivity after contraction/exercise is mediated by AMPK

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus; Munk-Hansen, Nanna; Birk, Jesper Bratz

    2017-01-01

    Earlier studies have demonstrated that muscle insulin sensitivity to stimulate glucose uptake is enhanced several hours after an acute bout of exercise. Using 5-aminoimidazole-4-carboxamide-ribonucleotide (AICAR), we recently demonstrated that prior activation of AMPK is sufficient to increase in....... Collectively, our data suggest that the AMPK-TBC1D4 signaling axis is likely mediating the improved muscle insulin sensitivity after contraction/exercise and illuminates an important and physiological relevant role of AMPK in skeletal muscle....... insulin sensitivity in mouse skeletal muscle. Here we aimed to determine whether activation of AMPK is also a prerequisite for the ability of muscle contraction to increase insulin sensitivity. We found that prior in situ contraction of m. extensor digitorum longus (EDL) and treadmill exercise increased...... muscle and whole body insulin sensitivity in wild type (WT) mice, respectively. These effects were not found in AMPKα1α2 muscle-specific knockout mice. Prior in situ contraction did not increase insulin sensitivity in m. soleus from either genotype. Improvement in muscle insulin sensitivity...

  14. Role of AMP-activated protein kinase for regulating post-exercise insulin sensitivity

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus; Wojtaszewski, Jørgen; Treebak, Jonas Thue

    2016-01-01

    Skeletal muscle insulin resistance precedes development of type 2 diabetes (T2D). As skeletal muscle is a major sink for glucose disposal, understanding the molecular mechanisms involved in maintaining insulin sensitivity of this tissue could potentially benefit millions of people that are diagno......Skeletal muscle insulin resistance precedes development of type 2 diabetes (T2D). As skeletal muscle is a major sink for glucose disposal, understanding the molecular mechanisms involved in maintaining insulin sensitivity of this tissue could potentially benefit millions of people...... that are diagnosed with insulin resistance. Regular physical activity in both healthy and insulin-resistant individuals is recognized as the single most effective intervention to increase whole-body insulin sensitivity and thereby positively affect glucose homeostasis. A single bout of exercise has long been known...... to increase glucose disposal in skeletal muscle in response to physiological insulin concentrations. While this effect is identified to be restricted to the previously exercised muscle, the molecular basis for an apparent convergence between exercise- and insulin-induced signaling pathways is incompletely...

  15. A two-week reduction of ambulatory activity attenuates peripheral insulin sensitivity

    DEFF Research Database (Denmark)

    Krogh-Madsen, Rikke; Thyfault, John P; Broholm, Christa

    2009-01-01

    possible biological cause for the public health problem of type 2 diabetes has been identified. Reduced ambulatory activity for two weeks in healthy, non-exercising young men significantly reduced peripheral insulin sensitivity, cardiovascular fitness, and lean leg mass. Key words: Inactivity, Insulin...... activity would influence peripheral insulin sensitivity. We aimed to explore if healthy, non-exercising subjects who went from a normal to a low level of ambulatory activity for two weeks would display metabolic alterations including reduced peripheral insulin sensitivity. -To do this, ten healthy young...... after step reduction, with a post hoc analysis revealing the most pronounced effect after 4 h of insulin infusion. In addition, the two-week period induced a 7% decline in VO2max (ml/min; cardiovascular fitness). Lean mass of legs, but not arms and truck, decreased concurrently. Taken together, one...

  16. Evidence of a causal relationship between adiponectin levels and insulin sensitivity: a Mendelian randomization study.

    Science.gov (United States)

    Gao, He; Fall, Tove; van Dam, Rob M; Flyvbjerg, Allan; Zethelius, Björn; Ingelsson, Erik; Hägg, Sara

    2013-04-01

    The adipocyte-secreted protein adiponectin is associated with insulin sensitivity in observational studies. We aimed to evaluate whether this relationship is causal using a Mendelian randomization approach. In a sample of Swedish men aged 71 years (n = 942) from the Uppsala Longitudinal Study of Adult Men (ULSAM), insulin sensitivity (M/I ratio) was measured by the euglycemic insulin clamp. We used three genetic variants in the ADIPOQ locus as instrumental variables (IVs) to estimate the potential causal effect of adiponectin on insulin sensitivity and compared these with results from conventional linear regression. The three ADIPOQ variants, rs17300539, rs3774261, and rs6444175, were strongly associated with serum adiponectin levels (all P ≤ 5.3 × 10(-9)) and were also significantly associated with M/I ratio in the expected direction (all P ≤ 0.022). IV analysis confirmed that genetically determined adiponectin increased insulin sensitivity (β = 0.47-0.81, all P ≤ 0.014) comparable with observational estimates (β = 0.50, all P(difference) ≥ 0.136). Adjustment for BMI and waist circumference partly explained the association of both genetically determined and observed adiponectin levels with insulin sensitivity. The observed association between higher adiponectin levels and increased insulin sensitivity is likely to represent a causal relationship partly mediated by reduced adiposity.

  17. Insulin sensitizing effect of 3 Indian medicinal plants: An in vitro study

    Directory of Open Access Journals (Sweden)

    Samidha A Kalekar

    2013-01-01

    Conclusion: The results suggest that one of the mechanisms for the anti-diabetic effect of Pe, Cl and Tc may be through an insulin sensitizing effect (stimulation of glucose uptake into adipocytes. Further studies using other target sites viz. skeletal muscle and hepatocytes models and in an insulin resistant state would help substantiate this conclusion.

  18. Prior AICAR stimulation increases insulin sensitivity in mouse skeletal muscle in an AMPK-dependent manner

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus; Treebak, Jonas T; Fentz, Joachim;

    2015-01-01

    An acute bout of exercise increases glucose uptake in skeletal muscle by an insulin-independent mechanism. In the period after exercise, insulin sensitivity to increased glucose uptake is enhanced. The molecular mechanisms underpinning this phenomenon are poorly understood but appear to involve a...

  19. The relative roles of growth hormone and IGF-1 in controlling insulin sensitivity

    OpenAIRE

    Clemmons, David R.

    2004-01-01

    IGF-1 and growth hormone (GH) interact with insulin to modulate its control of carbohydrate metabolism. A new study (see the related article beginning on page 96) shows that blocking the effect of GH in the presence of low serum IGF-1 concentrations enhances insulin sensitivity.

  20. Effect of Moderate Alcohol Consumption on Adiponectin, Tumor Necrosis Factor-α, and Insulin Sensitivity

    NARCIS (Netherlands)

    Sierksma, A.; Patel, H.; Ouchi, N.; Kihara, S.; Funahashi, T.; Heine, R.J.; Grobbee, D.E.; Kluft, C.; Hendriks, H.F.J.

    2004-01-01

    OBJECTIVE - Epidemiological studies suggest that moderate alcohol consumers have enhanced insulin sensitivity and a reduced risk of type 2 diabetes. Adiponectin, an adipocyte-derived plasma protein, has been found to be negatively associated with adiposity and positively associated with insulin sens

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

    Directory of Open Access Journals (Sweden)

    Judith Karschin

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

  2. Insulin Sensitivity and β-Cell Function Improve after Gastric Bypass in Severely Obese Adolescents

    Science.gov (United States)

    Inge, Thomas H.; Prigeon, Ronald L.; Elder, Deborah A.; Jenkins, Todd M.; Cohen, Robert M.; Xanthakos, Stavra A.; Benoit, Stephen C.; Dolan, Lawrence M.; Daniels, Stephen R.; D’Alessio, David A.

    2016-01-01

    Objective To test the hypothesis that insulin secretion and insulin sensitivity would be improved in adolescents after Roux-en-Y gastric bypass (RYGB). Study design A longitudinal study of 22 adolescents and young adults without diabetes undergoing laparoscopic RYGB (mean age 17.1 ± 1.42 years; range 14.5–20.1; male/female 8/14; Non-Hispanic White/African American 17/5) was conducted. Intravenous glucose tolerance tests were done to obtain insulin sensitivity (insulin sensitivity index), insulin secretion (acute insulin response to glucose), and the disposition index as primary outcome variables. These variables were compared over the 1 year of observation using linear mixed modeling. Results In the 1-year following surgery, body mass index fell by 38% from a mean of 61 ± 12.3 to 39 ± 8.0 kg/m2 (P < .01). Over the year following surgery, fasting glucose and insulin values declined by 54% and 63%, respectively. Insulin sensitivity index increased 300% (P < .01), acute insulin response to glucose decreased 56% (P < .01), leading to a nearly 2-fold increase in the disposition index (P < .01). Consistent with improved β-cell function, the proinsulin to C-peptide ratio decreased by 21% (P < .01). Conclusions RYGB reduced body mass index and improved both insulin sensitivity and β-cell function in severely obese teens and young adults. These findings demonstrate that RYGB is associated with marked metabolic improvements in obese young people even as significant obesity persists. Trial registration ClinicalTrials.gov: NCT00360373. PMID:26363548

  3. High intensity interval training improves liver and adipose tissue insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Katarina Marcinko

    2015-12-01

    Conclusions: These data indicate that HIIT lowers blood glucose levels by improving adipose and liver insulin sensitivity independently of changes in adiposity, adipose tissue inflammation, liver lipid content or AMPK phosphorylation of ACC.

  4. Why do anti-inflammatory therapies fail to improve insulin sensitivity?

    Institute of Scientific and Technical Information of China (English)

    Zhan-guo GAO; Jian-ping YE

    2012-01-01

    Chronic inflammation occurs in obese conditions in both humans and animals.It also contributes to the pathogenesis of type 2 diabetes (T2D) through insulin resistance,a status in which the body loses its ability to respond to insulin.Inflammation impairs insulin signaling through the functional inhibition of IRS-1 and PPARy.Insulin sensitizers (such as rosiglitazone and pioglitazone) inhibit inflammation while improving insulin sensitivity.Therefore,anti-inflammatory agents have been suggested as a treatment strategy for insulin resistance.This strategy has been tested in laboratory studies and clinical trials for more than 10 years; however,no significant progress has been made in any of the model systems.This status has led us to re-evaluate the biological significance of chronic inflammation in obesity.Recent studies have consistently asserted that obesity-associated inflammation helps to maintain insulin sensitivity.Inflammation stimulates local adipose tissue remodeling and promotes systemic energy expenditure.We propose that these beneficial activities of inflammation provide an underlying mechanism for the failure of anti-infiammatory therapy in the treatment of insulin resistance.Current literature will be reviewed in this article to present evidence that supports this viewpoint.

  5. Insulin-sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative in vitro

    Institute of Scientific and Technical Information of China (English)

    Hao-shu WU; Juan-hong YU; Ying-yin LI; Yu-she YANG; Qiao-jun HE; Yi-jia LOU; Ru-yun JI

    2007-01-01

    Aim: To examine the insulin sensitizing effects of a novel α-methyl-α-phenoxylpropionate derivative YY20 in insulin-sensitive cell lines. Methods: The peroxisome proliferator-activated receptorγ(PPARγ) agonist bioactivities of YY20 were detected by a preadipocyte differentiation assay. RT-PCR and Western blotting analysis were used to detect the expression of the target gene or protein.The effects of YY20 on insulin-mediated glucose consumption were determined in the HepG2 human hepatocellular carcinoma line. Results: YY20 could enhance the differentiation of preadipocytes to adipocytes and upregulate the gene ex-pression of PPAR),2, as well as the protein expression of insulin receptor sub-strate-1 (IRS-1), glucose transporter-4 (GLUT4), and adiponectin (ACRP30). The effects on GLUT4 and ACRP30 could be reversed by the PPARγinhibitor SR-202.Furthermore, YY20 efficiently reduced glucose consumptions in HepG2 cells after 24 h culture, and the effects were related to insulin and YY20 concentrations.Conclusion: YY20, a potential insulin-sensitizing agent like rosiglitazone, could enhance glucose consumption in HepG2 cells in a concentration- and insulin-dependent manner. It may improve the insulin resistance associated with type 2 diabetes.

  6. Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

    Directory of Open Access Journals (Sweden)

    Morgan Kristen

    2011-01-01

    Full Text Available Abstract Background We and others have demonstrated previously that ghrelin receptor (GhrR knock out (KO mice fed a high fat diet (HFD have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed GhrR KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in GhrR KO mice, we conducted both hyperglycemic (HG and hyperinsulinemic-euglycemic (HI-E clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity. Results Consistent with glucose tolerance-test data, in HG clamp experiments, GhrR KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1st phase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, GhrR KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed GhrR KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd, and decreased hepatic glucose production (HGP. HFD-fed GhrR KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. GhrR KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in GhrR KO mice relative to WT mice. Conclusions These results indicate that improved glucose homeostasis of GhrR KO mice is

  7. A low-fat diet improves peripheral insulin sensitivity in patients with Type 1 diabetes

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Almdal, T; Viggers, L;

    2006-01-01

    To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes.......To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes....

  8. Beneficial insulin-sensitizing and vascular effects of S15261 in the insulin-resistant JCR:LA-cp rat.

    Science.gov (United States)

    Russell, J C; Ravel, D; Pégorier, J P; Delrat, P; Jochemsen, R; O'Brien, S F; Kelly, S E; Davidge, S T; Brindley, D N

    2000-11-01

    S15261, a compound developed for the oral treatment of type II diabetes, is cleaved by esterases to the fragments Y415 and S15511. The aim was to define the insulin-sensitizing effects of S15261, the cleavage products, and troglitazone and metformin in the JCR:LA-cp rat, an animal model of the obesity/insulin resistance syndrome that exhibits an associated vasculopathy and cardiovascular disease. Treatment of the animals from 8 to 12 weeks of age with S15261 or S15511 resulted in reductions in food intake and body weights, whereas Y415 had no effect. Troglitazone caused a small increase in food intake (P JCR:LA-cp rat. S15261 may thus offer effective treatment for the insulin resistance syndrome and its associated vascular complications.

  9. KSR2 mutations are associated with obesity, insulin resistance, and impaired cellular fuel oxidation.

    Science.gov (United States)

    Pearce, Laura R; Atanassova, Neli; Banton, Matthew C; Bottomley, Bill; van der Klaauw, Agatha A; Revelli, Jean-Pierre; Hendricks, Audrey; Keogh, Julia M; Henning, Elana; Doree, Deon; Jeter-Jones, Sabrina; Garg, Sumedha; Bochukova, Elena G; Bounds, Rebecca; Ashford, Sofie; Gayton, Emma; Hindmarsh, Peter C; Shield, Julian P H; Crowne, Elizabeth; Barford, David; Wareham, Nick J; O'Rahilly, Stephen; Murphy, Michael P; Powell, David R; Barroso, Ines; Farooqi, I Sadaf

    2013-11-07

    Kinase suppressor of Ras 2 (KSR2) is an intracellular scaffolding protein involved in multiple signaling pathways. Targeted deletion of Ksr2 leads to obesity in mice, suggesting a role in energy homeostasis. We explored the role of KSR2 in humans by sequencing 2,101 individuals with severe early-onset obesity and 1,536 controls. We identified multiple rare variants in KSR2 that disrupt signaling through the Raf-MEKERK pathway and impair cellular fatty acid oxidation and glucose oxidation in transfected cells; effects that can be ameliorated by the commonly prescribed antidiabetic drug, metformin. Mutation carriers exhibit hyperphagia in childhood, low heart rate, reduced basal metabolic rate and severe insulin resistance. These data establish KSR2 as an important regulator of energy intake, energy expenditure, and substrate utilization in humans. Modulation of KSR2-mediated effects may represent a novel therapeutic strategy for obesity and type 2 diabetes.

  10. Increased abundance of insulin/insulin-like growth factor-I hybrid receptors in skeletal muscle of obese subjects is correlated with in vivo insulin sensitivity.

    Science.gov (United States)

    Federici, M; Porzio, O; Lauro, D; Borboni, P; Giovannone, B; Zucaro, L; Hribal, M L; Sesti, G

    1998-08-01

    We reported that in noninsulin-dependent diabetes melitus (NIDDM) patients expression of insulin/insulin-like growth factor I (IGF-I) hybrid receptors is increased in insulin target tissues. Whether this is a defect associated with NIDDM or represents a generalized abnormality associated with insulin resistant states is still unsettled. To address this, we applied a microwell-based immunoassay to measure abundance of insulin receptors, type 1 IGF receptors, and hybrid receptors in muscle of eight normal and eight obese subjects. Maximal insulin binding to insulin receptors was lower in obese than in control subjects (B/T = 1.8 +/- 0.20 and 2.6 +/- 0.30; P < 0.03, respectively) and was negatively correlated with insulinemia (r = -0.60; P < 0.01). Maximal IGF-I binding to type 1 IGF receptors was higher in obese than in controls (B/T = 1.9 +/- 0.20 and 0.86 +/- 0.10; P < 0.0001, respectively) and was negatively correlated with plasma IGF-I levels (r = -0.69; P < 0.003). Hybrid receptor abundance was higher in obese than in normal subjects (B/T = 1.21 +/- 0.14 and 0.44 +/- 0.06; P < 0.0003, respectively) and was negatively correlated with insulin binding (r = -0.60; P < 0.01) and positively correlated with IGF-I binding (r = 0.92; P < 0.0001). Increased abundance of hybrids was correlated with insulinemia (r = 0.70; P < 0.002) and body mass index (r = 0.71; P < 0.0019), whereas it was negatively correlated with in vivo insulin sensitivity measured by ITT (r = -0.67; P < 0.016). These results indicate that downregulation of insulin receptors or upregulation of type 1 IGF receptors because of changes in plasma insulin and IGF-I levels may result in modifications in hybrid receptor abundance.

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

    Science.gov (United States)

    Lampman, R M; Schteingart, D E

    1991-06-01

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

  12. A 2-wk reduction of ambulatory activity attenuates peripheral insulin sensitivity

    DEFF Research Database (Denmark)

    Krogh-Madsen, Rikke; Thyfault, John P; Broholm, Christa;

    2010-01-01

    US adults take between approximately 2,000 and approximately 12,000 steps per day, a wide range of ambulatory activity that at the low range could increase risk for developing chronic metabolic diseases. Dramatic reductions in physical activity induce insulin resistance; however, it is uncertain...... possible biological cause for the public health problem of Type 2 diabetes has been identified. Reduced ambulatory activity for 2 wk in healthy, nonexercising young men significantly reduced peripheral insulin sensitivity, cardiovascular fitness, and lean leg mass....... if and how low ambulatory activity would influence peripheral insulin sensitivity. We aimed to explore if healthy, nonexercising subjects who went from a normal to a low level of ambulatory activity for 2 wk would display metabolic alterations including reduced peripheral insulin sensitivity. To do this, ten...

  13. Total adiponectin and adiponectin multimeric complexes in relation to weight loss-induced improvements in insulin sensitivity in obese women

    DEFF Research Database (Denmark)

    Polak, J.; Kovacova, Z.; Holst, C.

    2008-01-01

    AIM: Adiponectin increases insulin sensitivity, protects arterial walls against atherosclerosis, and regulates glucose metabolism, and is decreased in obese, insulin resistant, and type 2 diabetic patients. Adiponectin circulates in plasma as high, medium, and low molecular weight forms (HMW, MMW...

  14. Normocaloric Diet Restores Weight Gain and Insulin Sensitivity in Obese Mice

    Directory of Open Access Journals (Sweden)

    Giovanni Enrico Lombardo

    2016-05-01

    Full Text Available An increased incidence of obesity is registered worldwide, and its association with insulin resistance and type 2 diabetes is closely related with increased morbidity and mortality for cardiovascular diseases. A major clinical problem in the management of obesity is the non-adherence or low adherence of patients to a hypo-caloric dietetic restriction. In this study we evaluated in obese mice the effects on insulin sensitivity of shifting from high-calorie foods to normal diet. Male C57BL/6JolaHsd mice (n=20 were fed with high fat diet for a 24 weeks period. Afterwards, body weight, energy and food intake were measured in all animals, together with parameters of insulin sensitivity by homeostatic model assessment of insulin resistance and plasma glucose levels in response to insulin administration. Moreover, in half of these mice, Glut4 mRNA levels were measured in muscle at the end of the high fat treatment, whereas the rest of the animals (n=10 were shifted to normocaloric diet for 10 weeks, after which the same analyses were carried out. A significant reduction of body weight was found after the transition from high to normal fat diet, and this decrease correlated well with an improvement in insulin sensitivity. In fact, we found a reduction in serum insulin levels and the recovery of insulin responsiveness in terms of glucose disposal measured by insulin tolerance test and Glut4 mRNA and protein expression. These results indicate that obesity related insulin resistance may be rescued by shifting from high fat diet to normocaloric diet.

  15. 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.

  16. Insulin sensitivity and carotid intima-media thickness

    DEFF Research Database (Denmark)

    Kozakova, Michaela; Natali, Andrea; Dekker, Jacqueline;

    2013-01-01

    Despite a wealth of experimental data in animal models, the independent association of insulin resistance with early carotid atherosclerosis in man has not been demonstrated. APPROACH AND RESULTS: We studied a European cohort of 525 men and 655 women (mean age, 44±8 years) free of conditions know...

  17. Peripheral insulin sensitivity as modified by diet and exercise training.

    Science.gov (United States)

    Grimditch, G K; Barnard, R J; Hendricks, L; Weitzman, D

    1988-07-01

    To determine which component of a high-fat sucrose diet (HFS) caused insulin resistance and whether exercise training or fiber could prevent it, six dietary treatments were tested in rats: low-fat complex carbohydrate (LFCC); high-fat complex carbohydrate (HFCC); low-fat sucrose (LFS); high-fat sucrose (HFS); HFS plus fiber (HFS + F); and HFS plus exercise training (HFS + EX). After 10 wk rats were subjected to an intravenous glucose-tolerance test. The HFS and HFS + F groups developed glucose intolerance, as indicated by significantly greater areas under their glucose curves compared with the LFCC group's areas. The LFS, HFS, HFS + F, and HFS + EX groups developed insulin resistance, as indicated by significantly greater areas under their insulin curves compared with the LFCC and HFCC groups' areas. Either the presence of sucrose or the absence of complex carbohydrates, not high fat, was responsible for the insulin resistance and it was not improved by adding fiber to the diet or by exercise training.

  18. Insulin sensitivity : modulation by the gut-brain axis

    NARCIS (Netherlands)

    Heijboer, Annemieke Corine

    2006-01-01

    Er zijn steeds meer aanwijzingen dat neuropeptiden in de hypothalamus en maagdarmhormonen die hun werking hebben op de hypothalamus en betrokken zijn bij de regulatie van voedselinname, ook betrokken zouden kunnen zijn bij de regulatie van insuline gevoeligheid. Daarom hebben we eerst de effecten va

  19. Determination of Insulin Secretory Defect and Insulin Sensitivity in Type 2 Diabetic Subjects in Bangladesh.

    Science.gov (United States)

    Ferdous, J; Ahmed, S; Laila, R; Islam, M T; Rahaman, M F; Snigdha, K R; Sarkar, S; Khan, A S; Sarkar, A K

    2016-01-01

    Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. This study was undertaken to explore the basic defect in type 2 diabetes patients in Bangladesh. This was an observational study with case control design, was conducted in the Biomedical Research Group, Research Division, Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine Metabolic Disorders (BIRDEM), Dhaka, Bangladesh, during the period of July 2008 to June 2009. A total of 153 subjects were included in study of which 63 belonged to type 2 diabetes mellitus group and 90 were healthy controls. Fasting and 2 hours postprandial blood glucose, serum insulin, HOMA%B, HOMA%S, QuickI, Glucose /insulin ratio, TG were measured and age, BMI, WHR were recorded. Waist-hip ratio (WHR), was significantly higher in T2DM as compared to control subjects [WHR, mean±SD, 0.94±0.12 vs. 0.88±0.06, pBangladesh.

  20. Preparation of isolated bovine adipocytes: validation of use for studies characterizing insulin sensitivity and binding.

    Science.gov (United States)

    Vasilatos, R; Etherton, T D; Wangsness, P J

    1983-05-01

    The present study was undertaken to develop techniques to isolate bovine adipocytes, to compare their rates of glucose metabolism and insulin sensitivity with adipocytes in adipose tissue, and to determine if isolated bovine adipocytes specifically bind insulin. Cell size and diameter distributions were the same for adipocytes fixed with OsO4 after isolation with collagenase and adipocytes liberated from OsO4-fixed adipose tissue slices. On a per cell basis, lipogenic rates were greater for isolated adipocytes compared with intact adipose tissue. Similar differences were found for glucose oxidation. In short term incubations, glucose oxidation and lipid synthesis were not stimulated by insulin (0-100 ng/ml) in either isolated adipocytes or tissue. Specific binding of [125I]iodoinsulin at 30 C was low (0.8%) in the first group of six beef cattle sampled, but increased with increasing cell concentration. Insulin degradation after 90 min was less than 5%. The specificity of [125I]iodoinsulin binding was studied in a second group of six animals. There was no specific binding of insulin in this group. In summary, bovine adipocytes can be isolated which are metabolically active and provide a valid system for studying hormone binding and action. In the present study, glucose metabolism in bovine adipocytes was not stimulated by insulin in vitro. This insensitivity to insulin was associated with a negligible capacity for insulin binding. These findings suggest that the lack of insulin sensitivity in bovine adipose tissue may be due to an inability to specifically bind insulin. This may be related to the unique metabolism of ruminant adipose tissue, which is less dependent upon glucose for fatty acid synthesis than is adipose tissue from nonruminant species.

  1. Insulin modulates cocaine-sensitive monoamine transporter function and impulsive behavior.

    Science.gov (United States)

    Schoffelmeer, Anton N M; Drukarch, Benjamin; De Vries, Taco J; Hogenboom, François; Schetters, Dustin; Pattij, Tommy

    2011-01-26

    Because insulin acutely enhances the function of dopamine transporters, the tyrosine kinase receptors activated by this hormone may modulate transporter-dependent neurochemical and behavioral effects of psychoactive drugs. In this respect, we examined the effects of insulin on exocytotic monoamine release and the efficacy of the monoamine transporter blocker cocaine in rat nucleus accumbens. Whereas insulin reduced electrically evoked exocytotic [(3)H]dopamine release in nucleus accumbens slices, the hormone potentiated the release-enhancing effect of cocaine thereon. The phosphatidylinositol 3-kinase inhibitor LY294002 abolished these effects, indicating the involvement of insulin receptors. Similar insulin effects were observed on the release of [(3)H]norepinephrine in nucleus accumbens slices, but not on that of [(3)H]serotonin, and were also apparent in medial prefrontal cortex slices. As might then be expected, insulin also potentiated the dopamine and norepinephrine release-enhancing effects of the selective monoamine uptake inhibitors GBR12909 and desmethylimipramine, respectively. In subsequent behavioral experiments, we investigated the role of insulin in motor impulsivity that depends on monoamine neurotransmission in the nucleus accumbens. Intracranial administration of insulin in the nucleus accumbens alone reduced premature responses in the five-choice serial reaction time task and enhanced the stimulatory effect of peripheral cocaine administration on impulsivity, resembling the observed neurochemical effects of the hormone. In contrast, cocaine-induced locomotor activity remained unchanged by intra-accumbal insulin application. These data reveal that insulin presynaptically regulates cocaine-sensitive monoamine transporter function in the nucleus accumbens and, as a consequence, impulsivity. Therefore, insulin signaling proteins may represent targets for the treatment of inhibitory control deficits such as addictive behaviors.

  2. Effects of 7 days of exercise training on insulin sensitivity and responsiveness in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Kirwan, John P; Solomon, Thomas; Wojta, Daniel M

    2009-01-01

    The objectives of this study were to determine whether 1) the improvement in insulin action induced by short-term exercise training in patients with type 2 diabetes is due to an improvement in insulin sensitivity, an improvement in insulin responsiveness, or a combination of improved insulin...... sensitivity and responsiveness and 2) short-term exercise training results in improved suppression of hepatic glucose production by insulin. Fourteen obese patients with type 2 diabetes, age 64 +/- 2 yr, underwent a two-stage hyperinsulinemic euglycemic clamp procedure, first stage 40 mU.m(-2).min(-1) insulin...... of vigorous exercise training can induce significant improvements in insulin action in type 2 diabetes. These improvements include increased peripheral insulin sensitivity and responsiveness as well as enhanced suppression of hepatic glucose production....

  3. Soy pinitol acts partly as an insulin sensitizer or insulin mediator in 3T3-L1 preadipocytes.

    Science.gov (United States)

    Do, Gyeong-Min; Choi, Myung-Sook; Kim, Hye-Jin; Woo, Myung-Nam; Lee, Mi-Kyung; Jeon, Seon-Min

    2008-02-01

    The blood glucose-lowering property of pinitol is mediated via the insulin signaling pathway. This study was carried out to evaluate the effects of soy pinitol on adipogenesis in a 3T3-L1 cell line; 3T3-L1 preadipocytes were treated with pinitol (0-1 mM) together with insulin for 9 days. The regulation of lipid metabolism was assessed by oil-red-O staining of intracellular lipids and real-time PCR of adipogenesis-related factors. The inhibition of cell proliferation was estimated by MTT assay. Pinitol treatment did not inhibit lipid accumulation, nor did it affect expression of adipogenesis-related factors, including ADD1, aP2 and FAS, in a dose-dependent manner. Expression of adiponectin, GLUT4, IRS, C/EBPalpha and PPARgamma mRNAs, however, increased in cells treated with 0.5 mM and/or 1 mM pinitol. Pinitol treatment did not affect the inhibition of cell growth and proliferation in a dose-dependent manner. Accordingly, we suggest that pinitol is nontoxic to this cell line, and that it enhances adipogenesis by acting as an insulin sensitizer or insulin mediator via the upregulation of adiponectin, GLUT4, IRS, C/EBPalpha and PPARgamma in 3T3-L1 preadipocytes.

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

    Science.gov (United States)

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

    2015-05-28

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

  5. Glut4 expression defines an insulin-sensitive hypothalamic neuronal population.

    Science.gov (United States)

    Ren, Hongxia; Yan, Shijun; Zhang, Baifang; Lu, Taylor Y; Arancio, Ottavio; Accili, Domenico

    2014-07-01

    Insulin signaling in the CNS modulates satiety and glucose metabolism, but insulin target neurons are poorly defined. We have previously shown that ablation of insulin receptors (InsR) in Glut4-expressing tissues results in systemic abnormalities of insulin action. We propose that Glut4 neurons constitute an insulin-sensitive neuronal subset. We determined their gene expression profiles using flow-sorted hypothalamic Glut4 neurons. Gene ontology analyses demonstrated that Glut4 neurons are enriched in olfacto-sensory receptors, M2 acetylcholine receptors, and pathways required for the acquisition of insulin sensitivity. Following genetic ablation of InsR, transcriptome profiling of Glut4 neurons demonstrated impairment of the insulin, peptide hormone, and cAMP signaling pathways, with a striking upregulation of anion homeostasis pathway. Accordingly, hypothalamic InsR-deficient Glut4 neurons showed reduced firing activity. The molecular signature of Glut4 neurons is consistent with a role for this neural population in the integration of olfacto-sensory cues with hormone signaling to regulate peripheral metabolism.

  6. Detection of Independent Associations of Plasma Lipidomic Parameters with Insulin Sensitivity Indices Using Data Mining Methodology

    Science.gov (United States)

    Schuhmann, Kai; Xu, Aimin; Schulte, Klaus-Martin; Simeonovic, Charmaine J.; Schwarz, Peter E. H.; Bornstein, Stefan R.; Shevchenko, Andrej; Graessler, Juergen

    2016-01-01

    Objective Glucolipotoxicity is a major pathophysiological mechanism in the development of insulin resistance and type 2 diabetes mellitus (T2D). We aimed to detect subtle changes in the circulating lipid profile by shotgun lipidomics analyses and to associate them with four different insulin sensitivity indices. Methods The cross-sectional study comprised 90 men with a broad range of insulin sensitivity including normal glucose tolerance (NGT, n = 33), impaired glucose tolerance (IGT, n = 32) and newly detected T2D (n = 25). Prior to oral glucose challenge plasma was obtained and quantitatively analyzed for 198 lipid molecular species from 13 different lipid classes including triacylglycerls (TAGs), phosphatidylcholine plasmalogen/ether (PC O-s), sphingomyelins (SMs), and lysophosphatidylcholines (LPCs). To identify a lipidomic signature of individual insulin sensitivity we applied three data mining approaches, namely least absolute shrinkage and selection operator (LASSO), Support Vector Regression (SVR) and Random Forests (RF) for the following insulin sensitivity indices: homeostasis model of insulin resistance (HOMA-IR), glucose insulin sensitivity index (GSI), insulin sensitivity index (ISI), and disposition index (DI). The LASSO procedure offers a high prediction accuracy and and an easier interpretability than SVR and RF. Results After LASSO selection, the plasma lipidome explained 3% (DI) to maximal 53% (HOMA-IR) variability of the sensitivity indexes. Among the lipid species with the highest positive LASSO regression coefficient were TAG 54:2 (HOMA-IR), PC O- 32:0 (GSI), and SM 40:3:1 (ISI). The highest negative regression coefficient was obtained for LPC 22:5 (HOMA-IR), TAG 51:1 (GSI), and TAG 58:6 (ISI). Conclusion Although a substantial part of lipid molecular species showed a significant correlation with insulin sensitivity indices we were able to identify a limited number of lipid metabolites of particular importance based on the LASSO approach. These

  7. MiR-155 Enhances Insulin Sensitivity by Coordinated Regulation of Multiple Genes in Mice

    Science.gov (United States)

    Lin, Taoyan; Lin, Xia; Chen, Li; Zeng, Hui; Han, Yanjiang; Wu, Lihong; Huang, Shun; Wang, Meng; Huang, Shenhao; Xie, Raoying; Liang, Liqi; Liu, Yu; Liu, Ruiyu; Zhang, Tingting; Li, Jing; Wang, Shengchun; Sun, Penghui; Huang, Wenhua; Yao, Kaitai; Xu, Kang; Du, Tao; Xiao, Dong

    2016-01-01

    miR-155 plays critical roles in numerous physiological and pathological processes, however, its function in the regulation of blood glucose homeostasis and insulin sensitivity and underlying mechanisms remain unknown. Here, we reveal that miR-155 levels are downregulated in serum from type 2 diabetes (T2D) patients, suggesting that miR-155 might be involved in blood glucose control and diabetes. Gain-of-function and loss-of-function studies in mice demonstrate that miR-155 has no effects on the pancreatic β-cell proliferation and function. Global transgenic overexpression of miR-155 in mice leads to hypoglycaemia, improved glucose tolerance and insulin sensitivity. Conversely, miR-155 deficiency in mice causes hyperglycemia, impaired glucose tolerance and insulin resistance. In addition, consistent with a positive regulatory role of miR-155 in glucose metabolism, miR-155 positively modulates glucose uptake in all cell types examined, while mice overexpressing miR-155 transgene show enhanced glycolysis, and insulin-stimulated AKT and IRS-1 phosphorylation in liver, adipose tissue or skeletal muscle. Furthermore, we reveal these aforementioned phenomena occur, at least partially, through miR-155-mediated repression of important negative regulators (i.e. C/EBPβ, HDAC4 and SOCS1) of insulin signaling. Taken together, these findings demonstrate, for the first time, that miR-155 is a positive regulator of insulin sensitivity with potential applications for diabetes treatment. PMID:27711113

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

    Directory of Open Access Journals (Sweden)

    Luca Giudici

    2013-11-01

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

  9. A Small Insulinomimetic Molecule Also Improves Insulin Sensitivity in Diabetic Mice

    Science.gov (United States)

    Mukherjee, Sandip; Chattopadhyay, Mrittika; Bhattacharya, Sushmita; Dasgupta, Suman; Hussain, Sahid; Bharadwaj, Saitanya K.; Talukdar, Dhrubajyoti; Usmani, Abul; Pradhan, Bhola S; Majumdar, Subeer S; Chattopadhyay, Pronobesh; Mukhopadhyay, Satinath; Maity, Tushar K; Chaudhuri, Mihir K.; Bhattacharya, Samir

    2017-01-01

    Dramatic increase of diabetes over the globe is in tandem with the increase in insulin requirement. This is because destruction and dysfunction of pancreatic β-cells are of common occurrence in both Type1 diabetes and Type2 diabetes, and insulin injection becomes a compulsion. Because of several problems associated with insulin injection, orally active insulin mimetic compounds would be ideal substitute. Here we report a small molecule, a peroxyvanadate compound i.e. DmpzH[VO(O2)2(dmpz)], henceforth referred as dmp, which specifically binds to insulin receptor with considerable affinity (KD-1.17μM) thus activating insulin receptor tyrosine kinase and its downstream signaling molecules resulting increased uptake of [14C] 2 Deoxy-glucose. Oral administration of dmp to streptozotocin treated BALB/c mice lowers blood glucose level and markedly stimulates glucose and fatty acid uptake by skeletal muscle and adipose tissue respectively. In db/db mice, it greatly improves insulin sensitivity through excess expression of PPARγ and its target genes i.e. adiponectin, CD36 and aP2. Study on the underlying mechanism demonstrated that excess expression of Wnt3a decreased PPARγ whereas dmp suppression of Wnt3a gene increased PPARγ expression which subsequently augmented adiponectin. Increased production of adiponectin in db/db mice due to dmp effected lowering of circulatory TG and FFA levels, activates AMPK in skeletal muscle and this stimulates mitochondrial biogenesis and bioenergetics. Decrease of lipid load along with increased mitochondrial activity greatly improves energy homeostasis which has been found to be correlated with the increased insulin sensitivity. The results obtained with dmp, therefore, strongly indicate that dmp could be a potential candidate for insulin replacement therapy. PMID:28072841

  10. Sensitive and precise quantification of insulin-like mRNA expression in Caenorhabditis elegans.

    Science.gov (United States)

    Baugh, L Ryan; Kurhanewicz, Nicole; Sternberg, Paul W

    2011-03-22

    Insulin-like signaling regulates developmental arrest, stress resistance and lifespan in the nematode Caenorhabditis elegans. However, the genome encodes 40 insulin-like peptides, and the regulation and function of individual peptides is largely uncharacterized. We used the nCounter platform to measure mRNA expression of all 40 insulin-like peptides as well as the insulin-like receptor daf-2, its transcriptional effector daf-16, and the daf-16 target gene sod-3. We validated the platform using 53 RNA samples previously characterized by high density oligonucleotide microarray analysis. For this set of genes and the standard nCounter protocol, sensitivity and precision were comparable between the two platforms. We optimized conditions of the nCounter assay by varying the mass of total RNA used for hybridization, thereby increasing sensitivity up to 50-fold and reducing the median coefficient of variation as much as 4-fold. We used deletion mutants to demonstrate specificity of the assay, and we used optimized conditions to assay insulin-like gene expression throughout the C. elegans life cycle. We detected expression for nearly all insulin-like genes and find that they are expressed in a variety of distinct patterns suggesting complexity of regulation and specificity of function. We identified insulin-like genes that are specifically expressed during developmental arrest, larval development, adulthood and embryogenesis. These results demonstrate that the nCounter platform provides a powerful approach to analyzing insulin-like gene expression dynamics, and they suggest hypotheses about the function of individual insulin-like genes.

  11. Sensitive and precise quantification of insulin-like mRNA expression in Caenorhabditis elegans.

    Directory of Open Access Journals (Sweden)

    L Ryan Baugh

    Full Text Available Insulin-like signaling regulates developmental arrest, stress resistance and lifespan in the nematode Caenorhabditis elegans. However, the genome encodes 40 insulin-like peptides, and the regulation and function of individual peptides is largely uncharacterized. We used the nCounter platform to measure mRNA expression of all 40 insulin-like peptides as well as the insulin-like receptor daf-2, its transcriptional effector daf-16, and the daf-16 target gene sod-3. We validated the platform using 53 RNA samples previously characterized by high density oligonucleotide microarray analysis. For this set of genes and the standard nCounter protocol, sensitivity and precision were comparable between the two platforms. We optimized conditions of the nCounter assay by varying the mass of total RNA used for hybridization, thereby increasing sensitivity up to 50-fold and reducing the median coefficient of variation as much as 4-fold. We used deletion mutants to demonstrate specificity of the assay, and we used optimized conditions to assay insulin-like gene expression throughout the C. elegans life cycle. We detected expression for nearly all insulin-like genes and find that they are expressed in a variety of distinct patterns suggesting complexity of regulation and specificity of function. We identified insulin-like genes that are specifically expressed during developmental arrest, larval development, adulthood and embryogenesis. These results demonstrate that the nCounter platform provides a powerful approach to analyzing insulin-like gene expression dynamics, and they suggest hypotheses about the function of individual insulin-like genes.

  12. Effect of weight reduction on insulin sensitivity, sex hormone-binding globulin, sex hormones and gonadotrophins in obese children

    DEFF Research Database (Denmark)

    Birkebaek, N H; Lange, Aksel; Holland-Fischer, P

    2010-01-01

    Obesity in men is associated with reduced insulin sensitivity and hypoandrogenism, while obesity in women is associated with reduced insulin sensitivity and hyperandrogenism. In children, the effect of obesity and weight reduction on the hypothalamo-pituitary-gonadal axis is rarely investigated....... The aim of the present study was to investigate the effect of weight reduction in obese Caucasian children on insulin sensitivity, sex hormone-binding globulin (SHBG), DHEAS and the hypothalamo-pituitary-gonadal axis....

  13. Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

    DEFF Research Database (Denmark)

    Olsen, Michael H; Fossum, Eigil; Høieggen, Aud;

    2005-01-01

    Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve...... insulin sensitivity through regression of peripheral vascular hypertrophy/rarefaction....

  14. Effects of Lactobacillus acidophilus NCFM on insulin sensitivity and the systemic inflammatory response in human subjects

    DEFF Research Database (Denmark)

    Andreasen, Anne Sofie; Larsen, Nadja; Pedersen-Skovsgaard, Theis

    2010-01-01

    According to animal studies, intake of probiotic bacteria may improve glucose homeostasis. We hypothesised that probiotic bacteria improve insulin sensitivity by attenuating systemic inflammation. Therefore, the effects of oral supplementation with the probiotic bacterium Lactobacillus acidophilus...... course with either L. acidophilus NCFM or placebo. L. acidophilus was detected in stool samples by denaturating gradient gel electrophoresis and real-time PCR. Separated by the 4-week intervention period, two hyperinsulinaemic-euglycaemic clamps were performed to estimate insulin sensitivity. Furthermore......, the systemic inflammatory response was evaluated by subjecting the participants to Escherichia coli lipopolysaccharide injection (0·3 ng/kg) before and after the treatment course. L. acidophilus NCFM was detected in 75 % of the faecal samples after treatment with the probiotic bacterium. Insulin sensitivity...

  15. Effect of cabergoline on insulin sensitivity, inflammation, and carotid intima media thickness in patients with prolactinoma.

    Science.gov (United States)

    Inancli, Serap Soytac; Usluogullari, Alper; Ustu, Yusuf; Caner, Sedat; Tam, Abbas Ali; Ersoy, Reyhan; Cakir, Bekir

    2013-08-01

    The aim of this study was to evaluate the effect of Cabergoline on insulin sensitivity, inflammatory markers, and carotid intima media thickness in prolactinoma patients. Twenty-one female, newly diagnosed patients with prolactinoma were included in the study. None of the patients were treated previously. Cabergoline was given as treatment, starting with 0.5 mg/day and tapered necessarily. Blood samples were taken for prolactin, highly sensitive C-reactive protein, homocysteine, total cholesterol, low density lipoprotein (LDL) cholesterol, fasting glucose, insulin, and HOMA (homeostasis model assessment of insulin resistance) score was calculated, prior to and 6 months after starting treatment. The body mass index (BMI) was measured and carotid intima media thickness (CIMT) was evaluated for each patient prior to and 6 months after the treatment. The prolactin levels and LDL decreased significantly after cabergoline treatment. Insulin sensitivity improved independently from the decrease in prolactin levels and BMI. The significant decrease in homocysteine and hs-CRP was not related with the decrease in prolactin levels. The significant decrease in CIMT was independent from the decrease in prolactin levels, HOMA score, and BMI. Our data suggest that cabergoline treatment causes an improvement in insulin sensitivity and inflammatory markers and causes a decrease in CIMT independent from the decrease in prolactin, LDL cholesterol, and BMI. We conclude that short term cabergoline treatment can improve endothelial function independently from the changes in metabolic disturbances and inflammatory markers.

  16. Central Administration of Galanin Receptor 1 Agonist Boosted Insulin Sensitivity in Adipose Cells of Diabetic Rats

    Directory of Open Access Journals (Sweden)

    Zhenwen Zhang

    2016-01-01

    Full Text Available Our previous studies testified the beneficial effect of central galanin on insulin sensitivity of type 2 diabetic rats. The aim of the study was further to investigate whether central M617, a galanin receptor 1 agonist, can benefit insulin sensitivity. The effects of intracerebroventricular administration of M617 on insulin sensitivity and insulin signaling were evaluated in adipose tissues of type 2 diabetic rats. The results showed that central injection of M617 significantly increased plasma adiponectin contents, glucose infusion rates in hyperinsulinemic-euglycemic clamp tests, GLUT4 mRNA expression levels, GLUT4 contents in plasma membranes, and total cell membranes of the adipose cells but reduced the plasma C-reactive protein concentration in nondiabetic and diabetic rats. The ratios of GLUT4 contents were higher in plasma membranes to total cell membranes in both nondiabetic and diabetic M617 groups than each control. In addition, the central administration of M617 enhanced the ratios of pAkt/Akt and pAS160/AS160, but not phosphorylative cAMP response element-binding protein (pCREB/CREB in the adipose cells of nondiabetic and diabetic rats. These results suggest that excitation of central galanin receptor 1 facilitates insulin sensitivity via activation of the Akt/AS160 signaling pathway in the fat cells of type 2 diabetic rats.

  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

    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...

  18. Gene and MicroRNA Expression Responses to Exercise; Relationship with Insulin Sensitivity.

    Directory of Open Access Journals (Sweden)

    Carrie S McLean

    Full Text Available Healthy individuals on the lower end of the insulin sensitivity spectrum also have a reduced gene expression response to exercise for specific genes. The goal of this study was to determine the relationship between insulin sensitivity and exercise-induced gene expression in an unbiased, global manner.Euglycemic clamps were used to measure insulin sensitivity and muscle biopsies were done at rest and 30 minutes after a single acute exercise bout in 14 healthy participants. Changes in mRNA expression were assessed using microarrays, and miRNA analysis was performed in a subset of 6 of the participants using sequencing techniques. Following exercise, 215 mRNAs were changed at the probe level (Bonferroni-corrected P<0.00000115. Pathway and Gene Ontology analysis showed enrichment in MAP kinase signaling, transcriptional regulation and DNA binding. Changes in several transcription factor mRNAs were correlated with insulin sensitivity, including MYC, r=0.71; SNF1LK, r=0.69; and ATF3, r= 0.61 (5 corrected for false discovery rate. Enrichment in the 5'-UTRs of exercise-responsive genes suggested regulation by common transcription factors, especially EGR1. miRNA species of interest that changed after exercise included miR-378, which is located in an intron of the PPARGC1B gene.These results indicate that transcription factor gene expression responses to exercise depend highly on insulin sensitivity in healthy people. The overall pattern suggests a coordinated cycle by which exercise and insulin sensitivity regulate gene expression in muscle.

  19. pH-Sensitive oral insulin delivery systems using Eudragit microspheres.

    Science.gov (United States)

    Mundargi, Raghavendra C; Rangaswamy, Vidhya; Aminabhavi, Tejraj M

    2011-08-01

    In this paper, we present in vitro and in vivo release data on pH-sensitive microspheres of Eudragit L100, Eudragit RS100 and their blend systems prepared by double emulsion-solvent evaporation technique for oral delivery of insulin. Of the three systems developed, Eudragit L100 was chosen for preclinical studies. Insulin was encapsulated and in vitro experiments performed on insulin-loaded microspheres in pH 1.2 media did not release insulin during the first 2 h, but maximum insulin was released in pH 7.4 buffer media from 4 to 6 h. The microspheres were characterized by scanning electron microscopy to understand particle size, shape and surface morphology. The size of microspheres ranged between 1 and 40 μm. Circular dichroism spectra indicated the structural integrity of insulin during encapsulation as well as after its release in pH 7.4 buffer media. The in vivo release studies on diabetic-induced rat models exhibited maximum inhibition of up to 86%, suggesting absorption of insulin in the intestine.

  20. Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review

    Institute of Scientific and Technical Information of China (English)

    Norberto C Chavez-Tapia; Tonatiuh Barrientos-Gutierrez; Felix I Tellez-(A)vila; Francisco Sánchez-(A)vila; Maria Antonieta Monta(n)o-Reyes; Misael Uribe

    2006-01-01

    AIM: To summarize the evidence available for the clinical effectiveness of insulin sensitizers in the treatment of nonalcoholic fatty liver disease (NAFLD) systematically.METHODS: Relevant articles were located using computer-assisted searches of Medline (1966-March 2006), EMBASE (1988-March 2006), CINAHL (1982-March 2003), Educational Resource Information Center (1966-March 2006), Library, Information Science & Technology Abstracts(1967-March 2006), Cochrane Database of Systematic Reviews, Database of Abstractsof Reviews of Effects (1994-2006), dissertations in ProQuest and FirstSearch databases. Manual searches were made in the Abstractsfrom meetings of the American Gastroenterological Association (1999-2006),and the American Association for the Study of Liver Diseases (2003-2005). Studies were retrieved using the following selection criteria: (1) clinical trials using insulin sensitizers in subjects with NAFLD, (2) adult patients, (3) published as full manuscripts or Abstracts and (4) English, Spanish, German, and French languages only. Data were Abstracts independently by two reviewers following standardized procedures. A face-toface comparison of data was conducted to ensure the completeness and reliability of the Abstracts process.RESULTS: Nine studies were included, six using metformin and three using thiazolidinediones. Only two studies were placebo-controlled trials. The median sample size for all studies was 18 subjects. In the placebo-controlled trials, metformin improved insulin resistance markers and liver function tests, but not histological scores. In the single-arm trials, metformin and thiazolidinediones improved insulin resistance markers and liver function tests, and beneficial histological changes were reported. There is limited high-quality information available from which to draw categorical conclusions about the clinical use of insulin sensitizers in NAFLD.CONCLUSION: Current information indicates that the use of insulin sensitizers in NAFLD

  1. Insulin sensitizers in treatment of nonalcoholic fatty liver disease: Systematic review

    Science.gov (United States)

    Chavez-Tapia, Norberto C; Barrientos-Gutierrez, Tonatiuh; Tellez-Ávila, Felix I; Sánchez-Ávila, Francisco; Montaño-Reyes, Maria Antonieta; Uribe, Misael

    2006-01-01

    AIM: To summarize the evidence available for the clinical effectiveness of insulin sensitizers in the treatment of nonalcoholic fatty liver disease (NAFLD) systematically. METHODS: Relevant articles were located using computer-assisted searches of Medline (1966-March 2006), EMBASE (1988-March 2006), CINAHL (1982-March 2003), Educational Resource Information Center (1966-March 2006), Library, Information Science & Technology Abstracts (1967-March 2006), Cochrane Database of Systematic Reviews, Database of Abstracts of Reviews of Effects (1994-2006), dissertations in ProQuest and FirstSearch databases. Manual searches were made in the abstracts from meetings of the American Gastroenterological Association (1999-2006), and the American Association for the Study of Liver Diseases (2003-2005). Studies were retrieved using the following selection criteria: (1) clinical trials using insulin sensitizers in subjects with NAFLD, (2) adult patients, (3) published as full manuscripts or abstracts, and (4) English, Spanish, German, and French languages only. Data were abstracted independently by two reviewers following standardized procedures. A face-to-face comparison of data was conducted to ensure the completeness and reliability of the abstraction process. RESULTS: Nine studies were included, six using metformin and three using thiazolidinediones. Only two studies were placebo-controlled trials. The median sample size for all studies was 18 subjects. In the placebo-controlled trials, metformin improved insulin resistance markers and liver function tests, but not histological scores. In the single-arm trials, metformin and thiazolidinediones improved insulin resistance markers and liver function tests, and beneficial histological changes were reported. There is limited high-quality information available from which to draw categorical conclusions about the clinical use of insulin sensitizers in NAFLD. CONCLUSION: Current information indicates that the use of insulin

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

    NARCIS (Netherlands)

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

    2011-01-01

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

  3. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis.

    Science.gov (United States)

    Boparai, Ravneet K; Arum, Oge; Khardori, Romesh; Bartke, Andrzej

    2010-10-01

    In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH over- expression on glucose homeostasis and insulin sensitivity has been conducted. We report that male and female adult GH transgenic mice have enhanced glucose tolerance compared to littermate controls and this effect is not dependent on age or on the particular heterologous GH transgene used. Furthermore, increased glucose-stimulated insulin secretion, augmented insulin sensitivity, and muted gluconeogenesis were also observed in bovine GH overexpressing mice. These results show that markedly increased systemic GH concentration in GH-transgenic mice exerts unexpected beneficial effects on glucose homeostasis, presumably via a compensatory increase in insulin release. The counterintuitive nature of these results challenges previously held presumptions of the physiology of these mice and other states of GH overexpression or suppression. In addition, they pose intriguing queries about the relationships between GH, endocrine control of metabolism, and aging.

  4. Nickel nanoparticle-modified electrode for ultra-sensitive electrochemical detection of insulin.

    Science.gov (United States)

    Yu, Yanan; Guo, Meisong; Yuan, Mengwei; Liu, Weitong; Hu, Jingbo

    2016-03-15

    An ultra-sensitive electrochemical sensor for the detection of insulin was fabricated, using low-cost and environmentally friendly nickel nanoparticles (NiNPs) by ion implantation. The morphology and structure of the NiNPs are characterized by scanning electron microscopy (SEM), revealing diameters ranging from 4 to 8 nm. The insulin assay performances were evaluated by cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and chronoamperometry (I-t). The NiNPs-modified indium tin oxide electrode (NiNPs/ITO) showed excellent analytical features, including ultra-high sensitivity (2140 μAμM(-1)) for detecting low concentrations of insulin, an incredibly low detection limit (10 pM) and a wide dynamic range (100 pM to 2400 pM and 1 nM to 125 nM). In addition, the NiNPs/ITO electrode was also used to analyze the insulin concentration in bovine insulin injections. The NiNPs/ITO electrode is expected to be used as a potential biosensor for insulin.

  5. Glucose tolerance, insulin sensitivity and insulin release in European non-diabetic carriers of a polymorphism upstream of CDKN2A and CDKN2B

    DEFF Research Database (Denmark)

    Hribal, M L; Presta, I; Procopio, T

    2011-01-01

    The aim of this study was to investigate the association of the rs10811661 polymorphism near the CDKN2B/CDKN2A genes with glucose tolerance, insulin sensitivity and insulin release in three samples of white people with European ancestry....

  6. Early enhancements of hepatic and later of peripheral insulin sensitivity combined with increased postprandial insulin secretion contribute to improved glycemic control after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Bojsen-Møller, Kirstine N; Dirksen, Carsten; Jørgensen, Nils Bruun;

    2014-01-01

    to an intravenous glucose-glucagon challenge as well as an oral glucose load. Already within 1 week, RYGB reduced basal glucose production, improved basal hepatic insulin sensitivity and increased insulin clearance highlighting the liver as an important organ responsible for the early effects on glucose metabolism...

  7. High Dose Astaxanthin Lowers Blood Pressure and Increases Insulin Sensitivity in Rats: Are These Effects Interdependent?

    Directory of Open Access Journals (Sweden)

    Harry G. Preuss, Bobby Echard, Eiji Yamashita, Nicholas V. Perricone

    2011-01-01

    Full Text Available The present investigation in Sprague-Dawley rats (SD was designed to examine effects of astaxanthin (Asta at different doses on elevated blood pressure (BP and glucose-insulin perturbations produced by heavy sucrose ingestion. We also examined effects of Asta on BP during restraint stress. SD were divided into six groups each containing eight rats. All SD ate a basic diet of ground regular rat chow with sucrose added at 30% w/w. The Control group received only the basic diet containing added sucrose, while the other five groups each received the same diet with added test material: captopril, (30 mg/Kg, pioglitazone (15.0 mg/Kg, low Asta (25 mg/Kg, medium Asta (50 mg/kg or high Asta (100 mg/Kg. Many tests were carried out to examine the mechanisms behind the effects of Asta on BP (serum ACE activity, losartan challenge, and LNAME challenge and the glucose-insulin system (glucose tolerance, HOMA measurement, and insulin challenge. In SD, a relatively low dose of Asta decreased SBP, but produced no major changes in the glucose-insulin system simulating results from a previous study using Zucker Fatty Rats. Increasing the dose of Asta resulted in both a lowering of elevated systolic BP and enhanced insulin sensitivity determined by many different estimations. BP lowering was consistent with changes in the renin-angiotensin (RAS and nitric oxide (NO systems. At the examined doses of each, captopril lowered BP in SD without influencing glucose-insulin metabolism, whereas pioglitazone favorably affected glucose-insulin metabolism while showing essentially no effects on BP. Accordingly, Asta beneficially affects both sucrose-induced elevations of BP and insulin resistance at relatively high doses in SD. Also, Asta at higher doses lessens restraint stress, whereas, captopril and pioglitazone did not at the doses examined, even though they influenced the BP and glucose-insulin systems respectively.

  8. Skeletal Muscle-Specific CPT1 Deficiency Elevates Lipotoxic Intermediates but Preserves Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Wanchun Shi

    2013-01-01

    Full Text Available Objective. By specific knockout of carnitine palmitoyl transferase 1b (CPT1b in skeletal muscles, we explored the effect of CPT1b deficiency on lipids and insulin sensitivity. Methods. Mice with specific knockout of CPT1b in skeletal muscles (CPT1b M−/− were used for the experiment group, with littermate C57BL/6 as controls (CPT1b. General and metabolic profiles were measured and compared between groups. mRNA expression and CPT1 activity were measured in skeletal muscle tissues and compared between groups. Mitochondrial fatty acid oxidation (FAO, triglycerides (TAGs, diglycerides (DAGs, and ceramides were examined in skeletal muscles in two groups. Phosphorylated AKT (pAkt and glucose transporter 4 (Glut4 were determined with real-time polymerase chain reaction (RT-PCR. Insulin tolerance test, glucose tolerance test, and pyruvate oxidation were performed in both groups. Results. CPT1b M−/− model was successfully established, with impaired muscle CPT1 activity. Compared with CPT1b mice, CPT1b M−/− mice had similar food intake but lower body weight or fat mass and higher lipids but similar glucose or insulin levels. Their mitochondrial FAO of skeletal muscles was impaired. There were lipids accumulations (TAGs, DAGs, and ceramides in skeletal muscle. However, pAkt and Glut4, insulin sensitivity, glucose tolerance, and pyruvate oxidation were preserved. Conclusion. Skeletal muscle-specific CPT1 deficiency elevates lipotoxic intermediates but preserves insulin sensitivity.

  9. Association of oxidative status and insulin sensitivity in periparturient dairy cattle: an observational study.

    Science.gov (United States)

    Abuelo, A; Hernández, J; Benedito, J L; Castillo, C

    2016-04-01

    Post-parturient insulin resistance (IR) is a common feature in all mammalian animals. However, in dairy cows, it can be exacerbated because of high milk yield, leading to excessive negative energy balance, which is related with increased disease incidence, reduced milk production and worsened reproductive performance. IR has been extensively investigated in humans suffering from diabetes mellitus. In these subjects, it is known that oxidative stress (OS) plays a causative role in the onset of IR. Although OS occurs in transitional dairy cattle, there are yet no studies that investigated the association between IR and OS in dairy cattle. Therefore, the aim of this study was to investigate whether there is a relationship between OS and IR in dairy cattle. Serum samples were taken repeatedly from 22 dairy cows from 2 months prior to the expected calving date to 2 months after calving and were analysed for markers of metabolic and redox balance. Surrogate indices of insulin sensitivity were also calculated. Generalised linear mixed models revealed an effect of the oxidative status on peripheral insulin concentration and on indices of insulin sensitivity. Hence, field trials should investigate the effectiveness of antioxidant therapy on insulin sensitivity in peripheral tissues during the transition period of dairy cattle.

  10. Vasopeptidase inhibition improves insulin sensitivity and endothelial function in the JCR:LA-cp rat.

    Science.gov (United States)

    Russell, James C; Kelly, Sandra E; Schäfer, Stefan

    2004-08-01

    The insulin-resistant, hyperinsulinemic, normoglycemic, and obese JCR:LA-cp rat was used to study the effects of ramipril (an ACE inhibitor) and AVE7688 (a dual inhibitor of ACE and neutral endopeptidases) on insulin sensitivity and vascular function. Both compounds reduced the surge of plasma insulin in a meal tolerance test by approximately 50%. Ramipril had no effect on acetylcholine-induced relaxation but increased the sensitivity to sodium nitroprus-side at low concentrations. AVE7688 significantly reduced the EC50 for acetylcholine to relax phenylephrine-contracted aortic rings. None of the compounds affected the baseline coronary flow and reactive hyperemia. Coronary flow response to bradykinin in AVE7688- and ramipril-treated rat hearts showed a significantly lower EC50 than in control rats. Maximum flow rate was not different between groups. In summary, both ramipril and AVE7688 had significant hypoinsulinemic and insulin-sensitizing effects. Whereas ramipril had limited vascular effects, AVE7688 had more marked beneficial vascular effects, probably of endothelial origin and possibly related to lowered insulin levels.

  11. Insulin sensitivity and complications in type 1 diabetes:New insights

    Institute of Scientific and Technical Information of China (English)

    Petter Bjornstad; Janet K Snell-Bergeon; Kristen J Nadeau; David M Maahs

    2015-01-01

    Despite improvements in glucose, lipids and bloodpressure control, vascular complications remain themost important cause of morbidity and mortality inpatients with type 1 diabetes. For that reason, there is aneed to identify additional risk factors to utilize in clinicalpractice or translate to novel therapies to preventvascular complications. Reduced insulin sensitivityis an increasingly recognized component of type 1diabetes that has been linked with the developmentand progression of both micro- and macrovascularcomplications. Adolescents and adults with type 1diabetes have reduced insulin sensitivity, even whencompared to their non-diabetic counterparts of similaradiposity, serum triglycerides, high-density lipoproteincholesterol, level of habitual physical activity, and inadolescents, pubertal stage. Reduced insulin sensitivityis thought to contribute both to the initiation andprogression of macro- and microvascular complicationsin type 1 diabetes. There are currently clinical trialsunderway examining the benefits of improving insulinsensitivity with regards to vascular complications in type1 diabetes. Reduced insulin sensitivity is an increasinglyrecognized component of type 1 diabetes, is implicatedin the pathogenesis of vascular complications and ispotentially an important therapeutic target to preventvascular complications. In this review, we will focus onthe pathophysiologic contribution of insulin sensitivity tovascular complications and summarize related ongoingclinical trials.

  12. Structure, antihyperglycemic activity and cellular actions of a novel diglycated human insulin

    DEFF Research Database (Denmark)

    O'Harte, F P; Boyd, A C; McKillop, A M;

    2000-01-01

    Human insulin was glycated under hyperglycemic reducing conditions and a novel diglycated form (M(r) 6135.1 Da) was purified by RP-HPLC. Endoproteinase Glu-C digestion combined with mass spectrometry and automated Edman degradation localized glycation to Gly(1) and Phe(1) of the insulin A- and B......-chains, respectively. Intraperitoneal (i.p.) administration of diglycated insulin to mice alone or in combination with glucose (7 nmol/kg) resulted in a 43-61% and 11-34% reduction in glucose lowering activity, respectively, compared with native insulin. Consistent with these findings, diglycated insulin (10(-9) to 10......(-7) mol/liter) was 22-38% less effective (P insulin in stimulating glucose uptake, glucose oxidation and glycogen production in isolated mouse abdominal muscle....

  13. Effect of training on insulin sensitivity of glucose uptake and lipolysis in human adipose tissue

    DEFF Research Database (Denmark)

    Stallknecht, Bente; Larsen, J J; Mikines, K J;

    2000-01-01

    Training increases insulin sensitivity of both whole body and muscle in humans. To investigate whether training also increases insulin sensitivity of adipose tissue, we performed a three-step hyperinsulinemic, euglycemic clamp in eight endurance-trained (T) and eight sedentary (S) young men...... [insulin infusion rates: 10,000 (step I), 20,000 (step II), and 150,000 (step III) microU x min(-1) x m(-2)]. Glucose and glycerol concentrations were measured in arterial blood and also by microdialysis in interstitial fluid in periumbilical, subcutaneous adipose tissue and in quadriceps femoris muscle...... (glucose only). Adipose tissue blood flow was measured by (133)Xe washout. In the basal state, adipose tissue blood flow tended to be higher in T compared with S subjects, and in both groups blood flow was constant during the clamp. The change from basal in arterial-interstitial glucose concentration...

  14. A low-fat Diet improves insulin sensitivity in patients with type 1 diabetes

    DEFF Research Database (Denmark)

    Rosenfalck, AM; Almdal, Thomas Peter; Viggers, Lone;

    2006-01-01

    diet (P = 0.039). The daily protein and carbohydrate intake increased (+4.4% of total energy intake, P = 0.0049 and +2.5%, P = 0.34, respectively), while alcohol intake decreased (-3.2% of total energy intake, P = 0.02). There was a significant improvement in insulin sensitivity on the isocaloric, low......AIMS: To compare the effects on insulin sensitivity, body composition and glycaemic control of the recommended standard weight-maintaining diabetes diet and an isocaloric low-fat diabetes diet during two, 3-month periods in patients with Type 1 diabetes. METHODS: Thirteen Type 1 patients were...... by the insulin clamp technique at baseline and after each of the diet intervention periods. RESULTS: On an isocaloric low-fat diet, Type 1 diabetic patients significantly reduced the proportion of fat in the total daily energy intake by 12.1% (or -3.6% of total energy) as compared with a conventional diabetes...

  15. Genetic Variants Associated With Glycine Metabolism and Their Role in Insulin Sensitivity and Type 2 Diabetes

    DEFF Research Database (Denmark)

    Xie, W. J.; Wood, A. R.; Lyssenko, V.;

    2013-01-01

    . The top-ranking metabolites were in the glutathione and glycine biosynthesis pathways. We aimed to identify common genetic variants associated with metabolites in these pathways and test their role in insulin sensitivity and type 2 diabetes. With 1,004 nondiabetic individuals from the RISC study, we...... performed a genome-wide association study (GWAS) of 14 insulin sensitivity-related metabolites and one metabolite ratio. We replicated our results in the Botnia study (n = 342). We assessed the association of these variants with diabetes-related traits in GWAS meta-analyses (GENESIS [including RISC, EUGENE2...... for association between these variants and insulin resistance or diabetes. Genetic variants associated with genes in the glycine biosynthesis pathways do not provide consistent evidence for a role of glycine in diabetes-related traits....

  16. Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity

    DEFF Research Database (Denmark)

    Søgaard, Ditte; Østergård, Torben; Blachnio-Zabielska, Agnieszka U;

    2016-01-01

    Ceramide and diacylglycerol (DAG) may be involved in the early phase of insulin resistance but data are inconsistent in man. We evaluated if an increase in insulin sensitivity after endurance training was accompanied by changes in these lipids in skeletal muscle. Nineteen first-degree type 2...... a hyperinsulinemic-euglycemic clamp and VO2max test were performed and muscle biopsies obtained. Insulin sensitivity was significantly lower in Offsprings compared to control subjects (p

  17. Liver-specific deletion of Ppp2cα enhances glucose metabolism and insulin sensitivity.

    Science.gov (United States)

    Xian, Li; Hou, Siyuan; Huang, Zan; Tang, An; Shi, Peiliang; Wang, Qinghua; Song, Anying; Jiang, Shujun; Lin, Zhaoyu; Guo, Shiying; Gao, Xiang

    2015-04-01

    Protein phosphatase 2A (PP2A) is a key negative regulator of phosphatidylinositol 3-kinase/Akt pathway. Previous study showed that, in the liver, the catalytic subunit of PP2A (PP2Ac) is closely associated with insulin resistance syndrome, which is characterized by glucose intolerance and dyslipidemia. Here we studied the role of liver PP2Ac in glucose metabolism and evaluated whether PP2Ac is a suitable therapeutic target for treating insulin resistance syndrome. Liver-specific Ppp2cα knockout mice (Ppp2cα(loxp/loxp): Alb) exhibited improved glucose homeostasis compared with littermate controls in both normal and high-fat diet conditions, despite no significant changes in body weight and liver weight under chow diet. Ppp2cα(loxp/loxp): Alb mice showed enhanced glycogen deposition, serum triglyceride, cholesterol, low density lipoprotein and high density lipoprotein, activated insulin signaling, decreased expressions of gluconeogenic genes G6P and PEPCK, and lower liver triglyceride. Liver-specific Ppp2cα knockout mice showed enhanced glucose homeostasis and increased insulin sensitivity by activation of insulin signaling through Akt. These findings suggest that inhibition of hepatic Ppp2cα may be a useful strategy for the treatment of insulin resistance syndrome.

  18. Modulation of age-related insulin sensitivity by VEGF-dependent vascular plasticity in adipose tissues.

    Science.gov (United States)

    Honek, Jennifer; Seki, Takahiro; Iwamoto, Hideki; Fischer, Carina; Li, Jingrong; Lim, Sharon; Samani, Nilesh J; Zang, Jingwu; Cao, Yihai

    2014-10-14

    Mechanisms underlying age-related obesity and insulin resistance are generally unknown. Here, we report age-related adipose vascular changes markedly modulated fat mass, adipocyte functions, blood lipid composition, and insulin sensitivity. Notably, VEGF expression levels in various white adipose tissues (WATs) underwent changes uninterruptedly in different age populations. Anti-VEGF and anti- VEGF receptor 2 treatment in different age populations showed marked variations of vascular regression, with midaged mice exhibiting modest sensitivity. Interestingly, anti-VEGF treatment produced opposing effects on WAT adipocyte sizes in different age populations and affected vascular density and adipocyte sizes in brown adipose tissue. Consistent with changes of vasculatures and adipocyte sizes, anti-VEGF treatment increased insulin sensitivity in young and old mice but had no effects in the midaged group. Surprisingly, anti-VEGF treatment significantly improved insulin sensitivity in midaged obese mice fed a high-fat diet. Our findings demonstrate that adipose vasculatures show differential responses to anti-VEGF treatment in various age populations and have therapeutic implications for treatment of obesity and diabetes with anti-VEGF-based antiangiogenic drugs.

  19. Aerobic exercise increases peripheral and hepatic insulin sensitivity in sedentary adolescents

    Science.gov (United States)

    The increasing prevalence of obesity and its consequences is a serious public health concern. The present study was undertaken to determine whether a controlled aerobic exercise program (without weight loss) improves insulin sensitivity and glucose metabolism in sedentary adolescents. Twenty nine p...

  20. Infection with Soil-Transmitted Helminths Is Associated with Increased Insulin Sensitivity

    NARCIS (Netherlands)

    Wiria, A.E.; Hamid, F.; Wammes, L.J.; Prasetyani, M.A.; Dekkers, O.M.; May, L.; Kaisar, M.M.; Verweij, J.J.; Guigas, B.; Partono, F.; Sartono, E.; Supali, T.; Yazdanbakhsh, M.; Smit, J.W.A.

    2015-01-01

    OBJECTIVE: Given that helminth infections have been shown to improve insulin sensitivity in animal studies, which may be explained by beneficial effects on energy balance or by a shift in the immune system to an anti-inflammatory profile, we investigated whether soil-transmitted helminth (STH)-infec

  1. Moderate alcohol consumption increases insulin sensitivity and ADIPOQ expression in postmenopausal women: A randomised, crossover trial

    NARCIS (Netherlands)

    Joosten, M.M.; Beulens, J.W.J.; Kersten, S.; Hendriks, H.F.J.

    2008-01-01

    Aims/hypothesis: To determine whether 6 weeks of daily, moderate alcohol consumption increases expression of the gene encoding adiponectin (ADIPOQ) and plasma levels of the protein, and improves insulin sensitivity in postmenopausal women. Methods: In a randomised, open-label, crossover trial conduc

  2. Aerobic Exercise Increases Peripheral and Hepatic Insulin Sensitivity in Sedentary Adolescents

    NARCIS (Netherlands)

    van der Heijden, Gert-Jan; Toffolo, Gianna; Manesso, Erica; Sauer, Pieter J. J.; Sunehag, Agneta L.

    2009-01-01

    Context: Data are limited on the effects of controlled aerobic exercise programs (without weight loss) on insulin sensitivity and glucose metabolism in children and adolescents. Objective: To determine whether a controlled aerobic exercise program (without weight loss) improves peripheral and hepati

  3. Strength Exercise Improves Muscle Mass and Hepatic Insulin Sensitivity in Obese Youth

    NARCIS (Netherlands)

    Van Der Heijden, Gert-Jan; Wang, Zhiyue J.; Chu, Zili; Toffolo, Gianna; Manesso, Erica; Sauer, Pieter J. J.; Sunehag, Agneta L.

    2010-01-01

    VAN DER HEIJDEN, G.-J., Z. J. WANG, Z. CHU, G. TOFFOLO, E. MANESSO, P. J. J. SAUER, and A. L. SUNEHAG. Strength Exercise Improves Muscle Mass and Hepatic Insulin Sensitivity in Obese Youth. Med. Sci. Sports Exerc., Vol. 42, No. 11, pp. 1973-1980, 2010. Introduction: Data on the metabolic effects of

  4. Short-term cold acclimation improves insulin sensitivity in patients with type 2 diabetes mellitus

    NARCIS (Netherlands)

    Hanssen, M.J.W.; Hoeks, J.; Brans, B.; Boekschoten, M.V.; Kersten, A.H.

    2015-01-01

    Cold exposure may be a potential therapy for diabetes by increasing brown adipose tissue (BAT) mass and activity. Here we report that 10 d of cold acclimation (14–15 °C) increased peripheral insulin sensitivity by ~43% in eight type 2 diabetes subjects. Basal skeletal muscle GLUT4 translocation mark

  5. Cellular automaton-based position sensitive detector equalization

    Energy Technology Data Exchange (ETDEWEB)

    Ferrando, Nestor [Grupo de Diseno de Sistemas Digitales, Instituto de Aplicaciones de las Tecnologias de la Informacion y de las Comunicaciones Avanzadas, Universidad Politecnica de Valencia, Camino de Vera s/n, 46022 Valencia (Spain)], E-mail: nesferjo@upvnet.upv.es; Herrero, V.; Cerda, J.; Lerche, C.W.; Colom, R.J.; Gadea, R.; Martinez, J.D.; Monzo, J.M.; Mateo, F.; Sebastia, A.; Benlloch, J.M. [Grupo de Diseno de Sistemas Digitales, Instituto de Aplicaciones de las Tecnologias de la Informacion y de las Comunicaciones Avanzadas, Universidad Politecnica de Valencia, Camino de Vera s/n, 46022 Valencia (Spain)

    2009-06-01

    Indirect position detectors based on scintillator crystals lack of spacial uniformity in their response. This happens due to crystal inhomogeneities and gain differences among the photomultiplier anodes. In order to solve this, PESIC, an integrated front-end for multianode photomultiplier based nuclear imaging devices was created. One of its main features is the digitally programmable gain adjustment for every photomultiplier output. On another front, cellular automata have been proved to be a useful method for dynamic system modeling. In this paper, a cellular automaton which emulates the behavior of the scintillator crystal, the photomultiplier and the front-end is introduced. Thanks to this model, an automatic energy-based calibration of the detector can be done by configuring the cellular automaton with experimental data and making it evolve up to an stable state. This can be useful as a precalibration method of the detector.

  6. Insulin-Sensitizing Effects of Omega-3 Fatty Acids: Lost in Translation?

    Directory of Open Access Journals (Sweden)

    Antigoni Z. Lalia

    2016-06-01

    Full Text Available Omega-3 polyunsaturated fatty acids (n-3 PUFA of marine origin, eicosapentaenoic acid (EPA, and docosahexaenoic acid (DHA, have been long studied for their therapeutic potential in the context of type 2 diabetes, insulin resistance, and glucose homeostasis. Glaring discordance between observations in animal and human studies precludes, to date, any practical application of n-3 PUFA as nutritional therapeutics against insulin resistance in humans. Our objective in this review is to summarize current knowledge and provide an up-to-date commentary on the therapeutic value of EPA and DHA supplementation for improving insulin sensitivity in humans. We also sought to discuss potential mechanisms of n-3 PUFA action in target tissues, in specific skeletal muscle, based on our recent work, as well as in liver and adipose tissue. We conducted a literature search to include all preclinical and clinical studies performed within the last two years and to comment on representative studies published earlier. Recent studies support a growing consensus that there are beneficial effects of n-3 PUFA on insulin sensitivity in rodents. Observational studies in humans are encouraging, however, the vast majority of human intervention studies fail to demonstrate the benefit of n-3 PUFA in type 2 diabetes or insulin-resistant non-diabetic people. Nevertheless, there are still several unanswered questions regarding the potential impact of n-3 PUFA on metabolic function in humans.

  7. Adiponectin Decreases Plasma Glucose and Improves Insulin Sensitivity in Diabetic Swine

    Institute of Scientific and Technical Information of China (English)

    Xiaobo HU; Meihua SHE; Hongjie HOU; Qinkai LI; Qingyun SHEN; Yi LUO; Weidong YIN

    2007-01-01

    To investigate the effects of recombinant human adiponectin on the metabolism of diabetic swine induced by feeding a high-fat/high-sucrose diet (HFSD), diabetic animal models were constructed by feeding swine with HFSD for 6 months. The effects of recombinant adiponectin were assessed by detecting the change of plasma glucose levels by commercially available enzymatic method test kits and evaluating the insulin sensitivity by oral glucose tolerance test (OGTT). About 1.5 g purified recombinant adiponectin was produced using a 15-liter fermenter. A single injection of purified recombinant human adiponectin to diabetic swine led to a 2- to 3-fold elevation in circulating adiponectin, which triggered a transient decrease in basal glucose level (P<0.05). This effect on glucose was not associated with an increase in insulin level. Moreover, after adiponectin injection, swine also showed improved insulin sensitivity compared with the control (P<0.05). Adiponectin might have the potential to be a glucose-lowering agent for metabolic disease. Adiponectin as a potent insulin enhancer linking adipose tissue and glucose metabolism could be useful to treat insulin resistance.

  8. Saffron (Crocus sativus L.) increases glucose uptake and insulin sensitivity in muscle cells via multipathway mechanisms.

    Science.gov (United States)

    Kang, Changkeun; Lee, Hyunkyoung; Jung, Eun-Sun; Seyedian, Ramin; Jo, MiNa; Kim, Jehein; Kim, Jong-Shu; Kim, Euikyung

    2012-12-15

    Saffron (Crocus sativus Linn.) has been an important subject of research in the past two decades because of its various biological properties, including anti-cancer, anti-inflammatory, and anti-atherosclerotic activities. On the other hand, the molecular bases of its actions have been scarcely understood. Here, we elucidated the mechanism of the hypoglycemic actions of saffron through investigating its signaling pathways associated with glucose metabolism in C(2)C(12) skeletal muscle cells. Saffron strongly enhanced glucose uptake and the phosphorylation of AMPK (AMP-activated protein kinase)/ACC (acetyl-CoA carboxylase) and MAPKs (mitogen-activated protein kinases), but not PI 3-kinase (Phosphatidylinositol 3-kinase)/Akt. Interestingly, the co-treatment of saffron and insulin further improved the insulin sensitivity via both insulin-independent (AMPK/ACC and MAPKs) and insulin-dependent (PI 3-kinase/Akt and mTOR) pathways. It also suggested that there is a crosstalk between the two signaling pathways of glucose metabolism in skeletal muscle cells. These results could be confirmed from the findings of GLUT4 translocation. Taken together, AMPK plays a major role in the effects of saffron on glucose uptake and insulin sensitivity in skeletal muscle cells. Our study provides important insights for the possible mechanism of action of saffron and its potential as a therapeutic agent in diabetic patients.

  9. Robert Feulgen Prize Lecture 1993. The journey of the insulin receptor into the cell: from cellular biology to pathophysiology.

    Science.gov (United States)

    Carpentier, J L

    1993-09-01

    The data that we have reviewed indicate that insulin binds to a specific cell-surface receptor. The complex then becomes involved in a series of steps which lead the insulin-receptor complex to be internalized and rapidly delivered to endosomes. From this sorting station, the hormone is targeted to lysosomes to be degraded while the receptor is recycled back to the cell surface. This sequence of events presents two degrees of ligand specificity: (a) The first step is ligand-dependent and requires insulin-induced receptor phosphorylation of specific tyrosine residues. It consists in the surface redistribution of the receptor from microvilli where it preferentially localizes in its unoccupied form. (b) The second step is more general and consists in the association with clathrin-coated pits which represents the internalization gate common to many receptors. This sequence of events participates in the regulation of the biological action of the hormone and can thus be implicated in the pathophysiology of diabetes mellitus and various extreme insulin resistance syndromes, including type A extreme insulin resistance, leprechaunism, and Rabson-Mendehall syndrome. Alterations of the internalization process can result either from intrinsic abnormalities of the receptor or from more general alteration of the plasma membrane or of the cell metabolism. Type I diabetes is an example of the latter possibility, since general impairment of endocytosis could contribute to extracellular matrix accumulation and to an increase in blood cholesterol. Thus, better characterization of the molecular and cellular biology of the insulin receptor and of its journey inside the cell definitely leads to better understanding of disease states, including diabetes.

  10. Chronic estradiol and progesterone treatment in conscious dogs: effects on insulin sensitivity and response to hypoglycemia

    OpenAIRE

    Batista, Marcia R.; Smith, Marta S.; Snead, Wanda L.; Connolly, Cynthia C.; Lacy, D. Brooks; Moore, Mary Courtney

    2005-01-01

    We evaluated the effect of chronic (3 wk) subcutaneous treatment with progesterone and estradiol (PE; producing serum levels observed in the 3rd trimester of pregnancy) or placebo (C) on hepatic and whole body insulin sensitivity and response to hypoglycemia in conscious, overnight-fasted nonpregnant female dogs, using tracer and arteriovenous difference techniques. Insulin was infused peripherally for 3 h at 1.8 mU·kg−1·min−1. Glucose was allowed to fall to 3 mM (Hypo) or maintained at 6 mM ...

  11. The effect of 30 months of low-dose replacement therapy with recombinant human growth hormone (rhGH) on insulin and C-peptide kinetics, insulin secretion, insulin sensitivity, glucose effectiveness, and body composition in GH-deficient adults

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Maghsoudi, S; Fisker, S

    2000-01-01

    the insulin sensitivity index, calculated from the frequently sampled iv glucose tolerance test, only decreased slightly. The clearance of C-peptide and insulin increased 100% and 60%, respectively, and the prehepatic insulin secretion was tripled during rhGH treatment; but related to the impairment...... an increase in lean body mass and a reduction of fat mass. Therefore, rhGH treatment may precipitate diabetes in some patients already susceptible to the disorder....

  12. Glucose metabolism, insulin sensitivity and β-cell function in type A insulin resistance syndrome around puberty: a 9-year follow-up.

    Science.gov (United States)

    Huang, Z; Liu, J; Ma, L; Wan, X; He, X; Fang, D; Liao, Z; Li, Y

    2014-01-01

    Diabetes mellitus is thought to be progressive. Insufficient insulin secretion in compensation for insulin resistance leads to glucose intolerance. A previously reported proband with type A insulin resistance syndrome and her younger twin brothers with and without the R1174W missense mutation in the insulin receptor gene were followed for 9 years to study the progression of glucose metabolism, insulin sensitivity, and β-cell function around puberty. Five-hour OGTT was performed in them at each visit. Areas under the curves of glucose, insulin and C-peptides, insulinogenic index, AIR, and Homa indices were assessed. Intramyocellular lipids (IMCLs) were quantified in the proband and compared to those of 12 nondiabetic subjects, 118 newly diagnosed type 2 diabetic patients. The proband maintained normal HbA1c (27-37 mmol/mol) and fasting plasma glucose (3.7-4.5 mmol/l), and her glucose tolerance ameliorated over years. The proband's Homa-IR decreased into adulthood, while her Homa-B, insulinogenic index, AIR, AUCs of insulin, and C-peptide decreased accordingly. Homa-B to Homa-IR ratios stayed significantly higher than normal. Homa-B, AUCs of insulin, and C-peptide of the twin brothers increased in response to the increment of Homa-IR as they entered middle and late puberty. The changes were more dramatic in the twin brothers carrying the mutation. IMCLs of the proband were lower than those of the nondiabetic counterparts and were disproportional for the degree of insulin resistance. Our longitudinal data of type A insulin resistance syndrome around puberty provide significant information for the study of insulin secretion in compensation for insulin resistance.

  13. Ectopic Fat Deposition on Insulin Sensitivity: Correlation of Hepatocellular Lipid Content and M Value

    Directory of Open Access Journals (Sweden)

    Beverly S. Hong

    2016-01-01

    Full Text Available Purpose. This study aimed to explore the relationship among insulin sensitivity and ectopic fat depots in participants with different glucose status. Methods. Fifty-nine men and women were enrolled in this study: 29 with normal glucose tolerance (NGT, 17 with impaired glucose tolerance (IGT, and 13 with type 2 diabetes mellitus (T2DM. All participants underwent a hyperinsulinemic-euglycemic clamp to assess the insulin sensitivity index (M value and magnetic resonance imaging to measure the hepatocellular lipid content (HCL, skeletal muscle fat content including intramyocellular lipid (IMCL and extramyocellular lipid (EMCL of tibialis anterior (ta, and soleus muscle (sol. Results. The M value of NGT group was higher than those of IGT and T2DM groups (P=0.001. Participants with T2DM had the highest HCL and IMCL (ta compared with those in NGT and IGT groups (P=0.001. The M value had an inverse relationship with HCL (r=-0.789, P=0.001, IMCL (sol (r=-0.427, P=0.002, and IMCL (ta (r=-0.419, P=0.002. Stepwise linear regression analysis showed that HCL (standardized β=-0.416; P=0.001 had an independent relationship with M value. Conclusions. Hepatocellular lipid content deposition happens earlier than skeletal muscle fat deposition. HCL is an independent risk factor for insulin resistance and may be used to evaluate the risk of developing T2DM as a noninvasive marker of insulin sensitivity index.

  14. An acute bout of endurance exercise but not sprint interval exercise enhances insulin sensitivity.

    Science.gov (United States)

    Brestoff, Jonathan R; Clippinger, Benjamin; Spinella, Thomas; von Duvillard, Serge P; Nindl, Bradley C; Nindl, Bradley; Arciero, Paul J

    2009-02-01

    An acute bout of endurance exercise (EE) enhances insulin sensitivity, but the effects of sprint interval exercise (SIE) have not yet been described. We sought to compare insulin sensitivity at baseline and after an acute bout of EE and SIE in healthy men (n = 8) and women (n = 5) (age, 20.7 +/- 0.3 years; peak oxygen consumption (VO2 peak), 42.6 +/- 1.7 mL.kg(-1).min(-1); men vs. women, p > 0.05). Pearson's correlation coefficients between ISI-COMP and ISI-HOMA for each condition were highly correlated (p < 0.01), and followed similar patterns of response. ISI-COMP(EE) was 71.4% higher than ISI-COMP(B) (8.4 +/- 1.4 vs. 4.9 +/- 1.0; p < 0.01) and 40.0% higher than ISI-COMPSIE (8.4 +/- 1.4 vs. 6.0 +/- 1.5; p < 0.05), but there was no difference between ISI-COMP(B) and ISI-COMP(SIE) (p = 0.182). VO(2 peak) was highly correlated with both ISI-COMP and ISI-HOMA during baseline and SIE test conditions (p < 0.02). These findings demonstrate that an acute bout of EE, but not SIE, increases insulin sensitivity relative to a no-exercise control condition in healthy males and females. While these findings underscore the use of regular EE as an effective intervention strategy against insulin resistance, additional research examining repeated sessions of SIE on insulin sensitivity is warranted.

  15. Alcohol acutely increases vascular reactivity together with insulin sensitivity in type 2 diabetic men.

    Science.gov (United States)

    Schaller, G; Kretschmer, S; Gouya, G; Haider, D G; Mittermayer, F; Riedl, M; Wagner, O; Pacini, G; Wolzt, M; Ludvik, B

    2010-01-01

    Moderate alcohol consumption is associated with increased insulin sensitivity and reduced cardiovascular risk. We hypothesized that this relates to a direct effect of alcohol and therefore investigated whether acute alcohol intake altered insulin sensitivity or endothelial function in patients with type 2 diabetes. In an open-label two period design, the effect of a single oral dose of 40 g of alcohol (168 ml 40% vodka) on an insulin-modified frequently sampled intravenous glucose tolerance test (FSIGT) and on endothelium-dependent (flow mediated, FMD) or endothelium-independent (glyceroltrinitrate (GTN)-induced) vasodilation of the brachial artery measured by ultrasound was studied. Experiments were carried out in twelve male patients with type 2 diabetes mellitus (64+/-6 years, body mass index 28.4+/-5.7 kg/m (2)). Baseline insulin sensitivity index (S (I)) was 1.10+/-0.34 min (-1).microU (-1).ml, baseline FMD was +4.1+/-3.0%, and GTN-induced vasodilation +7.4+/-2.3% from resting brachial artery diameter. Acute alcohol intake increased alcohol plasma levels to 0.33+/-0.04 per thousand, S (I) to 1.86+/-0.45 min (-1).microU (-1).ml (p<0.05), and FMD to +8.2+/-2.8% (p<0.05), while GTN-induced dilation remained unchanged. No relationship was detectable between the observed changes. We conclude that alcohol intake acutely increases endothelium-dependent brachial artery vasodilation in patients with type 2 diabetes together with insulin sensitivity. This acute effect might explain some beneficial effects of low alcohol consumption in epidemiological observations.

  16. Increase of insulin sensitivity in diabetic rats received Die-Huang-Wan, a herbal mixture used in Chinese traditional medicine

    Institute of Scientific and Technical Information of China (English)

    WU Yang-Chang; HSU Jen-Hao; LIU I-Min; LIOU Shorong-Shii; SU Hui-Chen; CHENG Juei-Tang

    2002-01-01

    AIM: Effects on insulin sensitivity of Die-Huang-Wan, the herbal mixture widely used to treat diabetic disorder in Chinese traditional medicine, were investigated in vivo. METHODS: The obese Zucker rats were employed as insulin-resistant animal model. Also, insulin-resistance was induced by the repeated intraperitoneal injections of long-acting human insulin at 0.5 U/kg three times daily into adult male Wistar rats. Insulin resistance was identified using the loss of tolbutamide (10 mg/kg) or electroacupuncture (EA)-induced plasma glucose lowering action. The plasma glucose concentration was examined by glucose oxidase assay. RESULTS: The plasma glucose-lowering action induced by tolbutamide was significantly enhanced in obese Zucker rats receiving the repeated administration of Die-Huang-Wan at dosage of 26 mg/kg for 3 d. Furthermore, administration of Die-Huang-Wan delayed the formation of insulin resistance in rats that were induced by the daily repeated injection of human long-acting insulin at 0.5 U/kg three times daily and identified by the loss of tolbutamide- or EA-induced hypoglycemia. In streptozotocininduced diabetic rats, oral administration of metformin at 320 mg/kg once daily made an increase of the response to exogenous short-acting human insulin 15 d later. This is consistent with the view that metformin can increase insulin sensitivity. Similar treatment with Die-Huang-Wan at an effective dose (26.0 mg/kg) also increased the plasma glucose lowering action of exogenous insulin at 10 d later. The effect of Die-Huang-Wan on insulin sensitivity seems to produce more rapidly than that of metformin. CONCLUSION: The present study found that oral administration of Die-Huang-Wan increased insulin sensitivity and delayed the development of insulin resistance in rats.

  17. Race Differences in the Effect of Oxidative Stress on Insulin Sensitivity

    Science.gov (United States)

    Fisher, Gordon; Alvarez, Jessica A.; Ellis, Amy C.; Granger, Wesley M.; Ovalle, Fernando; Man, Chiara Dalla; Cobelli, Claudio; Gower, Barbara A.

    2013-01-01

    In vitro and animal model studies have indicated that oxidative stress from exposure to excess glucose and fatty acids impairs insulin signaling. However, few clinical studies have examined the association between oxidative stress and insulin action, particularly in non-diabetic individuals. The objective of this study was to examine the association between insulin sensitivity and protein carbonyls, a systemic marker of oxidative stress, in healthy individuals, and to determine if the magnitude of the relationship differed in African Americans (AA), who are at elevated risk for type 2 diabetes, relative to European Americans (EA). Subjects were 53 normal-glucose-tolerant women (25 AA, mean BMI 28.4 ± 6.2, range BMI???; mean age 33.1 ± 13.5, range age????; 28 EA mean BMI 26.2 ± 5.9, range BMI???; mean age 31.6 ± 12.4, range age??? ) . Insulin sensitivity was determined using an intravenous glucose tolerance test incorporating [6,6-2H2]-glucose, and a two-compartment mathematical model. Multiple linear regression results indicated that insulin sensitivity was independently positively associated with protein carbonyls in AA (r = 0.33, P<0.05) but not EA (r = ??P=0.945), after adjusting for %body fat. In contrast, %body fat was significantly positively associated with insulin sensitivity in EA (r = 0.29, P<0.05) but not AA (r = ??P=0.196). Protein carbonyls were associated with free fatty acids (FFA) in AA (r = 0.58, P<0.01) but not EA (r = −0.11, P=0.59). When subjects were divided based on median levels of fasting glucose and FFA, those with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations (P<0.05). These results suggest that oxidative stress independently contributes to insulin sensitivity among AA women. Further, this association in AA may be mediated by circulating FFA and/or glucose. PMID:22173574

  18. 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

    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...

  19. Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training

    DEFF Research Database (Denmark)

    Yfanti, Christina; Nielsen, Anders R; Åkerström, Thorbjörn

    2011-01-01

    While production of reactive oxygen and nitrogen species (RONS) is associated with some of the beneficial adaptations to regular physical exercise, it is not established whether RONS play a role in the improved insulin-stimulated glucose uptake in skeletal muscle obtained by endurance training....... To assess the effect of antioxidant supplementation during endurance training on insulin-stimulated glucose uptake, twenty-one young healthy (age 29±1 y; BMI 25±3 Kg m(-2)) men were randomly assigned into either an antioxidant (AO; 500 mg vitamin C and 400 IU vitamin E (a-tocopherol) daily) or a placebo (PL...... results indicate that administration of antioxidants during strenuous endurance training has no effect on the training-induced increase in insulin sensitivity, in healthy individuals....

  20. Melatonin improves insulin sensitivity independently of weight loss in old obese rats.

    Science.gov (United States)

    Zanuto, Ricardo; Siqueira-Filho, Mário A; Caperuto, Luciana C; Bacurau, Reury F P; Hirata, Emiko; Peliciari-Garcia, Rodrigo A; do Amaral, Fernanda Gaspar; Marçal, Anderson C; Ribeiro, Luciene M; Camporez, João P G; Carpinelli, Angelo Rafael; Bordin, Silvana; Cipolla-Neto, José; Carvalho, Carla R O

    2013-09-01

    In aged rats, insulin signaling pathway (ISP) is impaired in tissues that play a pivotal role in glucose homeostasis, such as liver, skeletal muscle, and adipose tissue. Moreover, the aging process is also associated with obesity and reduction in melatonin synthesis from the pineal gland and other organs. The aim of the present work was to evaluate, in male old obese Wistar rats, the effect of melatonin supplementation in the ISP, analyzing the total protein amount and the phosphorylated status (immunoprecipitation and immunoblotting) of the insulin cascade components in the rat hypothalamus, liver, skeletal muscle, and periepididymal adipose tissue. Melatonin was administered in the drinking water for 8- and 12 wk during the night period. Food and water intake and fasting blood glucose remained unchanged. The insulin sensitivity presented a 2.1-fold increase both after 8- and 12 wk of melatonin supplementation. Animals supplemented with melatonin for 12 wk also presented a reduction in body mass. The acute insulin-induced phosphorylation of the analyzed ISP proteins increased 1.3- and 2.3-fold after 8- and 12 wk of melatonin supplementation. The total protein content of the insulin receptor (IR) and the IR substrates (IRS-1, 2) remained unchanged in all investigated tissues, except for the 2-fold increase in the total amount of IRS-1 in the periepididymal adipose tissue. Therefore, the known age-related melatonin synthesis reduction may also be involved in the development of insulin resistance and the adequate supplementation could be an important alternative for the prevention of insulin signaling impairment in aged organisms.

  1. Insulin sensitivity is normalized in the third generation (F3 offspring of developmentally programmed insulin resistant (F2 rats fed an energy-restricted diet

    Directory of Open Access Journals (Sweden)

    Martin John F

    2008-10-01

    Full Text Available Abstract Background/Aims The offspring and grandoffspring of female rats fed low protein diets during pregnancy and lactation, but fed nutritionally adequate diets thereafter, have been shown to exhibit altered insulin sensitivity in adulthood. The current study investigates the insulin sensitivity of the offspring and grandoffspring of female rats fed low protein diets during pregnancy, and then maintained on energy-restricted diets post weaning over three generations. Methods Female Sprague Dawley rats (F0 were mated with control males and protein malnourished during pregnancy/lactation. F1 offspring were then weaned to adequate but energy-restricted diets into adulthood. F1 dams were fed energy-restricted diets throughout pregnancy/lactation. F2 offspring were also fed energy-restricted diets post weaning. F2 pregnant dams were maintained as described above. Their F3 offspring were split into two groups; one was maintained on the energy-restricted diet, the other was maintained on an adequate diet consumed ad libitum post weaning. Results F2 animals fed energy-restricted diets were insulin resistant (p ad libitum postweaning diets (p Conclusion Maternal energy-restriction did not consistently program reduced insulin sensitivity in offspring over three consecutive generations. The reasons for this remain unclear. It is possible that the intergenerational transmission of developmentally programmed insulin resistance is determined in part by the relative insulin sensitivity of the mother during pregnancy/lactation.

  2. Fabrication of Glucose-Sensitive Layer-by-Layer Films for Potential Controlled Insulin Release Applications

    Directory of Open Access Journals (Sweden)

    Talusan Timothy Jemuel E.

    2015-01-01

    Full Text Available Self-regulated drug delivery systems (DDS are potential alternative to the conventional method of introducing insulin to the body due to their controlled drug release mechanism. In this study, Layer-by-Layer technique was utlized to manufacture drug loaded, pH responsive thin films. Insulin was alternated with pH-sensitive, [2-(dimethyl amino ethyl aminoacrylate] (PDMAEMA and topped of with polymer/glucose oxidase (GOD layers. Similarly, films using a different polymer, namely Poly(Acrylic Acid (PAA were also fabricated. Exposure of the films to glucose solutions resulted to the production of gluconic acid causing a polymer conformation change due to protonation, thus releasing the embedded insulin. The insulin release was monitored by subjecting the dipping glucose solutions to Bradford Assay. Films exhibited a reversal in drug release profile in the presence of glucose as compared to without glucose. PAA films were also found out to release more insulin compared to that of the PDMAEMA films.The difference in the profile of the two films were due to different polymer-GOD interactions, since both films exhibited almost identical profiles when embedded with Poly(sodium 4-styrenesulfonate (PSS instead of GOD.

  3. Bezafibrate Improves Insulin Sensitivity and Metabolic Flexibility in STZ-Induced Diabetic Mice.

    Science.gov (United States)

    Franko, Andras; Huypens, Peter; Neschen, Susanne; Irmler, Martin; Rozman, Jan; Rathkolb, Birgit; Neff, Frauke; Prehn, Cornelia; Dubois, Guillaume; Baumann, Martina; Massinger, Rebecca; Gradinger, Daniel; Przemeck, Gerhard K H; Repp, Birgit; Aichler, Michaela; Feuchtinger, Annette; Schommers, Philipp; Stöhr, Oliver; Sanchez-Lasheras, Carmen; Adamski, Jerzy; Peter, Andreas; Prokisch, Holger; Beckers, Johannes; Walch, Axel K; Fuchs, Helmut; Wolf, Eckhard; Schubert, Markus; Wiesner, Rudolf J; Hrabě de Angelis, Martin

    2016-09-01

    Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), has been generally used to treat hyperlipidemia for decades. Clinical trials with type 2 diabetes patients indicated that BEZ also has beneficial effects on glucose metabolism, although the underlying mechanisms of these effects remain elusive. Even less is known about a potential role for BEZ in treating type 1 diabetes. Here we show that BEZ markedly improves hyperglycemia and glucose and insulin tolerance in mice with streptozotocin (STZ)-induced diabetes, an insulin-deficient mouse model of type 1 diabetes. BEZ treatment of STZ mice significantly suppressed the hepatic expression of genes that are annotated in inflammatory processes, whereas the expression of PPAR and insulin target gene transcripts was increased. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Finally, we show that the number of pancreatic islets and the area of insulin-positive cells tended to be higher in BEZ-treated mice. Our data suggest that BEZ may improve impaired glucose metabolism by augmenting hepatic mitochondrial performance, suppressing hepatic inflammatory pathways, and improving insulin sensitivity and metabolic flexibility. Thus, BEZ treatment might also be useful for patients with impaired glucose tolerance or diabetes.

  4. Hypothalamic neurogenesis is not required for the improved insulin sensitivity following exercise training.

    Science.gov (United States)

    Borg, Melissa L; Lemus, Moyra; Reichenbach, Alex; Selathurai, Ahrathy; Oldfield, Brian J; Andrews, Zane B; Watt, Matthew J

    2014-11-01

    Neurons within the hypothalamic arcuate nucleus (ARC) are important regulators of energy balance. Recent studies suggest that neurogenesis in the ARC is an important regulator of body mass in response to pharmacological stressors. Regular exercise training improves insulin action, and is a primary treatment modality for obesity and type 2 diabetes. We examined whether exercise training causes hypothalamic neurogenesis and whether this contributes to exercise-induced improvements in insulin action. Short-term exercise in adult mice induced a proneurogenic transcriptional program involving growth factors, cell proliferation, and neurogenic regulators in the hypothalamus. Daily exercise training for 7 days increased hypothalamic cell proliferation 3.5-fold above that of sedentary mice, and exercise-induced cell proliferation was maintained in diet-induced obese mice. Colocalization studies indicated negligible neurogenesis in the ARC of sedentary or exercise-trained mice. Blocking cell proliferation via administration of the mitotic blocker arabinosylcytosine (AraC) did not affect food intake or body mass in obese mice. While 4 weeks of exercise training improved whole-body insulin sensitivity compared with sedentary mice, insulin action was not affected by AraC administration. These data suggest that regular exercise training induces significant non-neuronal cell proliferation in the hypothalamus of obese mice, but this proliferation is not required for enhanced insulin action.

  5. Myostatin inhibition in muscle, but not adipose tissue, decreases fat mass and improves insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Tingqing Guo

    Full Text Available Myostatin (Mstn is a secreted growth factor expressed in skeletal muscle and adipose tissue that negatively regulates skeletal muscle mass. Mstn(-/- mice have a dramatic increase in muscle mass, reduction in fat mass, and resistance to diet-induced and genetic obesity. To determine how Mstn deletion causes reduced adiposity and resistance to obesity, we analyzed substrate utilization and insulin sensitivity in Mstn(-/- mice fed a standard chow. Despite reduced lipid oxidation in skeletal muscle, Mstn(-/- mice had no change in the rate of whole body lipid oxidation. In contrast, Mstn(-/- mice had increased glucose utilization and insulin sensitivity as measured by indirect calorimetry, glucose and insulin tolerance tests, and hyperinsulinemic-euglycemic clamp. To determine whether these metabolic effects were due primarily to the loss of myostatin signaling in muscle or adipose tissue, we compared two transgenic mouse lines carrying a dominant negative activin IIB receptor expressed specifically in adipocytes or skeletal muscle. We found that inhibition of myostatin signaling in adipose tissue had no effect on body composition, weight gain, or glucose and insulin tolerance in mice fed a standard diet or a high-fat diet. In contrast, inhibition of myostatin signaling in skeletal muscle, like Mstn deletion, resulted in increased lean mass, decreased fat mass, improved glucose metabolism on standard and high-fat diets, and resistance to diet-induced obesity. Our results demonstrate that Mstn(-/- mice have an increase in insulin sensitivity and glucose uptake, and that the reduction in adipose tissue mass in Mstn(-/- mice is an indirect result of metabolic changes in skeletal muscle. These data suggest that increasing muscle mass by administration of myostatin antagonists may be a promising therapeutic target for treating patients with obesity or diabetes.

  6. Effect of Plasma Uric Acid on Antioxidant Capacity, Oxidative Stress, and Insulin Sensitivity in Obese Subjects

    Science.gov (United States)

    Fabbrini, Elisa; Serafini, Mauro; Colic Baric, Irena; Hazen, Stanley L.; Klein, Samuel

    2014-01-01

    Oxidative stress is purported to be involved in the pathogenesis of obesity-associated insulin resistance. We evaluated whether alterations in levels of circulating uric acid (UA), a systemic antioxidant, affects the following: 1) systemic (plasma and saliva) nonenzymatic antioxidant capacity (NEAC); 2) markers of systemic (urinary 8-iso-prostaglandin-F2α) and muscle (carbonylated protein content) oxidative stress; and 3) whole-body insulin sensitivity (percentage increase in glucose uptake during a hyperinsulinemic-euglycemic clamp procedure). Thirty-one obese subjects (BMI 37.1 ± 0.7 kg/m2) with either high serum UA (HUA; 7.1 ± 0.4 mg/dL; n = 15) or normal serum UA (NUA; 4.5 ± 0.2 mg/dL; n = 16) levels were studied; 13 subjects with HUA levels were studied again after reduction of serum UA levels to 0 by infusing a recombinant urate oxidase. HUA subjects had 20–90% greater NEAC, but lower insulin sensitivity (40%) and levels of markers of oxidative stress (30%) than subjects in the NUA group (all P < 0.05). Acute UA reduction caused a 45–95% decrease in NEAC and a 25–40% increase in levels of systemic and muscle markers of oxidative stress (all P < 0.05), but did not affect insulin sensitivity (from 168 ± 25% to 156 ± 17%, P = NS). These results demonstrate that circulating UA is a major antioxidant and might help protect against free-radical oxidative damage. However, oxidative stress is not a major determinant of insulin action in vivo. PMID:24353177

  7. Repetitive hyperbaric oxygen treatment increases insulin sensitivity in diabetes patients with acute intracerebral hemorrhage

    Science.gov (United States)

    Xu, Qian; Wei, Yi-ting; Fan, Shuang-bo; Wang, Liang; Zhou, Xiao-ping

    2017-01-01

    Aim The role of hyperbaric oxygen therapy (HBOT) in the treatment of acute ischemic stroke is controversial. This study aims to investigate whether the peripheral insulin sensitivity of type 2 diabetes patients suffering from intracerebral hemorrhage can be increased after HBOT. Methods Fifty-two type 2 diabetes participants were recruited after being diagnosed with intracerebral hemorrhage in our hospital. Insulin sensitivity was measured by the glucose infusion rate during a hyperinsulinemic euglycemic clamp (80 mU m−2 min−1) at baseline and 10 and 30 days after HBOT sessions. Serum insulin, fasting glucose, and hemoglobin A1C were measured in fasting serum at baseline and after HBOT sessions. In addition, early (∼10 days after onset) and late (1 month after onset) outcomes (National Institutes of Health Stroke Scale, NIHSS scores) and efficacy (changes of NIHSS scores) of HBOT were evaluated. Results In response to HBOT, the glucose infusion rate was increased by 37.8%±5.76% at 1 month after onset compared with baseline. Reduced serum insulin, fasting glucose, and hemoglobin A1C were observed after HBOT. Both early and late outcomes of the HBOT group were improved compared with baseline (P<0.001). In the control group, there was significant difference only in the late outcome (P<0.05). In the assessment of efficacy, there were statistically significant differences between the groups when comparing changes in NIHSS scores at 10 days and 1 month after onset (P<0.05). Conclusion Peripheral insulin sensitivity was increased following HBOT in type 2 diabetes patients with intracerebral hemorrhage. The HBOT used in this study may be effective for diabetes patients with acute stroke and is a safe and harmless adjunctive treatment. PMID:28228657

  8. Q192R Paraoxonase (PON)1 Polymorphism, Insulin Sensitivity, and Endothelial Function in Essential Hypertensive Men

    Science.gov (United States)

    Dell’Omo, Giulia; Penno, Giuseppe; Pucci, Laura; Lucchesi, Daniela; Prato, Stefano Del; Pedrinelli, Roberto

    2014-01-01

    AIMS Essential hypertension is characterized by increased reactive oxygen species (ROS) generation harmful for insulin sensitivity and nitric oxide (NO)-mediated vasomotor function, a noxious effect that paraoxonase (PON)1, an antioxidant circulating high-density lipoprotein (HDL)-bound esterase, may counteract. The PON1 gene contains several polymorphisms including a glutamine (Q) to arginine (R) transition at position 192 encoding circulating allozymes with higher antioxidant activity that might influence both parameters. METHODS Q192R was determined by polymerase chain reaction in 72 never-treated, glucose-tolerant, uncomplicated essential hypertensive men. Insulin sensitivity was assessed by homeostasis model assessment (HOMA) and endothelial function by forearm vasodilation (strain-gage venous plethysmography) to intra-arterial acetylcholine (ACH) with sodium nitroprusside (NIP) as a NO-independent control. Additional evaluation variables included 24-hour blood pressure (BP), lipids, BMI, smoking status, and metabolic syndrome (MetS) by Adult Treatment Panel (ATP)-III criteria. R192 was considered as the rare allele, and its associations analyzed by dominant models (Q/Q vs. Q/R + R/R). RESULTS Genotype frequencies were consistent with the Hardy–Weinberg equilibrium. HOMA was lower and insulin resistance (the upper fourth of HOMA values distribution) less prevalent in Q/R + R/R carriers in whom ACH-mediated vasodilatation was greater and endothelial dysfunction (the bottom fourth of ACHAUC values distribution) less frequent than in Q/Q homozygotes. Q192R polymorphism and MetS were unrelated parameters despite their common association with insulin resistance. 24-hour BP, BMI, lipids, and smoking habits were homogeneously distributed across genotypes. CONCLUSIONS Q192R polymorphism associates differentially with insulin sensitivity and endothelial function in essential hypertensive men. PMID:25089090

  9. Stevioside from Stevia rebaudiana Bertoni Increases Insulin Sensitivity in 3T3-L1 Adipocytes

    Directory of Open Access Journals (Sweden)

    Nabilatul Hani Mohd-Radzman

    2013-01-01

    Full Text Available Stevioside from Stevia rebaudiana has been reported to exert antihyperglycemic effects in both rat and human subjects. There have been few studies on these effects in vitro. In this paper, radioactive glucose uptake assay was implemented in order to assess improvements in insulin sensitivity in 3T3-L1 cells by elevation of glucose uptake following treatment with stevioside. Oil Red-O staining and MTT assay were utilized to confirm adipocyte differentiation and cell viability, respectively. Findings from this research showed a significant increase in absorbance values in mature adipocytes following Oil Red-O staining, confirming the differentiation process. Stevioside was noncytotoxic to 3T3-L1 cells as cell viability was reduced by a maximum of 17%, making it impossible to determine its IC50. Stevioside increased glucose uptake activities by 2.1 times (p<0.001 in normal conditions and up to 4.4 times (p<0.001 in insulin-resistant states. At times, this increase was higher than that seen in positive control group treated with rosiglitazone maleate, an antidiabetic agent. Expressions of pY20 and p-IRS1 which were measured via Western blot were improved by stevioside treatment. In conclusion, stevioside has direct effects on 3T3-L1 insulin sensitivity via increase in glucose uptake and enhanced expression of proteins involved in insulin-signalling pathway.

  10. Researching Effective Strategies to Improve Insulin Sensitivity in Children and Teenagers - RESIST. A randomised control trial investigating the effects of two different diets on insulin sensitivity in young people with insulin resistance and/or pre-diabetes.

    Directory of Open Access Journals (Sweden)

    De Sukanya

    2010-09-01

    Full Text Available Abstract Background Concomitant with the rise in childhood obesity there has been a significant increase in the number of adolescents with clinical features of insulin resistance and prediabetes. Clinical insulin resistance and prediabetes are likely to progress to type 2 diabetes and early atherosclerosis if not targeted for early intervention. There are no efficacy trials of lifestyle intervention in this group to inform clinical practice. The primary aim of this randomised control trial (RCT is to determine the efficacy and effectiveness of two different structured lifestyle interventions differing in diet composition on insulin sensitivity, in adolescents with clinical insulin resistance and/or prediabetes treated with metformin. Methods/design This study protocol describes the design of an ongoing RCT. We are recruiting 108 (54 each treatment arm 10 to 17 year olds with clinical features of insulin resistance and/or prediabetes, through physician referral, into a multi-centred RCT. All participants are prescribed metformin and participate in a diet and exercise program. The lifestyle program is the same for all participants except for diet composition. The diets are a high carbohydrate, low fat diet and a moderate carbohydrate, increased protein diet. The program commences with an intensive 3 month dietary intervention, implemented by trained dietitians, followed by a 3 month intensive gym and home based exercise program, supervised by certified physical trainers. To measure the longer term effectiveness, after the intensive intervention trial participants are managed by either their usual physician or study physician and followed up by the study dietitians for an additional 6 months. The primary outcome measure, change in insulin sensitivity, is measured at 3, 6 and 12 months. Discussion Clinical insulin resistance and prediabetes in the paediatric population are rapidly emerging clinical problems with serious health outcomes. With

  11. Effect of ethanolic extracts of Ananas comosus L. leaves on insulin sensitivity in rats and HepG2.

    Science.gov (United States)

    Xie, Weidong; Wang, Wei; Su, Hui; Xing, Dongming; Pan, Yang; Du, Lijun

    2006-08-01

    Ethanolic extracts of Ananas comosus L. leaves (AC) enriched with phenols have hypoglycemic activity in diabetic rats. Here, we investigated the effect of AC on insulin sensitivity in rats and HepG2. In high-fat diet-fed and low-dose streptozotozin-treated diabetic Wistar rats subjected to challenge with exogenous human insulin, AC treatment at an oral dose of 0.40 g/kg could significantly improve sensitivity to exogenous insulin. After a sub-acute treatment, AC also could inhibit the development of insulin resistance in high-fat diet-fed and low-dose streptozotozin-treated diabetic rats following the test of loss of tolbutamide-induced blood glucose lowering action. For intravenous insulin/glucose infusion test, high-fat diet-fed and low-dose alloxan-treated Wistar rats were associated with insulin resistance, which was improved after AC or fenofibrate treatment. AC application inhibited the development of insulin resistance in HepG2 cells. The above animal models were well developed to simulate type 2 diabetes. Taken together, our results suggest that AC may improve insulin sensitivity in type 2 diabetes and could be developed into a new potential natural product for handling of insulin resistance in diabetic patients.

  12. Short-Term Exercise Training Improves Insulin Sensitivity but Does Not Inhibit Inflammatory Pathways in Immune Cells from Insulin-Resistant Subjects

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    Sara M. Reyna

    2013-01-01

    Full Text Available Background. Exercise has an anti-inflammatory effect against, and immune cells play critical roles in the development, of insulin resistance and atherosclerotic vascular disease (AVD. Thus, the goal of this study was to determine whether exercise improves insulin sensitivity in insulin-resistant subjects by downregulating proinflammatory signaling in immune cells. Methods. Seventeen lean, 8 obese nondiabetic, and 11 obese type 2 diabetic individuals underwent an aerobic exercise program for 15 days and an insulin clamp before and after exercise. Peripheral mononuclear cells (PMNC were obtained for determination of Toll-like receptor (TLR 2 and 4 protein content and mitogen-activated protein kinase phosphorylation. Results. Compared with that in lean individuals, TLR4 protein content was increased by 4.2-fold in diabetic subjects. This increase in TLR4 content was accompanied by a 3.0-fold increase in extracellular signal-regulated kinase (ERK phosphorylation. Exercise improved insulin sensitivity in the lean, obese, and type 2 diabetes groups. However, exercise did not affect TLR content or ERK phosphorylation. Conclusions. TLR4 content and ERK phosphorylation are increased in PMNC of type 2 diabetic individuals. While exercise improves insulin sensitivity, this effect is not related to changes in TLR2/TLR4 content or ERK phosphorylation in PMNC of type 2 diabetic individuals.

  13. Interaction between leucine and phosphodiesterase 5 inhibition in modulating insulin sensitivity and lipid metabolism

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    Fu L

    2015-05-01

    Full Text Available Lizhi Fu,1 Fenfen Li,1 Antje Bruckbauer,2 Qiang Cao,1 Xin Cui,1 Rui Wu,1 Hang Shi,1 Bingzhong Xue,1 Michael B Zemel21Department of Biology, Center for Obesity Reversal, Georgia State University, Atlanta, GA, 2NuSirt Biopharma Inc., Nashville, TN, USA Purpose: Leucine activates SIRT1/AMP-activated protein kinase (AMPK signaling and markedly potentiates the effects of other sirtuin and AMPK activators on insulin signaling and lipid metabolism. Phosphodiesterase 5 inhibition increases nitric oxide–cGMP signaling, which in turn exhibits a positive feedback loop with both SIRT1 and AMPK, thus amplifying peroxisome proliferator-activated receptor γ co-activator α (PGC1α-mediated effects. Methods: We evaluated potential synergy between leucine and PDE5i on insulin sensitivity and lipid metabolism in vitro and in diet-induced obese (DIO mice. Results: Leucine (0.5 mM exhibited significant synergy with subtherapeutic doses (0.1–10 nM of PDE5-inhibitors (sildenafil and icariin on fat oxidation, nitric oxide production, and mitochondrial biogenesis in hepatocytes, adipocytes, and myotubes. Effects on insulin sensitivity, glycemic control, and lipid metabolism were then assessed in DIO-mice. DIO-mice exhibited fasting and postprandial hyperglycemia, insulin resistance, and hepatic steatosis, which were not affected by the addition of leucine (24 g/kg diet. However, the combination of leucine and a subtherapeutic dose of icariin (25 mg/kg diet for 6 weeks reduced fasting glucose (38%, P<0.002, insulin (37%, P<0.05, area under the glucose tolerance curve (20%, P<0.01, and fully restored glucose response to exogenous insulin challenge. The combination also inhibited hepatic lipogenesis, stimulated hepatic and muscle fatty acid oxidation, suppressed hepatic inflammation, and reversed high-fat diet-induced steatosis. Conclusion: These robust improvements in insulin sensitivity, glycemic control, and lipid metabolism indicate therapeutic potential for

  14. The impact of pegvisomant treatment on substrate metabolism and insulin sensitivity in patients with acromegaly

    DEFF Research Database (Denmark)

    Lindberg-Larsen, Rune; Møller, Niels; Schmitz, Ole

    2007-01-01

    vs. 1563 +/- 101 kcal/24 h, P = 0.03), but the rate of lipid oxidation did not change significantly. CONCLUSIONS: 1) Pegvisomant treatment for 4 wk improves peripheral and hepatic insulin sensitivity in acromegaly. 2) This is associated with a decrease in resting energy expenditure, whereas free...... fatty acid metabolism is unaltered. 3) The data support the important direct effects of GH on glucose metabolism and add additional benefits to pegvisomant treatment for acromegaly...

  15. Identification of adipokine clusters related to parameters of fat mass, insulin sensitivity and inflammation.

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    Gesine Flehmig

    Full Text Available In obesity, elevated fat mass and ectopic fat accumulation are associated with changes in adipokine secretion, which may link obesity to inflammation and the development of insulin resistance. However, relationships among individual adipokines and between adipokines and parameters of obesity, glucose metabolism or inflammation are largely unknown. Serum concentrations of 20 adipokines were measured in 141 Caucasian obese men (n = 67 and women (n = 74 with a wide range of body weight, glycemia and insulin sensitivity. Unbiased, distance-based hierarchical cluster analyses were performed to recognize patterns among adipokines and their relationship with parameters of obesity, glucose metabolism, insulin sensitivity and inflammation. We identified two major adipokine clusters related to either (1 body fat mass and inflammation (leptin, ANGPTL3, DLL1, chemerin, Nampt, resistin or insulin sensitivity/hyperglycemia, and lipid metabolism (vaspin, clusterin, glypican 4, progranulin, ANGPTL6, GPX3, RBP4, DLK1, SFRP5, BMP7, adiponectin, CTRP3 and 5, omentin. In addition, we found distinct adipokine clusters in subgroups of patients with or without type 2 diabetes (T2D. Logistic regression analyses revealed ANGPTL6, DLK1, Nampt and progranulin as strongest adipokine correlates of T2D in obese individuals. The panel of 20 adipokines predicted T2D compared to a combination of HbA1c, HOMA-IR and fasting plasma glucose with lower sensitivity (78% versus 91% and specificity (76% versus 94%. Therefore, adipokine patterns may currently not be clinically useful for the diagnosis of metabolic diseases. Whether adipokine patterns are relevant for the predictive assessment of intervention outcomes needs to be further investigated.

  16. The relationship between thyrotropin and low density lipoprotein cholesterol is modified by insulin sensitivity in healthy euthyroid subjects

    NARCIS (Netherlands)

    Bakker, SJL; ter Maaten, JC; Popp-Snijders, C; Slaets, JPJ; Heine, RJ; Gans, ROB

    2001-01-01

    High levels of TSH are associated with an increased cardiovascular risk. Many cardiovascular risk factors cluster within the insulin resistance syndrome. It is not known whether levels of TSH cluster as well. We conducted this research to test the hypothesis that TSH, insulin sensitivity, and levels

  17. Variable reliability of surrogate measures of insulin sensitivity after Roux-en-Y gastric bypass

    DEFF Research Database (Denmark)

    Bojsen-Møller, Kirstine N; Dirksen, Carsten; Svane, Maria Saur

    2017-01-01

    with HEC-estimated peripheral insulin sensitivity (Rd or Rd/I, depending on how the index was originally validated) and the tracer-determined hepatic insulin sensitivity index (HISI) in patients with preoperative type 2 diabetes (n=10) and normal glucose tolerance (n=10) 1 week, 3 months and 1 year...... postoperatively. Post-RYGB changes in inverse-HOMA-IR and HOMA2-%S did not correlate with changes in Rd at any visit, but were comparable to changes in HISI at 1 week. Changes in QUICKI and revised-QUICKI correlated with Rd/I after surgery. Changes in Matsuda and Gutt did not correlate with changes in Rd/I and Rd......) are frequently used, but have not been validated after RYGB. Our aim was to evaluate whether surrogate indices reliably estimate changes in insulin sensitivity after RYGB. Four fasting (inverse-HOMA-IR, HOMA2-%S, QUICKI, revised-QUICKI) and three OGTT-derived surrogates (Matsuda, Gutt, OGIS) were compared...

  18. Cellular therapies based on stem cells and their insulin-producing surrogates: a 2015 reality check.

    Science.gov (United States)

    Giannoukakis, Nick; Trucco, Massimo

    2015-05-01

    Stem cell technology has recently gained a substantial amount of interest as one method to create a potentially limitless supply of transplantable insulin-producing cells to treat, and possibly cure diabetes mellitus. In this review, we summarize the state-of-the art of stem cell technology and list the potential sources of stem cells that have been shown to be useful as insulin-expressing surrogates. We also discuss the milestones that have been reached and those that remain to be addressed to generate bona fide beta cell-similar, insulin-producing surrogates. The caveats, limitations, and realistic expectations are also considered for current and future technology. In spite of the tremendous technical advances realized in the past decade, especially in the field of reprogramming adult somatic cells to become stem cells, the state-of-the art still relies on lengthy and cumbersome in vitro culture methods that yield cell populations that are not particularly glucose-responsive when transplanted into diabetic hosts. Despite the current impediments toward clinical translation, including the potential for immune rejection, the availability of technology to generate patient-specific reprogrammable stem cells has, and will be critical for, important insights into the genetics, epigenetics, biology, and physiology of insulin-producing cells in normal and pathologic states. This knowledge could accelerate the time to reach the desired breakthrough for safe and efficacious beta cell surrogates.

  19. A genome-wide siRNA screen to identify modulators of insulin sensitivity and gluconeogenesis.

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    Ruojing Yang

    Full Text Available BACKGROUND: Hepatic insulin resistance impairs insulin's ability to suppress hepatic glucose production (HGP and contributes to the development of type 2 diabetes (T2D. Although the interests to discover novel genes that modulate insulin sensitivity and HGP are high, it remains challenging to have a human cell based system to identify novel genes. METHODOLOGY/PRINCIPAL FINDINGS: To identify genes that modulate hepatic insulin signaling and HGP, we generated a human cell line stably expressing beta-lactamase under the control of the human glucose-6-phosphatase (G6PC promoter (AH-G6PC cells. Both beta-lactamase activity and endogenous G6PC mRNA were increased in AH-G6PC cells by a combination of dexamethasone and pCPT-cAMP, and reduced by insulin. A 4-gene High-Throughput-Genomics assay was developed to concomitantly measure G6PC and pyruvate-dehydrogenase-kinase-4 (PDK4 mRNA levels. Using this assay, we screened an siRNA library containing pooled siRNA targeting 6650 druggable genes and identified 614 hits that lowered G6PC expression without increasing PDK4 mRNA levels. Pathway analysis indicated that siRNA-mediated knockdown (KD of genes known to positively or negatively affect insulin signaling increased or decreased G6PC mRNA expression, respectively, thus validating our screening platform. A subset of 270 primary screen hits was selected and 149 hits were confirmed by target gene KD by pooled siRNA and 7 single siRNA for each gene to reduce G6PC expression in 4-gene HTG assay. Subsequently, pooled siRNA KD of 113 genes decreased PEPCK and/or PGC1alpha mRNA expression thereby demonstrating their role in regulating key gluconeogenic genes in addition to G6PC. Last, KD of 61 of the above 113 genes potentiated insulin-stimulated Akt phosphorylation, suggesting that they suppress gluconeogenic gene by enhancing insulin signaling. CONCLUSIONS/SIGNIFICANCE: These results support the proposition that the proteins encoded by the genes identified in

  20. Associations of objective physical activity with insulin sensitivity and circulating adipokine profile: the Framingham Heart Study.

    Science.gov (United States)

    Spartano, N L; Stevenson, M D; Xanthakis, V; Larson, M G; Andersson, C; Murabito, J M; Vasan, R S

    2017-04-01

    The purpose of this study was to explore the relation of physical activity (PA) and sedentary time (SED) to insulin sensitivity and adipokines. We assessed PA and SED using Actical accelerometers and insulin resistance (HOMA-IR) in 2109 participants (free of type 1 and 2 diabetes mellitus) from Framingham Generation 3 and Omni 2 cohorts (mean age 46 years, 54% women). Systemic inflammation (C-reactive protein [CRP]) and circulating adipokines were measured 6 years earlier. Steps per day, moderate-to-vigorous PA (MVPA) and SED per wear time (%SED) were predictor variables in multivariable regression analyses, with HOMA-IR, CRP and circulating adipokines as outcome measures. We reported that higher MVPA and more steps per day were associated with lower HOMA-IR, adjusting for %SED (β = -0.036, P = 0.002; β = -0.041, P = 0.005). Steps were inversely associated with CRP, but were directly associated with insulin-like growth factor (IGF)-1 levels (β = -0.111, P = 0.002; β = 3.293, P = 0.007). %SED was positively associated with HOMA-IR (β = 0.033, P insulin resistance and inflammation, whereas SED influences FABPs.

  1. Alterations in Whole-Body Insulin Sensitivity Resulting From Repeated Eccentric Exercise of a Single Muscle Group: A Pilot Investigation.

    Science.gov (United States)

    Gonzalez, Javier T; Barwood, Martin J; Goodall, Stuart; Thomas, Kevin; Howatson, Glyn

    2015-08-01

    Unaccustomed eccentric exercise using large muscle groups elicits soreness, decrements in physical function and impairs markers of whole-body insulin sensitivity; although these effects are attenuated with a repeated exposure. Eccentric exercise of a small muscle group (elbow flexors) displays similar soreness and damage profiles in response to repeated exposure. However, it is unknown whether damage to small muscle groups impacts upon whole-body insulin sensitivity. This pilot investigation aimed to characterize whole-body insulin sensitivity in response to repeated bouts of eccentric exercise of the elbow flexors. Nine healthy males completed two bouts of eccentric exercise separated by 2 weeks. Insulin resistance (updated homeostasis model of insulin resistance, HOMA2-IR) and muscle damage profiles (soreness and physical function) were assessed before, and 48 h after exercise. Matsuda insulin sensitivity indices (ISI Matsuda) were also determined in 6 participants at the same time points as HOMA2-IR. Soreness was elevated, and physical function impaired, by both bouts of exercise (both p Eccentric exercise decreased ISI Matsuda after the first but not the second bout of eccentric exercise (time x bout interaction p Eccentric exercise performed with an isolated upper limb impairs whole-body insulin sensitivity after the first, but not the second, bout.

  2. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance.

    Science.gov (United States)

    Lee, Byung-Cheol; Lee, Jongsoon

    2014-03-01

    There is increasing evidence showing that inflammation is an important pathogenic mediator of the development of obesity-induced insulin resistance. It is now generally accepted that tissue-resident immune cells play a major role in the regulation of this obesity-induced inflammation. The roles that adipose tissue (AT)-resident immune cells play have been particularly extensively studied. AT contains most types of immune cells and obesity increases their numbers and activation levels, particularly in AT macrophages (ATMs). Other pro-inflammatory cells found in AT include neutrophils, Th1 CD4 T cells, CD8 T cells, B cells, DCs, and mast cells. However, AT also contains anti-inflammatory cells that counter the pro-inflammatory immune cells that are responsible for the obesity-induced inflammation in this tissue. These anti-inflammatory cells include regulatory CD4 T cells (Tregs), Th2 CD4 T cells, and eosinophils. Hence, AT inflammation is shaped by the regulation of pro- and anti-inflammatory immune cell homeostasis, and obesity skews this balance towards a more pro-inflammatory status. Recent genetic studies revealed several molecules that participate in the development of obesity-induced inflammation and insulin resistance. In this review, the cellular and molecular players that participate in the regulation of obesity-induced inflammation and insulin resistance are discussed, with particular attention being placed on the roles of the cellular players in these pathogeneses. This article is part of a Special Issue entitled: Modulation of Adipose Tissue in Health and Disease.

  3. A sensitive chemiluminescent enzyme immunoassay for the bioanalysis of carboxyl-terminal B-chain analogues of human insulin.

    Science.gov (United States)

    Cao, Y; Smith, W C; Bowsher, R R

    2001-08-01

    Quantification of analogues of human insulin in biological matrices is complicated by differences in their immunoreactivity and the presence of both the analogue and endogenous concentrations of insulin in test samples. To facilitate pharmacokinetic comparisons of carboxyl-terminal B-chain analogues of human insulin, we undertook development of a sensitive ELISA. The ELISA detection method was optimized systematically to permit routine analysis of 10-microl serum samples. Accordingly, a noncompetitive 'sandwich' chemiluminescent ELISA was validated for the quantification of carboxyl-terminal B-chain insulin analogues in human serum over a concentration range from 5 to 3125 pM. The mean bias (RE%) within the validated range varied from -10.3 to 4.3%, with an intermediate precision (inter-assay CV%) from 4.2 to 11.5%. The two-sided 90% expectation tolerance interval for total measurement error was within +/-25% of the nominal concentration for all levels of validation samples. Insulin lispro, human insulin, proinsulin, despentapeptide insulin (DPI) and porcine insulin displayed comparable crossreactivity in the ELISA. Potential utility of the new assay for insulin bioanalysis in nonhuman species was investigated by assessing the pharmacokinetic profile of DPI in rats following administration of a single subcutaneous dose. The sensitive chemiluminescent detection method is simple to perform and should be readily adaptable for ELISAs of other therapeutic proteins.

  4. Soybean fermentation with Bacillus licheniformis increases insulin sensitizing and insulinotropic activity.

    Science.gov (United States)

    Yang, Hye Jeong; Kwon, Dae Young; Moon, Na Rang; Kim, Min Jung; Kang, Hee Joo; Jung, Do Yeon; Park, Sunmin

    2013-11-01

    Traditionally fermented soybeans (chungkookjang; TFC) may have potent anti-diabetic activity, depending on the ambient microorganisms and conditions. We hypothesized that one of the major Bacillus species in TFC contributes to the anti-diabetic activity and could be used to standardize a highly functional TFC. We tested the hypothesis by using cell-based studies to evaluate insulin sensitizing and insulinotropic action of chungkookjangs fermented with various Bacillus spp. and fermentation periods. The 70% methanol and water extracts of chungkookjang fermented with Bacillus licheniformis (BL) for 48 h contained similar profiles of isoflavonoids and peptides to methanol and water extracts of TFC with potent anti-diabetic activity. Water extracts (mainly containing peptides) of TFC and BL fermented for 48 h and 72 h had a better insulin sensitizing action via activating peroxisome proliferator-activated receptor-γ (PPAR-γ) and increased the expression of PPAR-γ in 3T3-L1 adipocytes better than unfermented cooked soybeans (CSB). The 70% methanol extracts (predominantly isoflavone aglycones) of BL fermented for 48 h and 72 h improved glucose-stimulated insulin secretion and protected β-cell viability better than CSB in insulinoma cells, and the improvement by BL was similar to TFC. In conclusion, the BL water extract fermented for 48 h exhibited equal insulin sensitization as TFC and BL methanol extract exerted similar insulinotropic actions to those of TFC. B. licheniformis may be one of the major microorganisms responsible for anti-diabetic actions of chungkookjang. It is important to make chungkookjang that retains the anti-diabetic properties of the most efficacious traditional chungkookjang using a standardized method.

  5. Over-expression of Follistatin-like 3 attenuates fat accumulation and improves insulin sensitivity in mice

    DEFF Research Database (Denmark)

    Brandt, Claus; Hansen, Rasmus Hvass; Hansen, Jakob Bondo

    2015-01-01

    -fat feeding. Body weight, food intake, fat accumulation by MR scanning, and glucose, insulin and glucagon tolerance were evaluated, as was the response in body weight and metabolic parameters to 24h fasting. Effects of fstl3 on pancreatic insulin and glucagon content, and pancreatic islet morphology were...... through systemic fstl3 over-expression protects against diet-induced obesity and insulin resistance. METHODS: Fstl3 was over-expressed by DNA electrotransfer in tibialis anterior, quadriceps and gastrocnemius muscles in female C57BL/C mice, and the mice were subsequently randomized to chow or high....../glucagon ratio. Accordingly, fstl3 transfection improved counter-regulation to 24h fasting. CONCLUSION: Fstl3 over-expression regulates insulin and glucagon sensitivities through increased muscular insulin action, as well as increased hepatic glucagon sensitivity and pancreatic glucagon content....

  6. Insulin sensitivity and first-phase insulin secretion in obese Chinese with hyperglycemia in 30 and/or 60 min during glucose tolerance tests.

    Science.gov (United States)

    Hong, Jie; Zhang, Yi-Fei; Gu, Wei-qiong; Zhang, Yu-wen; Su, Yu-xia; Chi, Zhen-ni; Wang, Wei-qing; Li, Xiao-ying; Ning, Guang

    2008-01-01

    The purpose of this study was to investigate insulin sensitivity and first-phase insulin secretion in obesity with hyperglycemia in 30 and/or 60 min during oral glucose tolerance (OGTT, glucose > or = 11.1 mmol/l, post-loading hyperglycemia, PLH) in Chinese population. A total of 196 nondiabetic subjects were included in the present study, among them 99 had normal glucose tolerance (NGT, subdivided into 32 lean NGT and 67 obese NGT), 74 had obesity with impaired glucose tolerance (IGT) and 23 had obesity with PLH. A standard 75-g oral glucose tolerance test was performed after fasting and at 30 min, 1, 2 and 3 h. Insulin sensitivity index (S(I)) was assessed by the Bergman's minimal model method with frequently sampled intravenous glucose tolerance test (FSIGTT), insulin secretion was determined by acute insulin response to glucose (AIRg). The disposition index (DI), the product of AIRg and S(I) was used to determine whether AIRg was adequate to compensate for insulin resistance. S(I) was significantly equally lower in three obese subgroups. AIRg was significantly increased in obese NGT as compared with lean NGT controls, and reduced to the same extent in IGT and PLH subjects. There was no significant difference among lean NGT, IGT and PLH subjects. DI value was reduced from obese NGT individuals, IGT and PLH subjects had a similar lower level of DI. In conclusion, our present results demonstrated that the pathophysiological basis of obese subjects with PLH were clearly insulin resistance and defective in first-phase insulin secretion as that in IGT subjects in Chinese population.

  7. Fasting plasma chenodeoxycholic acid and cholic acid concentrations are inversely correlated with insulin sensitivity in adults

    Directory of Open Access Journals (Sweden)

    Laville Martine

    2011-07-01

    Full Text Available Abstract Background Accumulating data suggest a novel role for bile acids (BAs in modulating metabolic homeostasis. BA treatment has been shown to improve glucose tolerance and to increase energy expenditure in mice. Here, we investigated the relationship between fasting plasma BAs concentrations and metabolic parameters in humans. Findings Fasting plasma glucose, insulin and lipid profile were measured in 14 healthy volunteers, 20 patients with type 2 diabetes (T2D, and 22 non-diabetic abdominally obese subjects. Insulin sensitivity was also assessed by the determination of the glucose infusion rate (GIR during a hyperinsulinemic-euglycemic clamp in a subgroup of patients (9 healthy and 16 T2D subjects. Energy expenditure was measured by indirect calorimetry. Plasma cholic acid (CA, chenodeoxycholic acid (CDCA and deoxycholic acid (DCA concentrations were analyzed by gas chromatograph-mass spectrometry. In univariable analysis, a positive association was found between HOMA-IR and plasma CDCA (β = 0.09, p = 0.001, CA (β = 0.03, p = 0.09 and DCA concentrations (β = 0.07, p Conclusions Both plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a wide range of subjects.

  8. Effects of intracerebroventricular (ICV) olanzapine on insulin sensitivity and secretion in vivo: an animal model.

    Science.gov (United States)

    Hahn, Margaret K; Chintoh, Araba; Remington, Gary; Teo, Celine; Mann, Steve; Arenovich, Tamara; Fletcher, Paul; Lam, Loretta; Nobrega, Jose; Guenette, Melanie; Cohn, Tony; Giacca, Adria

    2014-03-01

    The atypical antipsychotics (AAPs) have been associated with an increased risk of type 2 diabetes. While weight gain associated with AAPs is a risk factor for diabetes, preclinical work suggests that among these medications, olanzapine, when given peripherally in a single dose, causes pronounced effects on insulin sensitivity and secretion. Given a critical role of the hypothalamus in control of glucose metabolism, we examined the effect of central administration of olanzapine. Sprague-Dawley rats were treated with a single 75 μg intracerebroventricular (ICV) dose of olanzapine and tested using separate hyperinsulinemic-euglycemic and hyperglycemic clamps. Dosing of olanzapine was established based on inhibition of amphetamine-induced locomotion. In contrast to the single dosing peripheral paradigm, there was no effect of central olanzapine on insulin sensitivity, either with respect to hepatic glucose production or peripheral glucose uptake. Analogous to the peripheral model, a single ICV dose of olanzapine followed by the hyperglycemic clamp decreased insulin (p=0.0041) and C-peptide response (p=0.0039) to glucose challenge as compared to vehicle, mirrored also by a decrease in the steady state glucose infusion rate required to maintain hyperglycemia (p=0.002). In conclusion, we demonstrate novel findings that at least part of the effect of olanzapine on beta-cell function in vivo is central.

  9. Caffeine ingestion impairs insulin sensitivity in a dose-dependent manner in both men and women.

    Science.gov (United States)

    Beaudoin, Marie-Soleil; Allen, Brian; Mazzetti, Gillian; Sullivan, Peter J; Graham, Terry E

    2013-02-01

    The effects of alkaloid caffeine on insulin sensitivity have been investigated primarily in men, and with a single caffeine dose most commonly of 5-6 mg·kg(-1) of body weight (BW). It is unknown if the effects of caffeine on glucose homeostasis are sex-specific and (or) dose-dependent. This study examined whether caffeine ingestion would disrupt glucose homeostasis in a dose-dependent or threshold manner. It also examined whether sex-specific responses to caffeine exist. It was hypothesized that women would have an exaggerated response to caffeine, and that caffeine would only impair glucose metabolism once a threshold was reached. Twenty-four healthy volunteers (12 males, 12 females) participated in 4 trials, in a crossover, randomized, and double-blind fashion. They ingested caffeine (1, 3, or 5 mg·kg(-1) of BW) or placebo followed, 1 h later, by a 2-h oral glucose tolerance test. Glucose, insulin, C-peptide area under the curve (AUC), and insulin sensitivity index data were fitted to a segmented linear model to determine dose-responses. There were no differences between sexes for any endpoints. Regression slopes were significantly different from zero (p fashion beginning at very low doses (0-1 mg·kg(-1) BW) in both healthy men and women.

  10. Relationship between Adiponectin Level, Insulin Sensitivity, and Metabolic Syndrome in Type 1 Diabetic Patients

    Directory of Open Access Journals (Sweden)

    Kristina Blaslov

    2013-01-01

    Full Text Available Objective. Adiponectin is known to be decreased in insulin resistance (IR and metabolic syndrome (MS which can be present in patients with type 1 diabetes mellitus (T1DM. The aim of this study was to evaluate the relationship between adiponectin level, MS, and insulin sensitivity in T1DM. Research Design and Methods. The study included 77 T1DM patients divided into two groups based on the total plasma adiponectin median value. Insulin sensitivity was calculated with the equation for eGDR, and MS was defined according to International Diabetes Federation criteria. Results. Patients with higher adiponectin level ( had significantly lower waist circumference (, fasting venous glucose levels (, higher HDL3-cholesterol (, and eGDR ( in comparison to the group with lower adiponectin who showed higher prevalence of MS (. eGDR increased for 1.09 mg/kg−1 min−1 by each increase of 1 µg/mL total fasting plasma adiponectin (. In the logistic regression model, adiponectin was inversely associated with the presence of MS (. Conclusion. Higher adiponectin concentration is associated with lower prevalence of MS in T1DM. Whether higher adiponectin concentration has a protective role in the development of the MS in T1DM needs to be clarified in future follow-up studies.

  11. Relationship between Adiponectin Level, Insulin Sensitivity, and Metabolic Syndrome in Type 1 Diabetic Patients

    Science.gov (United States)

    Blaslov, Kristina; Zibar, Karin; Duvnjak, Lea

    2013-01-01

    Objective. Adiponectin is known to be decreased in insulin resistance (IR) and metabolic syndrome (MS) which can be present in patients with type 1 diabetes mellitus (T1DM). The aim of this study was to evaluate the relationship between adiponectin level, MS, and insulin sensitivity in T1DM. Research Design and Methods. The study included 77 T1DM patients divided into two groups based on the total plasma adiponectin median value. Insulin sensitivity was calculated with the equation for eGDR, and MS was defined according to International Diabetes Federation criteria. Results. Patients with higher adiponectin level (n = 39) had significantly lower waist circumference (P < 0.002), fasting venous glucose levels (P < 0.001), higher HDL3-cholesterol (P = 0.011), and eGDR (P = 0.003) in comparison to the group with lower adiponectin who showed higher prevalence of MS (P = 0.045). eGDR increased for 1.09 mg/kg−1 min−1 by each increase of 1 µg/mL total fasting plasma adiponectin (P = 0.003). In the logistic regression model, adiponectin was inversely associated with the presence of MS (P = 0.014). Conclusion. Higher adiponectin concentration is associated with lower prevalence of MS in T1DM. Whether higher adiponectin concentration has a protective role in the development of the MS in T1DM needs to be clarified in future follow-up studies. PMID:23956744

  12. Anxiety sensitivity in adolescents with somatoform autonomic dysfunction and adolescents with insulin dependent diabetes mellitus

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    Pisarić Maja

    2011-01-01

    Full Text Available Anxiety sensitivity is defined as a belief that anxiety or fear may cause illness, embarrassment, or additional anxiety. The main purpose of this study was to find out if there were differences among adolescents with insulin dependent diabetes mellitus, adolescents with somatoform autonomic dysfunction and their healthy peers in different aspects of psychological functioning and anxiety sensitivity. The sample consisted of 93 subjects, aged 12 to 16. Hamburg Neuroticism and Extraversion Scale, Child Behaviour Checklist and Childhood Anxiety Sensitivity Index were administrated. The adolescents with somatoform autonomic dysfunction had significantly higher scores on neuroticism scale, different Child Behaviour Checklist subscales, and on anxiety sensitivity. Both groups with diagnosed illness had lower scores on extraversion scale compared to healthy peers. This study has shown that the adolescents with somatoform autonomic dysfunction are more prone to fears regarding bodily functioning, and that they are at a higher risk of developing an anxiety disorder.

  13. Insulin-sensitizing and Anti-proliferative Effects of Argania spinosa Seed Extracts

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    Samira Samane

    2006-01-01

    Full Text Available Argania spinosa is an evergreen tree endemic of southwestern Morocco. Many preparations have been used in traditional Moroccan medicine for centuries to treat several illnesses including diabetes. However, scientific evidence supporting these actions is lacking. Therefore, we prepared various extracts of the argan fruit, namely keel, cake and argan oil extracts, which we tested in the HTC hepatoma cell line for their potential to affect cellular insulin responses. Cell viability was measured by Trypan Blue exclusion and the response to insulin evaluated by the activation of the extracellular regulated kinase (ERK1/2, ERK kinase (MEK1/2 and protein kinase B (PKB/Akt signaling components. None of the extracts demonstrated significant cytotoxic activity. Certain extracts demonstrated a bi-phasic effect on ERK1/2 activation; low doses of the extract slightly increased ERK1/2 activation in response to insulin, whereas higher doses completely abolished the response. In contrast, none of the extracts had any significant effect on MEK whereas only a cake saponin subfraction enhanced insulin-induced PKB/Akt activation. The specific action of argan oil extracts on ERK1/2 activation made us consider an anti-proliferative action. We have thus tested other transformed cell lines (HT-1080 and MSV-MDCK-INV cells and found similar results. Inhibition of ERK1/2 activation was also associated with decreased DNA synthesis as evidenced by [3H]thymidine incorporation experiments. These results suggest that the products of Argania spinosa may provide a new therapeutic avenue against proliferative diseases.

  14. Insulin-sensitizing and anti-proliferative effects of Argania spinosa seed extracts.

    Science.gov (United States)

    Samane, Samira; Noël, Josette; Charrouf, Zoubida; Amarouch, Hamid; Haddad, Pierre Selim

    2006-09-01

    Argania spinosa is an evergreen tree endemic of southwestern Morocco. Many preparations have been used in traditional Moroccan medicine for centuries to treat several illnesses including diabetes. However, scientific evidence supporting these actions is lacking. Therefore, we prepared various extracts of the argan fruit, namely keel, cake and argan oil extracts, which we tested in the HTC hepatoma cell line for their potential to affect cellular insulin responses. Cell viability was measured by Trypan Blue exclusion and the response to insulin evaluated by the activation of the extracellular regulated kinase (ERK1/2), ERK kinase (MEK1/2) and protein kinase B (PKB/Akt) signaling components. None of the extracts demonstrated significant cytotoxic activity. Certain extracts demonstrated a bi-phasic effect on ERK1/2 activation; low doses of the extract slightly increased ERK1/2 activation in response to insulin, whereas higher doses completely abolished the response. In contrast, none of the extracts had any significant effect on MEK whereas only a cake saponin subfraction enhanced insulin-induced PKB/Akt activation. The specific action of argan oil extracts on ERK1/2 activation made us consider an anti-proliferative action. We have thus tested other transformed cell lines (HT-1080 and MSV-MDCK-INV cells) and found similar results. Inhibition of ERK1/2 activation was also associated with decreased DNA synthesis as evidenced by [(3)H]thymidine incorporation experiments. These results suggest that the products of Argania spinosa may provide a new therapeutic avenue against proliferative diseases.

  15. Short term low-calorie diet improves insulin sensitivity and metabolic parameters in obese women

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    Grazielle Vilas Bôas Huguenin

    2014-07-01

    Full Text Available Obesity and insulin resistance are associated with an increase of cardiovascular risk factors, including adipocytokines. The aim of this study was to investigate the effect of low-calorie diet on serum lipids, adipokines, insulin resistance and body composition in obese women. It was a clinical trial with class I obese women aged 30-45 years submitted to hypocaloric diet for 90 days. Dietary intake, anthropometric parameters, body composition, serum lipids, glucose, insulin, leptin, adiponectin, HOMA-IR and QUICKI indexes were evaluated at the baseline, 30, 60 and 90 days. There was 30% significant decrease in energy intake, and also decrease in body weight, body mass index and waist circumference (p < 0.01 throughout the treatment period. Despite the amount of lean body mass (kg reduced in average, it was observed that lean body mass (% had increased (p < 0.01 and that the amount of fat body mass (kg had decreased significantly in the third month (p < 0.05. Systolic blood pressure reduced up to -5mmHg (p < 0.05 after 90 days. Was observed a decrease (p < 0.05 on serum insulin and HOMA-IR until the 60th day, while the serum adiponectin increased (p < 0.01 during treatment. Corroborating with the reduction of fat body mass and weight, serum leptin also reduced (p < 0.01. These results suggest that the short-term low-calorie diet reduces total body fat, mainly found in the abdominal region, and efficiently improve insulin sensitivity decreasing cardiovascular risk in obese women.

  16. An isocaloric low glycemic index diet improves insulin sensitivity in women with polycystic ovary syndrome.

    Science.gov (United States)

    Barr, Suzanne; Reeves, Sue; Sharp, Kay; Jeanes, Yvonne M

    2013-11-01

    Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting 5% to 10% of women worldwide. Approximately half of women with PCOS are lean, yet may still present with central obesity and metabolic disturbances. Low-glycemic index (GI) dietary intervention studies have demonstrated improvements in insulin sensitivity in insulin-resistant populations; however, there is little evidence of this effect in women with PCOS. This research aimed to determine the efficacy of an isocaloric low-GI dietary intervention on insulin sensitivity, independent of weight change, in women with PCOS. A nonrandomized 12-week low-GI dietary intervention, preceded by a 12-week habitual diet control phase and proceeded by a 12-week follow-up phase was conducted. Dietary intake, body composition, and metabolic risk markers were determined at baseline, after completion of the habitual diet control phase, and after the low-GI dietary intervention. Twenty-six participants were recruited at baseline, 22 commenced and 21 participants completed the low-GI dietary intervention phase. The primary outcome was change in insulin sensitivity. Secondary outcomes included assessment of changes to lipids, body composition, and estimated macronutrient intake. Repeated measures analysis of variance with Bonferroni correction were used to detect changes to outcomes across study timepoints. Twenty-one women with PCOS with mean (± standard deviation) age of 32.1±6.7 years completed the 12-week low-GI dietary intervention. As expected, no significant changes occurred during the 12-week habitual diet control phase. However, during the dietary intervention phase, dietary GI decreased from 54.5±3.5 to 48.6±5.1 (P<0.001) with a concurrent small reduction in saturated fat intake (12.4%±3% to 11.7%±3% contribution from energy, P=0.03), despite no specific recommendations to modify fat intake. Measures of insulin sensitivity and nonesterified fatty acid improved after intervention (P=0.03 and P=0

  17. Pioglitazone improves insulin sensitivity, reduces visceral fat and stimulates lipolysis in non diabetic dialyzed patients

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    Anne Zanchi

    2012-06-01

    Full Text Available Insulin resistance is common in dialyzed patients and is associated with increased mortality and protein-energy wasting. The aim of this study was to investigate the effect of pioglitazone (PIO, a powerful insulin sensitizer, on insulin sensitivity, body composition and adipose tissue metabolism, in dialyzed patients. A double blind randomized cross-over study was performed in non diabetic dialysis patients. Each patient followed 2 treatment phases of 16 weeks, starting either with oral PIO 45 mg/d or placebo (PL, and then switched to the other phase. At the end of each phase, patients underwent hyperinsulinemic euglycemic clamps, dual energy X-ray absorptiometry, an abdominal CT, and extensive plasma biochemical analysis. Twelve patients including 8 HD (59.6±4.4 y and 4 PD patients (43.5±3.6 y were recruited. Nine patients completed both phases and 3 patients dropped out (renal transplantation/2 HD and peritonitis/1 PD. PIO was safe and well tolerated. Under PIO, insulin sensitivity improved, as assessed by increased total glucose disposal rate (1.98±0.24 for PIO versus 1.58±0.12 umol/kg/min for PL, p<0.05, and reduced glucose endogenous hepatic production. PIO did not affect post-dialysis body weight, total fat and lean body mass, but significantly reduced visceral adipose tissue (VAT area and the VAT/SAT (subcutaneous adipose tissue ratio. HDL-cholesterol significantly increased. PIO decreased CRP (3.96±1.44 mg/l vs 7.88±2.56, p<0.05, plasma leptin, and dramatically reduced leptin/adiponectin ratio. Glycerol turnover, circulating glycerol and non esterified fatty acids were paradoxically increased. In conclusion, the improvement in insulin sensitivity by PIO, in non diabetic dialyzed patients, was associated with favorable metabolic effects, reduction in inflammation and body fat redistribution. The stimulation of systemic lipolysis was a surprising finding which may reflect adipose tissue remodeling and/or a paradoxical lypolitic

  18. Effect of Feeding Status on Adjuvant Arthritis Severity, Cachexia, and Insulin Sensitivity in Male Lewis Rats

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    Andrea Stofkova

    2010-01-01

    Full Text Available We studied the effect of food restriction, overfeeding, and normofeeding on cachexia, inflammatory and metabolic parameters, and insulin sensitivity in chronic adjuvant arthritis (AA in rats. Food restriction during AA increased circulating ghrelin, corticosterone, decreased leptin, and ameliorated arthrogram score and systemic inflammation compared to normofeeding. Overfeeding worsened arthrogram score and systemic inflammation, and led to lipid accumulation in the liver, but not to alterations of adipokine and ghrelin plasma levels relative to normofeeding. Independently of feeding status, AA induced cachexia, in which modulation of mRNA expressions for appetite-regulating neuropeptides (NPY, AgRP, POMC, CART in the arcuate nucleus (ARC does not play a primary role. The overexpression of IL-1β mRNA in the ARC suggests its role in the mechanisms of impaired energy balance during AA under all feeding conditions. Normal HOMA index in all arthritic groups does not indicate the development of insulin resistance by feeding interventions in these rats.

  19. Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells

    DEFF Research Database (Denmark)

    Prawitt, Janne; Niemeier, Andreas; Kassem, Moustapha

    2008-01-01

    There is a great demand for cell models to study human adipocyte function. Here we describe the adipogenic differentiation of a telomerase-immortalized human mesenchymal stem cell line (hMSC-Tert) that maintains numerous features of terminally differentiated adipocytes even after prolonged......, the presence of the PPARgamma agonist rosiglitazone was not required for the stable expression of lipoprotein lipase, adipocyte fatty acid binding protein and perilipin on mRNA and protein levels. Adiponectin expression was post-transcriptionally down-regulated in the absence of rosiglitazone. Insulin...... sensitivity as measured by insulin-induced phosphorylation of Akt and S6 ribosomal protein was also independent of rosiglitazone. In addition to commonly used adipogenic markers, we investigated further PPARgamma-stimulated proteins with a role in lipid metabolism. We observed an increase of lipoprotein...

  20. Increased insulin binding to adipocytes and monocytes and increased insulin sensitivity of glucose transport and metabolism in adipocytes from non-insulin-dependent diabetics after a low-fat/high-starch/high-fiber diet.

    Science.gov (United States)

    Hjøllund, E; Pedersen, O; Richelsen, B; Beck-Nielsen, H; Sørensen, N S

    1983-11-01

    Nine non-insulin-dependent diabetics were studied before and after 3 weeks on an isoenergetic high-fiber/high-starch/low-fat diet (alternative diet), and nine non-insulin-dependent diabetics were studied on their usual diet. In the group that ate the alternative diet, the intake of fiber and starch increased 120% and 53%, whereas fat intake decreased 31%. Diabetes control improved as demonstrated by decreased fasting plasma glucose (P less than 0.05) and 24-hour urinary glucose excretion (P less than 0.05). The in vivo insulin action increased (KIVITT increased, P less than 0.05) with no change in fasting serum insulin levels. In fat cells obtained from patients in the alternative-diet group, insulin receptor binding increased (P less than 0.05) after the change of diet. Insulin binding to purified monocytes (more than 95% monocytes) also increased (P less than 0.05), whereas no change was found in insulin binding to erythrocytes. When lipogenesis was studied at a tracer glucose concentration at which glucose transport seems to be rate limiting, insulin sensitivity increased (P less than 0.02). This is the predicted consequence of increased receptor binding. Moreover, when CO2 production and lipogenesis were studied at a higher glucose concentration, where steps beyond transport seem to be rate limiting for glucose metabolism, increased insulin sensitivity was also observed. In contrast, no change was found in maximal insulin responsiveness. Fat and blood cells from the patients who continued on their usual diet showed no changes of the mentioned quantities.(ABSTRACT TRUNCATED AT 250 WORDS)

  1. Sorting of GLUT4 into its insulin-sensitive store requires the Sec1/Munc18 protein mVps45.

    Science.gov (United States)

    Roccisana, Jennifer; Sadler, Jessica B A; Bryant, Nia J; Gould, Gwyn W

    2013-08-01

    Insulin stimulates glucose transport in fat and muscle cells by regulating delivery of the facilitative glucose transporter, glucose transporter isoform 4 (GLUT4), to the plasma membrane. In the absence of insulin, GLUT4 is sequestered away from the general recycling endosomal pathway into specialized vesicles, referred to as GLUT4-storage vesicles. Understanding the sorting of GLUT4 into this store is a major challenge. Here we examine the role of the Sec1/Munc18 protein mVps45 in GLUT4 trafficking. We show that mVps45 is up-regulated upon differentiation of 3T3-L1 fibroblasts into adipocytes and is expressed at stoichiometric levels with its cognate target-soluble N-ethylmaleimide-sensitive factor attachment protein receptor, syntaxin 16. Depletion of mVps45 in 3T3-L1 adipocytes results in decreased GLUT4 levels and impaired insulin-stimulated glucose transport. Using sub-cellular fractionation and an in vitro assay for GLUT4-storage vesicle formation, we show that mVps45 is required to correctly traffic GLUT4 into this compartment. Collectively our data reveal a crucial role for mVps45 in the delivery of GLUT4 into its specialized, insulin-regulated compartment.

  2. Changes in androgens and insulin sensitivity indexes throughout pregnancy in women with polycystic ovary syndrome (PCOS: relationships with adverse outcomes

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    Falbo Angela

    2010-10-01

    Full Text Available Abstract Background Given the high rate of pregnancy and perinatal complications recently observed in patients with polycystic ovary syndrome (PCOS and the lack of data on the serum variations in androgens and insulin sensitivity indexes in pregnant women with PCOS, the current study was aimed to assess these changes and their potential effect on pregnancy outcomes in a population of women with PCOS. Methods Forty-five pregnant patients with ovulatory PCOS (PCOS group and other 42 healthy pregnant women (control group were studied assaying serum androgen levels and insulin sensitivity indexes throughout pregnancy serially, and recording obstetrical outcomes. Results Serum androgen levels and insulin resistance indexes were significantly (p p p Conclusions PCOS patients have impaired changes in serum androgen levels and insulin sensitivity indexes during pregnancy. These alterations could be implicated in the pregnancy and neonatal complications frequently observed in women affected by PCOS.

  3. Lipid accumulation in overweight type 2 diabetic subjects: relationships with insulin sensitivity and adipokines.

    Science.gov (United States)

    Sambataro, Maria; Perseghin, Gianluca; Lattuada, Guido; Beltramello, Giampietro; Luzi, Livio; Pacini, Giovanni

    2013-06-01

    Adipokines are known to play a fundamental role in the etiology of obesity, that is, in the impaired balance between increased feeding and decreased energy expenditure. While the adipokine-induced changes of insulin resistance in obese diabetic and nondiabetic subjects are well known, the possible role of fat source in modulating insulin sensitivity (IS) remains controversial. The aim of our study was to explore in overweight type 2 diabetic patients (T2DM) with metabolic syndrome IS in different energy storage conditions (basal and dynamic) for relating it to leptin and adiponectin. Sixteen T2DM (5/11 F/M; 59 ± 2 years; 29.5 ± 1.1 kg/m(2)) and 16 control (CNT 5/11; 54 ± 2; 29.1 ± 1.0) underwent an oral glucose tolerance test. Fasting IS was measured by QUICKI, while the dynamic one with OGIS. The insulinogenic index (IGI) described beta cell function. Also, the lipid accumulation product parameter (LAP) was assessed. LAP accounts for visceral abdominal fat and triglycerides, and it is known to be related to IS. Possible interrelationships between LAP and adipokines were explored. In T2DM and CNT, adiponectin (7.4 ± 0.5 vs. 7.8 ± 0.9 μg/mL), leptin (13.3 ± 3.0 vs. 12.4 ± 2.6 ng/mL), and QUICKI (0.33 ± 0.01 vs. 0.33 ± 0.01) were not different (P > 0.40), at variance with OGIS (317 ± 11 vs. 406 ± 13 mL/min/m(2); P = 0.006) and IGI (0.029 ± 0.005 vs. 0.185 ± 0.029 × 10(3) pmolI/mmolG; P = 0.00001). LAP was 85 ± 15 cm × mg/dL in T2DM and 74 ± 10 in CNT (P > 0.1), correlated with OGIS in all subjects (R = -0.42, P = 0.02) and QUICKI (R = -0.56, P = 0.025) in T2DM. Leptin correlated with QUICKI (R = -0.45, P = 0.009), and adiponectin correlated with OGIS (R = 0.43, P = 0.015). In overweight T2DM, insulin sensitivity in basal condition appears to be multifaceted with respect to the dynamic one, because it should be more fat-related. Insulin sensitivity appears to be incompletely described by functions of fasting glucose and insulin values alone and the

  4. Cannabinoid 2 Receptor Agonist Improves Systemic Sensitivity to Insulin in High-Fat Diet/Streptozotocin-Induced Diabetic Mice

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    Xiuyuan Zhang

    2016-12-01

    Full Text Available Background/Aims: The endocannabinoid signalling (ECS system has been known to regulate glucose homeostasis. Previous studies have suggested that the cannabinoid 2 (CB2 receptor may play a regulatory role on insulin secretion, immune modulation and insulin resistance. Given that diabetes and insulin resistance are attributable to elevated inflammatory tone, we investigated the role of CB2 receptor on glucose tolerance and insulin sensitivity in high-fat diet (HFD/streptozotocin (STZ-induced mice. Methods: Diabetes was induced in male ICR mice by HFD/STZ and exposed to a CB2 receptor agonist, SER601, for 2- or 4-weeks via subcutaneous implantation of osmotic minipumps. Glucose and insulin tolerance tests were performed at the end of treatment. Islets were isolated for assessment of β-cell function. Pancreases and skeletal muscles were also obtained for histological analyses. Results: Despite a lack of impact on glucose tolerance, substantial improvement on insulin sensitivity was observed in SER601-treated mice, which could partly be attributed to improved islet β-cell function, shown as increased glucose-induced insulin secretion and insulin content. No changes on islet macrophage infiltration or skeletal muscle fat deposition were detectable from SER601-treated mice. However, a major decrease in body weight was recorded at the end of 4-week SER601 exposure, accompanied by a lack of epididymal adipose mass in SER601-treated mice. Conclusion: Our data suggest a lipolytic role of SER601 in HFD/STZ-induced diabetic mice, which results in significant improvement of systemic insulin sensitivity. Thus, the CB2 receptor may be considered a promising target for therapeutic development against insulin resistance and obesity-related diabetes.

  5. Effects of insulin sensitizers on plaque vulnerability associated with elevated lipid content in atheroma in ApoE-knockout mice.

    Science.gov (United States)

    Cefalu, W T; Wang, Z Q; Schneider, D J; Absher, P M; Baldor, L C; Taatjes, D J; Sobel, B E

    2004-03-01

    Acute coronary syndromes are generally precipitated by rupture of lipid-laden, relatively acellular, vulnerable atherosclerotic plaques with thin fibrous caps. We investigated whether a high-fat diet alters insulin sensitivity and whether insulin sensitizers (troglitazone and rosiglitazone) alter the composition of otherwise lipidladen atherosclerotic plaques in mice deficient in apolipoprotein E (ApoE). ApoE-knockout mice were fed a high-fat (n=30) or standard chow (n=10) diet for two weeks. Thereafter, those fed the high-fat diet were treated with troglitazone (n=10), rosiglitazone (n=10) or no drug (n=10) for 16 weeks beginning at 8 weeks of age. Carbohydrate metabolism was assessed with intraperitoneal glucose tolerance tests and insulin tolerance tests. Plaque composition was characterised with confocal laser scanning microscopy. The high-fat diet induced insulin resistance in the absence of weight gain. Compared with control animals on the high-fat diet, animals given troglitazone (400 mg/kg/day) or rosiglitazone (4 mg/kg/day) had significantly less area under the curve (AUC) for insulin ( p<0.05) and glucose disposal ( p<0.05). Despite significant increases in insulin sensitivity with drug treatment, no change in HDL-cholesterol and triglyceride levels, nor reduction in atheroma size or lipid content was noted. Thus, improvement in insulin resistance induced by a high-fat diet in this animal model of vasculopathy did not alter plaque composition.

  6. Hepatic Cholesterol-25-Hydroxylase Overexpression Improves Systemic Insulin Sensitivity in Mice

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    Britta Noebauer

    2017-01-01

    Full Text Available Obesity is a major risk factor for several diseases including diabetes, heart disease, and some forms of cancer and due to its rapidly increasing prevalence it has become one of the biggest problems medicine is facing today. All the more surprising, a substantial percentage of obese patients are metabolically healthy when classified based on insulin resistance and systemic inflammation. Oxysterols are naturally occurring molecules that play important role in various metabolic and inflammatory processes and their levels are elevated in patients suffering from obesity and diabetes. 25-Hydroxycholesterol (25-OHC is produced in cells from cholesterol by the enzyme cholesterol 25-hydroxylase (Ch25h and is involved in lipid metabolism, inflammatory processes, and cell proliferation. Here, we investigated the role of hepatic Ch25h in the transition from metabolically healthy obesity to insulin resistance and diabetes. Using several different experimental approaches, we demonstrated the significance of Ch25h on the border of “healthy” and “diseased” states of obesity. Adenovirus-mediated Ch25h overexpression in mice improved glucose tolerance and insulin sensitivity and lowered HOMA-IR. Our data suggest that low hepatic Ch25h levels could be considered a risk marker for unhealthy obesity.

  7. Impact of oral vancomycin on gut microbiota, bile acid metabolism, and insulin sensitivity

    DEFF Research Database (Denmark)

    Vrieze, Anne; Out, Carolien; Fuentes, Susana

    2014-01-01

    in humans would affect fecal microbiota composition and subsequently bile acid and glucose metabolism. METHODS: In this single blinded randomized controlled trial, 20 male obese subjects with metabolic syndrome were randomized to 7 days of amoxicillin 500 mg t.i.d. or 7 days of vancomycin 500 mg t.i.d....... At baseline and after 1 week of therapy, fecal microbiota composition (Human Intestinal Tract Chip phylogenetic microarray), fecal and plasma bile acid concentrations as well as insulin sensitivity (hyperinsulinemic euglycemic clamp using [6,6-(2)H2]-glucose tracer) were measured. RESULTS: Vancomycin reduced...

  8. Palmitate stimulates glucose transport in rat adipocytes by a mechanism involving translocation of the insulin sensitive glucose transporter (GLUT4)

    Science.gov (United States)

    Hardy, R. W.; Ladenson, J. H.; Henriksen, E. J.; Holloszy, J. O.; McDonald, J. M.

    1991-01-01

    In rat adipocytes, palmitate: a) increases basal 2-deoxyglucose transport 129 +/- 27% (p less than 0.02), b) decreases the insulin sensitive glucose transporter (GLUT4) in low density microsomes and increases GLUT4 in plasma membranes and c) increases the activity of the insulin receptor tyrosine kinase. Palmitate-stimulated glucose transport is not additive with the effect of insulin and is not inhibited by the protein kinase C inhibitors staurosporine and sphingosine. In rat muscle, palmitate: a) does not affect basal glucose transport in either the soleus or epitrochlearis and b) inhibits insulin-stimulated glucose transport by 28% (p less than 0.005) in soleus but not in epitrochlearis muscle. These studies demonstrate a potentially important differential role for fatty acids in the regulation of glucose transport in different insulin target tissues.

  9. Trans fatty acid intake is associated with insulin sensitivity but independently of inflammation

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    C.T. Angelieri

    2012-07-01

    Full Text Available High saturated and trans fatty acid intake, the typical dietary pattern of Western populations, favors a proinflammatory status that contributes to generating insulin resistance (IR. We examined whether the consumption of these fatty acids was associated with IR and inflammatory markers. In this cross-sectional study, 127 non-diabetic individuals were allocated to a group without IR and 56 to another with IR, defined as homeostasis model assessment-IR (HOMA-IR >2.71. Diet was assessed using 24-h food recalls. Multiple linear regression was employed to test independent associations with HOMA-IR. The IR group presented worse anthropometric, biochemical and inflammatory profiles. Energy intake was correlated with abdominal circumference and inversely with adiponectin concentrations (r = -0.227, P = 0.002, while saturated fat intake correlated with inflammatory markers and trans fat with HOMA-IR (r = 0.160, P = 0.030. Abdominal circumference was associated with HOMA-IR (r = 0.430, P < 0.001. In multiple analysis, HOMA-IR remained associated with trans fat intake (β = 1.416, P = 0.039 and body mass index (β = 0.390, P < 0.001, and was also inversely associated with adiponectin (β = -1.637, P = 0.004. Inclusion of other nutrients (saturated fat and added sugar or other inflammatory markers (IL-6 and CRP into the models did not modify these associations. Our study supports that trans fat intake impairs insulin sensitivity. The hypothesis that its effect could depend on transcription factors, resulting in expression of proinflammatory genes, was not corroborated. We speculate that trans fat interferes predominantly with insulin signaling via intracellular kinases, which alter insulin receptor substrates.

  10. Insulin sensitivity affects propensity to obesity in an ethnic-specific manner: results from two controlled weight loss intervention studies

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    Gower Barbara A

    2013-01-01

    Full Text Available Abstract Background Risk for obesity differs with ethnicity/race and is associated with insulin sensitivity (SI, insulin responsiveness, and dietary glycemic load (GL. The objective of this study was to test the hypotheses that, 1 obesity-prone, normal weight, African-American (AA women would be more insulin sensitive than BMI-matched, never overweight AA women; 2 increased adiposity over time would be associated with greater baseline SI and higher dietary GL in AA but not European-American (EA women; and 3 increased adiposity over time would be predicted by SI in women with high but not low acute insulin response to glucose (AIRg. Methods Two controlled weight loss interventions were conducted involving overweight (BMI 25.0-29.9 kg/m2 premenopausal AA and EA women. The first included matching with normal-weight (BMI 2 controls following weight loss, and then comparing SI. The second included a 1-year follow-up of weight-reduced participants to identify predictors of change in %body fat. Main outcome measure in the first study was insulin sensitivity (SI as assessed with intravenous glucose tolerance test (IVGTT, and in the second study was change in %fat, as assessed with DXA, over one year. AIRg was assessed during IVGTT, and free-living diet was determined by food record. Results In the first study, formerly overweight AA women were 43% more insulin sensitive than BMI-matched never overweight AA (P I was positively associated with change in %fat over 1 year only in AA women (P P P = 0.086 for diet x SI interaction. In both studies, AA women had higher AIRg (P  Conclusions Formerly overweight (obesity-prone AA women were more insulin sensitive than never overweight AA women, a quality that may predispose to adiposity, particularly when combined with a high GL diet. This ethnicity/race-specific effect may be due to high insulin responsiveness among AA.

  11. Human Cortical Neural Stem Cells Expressing Insulin-Like Growth Factor-I: A Novel Cellular Therapy for Alzheimer's Disease.

    Science.gov (United States)

    McGinley, Lisa M; Sims, Erika; Lunn, J Simon; Kashlan, Osama N; Chen, Kevin S; Bruno, Elizabeth S; Pacut, Crystal M; Hazel, Tom; Johe, Karl; Sakowski, Stacey A; Feldman, Eva L

    2016-03-01

    Alzheimer's disease (AD) is the most prevalent age-related neurodegenerative disorder and a leading cause of dementia. Current treatment fails to modify underlying disease pathologies and very little progress has been made to develop effective drug treatments. Cellular therapies impact disease by multiple mechanisms, providing increased efficacy compared with traditional single-target approaches. In amyotrophic lateral sclerosis, we have shown that transplanted spinal neural stem cells (NSCs) integrate into the spinal cord, form synapses with the host, improve inflammation, and reduce disease-associated pathologies. Our current goal is to develop a similar "best in class" cellular therapy for AD. Here, we characterize a novel human cortex-derived NSC line modified to express insulin-like growth factor-I (IGF-I), HK532-IGF-I. Because IGF-I promotes neurogenesis and synaptogenesis in vivo, this enhanced NSC line offers additional environmental enrichment, enhanced neuroprotection, and a multifaceted approach to treating complex AD pathologies. We show that autocrine IGF-I production does not impact the cell secretome or normal cellular functions, including proliferation, migration, or maintenance of progenitor status. However, HK532-IGF-I cells preferentially differentiate into gamma-aminobutyric acid-ergic neurons, a subtype dysregulated in AD; produce increased vascular endothelial growth factor levels; and display an increased neuroprotective capacity in vitro. We also demonstrate that HK532-IGF-I cells survive peri-hippocampal transplantation in a murine AD model and exhibit long-term persistence in targeted brain areas. In conclusion, we believe that harnessing the benefits of cellular and IGF-I therapies together will provide the optimal therapeutic benefit to patients, and our findings support further preclinical development of HK532-IGF-I cells into a disease-modifying intervention for AD.

  12. Beneficial effects of canagliflozin in combination with pioglitazone on insulin sensitivity in rodent models of obese type 2 diabetes.

    Directory of Open Access Journals (Sweden)

    Yoshinori Watanabe

    Full Text Available Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2 inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity.Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF rats.In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity.Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes.

  13. Proof of Concept: Matrix metalloproteinase inhibitor decreases inflammation and improves muscle insulin sensitivity in people with type 2 diabetes

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    Frankwich Karen

    2012-10-01

    Full Text Available Abstract Background Obesity is a state of subclinical inflammation resulting in loss of function of insulin receptors and decreased insulin sensitivity. Inhibition of the inflammatory enzymes, matrix metalloproteinases (MMPs, for 6 months in rodent models restores insulin receptor function and insulin sensitivity. Methods This 12-week double-blind, randomized, placebo (PL-controlled proof-of-concept study was performed to determine if the MMP inhibitor (MMPI, doxycycline, decreased global markers of inflammation and enhanced muscle insulin sensitivity in obese people with type 2 diabetes (DM2. The study included non-DM2 controls (n = 15, and DM2 subjects randomized to PL (n = 13 or doxycycline 100 mg twice daily (MMPI; n = 11. All participants were evaluated on Day 1; MMPI and PL groups were also evaluated after 84 days of treatment. Results There was a significant decrease in inflammatory markers C-reactive protein (P  Conclusions This study demonstrated short term treatment of people with diabetes with an MMPI resulted in decreased inflammation and improved insulin sensitivity. Larger, longer studies are warranted to determine if doxycycline can improve glucose control in people with diabetes. Trial Registration Clinicaltrials.gov NCT01375491

  14. Beneficial Effects of Canagliflozin in Combination with Pioglitazone on Insulin Sensitivity in Rodent Models of Obese Type 2 Diabetes

    Science.gov (United States)

    Watanabe, Yoshinori; Nakayama, Keiko; Taniuchi, Nobuhiko; Horai, Yasushi; Kuriyama, Chiaki; Ueta, Kiichiro; Arakawa, Kenji; Senbonmatsu, Takaaki; Shiotani, Masaharu

    2015-01-01

    Background Despite its insulin sensitizing effects, pioglitazone may induce weight gain leading to an increased risk of development of insulin resistance. A novel sodium glucose co-transporter 2 (SGLT2) inhibitor, canagliflozin, provides not only glycemic control but also body weight reduction through an insulin-independent mechanism. The aim of this study was to investigate the combined effects of these agents on body weight control and insulin sensitivity. Methods Effects of combination therapy with canagliflozin and pioglitazone were evaluated in established diabetic KK-Ay mice and prediabetic Zucker diabetic fatty (ZDF) rats. Results In the KK-Ay mice, the combination therapy further improved glycemic control compared with canagliflozin or pioglitazone monotherapy. Furthermore, the combination significantly attenuated body weight and fat gain induced by pioglitazone and improved hyperinsulinemia. In the ZDF rats, early intervention with pioglitazone monotherapy almost completely prevented the progressive development of hyperglycemia, and no further improvement was observed by add-on treatment with canagliflozin. However, the combination significantly reduced pioglitazone-induced weight gain and adiposity and improved the Matsuda index, suggesting improved whole-body insulin sensitivity. Conclusions Our study indicates that combination therapy with canagliflozin and pioglitazone improves insulin sensitivity partly by preventing glucotoxicity and, at least partly, by attenuating pioglitazone-induced body weight gain in two different obese diabetic animal models. This combination therapy may prove to be a valuable option for the treatment and prevention of obese type 2 diabetes. PMID:25615826

  15. WWP-1 is a novel modulator of the DAF-2 insulin-like signaling network involved in pore-forming toxin cellular defenses in Caenorhabditis elegans.

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    Chang-Shi Chen

    Full Text Available Pore-forming toxins (PFTs are the single largest class of bacterial virulence factors. The DAF-2 insulin/insulin-like growth factor-1 signaling pathway, which regulates lifespan and stress resistance in Caenorhabditis elegans, is known to mutate to resistance to pathogenic bacteria. However, its role in responses against bacterial toxins and PFTs is as yet unexplored. Here we reveal that reduction of the DAF-2 insulin-like pathway confers the resistance of Caenorhabditis elegans to cytolitic crystal (Cry PFTs produced by Bacillus thuringiensis. In contrast to the canonical DAF-2 insulin-like signaling pathway previously defined for aging and pathogenesis, the PFT response pathway diverges at 3-phosphoinositide-dependent kinase 1 (PDK-1 and appears to feed into a novel insulin-like pathway signal arm defined by the WW domain Protein 1 (WWP-1. In addition, we also find that WWP-1 not only plays an important role in the intrinsic cellular defense (INCED against PFTs but also is involved in innate immunity against pathogenic bacteria Pseudomonas aeruginosa and in lifespan regulation. Taken together, our data suggest that WWP-1 and DAF-16 function in parallel within the fundamental DAF-2 insulin/IGF-1 signaling network to regulate fundamental cellular responses in C. elegans.

  16. Plasma semicarbazide-sensitive amine oxidase is moderately decreased by pronounced exogenous hyperinsulinemia but is not associated with insulin sensitivity and body fat

    NARCIS (Netherlands)

    Dullaart, R. P. F.; Riemens, S. C.; Boomsma, F.

    2006-01-01

    Objective. Semicarbazide-sensitive amine oxidase (SSAO) is widely expressed in adipose tissue, where it may contribute to stimulation of glucose transport via GLUT4 recruitment. We tested the relationships of soluble SSAO, as reflected by its plasma activity, with insulin sensitivity and indices of

  17. Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity

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    Masharani Umesh

    2012-11-01

    Full Text Available Abstract Background The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity. Methods A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 μg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan. Results After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83. There was, however, a strong association between serum chromium and change in insulin resistance (β = -0.83, p=0.01, where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy. Conclusions Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement. Trial registration The study was registered on the NIH registry (clinicaltrials.gov and the identifier is NCT00846248

  18. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice

    OpenAIRE

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2015-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests...

  19. Beef Fat Enriched with Polyunsaturated Fatty Acid Biohydrogenation Products Improves Insulin Sensitivity Without Altering Dyslipidemia in Insulin Resistant JCR:LA-cp Rats.

    Science.gov (United States)

    Diane, Abdoulaye; Borthwick, Faye; Mapiye, Cletos; Vahmani, Payam; David, Rolland C; Vine, Donna F; Dugan, Michael E R; Proctor, Spencer D

    2016-07-01

    The main dietary sources of trans fatty acids are partially hydrogenated vegetable oils (PHVO), and products derived from polyunsaturated fatty acid biohydrogenation (PUFA-BHP) in ruminants. Trans fatty acid intake has historically been associated with negative effects on health, generating an anti-trans fat campaign to reduce their consumption. The profiles and effects on health of PHVO and PUFA-BHP can, however, be quite different. Dairy products naturally enriched with vaccenic and rumenic acids have many purported health benefits, but the putative benefits of beef fat naturally enriched with PUFA-BHP have not been investigated. The objective of the present experiment was to determine the effects of beef peri-renal fat (PRF) with differing enrichments of PUFA-BHP on lipid and insulin metabolism in a rodent model of dyslipidemia and insulin resistance (JCR:LA-cp rat). The results showed that 6 weeks of diet supplementation with beef PRF naturally enriched due to flaxseed (FS-PRF) or sunflower-seed (SS-PRF) feeding to cattle significantly improved plasma fasting insulin levels and insulin sensitivity, postprandial insulin levels (only in the FS-PRF) without altering dyslipidemia. Moreover, FS-PRF but not SS-PRF attenuated adipose tissue accumulation. Therefore, enhancing levels of PUFA-BHP in beef PRF with FS feeding may be a useful approach to maximize the health-conferring value of beef-derived fats.

  20. Knock-down of IL-1Ra in obese mice decreases liver inflammation and improves insulin sensitivity.

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    Niclas Franck

    Full Text Available Interleukin 1 Receptor antagonist (IL-1Ra is highly elevated in obesity and is widely recognized as an anti-inflammatory cytokine. While the anti-inflammatory role of IL-1Ra in the pancreas is well established, the role of IL-1Ra in other insulin target tissues and the contribution of systemic IL-1Ra levels to the development of insulin resistance remains to be defined. Using antisense knock down of IL-1Ra in vivo, we show that normalization of IL-1Ra improved insulin sensitivity due to decreased inflammation in the liver and improved hepatic insulin sensitivity and these effects were independent of changes in body weight. A similar effect was observed in IL1-R1 KO mice, suggesting that at high concentrations of IL-1Ra typically observed in obesity, IL-1Ra can contribute to the development of insulin resistance in a mechanism independent of IL-1Ra binding to IL-1R1. These results demonstrate that normalization of plasma IL-1Ra concentration improves insulin sensitivity in diet- induced obese mice.

  1. Relationships of serum soluble E-selectin concentration with insulin sensitivity and metabolic flexibility in lean and obese women.

    Science.gov (United States)

    Adamska, Agnieszka; Karczewska-Kupczewska, Monika; Nikołajuk, Agnieszka; Otziomek, Elżbieta; Górska, Maria; Kowalska, Irina; Strączkowski, Marek

    2014-04-01

    The markers of endothelial dysfunction, including soluble E-selectin (sE-selectin), are related to insulin resistance, which is associated with metabolic inflexibility, i.e., impaired stimulation of carbohydrate oxidation and impaired inhibition of lipid oxidation by insulin. Endothelial dysfunction may also be important in the metabolic syndrome. The aim of our study was to analyze the association of sE-selectin with insulin sensitivity and metabolic flexibility in lean and obese women. We examined 22 lean women (BMI 25 kg m(-2)) with normal glucose tolerance. A hyperinsulinemic euglycemic clamp and indirect calorimetry were performed. An increase in the respiratory exchange ratio in response to insulin was used as a measure of metabolic flexibility. Obese women had lower insulin sensitivity (P rate of carbohydrate oxidation at the baseline state (r = 0.31, P = 0.007) and was negatively correlated with metabolic flexibility (r = -0.34, P = 0.003). MS Z-score correlated positively with sE-selectin level and negatively with metabolic flexibility and insulin sensitivity (r = 0.49, P flexibility and sE-selectin (β = -0.36; P = 0.004) was independent of the other evaluated factors. Our data suggest that endothelial dysfunction as assessed by plasma sE-selectin is associated with metabolic flexibility, inversely and independently of the other estimated factors.

  2. Serum Level of Adiponectin and Its Association with Insulin Sensitivity in Overweight Diabetic and Non-Diabetic Iranian Men

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    B Larijani

    2008-07-01

    Full Text Available Background: Adiponectin is a protein produced exclusively by adipose tissue; the reduced level of which has been shown to be involved in a variety of obesity-related disorders, such as insulin resistance and diabetes, in different ethnic groups. This cross-sectional study was conducted to determine adiponectin level and its association with insulin sensitivity in 20 adult overweight type-2 diabetic and 20 healthy over-weight non-diabetic Iranian men for the first time. Methods: Body fat mass (Bio-electric impedance, serum level of adiponectin (ELISA, fasting blood sugar and fasting insulin were measured. Insulin sensitivity was calculated using QUICKI. Results: As expected, the mean adiponectin concentration was lower in diabetics (7.7 ±3µg/ml than non-diabetics (8.1 ± 2µg/ml; however, the difference did not achieve statistical significance (P= 0.5. Adiponectin negatively correlated with fat mass. This correlation was stronger in diabetics with a higher fat mass (r= -0.3 in diabetics vs. r= -0.01 in non-diabetics; p: N.S.. Adiponectin positively related with insulin sensitivity in both groups, although this relation was only statistically significant in non-diabetics (r= +0.5; P= 0.04. The relation between insulin sensitivity and mean of adiponectin level was marginally significant even after adjustment for group (diabetic and non-diabetic, age and fat mass. Conclusion: Our findings are consistent with the studies on different ethnic groups which have indicated lower adiponectin levels in diabetics. Also our results confirm the relationship between a low adiponectin level and insulin sensitivity reported in earlier studies.

  3. Macro fat and micro fat: insulin sensitivity and gender dependent response of adipose tissue to isocaloric diet change.

    Science.gov (United States)

    Li, Yanjun; Gaillard, Jonathan R; McLaughlin, Tracey; Sørensen, Thorkild Ia; Periwal, Vipul

    2015-01-01

    The adipose cell-size distribution is a quantitative characterization of adipose tissue morphology. At a population level, the adipose cell-size distribution is insulin-sensitivity dependent, and the observed correlation between obesity and insulin resistance is believed to play a key role in the metabolic syndrome. Changes in fat mass can be induced by altered energy intake or even diet composition. These macroscopic changes must manifest themselves as dynamic adipose cell-size distribution alterations at the microscopic level. The dynamic relationship between these 2 independent measurements of body fat is unknown. In this study, we investigate adipose tissue dynamics in response to various isocaloric diet compositions, comparing gender- and insulin sensitivity-dependent differences. A body composition model is used to predict fat mass changes in response to changes in diet composition for 28 individuals, separated into 4 subgroups according to gender and insulin sensitivity/resistance. Adipose cell-size distribution changes in each individual are simulated with a dynamic model and parameters corresponding to lipid turnover and cell growth rates are determined for each subgroup to match the relative change of fat mass for each diet composition, respectively. We find that adipose cell-size dynamics are associated with different modulations dependent on gender and insulin resistance. Larger turnover and growth/shrinkage rates in insulin resistant individuals suggest they may be more sensitive to changes in energy intake and diet composition than insulin sensitive subjects. The different cell-size distribution changes of adipose cells of various sizes in different subject groups further suggest distinct modulations of adipose cell dynamics.

  4. Exercise-induced increase in IL-6 level enhances GLUT4 expression and insulin sensitivity in mouse skeletal muscle.

    Science.gov (United States)

    Ikeda, Shin-Ichi; Tamura, Yoshifumi; Kakehi, Saori; Sanada, Hiromi; Kawamori, Ryuzo; Watada, Hirotaka

    2016-05-13

    A single bout of exercise is known to increase the insulin sensitivity of skeletal muscle; however, the underlying mechanism of this phenomenon is not fully understood. Because a single bout of exercise induces a transient increase in blood interleukin-6 (IL-6) level, we hypothesized that the enhancement of insulin sensitivity after a single bout of exercise in skeletal muscle is mediated at least in part through IL-6-dependent mechanisms. To test this hypothesis, C57BL6J mice were intravenously injected with normal IgG or an IL-6 neutralizing antibody before exercise. Twenty-four hours after a single bout of exercise, the plantaris muscle was harvested to measure insulin sensitivity and glucose transporter (GLUT)-4 expression levels by ex-vivo insulin-stimulated 2-deoxyglucose (2-DG) uptake and Western blotting, respectively. Compared with sedentary mice, mice that performed exercise showed enhanced IL-6 concentration, insulin-stimulated 2-DG uptake, and GLUT-4 expression in the plantaris muscle. The enhanced insulin sensitivity and GLUT4 expression were canceled by injection of the IL-6 neutralizing antibody before exercise. In addition, IL-6 injection increased GLUT4 expression, both in the plantaris muscle and the soleus muscle in C57BL6J mice. Furthermore, a short period of incubation with IL-6 increased GLUT4 expression in differentiated C2C12 myotubes. In summary, these results suggested that IL-6 increased GLUT4 expression in muscle and that this phenomenon may play a role in the post-exercise enhancement of insulin sensitivity in skeletal muscle.

  5. Involvement of insulin-degrading enzyme in insulin- and atrial natriuretic peptide-sensitive internalization of amyloid-β peptide in mouse brain capillary endothelial cells.

    Science.gov (United States)

    Ito, Shingo; Ohtsuki, Sumio; Murata, Sho; Katsukura, Yuki; Suzuki, Hiroya; Funaki, Miho; Tachikawa, Masanori; Terasaki, Tetsuya

    2014-01-01

    Cerebral clearance of amyloid-β peptide (Aβ), which is implicated in Alzheimer's disease, involves elimination across the blood-brain barrier (BBB), and we previously showed that an insulin-sensitive process is involved in the case of Aβ1-40. The purpose of this study was to clarify the molecular mechanism of the insulin-sensitive Aβ1-40 elimination across mouse BBB. An in vivo cerebral microinjection study demonstrated that [125I]hAβ1-40 elimination from mouse brain was inhibited by human natriuretic peptide (hANP), and [125I]hANP elimination was inhibited by hAβ1-40, suggesting that hAβ1-40 and hANP share a common elimination process. Internalization of [125I]hAβ1-40 into cultured mouse brain capillary endothelial cells (TM-BBB4) was significantly inhibited by either insulin, hANP, other natriuretic peptides or insulin-degrading enzyme (IDE) inhibitors, but was not inhibited by phosphoramidon or thiorphan. Although we have reported the involvement of natriuretic peptide receptor C (Npr-C) in hANP internalization, cells stably expressing Npr-C internalized [125I]hANP but not [125I]hAβ1-40, suggesting that there is no direct interaction between Npr-C and hAβ1-40. IDE was detected in plasma membrane of TM-BBB4 cells, and internalization of [125I]hAβ1-40 by TM-BBB4 cells was reduced by IDE-targeted siRNAs. We conclude that elimination of hAβ1-40 from mouse brain across the BBB involves an insulin- and ANP-sensitive process, mediated by IDE expressed in brain capillary endothelial cells.

  6. The Relationship between Adiposity and Insulin Sensitivity in African Women Living with the Polycystic Ovarian Syndrome: A Clamp Study

    Science.gov (United States)

    Dohbit, Sama; Tchana-Sinou, Mycilline; Foumane, Pascal; Donfack, Olivier Trésor; Doh, Anderson S.

    2016-01-01

    Objectives. We aimed to assess the variation of insulin sensitivity in relation to obesity in women living with PCOS in a sub-Sahara African setting. Methods. We studied body composition, insulin sensitivity, and resting energy expenditure in 14 PCOS patients (6 obese and 8 nonobese) compared to 10 matched nonobese non-PCOS subjects. Insulin sensitivity was assessed using the gold standard 80 mU/m2/min euglycemic-hyperinsulinemic clamp and resting energy expenditure was measured by indirect calorimetry. Results. Insulin sensitivity adjusted to lean mass was lowest in obese PCOS subjects and highest in healthy subjects (11.2 [10.1–12.4] versus 12.9 [12.1–13.8] versus 16.6 [13.8–17.9], p = 0.012); there was a tendency for resting energy expenditure adjusted for total body mass to decrease across the groups highest in obese PCOS subjects (1411 [1368–1613] versus 1274 [1174–1355] versus 1239 [1195–1454], p = 0.306). Conclusion. In this sub-Saharan population, insulin resistance is associated with PCOS per se but is further aggravated by obesity. Obesity did not seem to be explained by low resting energy expenditure suggesting that dietary intake may be a determinant of the obesity in this context. PMID:27672393

  7. Control of in vivo (cellular) phleomycin sensitivity by nuclear genotype, growth phase, and metal ions

    Energy Technology Data Exchange (ETDEWEB)

    Moore, C.W.

    1982-03-01

    Nuclear genotype, growth phase, and the presence of metal ions all proved to be important in controlling the lethal effects of phleomycin in eukaryotic Saccharomyces cerevisiae. Among 120 normal and radiation-sensitive strains compared for their sensitivities to lethal effects of phleomycin, all mutant strains exhibiting enhanced sensitivities to phleomycin killing were also sensitive to killing by ionizing radiation. Mutants exhibiting sensitivities to phleomycin similar to normal strains of the same ploidy were sensitive to ultraviolet radiation. We conclude that cellular recovery from phleomycin-induced damage in yeast depends upon the function of some or all of 13 independent genes and upon at least some of the same steps in cellular pathways for the biological repair of damage by ionizing radiation. In this respect, the action of phleomycin is similar to the action of its structurally similar analog, bleomycin, even though phleomycin was substantially more cytotoxic. Stationary-phase haploid yeast cells were more sensitive than exponentially growing cells to killing by phleomycin. Survival of stationary-phase yeast was reduced to 0.3 +/- 0.07% (S.E.) after 20-min exposures to phleomycin (1 microgram/ml; approximately 6.7 x 10(-7) M), but lethal effects of phleomycin were completely eradicated (98% survival) by the presence of 0.05 M ethylenediaminetetraacetate during the treatment period. The inactivation indicates an important role for one or more metal ion(s) in the in vivo toxicity of the phleomycin-bleomycin group of anticancer antibiotics.

  8. Soy pinitol acts partly as an insulin sensitizer or insulin mediator in 3T3-L1 preadipocytes

    OpenAIRE

    Do, Gyeong-Min; Choi, Myung-Sook; Kim, Hye-Jin; Woo, Myung-Nam; Lee, Mi-Kyung; Jeon, Seon-Min

    2007-01-01

    The blood glucose-lowering property of pinitol is mediated via the insulin signaling pathway. This study was carried out to evaluate the effects of soy pinitol on adipogenesis in a 3T3-L1 cell line; 3T3-L1 preadipocytes were treated with pinitol (0–1 mM) together with insulin for 9 days. The regulation of lipid metabolism was assessed by oil-red-O staining of intracellular lipids and real-time PCR of adipogenesis-related factors. The inhibition of cell proliferation was estimated by MTT assay...

  9. Effects of chronic calorie restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate, Microcebus murinus.

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    Julia Marchal

    Full Text Available The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV, a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1·kg(-1. Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT and the homeostasis model assessment of insulin resistance (HOMA-IR index evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic

  10. Gender differences in non-glycemic responses to improved insulin sensitivity by pioglitazone treatment in patients with type 2 diabetes.

    Science.gov (United States)

    Arnetz, Lisa; Dorkhan, Mozhgan; Alvarsson, Michael; Brismar, Kerstin; Ekberg, Neda Rajamand

    2014-04-01

    Excess cortisol and GH induce insulin resistance, a central feature of type 2 diabetes (T2D). To study whether the insulin sensitizer pioglitazone affects basal cortisol levels and the GH-IGF-I axis in patients with T2D. Forty-eight patients with T2D (men/women = 28:20, age 61 ± 1 years, BMI 31 ± 0.6 kg/m(2)) were treated for 26 weeks with pioglitazone 30-45 mg daily in addition to their preexisting therapy. Insulin, proinsulin, HbA(1c), IGF-I, IGFBP-1, and basal cortisol were analyzed before and after treatment. Pioglitazone decreased proinsulin/insulin ratio and HbA(1c) decreased (HbA(1c) from 7.8 ± 0.2 to 6.6 ± 0.2% in men and from 7.6 ± 0.2 to 6.1 ± 0.2% in women, p pioglitazone increased IGF-I regardless of gender and in women also increased basal cortisol. Increased IGF-I may contribute to improved insulin sensitivity after treatment. There seems to be gender differences in treatment responses to pioglitazone on lipid metabolism and basal cortisol, perhaps correcting different mechanisms of insulin resistance between genders.

  11. EFFECT OF CHRONIC ACE INHIBITION ON GLUCOSE TOLERANCE AND INSULIN SENSITIVITY IN HYPERTENSIVE TYPE 2 DIABETIC PATIENTS

    Institute of Scientific and Technical Information of China (English)

    尹卫东; G.Seghieri; C.Boni,G,Sanna; R.Anichinl; G.Bartolomei; E.Ferrannini

    1994-01-01

    We studied 14 moderately overweight Type 2 diabetic patients with essential hypertension in stable metabolic control after a run-in period,and again after 3 months of antihypertensive treatment with the angiotensin-convert-ing enzyme(ACE)inhibitor captopril.Glucose tolerance was tested with a 75g oral glucose load (OGTT) and in-sulin sensitivity was measured by the insulin suppression test (IST)while dietary and drug treatment of the hyper-glycemia was maintained constant.In the whole group,mean blood pressure (MBP) fell progressively over 3 months from a baseline value of 123±3mmHg(1 mmHg=0.133kpa)to a final value of 115±2mmHg(P<0.005).After treatment,fasting plasma glucose,insulin,free fatty acid (FFA),potassium,and glycosylated hemoglobin concentrations were unchanged from baseling.There were no significant differences in glucose toler-ance and insulin sensitivity between pre-and post-trearment values.Neither endogenous (oral glucose)nor exoge-nous(IST)insulin caused any change in plasma potassium concentration. This resistance to the hypokalemic action of insulin was not affected by captopril.

  12. Routine OGTT: a robust model including incretin effect for precise identification of insulin sensitivity and secretion in a single individual.

    Directory of Open Access Journals (Sweden)

    Andrea De Gaetano

    Full Text Available In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT, impaired glucose tolerance (IGT, impaired fasting glucose (IFG, IFG+IGT, and Type 2 Diabetes Mellitus (T2DM. A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO and the 2002 Dalla Man (Dalla Man MOdel, DMMO models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO. ANOVA on kxgi values across groups resulted significant overall (P<0.001, and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5±9.36×10(-5 min(-1pM(-1, IFG (5.30×10(-5±5.18×10(-5 and combined IGT, IFG+IGT and T2DM (2.09×10(-5±1.95×10(-5, 2.38×10(-5±2.28×10(-5 and 2.38×10(-5±2.09×10(-5 respectively. No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%, with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically

  13. Routine OGTT: a robust model including incretin effect for precise identification of insulin sensitivity and secretion in a single individual.

    Science.gov (United States)

    De Gaetano, Andrea; Panunzi, Simona; Matone, Alice; Samson, Adeline; Vrbikova, Jana; Bendlova, Bela; Pacini, Giovanni

    2013-01-01

    In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5)±9.36×10(-5) min(-1)pM(-1)), IFG (5.30×10(-5)±5.18×10(-5)) and combined IGT, IFG+IGT and T2DM (2.09×10(-5)±1.95×10(-5), 2.38×10(-5)±2.28×10(-5) and 2.38×10(-5)±2.09×10(-5) respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically

  14. Characterization of lipid metabolism in insulin-sensitive adipocytes differentiated from immortalized human mesenchymal stem cells.

    Science.gov (United States)

    Prawitt, Janne; Niemeier, Andreas; Kassem, Moustapha; Beisiegel, Ulrike; Heeren, Joerg

    2008-02-15

    There is a great demand for cell models to study human adipocyte function. Here we describe the adipogenic differentiation of a telomerase-immortalized human mesenchymal stem cell line (hMSC-Tert) that maintains numerous features of terminally differentiated adipocytes even after prolonged withdrawal of the peroxisome proliferator activated receptor gamma (PPARgamma) agonist rosiglitazone. Differentiated hMSC-Tert developed the characteristic monolocular phenotype of mature adipocytes. The expression of adipocyte specific markers was highly increased during differentiation. Most importantly, the presence of the PPARgamma agonist rosiglitazone was not required for the stable expression of lipoprotein lipase, adipocyte fatty acid binding protein and perilipin on mRNA and protein levels. Adiponectin expression was post-transcriptionally down-regulated in the absence of rosiglitazone. Insulin sensitivity as measured by insulin-induced phosphorylation of Akt and S6 ribosomal protein was also independent of rosiglitazone. In addition to commonly used adipogenic markers, we investigated further PPARgamma-stimulated proteins with a role in lipid metabolism. We observed an increase of lipoprotein receptor (VLDLR, LRP1) and apolipoprotein E expression during differentiation. Despite this increased expression, the receptor-mediated endocytosis of lipoproteins was decreased in differentiated adipocytes, suggesting that these proteins may have an additional function in adipose tissue beyond lipoprotein uptake.

  15. Ethnic differences in glucose disposal, hepatic insulin sensitivity, and endogenous glucose production among African American and European American women.

    Science.gov (United States)

    Ellis, Amy C; Alvarez, Jessica A; Granger, Wesley M; Ovalle, Fernando; Gower, Barbara A

    2012-05-01

    Intravenous glucose tolerance tests have demonstrated lower whole-body insulin sensitivity (S(I)) among African Americans (AA) compared with European Americans (EA). Whole-body S(I) represents both insulin-stimulated glucose disposal, primarily by skeletal muscle, and insulin's suppression of endogenous glucose production (EGP) by liver. A mathematical model was recently introduced that allows for distinction between disposal and hepatic S(I). The purpose of this study was to examine specific indexes of S(I) among AA and EA women to determine whether lower whole-body S(I) in AA may be attributed to insulin action at muscle, liver, or both. Participants were 53 nondiabetic, premenopausal AA and EA women. Profiles of EGP and indexes of Disposal S(I) and Hepatic S(I) were calculated by mathematical modeling and incorporation of a stable isotope tracer ([6,6-(2)H(2)]glucose) into the intravenous glucose tolerance test. Body composition was assessed by dual-energy x-ray absorptiometry. After adjustment for percentage fat, both Disposal S(I) and Hepatic S(I) were lower among AA (P = .009 for both). Time profiles for serum insulin and EGP revealed higher peak insulin response and corresponding lower EGP among AA women compared with EA. Indexes from a recently introduced mathematical model suggest that lower whole-body S(I) among nondiabetic AA women is due to both hepatic and peripheral components. Despite lower Hepatic S(I), AA displayed lower EGP, resulting from higher postchallenge insulin levels. Future research is needed to determine the physiological basis of lower insulin sensitivity among AA and its implications for type 2 diabetes mellitus risk.

  16. Insulin sensitivity and inhibition by forskolin, dipyridamole and pentobarbital of glucose transport in three L6 muscle cell lines

    Institute of Scientific and Technical Information of China (English)

    2007-01-01

    L6 skeletal muscle myoblasts stably overexpressing glucose transporter GLUT1 or GLUT4 with exofacial myc-epitope tags were characterized for their response to insulin. In clonally selected cultures, 2-deoxyglucose uptake into L6-GLUT1myc myoblasts and myotubes was linear within the time of study. In L6-GLUT1myc and L6-GLUT4myc myoblasts, 100 nmol/L insulin treatment increased the GLUT1 content of the plasma membrane by 1.58±0.01 fold and the GLUT4 content 1.96±0.11 fold, as well as the 2-deoxyglucose uptake 1.53±0.09 and 1.86±0.17 fold respectively, all by a wortmannin-inhibitable manner. The phosphorylation of Akt in these two cell lines was increased by insulin. L6-GLUT1myc myoblasts showed a dose-dependent stimulation of glucose uptake by insulin, with unaltered sensitivity and maximal responsiveness compared with wild type cells. By contrast, the improved insulin responsiveness and sensitivity of glucose uptake were observed in L6-GLUT4myc myoblasts. Earlier studies indicated that forskolin might affect insulin-stimulated GLUT4 translocation. A 65% decrease of insulin-stimulated 2-deoxyglucose uptake in GLUT4myc cells was not due to an effect on GLUT4 mobilization to the plasma membrane, but instead on direct inhibition of GLUT4. Forskolin and dipyridamole are more potent inhibitors of GLUT4 than GLUT1. Alternatively, pentobarbital inhibits GLUT1 more than GLUT4. The use of these inhibitors confirmed that the overexpressed GLUT1 or GLUT4 are the major functional glucose transporters in unstimulated and insulin-stimulated L6 myoblasts. Therefore, L6-GLUT1myc and L6-GLUT4myc cells provide a platform to screen compounds that may have differential effects on GLUT isoform activity or may influence GLUT isoform mobilization to the cell surface of muscle cells.

  17. Circadian rhythms, metabolism, and insulin sensitivity: transcriptional networks in animal models.

    Science.gov (United States)

    Kitazawa, Masashi

    2013-04-01

    Homeostatic systems have adapted to respond to the diurnal light/dark cycle. Numerous physiological pathways, including metabolism, are coordinated by this 24-h cycle. Animals with mutations in clock genes show abnormal glucose and lipid metabolism, indicating a critical relationship between the circadian clock and metabolism. Energy homeostasis is achieved through circadian regulation of the expression and activity of several key metabolic enzymes. Temporal organization of tissue metabolism is coordinated by reciprocal cross-talk between the core clock mechanism and key metabolic enzymes and transcriptional activators. The aim of this review is to define the role of the circadian clock in the regulation of insulin sensitivity by describing the interconnection between the circadian clock and metabolic pathways.

  18. Jicama (Pachyrhizus erosus) extract increases insulin sensitivity and regulates hepatic glucose in C57BL/Ksj-db/db mice.

    Science.gov (United States)

    Park, Chan Joo; Lee, Hyun-Ah; Han, Ji-Sook

    2016-01-01

    This study investigated the effect of jicama extract on hyperglycemia and insulin sensitivity in an animal model of type 2 diabetes. Male C57BL/Ksj-db/db mice were divided into groups subsequently fed a regular diet (controls), or diet supplemented with jicama extract, and rosiglitazone. After 6 weeks, blood levels of glucose and glycosylated hemoglobin were significantly lower in animals administered the jicama extract than the control group. Additionally, glucose and insulin tolerance tests showed that jicama extract increased insulin sensitivity. The homeostatic index of insulin resistance was lower in the jicama extract-treated group than in the diabetic control group. Administration of jicama extract significantly enhanced the expressions of the phosphorylated AMP-activated protein kinase and Akt substrate of 160 kDa, and plasma membrane glucose transporter type 4 in skeletal muscle. Jicama extract administration also decreased the expressions of glucose 6-phosphatase and phosphoenol pyruvate carboxykinase in the liver. Jicama extract may increases insulin sensitivity and inhibites the gluconeogenesis in the liver.

  19. Resistance training associated with the administration of anabolic-androgenic steroids improves insulin sensitivity in ovariectomized rats

    Directory of Open Access Journals (Sweden)

    Urtado CB

    2011-11-01

    Full Text Available Christiano Bertoldo Urtado1,2, Guilherme Borges Pereira3, Marilia Bertoldo Urtado4, Érica Blascovi de Carvalho2, Gerson dos Santos Leite1, Felipe Fedrizzi Donatto1, Claudio de Oliveira Assumpção1, Richard Diego Leite3, Carlos Alberto da Silva1, Marcelo Magalhães de Sales5, Ramires Alsamir Tibana5, Silvia Cristina Crepaldi Alves1, Jonato Prestes51Health Sciences, Methodist University of Piracicaba, Piracicaba, SP, 2Center for Investigation in Pediatrics, Faculty of Medical Sciences, State University of Campinas, Campinas, SP, 3Department of Physiological Sciences, Federal University of São Carlos, São Carlos, SP, 4Laboratory of Orofacial Pain, Division of Oral Physiology, Piracicaba Dental School, State University of Campinas, Campinas, SP, 5Graduation Program in Physical Education, Catholic University of Brasilia, Brasilia, DF, BrazilAbstract: The aim of the present study was to investigate the effects of anabolic-androgenic steroids and resistance training (RT on insulin sensitivity in ovariectomized rats. Adult female Wistar rats were divided into ten experimental groups (n = 5 animals per group: (1 sedentary (Sed-Intact; (2 sedentary ovariectomized (Sed-Ovx; (3 sedentary nandrolone (Sed-Intact-ND; (4 sedentary ovariectomized plus nandrolone (Sed-Ovx-ND; (5 trained (TR-Intact; (6 trained nandrolone (TR-Intact-ND; (7 trained ovariectomized (TR-Ovx; (8 trained ovariectomized plus nandrolone; (9 trained sham; and (10 trained ovariectomized plus sham. Four sessions of RT were used, during which the animals climbed a 1.1 m vertical ladder with weights attached to their tails. The sessions were performed once every 3 days, with between four and nine climbs and with eight to twelve dynamic movements per climb. To test the sensitivity of insulin in the pancreas, glucose and insulin tolerance tests were performed. For insulin sensitivity, there was a statistically significant interaction for the TR-Ovx group, which presented higher sensitivity

  20. Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass.

    Directory of Open Access Journals (Sweden)

    Amandine Girousse

    Full Text Available When energy is needed, white adipose tissue (WAT provides fatty acids (FAs for use in peripheral tissues via stimulation of fat cell lipolysis. FAs have been postulated to play a critical role in the development of obesity-induced insulin resistance, a major risk factor for diabetes and cardiovascular disease. However, whether and how chronic inhibition of fat mobilization from WAT modulates insulin sensitivity remains elusive. Hormone-sensitive lipase (HSL participates in the breakdown of WAT triacylglycerol into FAs. HSL haploinsufficiency and treatment with a HSL inhibitor resulted in improvement of insulin tolerance without impact on body weight, fat mass, and WAT inflammation in high-fat-diet-fed mice. In vivo palmitate turnover analysis revealed that blunted lipolytic capacity is associated with diminution in FA uptake and storage in peripheral tissues of obese HSL haploinsufficient mice. The reduction in FA turnover was accompanied by an improvement of glucose metabolism with a shift in respiratory quotient, increase of glucose uptake in WAT and skeletal muscle, and enhancement of de novo lipogenesis and insulin signalling in liver. In human adipocytes, HSL gene silencing led to improved insulin-stimulated glucose uptake, resulting in increased de novo lipogenesis and activation of cognate gene expression. In clinical studies, WAT lipolytic rate was positively and negatively correlated with indexes of insulin resistance and WAT de novo lipogenesis gene expression, respectively. In obese individuals, chronic inhibition of lipolysis resulted in induction of WAT de novo lipogenesis gene expression. Thus, reduction in WAT lipolysis reshapes FA fluxes without increase of fat mass and improves glucose metabolism through cell-autonomous induction of fat cell de novo lipogenesis, which contributes to improved insulin sensitivity.

  1. Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity

    DEFF Research Database (Denmark)

    Bonfils, Linéa; Ellervik, Christina; Friedrich, Nele

    2015-01-01

    Aims/hypothesis: Elevated serum ferritin levels are associated with an increased risk of type 2 diabetes, but the nature of this association remains elusive. The aim of this study was to test the hypothesis that an elevated fasting serum ferritin level is associated with an increased risk of type 2...... diabetes due to its association with impaired beta cell function and decreased insulin sensitivity. Methods: We investigated 6,392 individuals from the Danish general population. Surrogate measures of beta cell function and insulin sensitivity were calculated for approximately 6,100 individuals based...... glucose levels at 0, 30 and 120 min (p beta cell function estimated as the insulinogenic index and corrected insulin response (p 

  2. A paradox: Insulin inhibits expression and secretion of resistin which induces insulin resistance

    Institute of Scientific and Technical Information of China (English)

    Feng Liu; Mei Guo; Rong-Hua Chen; Xi-Rong Guo; Hong-Qi Fan; Jie Qiu; Bin Wang; Min Zhang; Nan Gu; Chun-Mei Zhang; Li Fei; Xiao-Qing Pan

    2008-01-01

    AIM:To confirm whether insulin regulates resistin expression and secretion during differentiation of 3T3-L1 preadipocytes and the relationship of resistin with insulin resistance both in vivo and in vitro. METHODS: Supernatant resistin was measured during differentiation of 3T3-L1 preadipocytes. L6 rat myoblasts and hepatoma cell line H4IIE were used to confirm the cellular function of resistin. Diet-induced obese rats were used as an insulin resistance model to study the relationship of resistin with insulin resistance.RESULTS: Resistin expression and secretion were enhanced during differentiation 3T3-L1 preadipocytes. This cellular differentiation stimulated resistin expression and secretion, but was suppressed by insulin. Resistin also induced insulin resistance in H4IIE hepatocytes and L6 myoblasts. In diet-induced obese rats, serum resistin levels were negatively correlated with insulin sensitivity,but not with serum insulin. CONCLUSION: Insulin can inhibit resistin expression and secretion in vitro, but insulin is not a major regulator of resistin in vivo. Fat tissue mass affects insulin sensitivity by altering the expression and secretion of resistin.

  3. A common polymorphism near the interleukin-6 gene modifies the association between dietary fat intake and insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Cuda C

    2012-01-01

    Full Text Available Cristina Cuda1, Bibiana Garcia-Bailo1,2, Mohamed Karmali1,2, Ahmed El-Sohemy1, Alaa Badawi21Department of Nutritional Sciences, University of Toronto, 2Office of Biotechnology, Genomics and Population Health, Public Health Agency of Canada, Toronto, Ontario, CanadaBackground: Increasing evidence suggests a role for inflammation in the development of type 2 diabetes. Elevated levels of inflammatory cytokines, including interleukin-6, have been associated with insulin resistance, and dietary lipids can increase cytokine production. The objective of this study was to determine whether a single nucleotide polymorphism near the IL6 gene (rs7801406 modifies the relationship between dietary fat and markers of insulin sensitivity.Methods: Subjects were healthy men and women aged 20–29 years from the Toronto Nutrigenomics and Health Study. Dietary intake was estimated using a one-month semiquantitative food frequency questionnaire. Fasting blood samples were taken for genotyping and biomarker measurement.Results: The single nucleotide polymorphism was not associated with any of the measures of insulin sensitivity. However, it modified the relationship between total dietary fat and the homeostasis model assessment of insulin resistance (P = 0.053 for interaction. Total fat intake was positively related to HOMA-IR in individuals homozygous for the G allele (ß = 0.005 ± 0.002, P = 0.03, but not among heterozygotes. There was an inverse relationship between total fat intake and HOMA-IR in individuals who were homozygous for the A allele (β= –0.012 ± 0.006, P = 0.047.Conclusion: These findings suggest that dietary fat influences insulin sensitivity differently depending on genotype.Keywords: interleukin-6, insulin sensitivity, nutrigenomics, dietary fat

  4. Effect of moxonidine and amlodipine on serum YKL-40, plasma lipids and insulin sensitivity in insulin-resistant hypertensive patients-a randomized, crossover trial.

    Science.gov (United States)

    Masajtis-Zagajewska, Anna; Majer, Jacek; Nowicki, Michał

    2010-04-01

    Moxonidine is a selective imidazoline receptor agonist with comparable blood pressure-lowering efficacy to first-line antihypertensives and favorable metabolic effects. YKL-40 (chitinase-3-1-protein) has been proposed as a new marker of inflammation, atherosclerosis and endothelial dysfunction in neoplastic, cardiovascular and metabolic diseases but has not yet been studied in the context of essential hypertension. Fifteen patients (10 M, 5 F; age 48+/-14 years) with arterial hypertension and insulin resistance (HOMA-IR index >2.77) on at least two antihypertensive drugs were randomized to receive either moxonidine (0.4 mg) or amlodipine (10 mg) for two 8-week periods with a 7-day wash-out. Serum insulin, glucose, C-reactive protein (CRP), lipids, uric acid, YKL-40 and blood pressure were measured and insulin sensitivity was calculated (HOMA) at the beginning and end of each study phase. Mean BP decreased significantly with both moxonidine and amlodipine (-9.8+/-7.6 and -10.4+/-7.3 mm Hg, respectively). Serum high-density lipoprotein cholesterol increased with both therapies, but only moxonidine-affected serum triglycerides. No significant changes in serum uric acid, CRP, YKL-40 (2.3 and 3.3 ng ml(-1), respectively) or HOMA index (0.70+/-2.4 and 0.76+/-2.8) were observed. There was a strong negative correlation between serum uric acid and YKL-40 concentration at baseline (r=-0.77, P=0.01). Serum YKL-40 did not correlate with blood pressure, biochemical parameters or HOMA index. Moxonidine is an effective adjunctive antihypertensive agent for use in patients with hypertension and insulin resistance that induces beneficial effects on serum lipid profile but does not reduce insulin resistance, inflammation or serum YKL-40 concentration.

  5. A 12 week aerobic exercise program improves fitness, hepatic insulin sensitivity and glucose metabolism in obese Hispanic adolescents

    Science.gov (United States)

    The rise in obesity related morbidity in children and adolescents requires urgent prevention and treatment strategies. Strictly controlled exercise programs might be useful tools to improve insulin sensitivity and glucose kinetics. Our objective was to test the hypothesis that a 12-wk aerobic exerci...

  6. Age-dependent nongenetic influences of birth weight and adult body fat on insulin sensitivity in twins

    DEFF Research Database (Denmark)

    Monrad, Rikke Nygaard; Grunnet, Louise Groth; Rasmussen, Eva Lind

    2009-01-01

    We hypothesized a nongenetic influence of birth weight (BW) and twin and zygosity status on dual-energy x-ray absorptiometry determined adult total and regional body composition and a quantitative equal, although independent, importance of adult body composition and BW for insulin sensitivity....

  7. Intima-Media Thickness of Carotid Artery is Associated with Insulin Sensitivity and Glucose Tolerance in Elderly Chinese

    Institute of Scientific and Technical Information of China (English)

    Yi-na Zhang; Can Cui; Ying Fan; Man-li Chang; Wei Wu; Wei-gang Yu; Ning Tan; Feng-chen Liu; Jin-chao Zhang

    2005-01-01

    @@ Previous studies have shown that patients with type 2 diabetes and even those with impaired glucose tolerance (IGT)have marked higher risk of atherosclerosis than nondiabetic subjects. The relationship between carotid atherosclerosis intima-media thickness (IMT) with glucose tolerance status and insulin sensitivity was studied in the elderly Chinese subjects.

  8. Bezafibrate ameliorates diabetes via reduced steatosis and improved hepatic insulin sensitivity in diabetic TallyHo mice

    Directory of Open Access Journals (Sweden)

    Andras Franko

    2017-03-01

    Conclusions: Our data showed that BEZ ameliorates diabetes probably via reduced steatosis, enhanced hepatic mitochondrial mass, improved metabolic flexibility and elevated hepatic insulin sensitivity in TallyHo mice, suggesting that BEZ treatment could be beneficial for patients with NAFLD and impaired glucose metabolism.

  9. Changes in glucose tolerance and insulin sensitivity following 2 weeks of daily cinnamon ingestion in healthy humans

    DEFF Research Database (Denmark)

    Solomon, Thomas; Blannin, Andrew K

    2009-01-01

    Cinnamon can improve fasting glucose in humans yet data on insulin sensitivity are limited and controversial. Eight male volunteers (aged 25 +/- 1 years, body mass 76.5 +/- 3.0 kg, BMI 24.0 +/- 0.7 kg m(-2); mean +/- SEM) underwent two 14-day interventions involving cinnamon or placebo supplement...

  10. The dipeptidyl peptidase-4 inhibitor vildagliptin improves beta-cell function and insulin sensitivity in subjects with impaired fasting glucose

    DEFF Research Database (Denmark)

    Utzschneider, Kristina M; Tong, Jenny; Montgomery, Brenda;

    2007-01-01

    OBJECTIVE: To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCH DESIGN AND METHODS: A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD...

  11. Replacing Fish Oil with Vegetable Oils in Salmon Feed Increases Hepatic Lipid Accumulation and Reduces Insulin Sensitivity in Mice

    DEFF Research Database (Denmark)

    Midtbø, Lisa Kolden

    %) of FO with different vegetable oils (VOs); rape seed oil (WDRO), olive oil (WD-OO) or soybean oil (WD-SO). These diets were given to C57BL/6J mice, and mice had higher hepatic lipid accumulation and lower insulin sensitivity when given WD-SO compared with WD-FO. Mice given WD-SO had higher hepatic...

  12. Effect of moderate alcohol consumption on adipokines and insulin sensitivity in lean and overweight men: A diet intervention study

    NARCIS (Netherlands)

    Beulens, J.W.J.; Zoete, E.C.de; Kok, F.J.; Schaafsma, G.; Hendriks, H.F.J.

    2008-01-01

    Objective: Moderate alcohol consumption is associated with a decreased risk of type II diabetes. This study investigates the effect of moderate alcohol consumption on adipokines and insulin sensitivity. Subjects: Twenty healthy, lean (body mass index (BMI) 18.5-25 kg/m2; n=11) or overweight (BMI>27

  13. Adiponectin concentration is associated with muscle insulin sensitivity, AMPK phosphorylation and ceramide content in skeletal muslce of men, but not women

    DEFF Research Database (Denmark)

    Høeg, Louise Dalgas; Sjøberg, Kim Anker; Lundsgaard, Anne-Marie;

    2013-01-01

    Adiponectin is an adipokine that regulates metabolism and increases insulin sensitivity. Mechanisms behind this insulin sensitizing effect have been investigated in rodents, but little is known in humans especially in skeletal muscle. Women have higher serum concentrations of adiponectin than men...

  14. Diabetes Alters the Expression and Translocation of the Insulin-Sensitive Glucose Transporters 4 and 8 in the Atria.

    Directory of Open Access Journals (Sweden)

    Zahra Maria

    Full Text Available Although diabetes has been identified as a major risk factor for atrial fibrillation, little is known about glucose metabolism in the healthy and diabetic atria. Glucose transport into the cell, the rate-limiting step of glucose utilization, is regulated by the Glucose Transporters (GLUTs. Although GLUT4 is the major isoform in the heart, GLUT8 has recently emerged as a novel cardiac isoform. We hypothesized that GLUT-4 and -8 translocation to the atrial cell surface will be regulated by insulin and impaired during insulin-dependent diabetes. GLUT protein content was measured by Western blotting in healthy cardiac myocytes and type 1 (streptozotocin-induced, T1Dx diabetic rodents. Active cell surface GLUT content was measured using a biotinylated photolabeled assay in the perfused heart. In the healthy atria, insulin stimulation increased both GLUT-4 and -8 translocation to the cell surface (by 100% and 240%, respectively, P<0.05. Upon insulin stimulation, we reported an increase in Akt (Th308 and s473 sites and AS160 phosphorylation, which was positively (P<0.05 correlated with GLUT4 protein content in the healthy atria. During diabetes, active cell surface GLUT-4 and -8 content was downregulated in the atria (by 70% and 90%, respectively, P<0.05. Akt and AS160 phosphorylation was not impaired in the diabetic atria, suggesting the presence of an intact insulin signaling pathway. This was confirmed by the rescued translocation of GLUT-4 and -8 to the atrial cell surface upon insulin stimulation in the atria of type 1 diabetic subjects. In conclusion, our data suggest that: 1 both GLUT-4 and -8 are insulin-sensitive in the healthy atria through an Akt/AS160 dependent pathway; 2 GLUT-4 and -8 trafficking is impaired in the diabetic atria and rescued by insulin treatment. Alterations in atrial glucose transport may induce perturbations in energy production, which may provide a metabolic substrate for atrial fibrillation during diabetes.

  15. Thrombospondin1 deficiency reduces obesity-associated inflammation and improves insulin sensitivity in a diet-induced obese mouse model.

    Directory of Open Access Journals (Sweden)

    Yanzhang Li

    Full Text Available BACKGROUND: Obesity is prevalent worldwide and is associated with insulin resistance. Advanced studies suggest that obesity-associated low-grade chronic inflammation contributes to the development of insulin resistance and other metabolic complications. Thrombospondin 1 (TSP1 is a multifunctional extracellular matrix protein that is up-regulated in inflamed adipose tissue. A recent study suggests a positive correlation of TSP1 with obesity, adipose inflammation, and insulin resistance. However, the direct effect of TSP1 on obesity and insulin resistance is not known. Therefore, we investigated the role of TSP1 in mediating obesity-associated inflammation and insulin resistance by using TSP1 knockout mice. METHODOLOGY/PRINCIPAL FINDINGS: Male TSP1-/- mice and wild type littermate controls were fed a low-fat (LF or a high-fat (HF diet for 16 weeks. Throughout the study, body weight and fat mass increased similarly between the TSP1-/- mice and WT mice under HF feeding conditions, suggesting that TSP1 deficiency does not affect the development of obesity. However, obese TSP1-/- mice had improved glucose tolerance and increased insulin sensitivity compared to the obese wild type mice. Macrophage accumulation and inflammatory cytokine expression in adipose tissue were reduced in obese TSP1-/- mice. Consistent with the local decrease in pro-inflammatory cytokine levels, systemic inflammation was also decreased in the obese TSP1-/- mice. Furthermore, in vitro data demonstrated that TSP1 deficient macrophages had decreased mobility and a reduced inflammatory phenotype. CONCLUSION: TSP1 deficiency did not affect the development of high-fat diet induced obesity. However, TSP1 deficiency reduced macrophage accumulation in adipose tissue and protected against obesity related inflammation and insulin resistance. Our data demonstrate that TSP1 may play an important role in regulating macrophage function and mediating obesity-induced inflammation and insulin

  16. Adipose Tissue Promotes a Serum Cytokine Profile Related to Lower Insulin Sensitivity after Chronic Central Leptin Infusion

    Science.gov (United States)

    Burgos-Ramos, Emma; Canelles, Sandra; Perianes-Cachero, Arancha; Arilla-Ferreiro, Eduardo; Argente, Jesús; Barrios, Vicente

    2012-01-01

    Obesity is an inflammatory state characterized by an augment in circulating inflammatory factors. Leptin may modulate the synthesis of these factors by white adipose tissue decreasing insulin sensitivity. We have examined the effect of chronic central administration of leptin on circulating levels of cytokines and the possible relationship with cytokine expression and protein content as well as with leptin and insulin signaling in subcutaneous and visceral adipose tissues. In addition, we analyzed the possible correlation between circulating levels of cytokines and peripheral insulin resistance. We studied 18 male Wistar rats divided into controls (C), those treated icv for 14 days with a daily dose of 12 μg of leptin (L) and a pair-fed group (PF) that received the same food amount consumed by the leptin group. Serum leptin and insulin were measured by ELISA, mRNA levels of interferon-γ (IFN-γ), interleukin-2 (IL-2), IL-4, IL-6, IL-10 and tumor necrosis factor-α (TNF-α) by real time PCR and serum and adipose tissue levels of these cytokines by multiplexed bead immunoassay. Serum leptin, IL-2, IL-4, IFN-γ and HOMA-IR were increased in L and TNF-α was decreased in PF and L. Serum leptin and IL-2 levels correlate positively with HOMA-IR index and negatively with serum glucose levels during an ip insulin tolerance test. In L, an increase in mRNA levels of IL-2 was found in both adipose depots and IFN-γ only in visceral tissue. Activation of leptin signaling was increased and insulin signaling decreased in subcutaneous fat of L. In conclusion, leptin mediates the production of inflammatory cytokines by adipose tissue independent of its effects on food intake, decreasing insulin sensitivity. PMID:23056516

  17. The association of adipose-derived dimethylarginine dimethylaminohydrolase-2 with insulin sensitivity in experimental type 2 diabetes mellitus

    Institute of Scientific and Technical Information of China (English)

    Jie Zheng; Kuansong Wang; Ping Jin; Changsheng Dong; Qiong Yuan; Yuanjian Li; Zhichun Yang

    2013-01-01

    Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOS),which can be hydrolyzed by dimethylarginine-dimethylaminohydrolase (DDAH).It has been reported that adipocytes can produce DDAH/ADMA,but its role remains unknown.In the present study,we examined the effects of adipocyte-derived DDAH/ADMA on insulin sensitivity using animal and cell models.Results showed that in adipose tissue of high fat diet-fed diabetic rats,as well as in high glucose (25 mM) plus insulin (100nM)-treated 3T3-L1 adipocytes,expression levels of insulin receptor substance-1 (IRS-1),glucose transporter-4 (GLUT-4),and DDAH isoform-2 (DDAH-2) were down-regulated compared with control,although DDAH-1 expression showed no significant changes.We also observed that nitric oxide bioavailability,DDAH and NOS activities were subsequently decreased,while the local ADMA content was elevated in diabetic adipose tissue.Transfection of human DDAH-2 gene into high glucose-and insulin-treated 3T3-L1 adipocytes significantly ameliorated DDAH activity,reduced ADMA contents,and up-regulated the mRNA expression levels of IRS-1 and GLUT-4.These findings suggested that in the development of type 2 diabetes mellitus,local DDAH-2 in adipocytes might play an important role in regulating insulin sensitivity.

  18. Prep1 deficiency induces protection from diabetes and increased insulin sensitivity through a p160-mediated mechanism.

    Science.gov (United States)

    Oriente, Francesco; Fernandez Diaz, Luis Cesar; Miele, Claudia; Iovino, Salvatore; Mori, Silvia; Diaz, Victor Manuel; Troncone, Giancarlo; Cassese, Angela; Formisano, Pietro; Blasi, Francesco; Beguinot, Francesco

    2008-09-01

    We have examined glucose homeostasis in mice hypomorphic for the homeotic transcription factor gene Prep1. Prep1-hypomorphic (Prep1(i/i)) mice exhibit an absolute reduction in circulating insulin levels but normal glucose tolerance. In addition, these mice exhibit protection from streptozotocin-induced diabetes and enhanced insulin sensitivity with improved glucose uptake and insulin-dependent glucose disposal by skeletal muscle. This muscle phenotype does not depend on reduced expression of the known Prep1 transcription partner, Pbx1. Instead, in Prep1(i/i) muscle, we find normal Pbx1 but reduced levels of the recently identified novel Prep1 interactor p160. Consistent with this reduction, we find a muscle-selective increase in mRNA and protein levels of PGC-1alpha, accompanied by enhanced expression of the GLUT4 transporter, responsible for insulin-stimulated glucose uptake in muscle. Indeed, using L6 skeletal muscle cells, we induced the opposite effects by overexpressing Prep1 or p160, but not Pbx1. In vivo skeletal muscle delivery of p160 cDNA in Prep1(i/i) mice also reverses the molecular phenotype. Finally, we show that Prep1 controls the stability of the p160 protein. We conclude that Prep1 controls insulin sensitivity through the p160-GLUT4 pathway.

  19. Pterocarpan-enriched soy leaf extract ameliorates insulin sensitivity and pancreatic β-cell proliferation in type 2 diabetic mice.

    Science.gov (United States)

    Kim, Un-Hee; Yoon, Jeong-Hyun; Li, Hua; Kang, Ji-Hyun; Ji, Hyeon-Seon; Park, Ki Hun; Shin, Dong-Ha; Park, Ho-Yong; Jeong, Tae-Sook

    2014-11-13

    In Korea, soy (Glycine max (L.) Merr.) leaves are eaten as a seasonal vegetable or pickled in soy sauce. Ethyl acetate extracts of soy leaves (EASL) are enriched in pterocarpans and have potent α-glucosidase inhibitory activity. This study investigated the molecular mechanisms underlying the anti-diabetic effect of EASL in C57BL/6J mice with high-fat diet (HFD)-induced type 2 diabetes. Mice were randomly divided into normal diet (ND), HFD (60 kcal% fat diet), EASL (HFD with 0.56% (wt/wt) EASL), and Pinitol (HFD with 0.15% (wt/wt) pinitol) groups. Weight gain and abdominal fat accumulation were significantly suppressed by EASL. Levels of plasma glucose, HbA1c, and insulin in the EASL group were significantly lower than those of the HFD group, and the pancreatic islet of the EASL group had greater size than those of the HFD group. EASL group up-regulated neurogenin 3 (Ngn3), paired box 4 (Pax4), and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA), which are markers of pancreatic cell development, as well as insulin receptor substrate 1 (IRS1), IRS2, and glucose transporter 4 (GLUT4), which are related to insulin sensitivity. Furthermore, EASL suppressed genes involved in hepatic gluconeogenesis and steatosis. These results suggest that EASL improves plasma glucose and insulin levels in mice with HDF-induced type 2 diabetes by regulating β-cell proliferation and insulin sensitivity.

  20. Inverse regulation of inflammation and mitochondrial function in adipose tissue defines extreme insulin sensitivity in morbidly obese patients.

    Science.gov (United States)

    Qatanani, Mohammed; Tan, Yejun; Dobrin, Radu; Greenawalt, Danielle M; Hu, Guanghui; Zhao, Wenqing; Olefsky, Jerrold M; Sears, Dorothy D; Kaplan, Lee M; Kemp, Daniel M

    2013-03-01

    Obesity is associated with insulin resistance, a major risk factor for type 2 diabetes and cardiovascular disease. However, not all obese individuals are insulin resistant, which confounds our understanding of the mechanistic link between these conditions. We conducted transcriptome analyses on 835 obese subjects with mean BMI of 48.8, on which we have previously reported genetic associations of gene expression. Here, we selected ~320 nondiabetic (HbA(1c) immune response and inflammation-related genes were significantly downregulated in the omental adipose tissue of obese individuals with extreme insulin sensitivity and, to a much lesser extent, in subcutaneous adipose tissue. In contrast, genes related to β-oxidation and the citric acid cycle were relatively overexpressed in adipose of insulin-sensitive patients. These observations were verified by querying an independent cohort of our published dataset of 37 subjects whose subcutaneous adipose tissue was sampled before and after treatment with thiazolidinediones. Whereas the immune response and inflammation pathway genes were downregulated by thiazolidinedione treatment, β-oxidation and citric acid cycle genes were upregulated. This work highlights the critical role that omental adipose inflammatory pathways might play in the pathophysiology of insulin resistance, independent of body weight.

  1. Pterocarpan-Enriched Soy Leaf Extract Ameliorates Insulin Sensitivity and Pancreatic β-Cell Proliferation in Type 2 Diabetic Mice

    Directory of Open Access Journals (Sweden)

    Un-Hee Kim

    2014-11-01

    Full Text Available In Korea, soy (Glycine max (L. Merr. leaves are eaten as a seasonal vegetable or pickled in soy sauce. Ethyl acetate extracts of soy leaves (EASL are enriched in pterocarpans and have potent α-glucosidase inhibitory activity. This study investigated the molecular mechanisms underlying the anti-diabetic effect of EASL in C57BL/6J mice with high-fat diet (HFD-induced type 2 diabetes. Mice were randomly divided into normal diet (ND, HFD (60 kcal% fat diet, EASL (HFD with 0.56% (wt/wt EASL, and Pinitol (HFD with 0.15% (wt/wt pinitol groups. Weight gain and abdominal fat accumulation were significantly suppressed by EASL. Levels of plasma glucose, HbA1c, and insulin in the EASL group were significantly lower than those of the HFD group, and the pancreatic islet of the EASL group had greater size than those of the HFD group. EASL group up-regulated neurogenin 3 (Ngn3, paired box 4 (Pax4, and v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA, which are markers of pancreatic cell development, as well as insulin receptor substrate 1 (IRS1, IRS2, and glucose transporter 4 (GLUT4, which are related to insulin sensitivity. Furthermore, EASL suppressed genes involved in hepatic gluconeogenesis and steatosis. These results suggest that EASL improves plasma glucose and insulin levels in mice with HDF-induced type 2 diabetes by regulating β-cell proliferation and insulin sensitivity.

  2. A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun.

    Science.gov (United States)

    Xiao, Fei; Deng, Jiali; Yu, Junjie; Guo, Yajie; Chen, Shanghai; Guo, Feifan

    2016-01-01

    Insulin resistance is one of the major factors contributing to metabolic diseases, but the underlying mechanisms are still poorly understood. As an important cofactor, B-cell translocation gene 1 (BTG1) is involved in many physiologic processes; however, the direct effect of BTG1 on insulin sensitivity has not been described. In our study, BTG1 overexpression or knockdown improved or impaired insulin signaling in vitro, respectively. In addition, adenovirus-mediated BTG1 overexpression improved insulin sensitivity in wild-type (WT) and insulin-resistant leptin-receptor mutated (db/db) mice. In addition, transgenic BTG1-overexpressing mice were resistant to high-carbohydrate diet-induced insulin resistance. Adenovirus-mediated BTG1 knockdown consistently impaired insulin sensitivity in WT and insulin-sensitive leucine-deprived mice. Moreover, hepatic BTG1 expression was increased by leucine deprivation via the mammalian target of rapamycin/ribosomal protein S6 kinase 1 pathway. Furthermore, c-Jun expression was up-regulated by BTG1, and adenovirus-mediated c-Jun knockdown blocked BTG1-improved insulin signaling and insulin sensitivity in vitro and in vivo. Finally, BTG1 promoted c-Jun expression via stimulating c-Jun and retinoic acid receptor activities. Taken together, these results identify a novel function for BTG1 in the regulation of hepatic insulin sensitivity and provide important insights into the nutritional regulation of BTG1 expression.- Xiao, F., Deng, J., Yu, J., Guo, Y., Chen, S., Guo, F. A novel function of B-cell translocation gene 1 (BTG1) in the regulation of hepatic insulin sensitivity in mice via c-Jun.

  3. Enhanced insulin sensitivity mediated by adipose tissue browning perturbs islet morphology and hormone secretion in response to autonomic nervous activation in female mice.

    Science.gov (United States)

    Omar, Bilal A; Kvist-Reimer, Martina; Enerbäck, Sven; Ahrén, Bo

    2016-01-01

    Insulin resistance results in a compensatory increase in insulin secretion to maintain normoglycemia. Conversely, high insulin sensitivity results in reduced insulin secretion to prevent hypoglycemia. The mechanisms for this inverse adaptation are not well understood. We utilized highly insulin-sensitive mice, due to adipocyte-specific overexpression of the FOXC2 transcription factor, to study mechanisms of the reversed islet adaptation to increased insulin sensitivity. We found that Foxc2TG mice responded to mild hyperglycemia with insulin secretion significantly lower than that of wild-type mice; however, when severe hyperglycemia was induced, Foxc2TG mice demonstrated insulin secretion equal to or greater than that of wild-type mice. In response to autonomic nervous activation by 2-deoxyglucose, the acute suppression of insulin seen in wild-type mice was absent in Foxc2TG mice, suggesting impaired sympathetic signaling to the islet. Basal glucagon was increased in Foxc2TG mice, but they displayed severely impaired glucagon responses to cholinergic and autonomic nervous stimuli. These data suggest that the autonomic nerves contribute to the islet adaptation to high insulin sensitivity, which is compatible with a neuro-adipo regulation of islet function being instrumental for maintaining glucose regulation.

  4. Synergistic effects of leucine and resveratrol on insulin sensitivity and fat metabolism in adipocytes and mice

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    Bruckbauer Antje

    2012-08-01

    Full Text Available Abstract Background Sirtuins are important regulators of glucose and fat metabolism, and sirtuin activation has been proposed as a therapeutic target for insulin resistance and diabetes. We have shown leucine to increase mitochondrial biogenesis and fat oxidation via Sirt1 dependent pathways. Resveratrol is a widely recognized activator of Sirt; however, the biologically-effective high concentrations used in cell and animal studies are generally impractical or difficult to achieve in humans. Accordingly, we sought to determine whether leucine would exhibit synergy with low levels of resveratrol on sirtuin-dependent outcomes in adipocytes and in diet-induced obese (DIO mice. Methods 3T3-L1 mouse adipocytes were treated with Leucine (0.5 mM, β-hydroxy-β-methyl butyrate (HMB (5 μM or Resveratrol (200 nM alone or in combination. In addition, diet-induced obese mice were treated for 6-weeks with low (2 g/kg diet or high (10 g/kg diet dose HMB, Leucine (24 g/kg diet; 200% of normal level or low (12.5 mg/kg diet or high (225 mg/kg diet dose resveratrol, alone or as combination with leucine-resveratrol or HMB-resveratrol. Results Fatty acid oxidation, AMPK, Sirt1 and Sirt3 activity in 3T3-L1 adipocytes and in muscle cells, were significantly increased by the combinations compared to the individual treatments. Similarly, 6-week feeding of low-dose resveratrol combined with either leucine or its metabolite HMB to DIO mice increased adipose Sirt1 activity, muscle glucose and palmitate uptake (measured via PET/CT, insulin sensitivity (HOMAIR, improved inflammatory stress biomarkers (CRP, IL-6, MCP-1, adiponectin and reduced adiposity comparable to the effects of high dose resveratrol, while low-dose resveratrol exerted no independent effect. Conclusion These data demonstrate that either leucine or its metabolite HMB may be combined with a low concentration of resveratrol to exert synergistic effects on Sirt1-dependent outcomes; this may result in more

  5. Serum Resistin Levels Are Associated with Adiposity and Insulin Sensitivity in Obese Hispanic Subjects

    Science.gov (United States)

    Nieva-Vazquez, Adriana; Torres-Rasgado, Enrique; López-López, José G.; Romero, Jose R.

    2014-01-01

    Abstract Background and Aims: Resistin is involved in the development of obesity and insulin resistance (IR) in mice and may play a similar role in humans through mechanisms that remain unresolved. The objective of this study was to characterize the relationship between resistin levels in obese subjects with and without IR among Hispanic subjects. Material and Methods: A cross-sectional study was performed on 117 nondiabetic Hispanic subjects of both genders that were allocated into three study groups: A control group (n=47) of otherwise healthy individuals in metabolic balance, a group with obesity (OB) (n=36), and a group with obesity and IR (OB-IR) (n=34). Anthropometric and clinical characterization was carried out, and resistin levels were determined by enzyme-linked immunosorbent assay (ELISA). Results: We found that resistin levels were higher in OB and OB-IR groups when compared to the control group (1331.79±142.15 pg/mL, 1266.28±165.97 pg/mL vs. 959.21±171.43 pg/mL; P<0.05), an effect that was not confounded by age (control, 34.04±10.00 years; OB, 37.30±10.78 years; and OB-IR, 35.67±10.15 years). In addition, we observed a significant correlation (P<0.001) between resistin levels and higher adiposity and insulin sensitivity (IS) in our cohort. Conclusions: Our results suggest that higher resistin levels are associated with higher adiposity and lower IS among obese Hispanic subjects. PMID:24266722

  6. Antidiabetic property of Symplocos cochinchinensis is mediated by inhibition of alpha glucosidase and enhanced insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Kalathookunnel Antony Antu

    Full Text Available The study is designed to find out the biochemical basis of antidiabetic property of Symplocos cochinchinensis (SC, the main ingredient of 'Nisakathakadi' an Ayurvedic decoction for diabetes. Since diabetes is a multifactorial disease, ethanolic extract of the bark (SCE and its fractions (hexane, dichloromethane, ethyl acetate and 90% ethanol were evaluated by in vitro methods against multiple targets relevant to diabetes such as the alpha glucosidase inhibition, glucose uptake, adipogenic potential, oxidative stress, pancreatic beta cell proliferation, inhibition of protein glycation, protein tyrosine phosphatase-1B (PTP-1B and dipeptidyl peptidase-IV (DPP-IV. Among the extracts, SCE exhibited comparatively better activity like alpha glucosidase inhibition (IC50 value-82.07 ± 2.10 µg/mL, insulin dependent glucose uptake (3 fold increase in L6 myotubes, pancreatic beta cell regeneration in RIN-m5F (3.5 fold increase and reduced triglyceride accumulation (22% decrease in 3T3L1 cells, protection from hyperglycemia induced generation of reactive oxygen species in HepG2 cells (59.57% decrease with moderate antiglycation and PTP-1B inhibition. Chemical characterization by HPLC revealed the superiority of SCE over other extracts due to presence and quantity of bioactives (beta-sitosterol, phloretin 2'glucoside, oleanolic acid in addition to minerals like magnesium, calcium, potassium, sodium, zinc and manganese. So SCE has been subjected to oral sucrose tolerance test to evaluate its antihyperglycemic property in mild diabetic and diabetic animal models. SCE showed significant antihyperglycemic activity in in vivo diabetic models. We conclude that SC mediates the antidiabetic activity mainly via alpha glucosidase inhibition, improved insulin sensitivity, with moderate antiglycation and antioxidant activity.

  7. Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity.

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    Kate S Collison

    Full Text Available Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (P<0.05. Females were less affected, but had significantly raised fasting glucose levels. During spatial learning trials in the MWM (acquisition training, the escape latencies of male aspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (P<0.05. Spatial learning of female aspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime

  8. Gender dimorphism in aspartame-induced impairment of spatial cognition and insulin sensitivity.

    Science.gov (United States)

    Collison, Kate S; Makhoul, Nadine J; Zaidi, Marya Z; Saleh, Soad M; Andres, Bernard; Inglis, Angela; Al-Rabiah, Rana; Al-Mohanna, Futwan A

    2012-01-01

    Previous studies have linked aspartame consumption to impaired retention of learned behavior in rodents. Prenatal exposure to aspartame has also been shown to impair odor-associative learning in guinea pigs; and recently, aspartame-fed hyperlipidemic zebrafish exhibited weight gain, hyperglycemia and acute swimming defects. We therefore investigated the effects of chronic lifetime exposure to aspartame, commencing in utero, on changes in blood glucose parameters, spatial learning and memory in C57BL/6J mice. Morris Water Maze (MWM) testing was used to assess learning and memory, and a random-fed insulin tolerance test was performed to assess glucose homeostasis. Pearson correlation analysis was used to investigate the associations between body characteristics and MWM performance outcome variables. At 17 weeks of age, male aspartame-fed mice exhibited weight gain, elevated fasting glucose levels and decreased insulin sensitivity compared to controls (Paspartame-fed mice were consistently higher than controls, indicative of learning impairment. Thigmotactic behavior and time spent floating directionless was increased in aspartame mice, who also spent less time searching in the target quadrant of the maze (Paspartame-fed mice was not significantly different from controls. Reference memory during a probe test was affected in both genders, with the aspartame-fed mice spending significantly less time searching for the former location of the platform. Interestingly, the extent of visceral fat deposition correlated positively with non-spatial search strategies such as floating and thigmotaxis, and negatively with time spent in the target quadrant and swimming across the location of the escape platform. These data suggest that lifetime exposure to aspartame, commencing in utero, may affect spatial cognition and glucose homeostasis in C57BL/6J mice, particularly in males.

  9. "Regulation of the intracerebroventricular administration of brain-derived neurotrophic factor on baroreflex function and insulin sensitivity in rats".

    Science.gov (United States)

    Wang, Ming-Fu; Chan, Yin-Ching; Lee, Hsu-Tung; Hong, Ling-Zong

    2012-06-30

    "In addition to its well-established neurotrophic effects, brain-derived neurotrophic factor (BDNF) has also been shown to regulate glucose metabolism. The present study was conducted to determine whether BDNF has effects on baroreflex sensitivity (BRS) and whole-body insulin sensitivity through modulation of autonomic nervous function in normal rats. Male Sprague-Dawley rats were treated with intracerebroventricular BDNF (20 μg per rat, 10μl; BDNF) or artificial cerebrospinal fluid (10 μl; control) at an infusion rate of 1 μl/min in conscious state. The whole-body insulin sensitivity was determined by the euglycemic hyperinsulinemic clamp technique. BRS in response to phenylephrine (PE-BRS) or sodium nitroprusside (NP-BRS) was assessed using linear regression analysis. The sympathetic and parasympathetic influences on BRS were investigated by pharmacological autonomic blockade. When compared to the control rats, blood glucose levels were slightly but significantly decreased in BDNF-treated rats. However, plasma insulin levels were reduced by about 30%. The whole-body insulin sensitivity was increased in BDNF-treated rats. In addition, blood pressure was increased but heart rate remained unchanged after BDNF treatment. Enhanced PE-BRS was also observed in the BDNF-treated rats, which was attributed to the abnormal parasympathetic activation as revealed by the results of the pharmacological blockade study with methylatropine. Results of the present demonstrate that central BDNF plays an important role in the regulation of whole-body insulin sensitivity and baroreflex function. The data indicate that the alteration of autonomic nervous function may play a role in the effects of BDNF."

  10. Insulin-sensitizing and cardiovascular effects of the sodium-hydrogen exchange inhibitor, cariporide, in the JCR: LA-cp rat and db/db mouse.

    Science.gov (United States)

    Russell, J C; Proctor, S D; Kelly, S E; Löhn, M; Busch, A E; Schäfer, S

    2005-12-01

    The effects of the sodium-hydrogen (Na/H) exchange inhibitor cariporide (HOE642), on insulin sensitivity and vascular function were studied in the JCR:LA-cp rat and the db/db mouse. In the insulin-resistant rat, cariporide reduced fasting insulin levels (42%, P JCR:LA-cp insulin-resistant rat, which develops advanced cardiovascular disease and ischemic myocardial lesions. It also improved vascular function in a similar mouse model of insulin resistance. These effects were markedly greater than those of ramipril.

  11. Mediterranean diet and insulin sensitivity, lipid profile and blood pressure levels, in overweight and obese people; The Attica study

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    Zampelas Antonis

    2007-09-01

    Full Text Available Abstract Background We aimed to investigate if overweight and obese adults "close" to Mediterranean diet present better insulin, lipids profile and better pressure levels, compared to individuals close to a more Westernized diet. Methods The ATTICA study is a population-based cohort that has randomly enrolled 3042 adult men and women, stratified by age – gender, from the greater area of Athens, during 2001–2002. Of them, in this work were have studied 1762 participants with excess body weight, meaning overweight (BMI: 25–29.9 kg/m2 and obese (BMI>30 kg/m2. 1064 were men and 698 women (20–89 years old. Adherence to Mediterranean diet was assessed through a diet-score that was based on a validated food-frequency questionnaire. Blood pressure was measured and also fasting glucose, insulin and blood lipids. Insulin sensitivity was also assessed by the homeostasis model assessment (HOMA approach (glucose × insulin/22.5. Results Individuals with excess bodyweight in the highest tertile of diet score, were more insulin sensitive than those in the lowest tertile (11.4% lower HOMA, p = 0.06, had 13% lower levels of total cholesterol (p = 0.001 and 3 mmHg decrease of systolic blood pressure levels (p Conclusion Adherence to Mediterranean diet is modeslty associated with a better insulin sensitivity, lower levels of total cholesterol and lower levels of systolic blood pressure in overweight and obese subjects. This may suggest that compared to general population, the beneficial effect of this diet in cardiovascular system of excess body weight people is limited.

  12. Actinic reticuloid idiopathic photodermatosis with cellular sensitivity to near ultraviolet radiation

    Energy Technology Data Exchange (ETDEWEB)

    Botcherby, P.K.; Marimo, B.; Giannelli, F. (Guy' s Hospital Medical School, London (UK)); Magnus, I.A. (Institute of Dermatology, London (UK))

    1984-05-01

    Long wavelength UV radiations (320-400 nm) cause persistent inhibition of RNA synthesis and marked cytopathic changes in fibroblasts from patients with actinic reticuloid (AR) but not in those from patients with Bloom syndrome or xeroderma pigmentosum. Furthermore, the AR cells show abnormal DNA fragmentation when they are irradiated at temperatures compatible with enzyme activity. Germicidal UVR (ca. 95% 254 nm) stimulates DNA repair synthesis and inhibits DNA replication to a normal extent in the AR cells. Thus, actinic reticuloid, a severe photodermatosis, characterised by skin sensitivity to UV-B, UV-A and part of the visible spectrum and infiltrates reminiscent of mycosis fungoides, is a human disease with in vitro cellular sensitivity to UV-A and is also the first to be reported. A hypothesis is advanced that inefficient cellular neutralisation of free radicals may explain the cellular phenotype of actinic reticuloid and contribute to the establishment of a vicious circle that would favour the chronic clinical course and persistent lympho-histiocytic skin infiltrates characteristic of the disease.

  13. Endurance training improves insulin sensitivity and body composition in prostate cancer patients treated with androgen deprivation therapy

    DEFF Research Database (Denmark)

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders;

    2013-01-01

    Insulin resistance and changes in body composition are side effects of androgen deprivation therapy (ADT) given to prostate cancer patients. The present study investigated whether endurance training improves insulin sensitivity and body composition in ADT-treated prostate cancer patients. Nine men...... and magnetic resonance imaging). The secondary endpoint was systemic inflammation. Statistical analysis was carried out using two-way ANOVA. Endurance training increased VO2max (ml(O2)/min per kg) by 11 and 13% in the patients and controls respectively (P...

  14. Limitations in the use of indices using glucose and insulin levels to predict insulin sensitivity: impact of race and gender and superiority of the indices derived from oral glucose tolerance test in African Americans.

    Science.gov (United States)

    Pisprasert, Veeradej; Ingram, Katherine H; Lopez-Davila, Maria F; Munoz, A Julian; Garvey, W Timothy

    2013-04-01

    OBJECTIVE To examine the utility of commonly used insulin sensitivity indices in nondiabetic European Americans (EAs) and African Americans (AAs). RESEARCH DESIGN AND METHODS Two-hundred forty nondiabetic participants were studied. Euglycemic-hyperinsulinemic clamp was the gold standard approach to assess glucose disposal rates (GDR) normalized by lean body mass. The homeostatic model assessment for insulin resistance (HOMA-IR) and the quantitative insulin sensitivity check index (QUICKI) were calculated from fasting plasma glucose and insulin (FIL). Oral glucose tolerance test (OGTT) was performed to determine Matsuda index, the simple index assessing insulin sensitivity (SI(is)OGTT), Avignon index, and Stomvoll index. Relationships among these indices with GDR were analyzed by multiple regression. RESULTS GDR values were similar in EA and AA subgroups; even so, AA exhibited higher FIL and were insulin-resistant compared with EA, as assessed by HOMA-IR, QUICKI, Matsuda index, SI(is)OGTT, Avignon index, and Stumvoll index. In the overall study population, GDR was significantly correlated with all studied insulin sensitivity indices (/r/ = 0.381-0.513); however, these indices were not superior to FIL in predicting GDR. Race and gender affected the strength of this relationship. In AA males, FIL and HOMA-IR were not correlated with GDR. In contrast, Matsuda index and SI(is)OGTT were significantly correlated with GDR in AA males, and Matsuda index was superior to HOMA-IR and QUICKI in AAs overall. CONCLUSIONS Insulin sensitivity indices based on glucose and insulin levels should be used cautiously as measures of peripheral insulin sensitivity when comparing mixed gender and mixed race populations. Matsuda index and SI(is)OGTT are reliable in studies that include AA males.

  15. Insulin-like growth factor 2 silencing restores taxol sensitivity in drug resistant ovarian cancer.

    Science.gov (United States)

    Brouwer-Visser, Jurriaan; Lee, Jiyeon; McCullagh, KellyAnne; Cossio, Maria J; Wang, Yanhua; Huang, Gloria S

    2014-01-01

    Drug resistance is an obstacle to the effective treatment of ovarian cancer. We and others have shown that the insulin-like growth factor (IGF) signaling pathway is a novel potential target to overcome drug resistance. The purpose of this study was to validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and to determine the efficacy of targeting IGF2 in vivo. An analysis of The Cancer Genome Atlas (TCGA) data in the serous ovarian cancer cohort showed that high IGF2 mRNA expression is significantly associated with shortened interval to disease progression and death, clinical indicators of drug resistance. In a genetically diverse panel of ovarian cancer cell lines, the IGF2 mRNA levels measured in cell lines resistant to various microtubule-stabilizing agents including Taxol were found to be significantly elevated compared to the drug sensitive cell lines. The effect of IGF2 knockdown on Taxol resistance was investigated in vitro and in vivo. Transient IGF2 knockdown significantly sensitized drug resistant cells to Taxol treatment. A Taxol-resistant ovarian cancer xenograft model, developed from HEY-T30 cells, exhibited extreme drug resistance, wherein the maximal tolerated dose of Taxol did not delay tumor growth in mice. Blocking the IGF1R (a transmembrane receptor that transmits signals from IGF1 and IGF2) using a monoclonal antibody did not alter the response to Taxol. However, stable IGF2 knockdown using short-hairpin RNA in HEY-T30 effectively restored Taxol sensitivity. These findings validate IGF2 as a potential therapeutic target in drug resistant ovarian cancer and show that directly targeting IGF2 may be a preferable strategy compared with targeting IGF1R alone.

  16. Sensitivity analysis of FBMC-based multi-cellular networks to synchronization errors and HPA nonlinearities

    Science.gov (United States)

    Elmaroud, Brahim; Faqihi, Ahmed; Aboutajdine, Driss

    2017-01-01

    In this paper, we study the performance of asynchronous and nonlinear FBMC-based multi-cellular networks. The considered system includes a reference mobile perfectly synchronized with its reference base station (BS) and K interfering BSs. Both synchronization errors and high-power amplifier (HPA) distortions will be considered and a theoretical analysis of the interference signal will be conducted. On the basis of this analysis, we will derive an accurate expression of signal-to-noise-plus-interference ratio (SINR) and bit error rate (BER) in the presence of a frequency-selective channel. In order to reduce the computational complexity of the BER expression, we applied an interesting lemma based on the moment generating function of the interference power. Finally, the proposed model is evaluated through computer simulations which show a high sensitivity of the asynchronous FBMC-based multi-cellular network to HPA nonlinear distortions.

  17. Essential role of PSM/SH2-B variants in insulin receptor catalytic activation and the resulting cellular responses.

    Science.gov (United States)

    Zhang, Manchao; Deng, Youping; Tandon, Ruchi; Bai, Cheng; Riedel, Heimo

    2008-01-01

    The positive regulatory role of PSM/SH2-B downstream of various mitogenic receptor tyrosine kinases or gene disruption experiments in mice support a role of PSM in the regulation of insulin action. Here, four alternative PSM splice variants and individual functional domains were compared for their role in the regulation of specific metabolic insulin responses. We found that individual PSM variants in 3T3-L1 adipocytes potentiated insulin-mediated glucose and amino acid transport, glycogenesis, lipogenesis, and key components in the metabolic insulin response including p70 S6 kinase, glycogen synthase, glycogen synthase kinase 3 (GSK3), Akt, Cbl, and IRS-1. Highest activity was consistently observed for PSM alpha, followed by beta, delta, and gamma with decreasing activity. In contrast, dominant-negative peptide mimetics of the PSM Pro-rich, pleckstrin homology (PH), or src homology 2 (SH2) domains inhibited any tested insulin response. Potentiation of the insulin response originated at the insulin receptor (IR) kinase level by PSM variant-specific regulation of the Km (ATP) whereas the Vmax remained unaffected. IR catalytic activation was inhibited by peptide mimetics of the PSM SH2 or dimerization domain (DD). Either peptide should disrupt the complex of a PSM dimer linked to IR via SH2 domains as proposed for PSM activation of tyrosine kinase JAK2. Either peptide abolished downstream insulin responses indistinguishable from PSM siRNA knockdown. Our results implicate an essential role of the PSM variants in the activation of the IR kinase and the resulting metabolic insulin response. PSM variants act as internal IR ligands that in addition to potentiating the insulin response stimulate IR catalytic activation even in the absence of insulin.

  18. Lactose in milk replacer can partly be replaced by glucose, fructose, or glycerol without affecting insulin sensitivity in veal calves.

    Science.gov (United States)

    Pantophlet, A J; Gilbert, M S; van den Borne, J J G C; Gerrits, W J J; Roelofsen, H; Priebe, M G; Vonk, R J

    2016-04-01

    Calf milk replacer (MR) contains 40 to 50% lactose. Lactose strongly fluctuates in price and alternatives are desired. Also, problems with glucose homeostasis and insulin sensitivity (i.e., high incidence of hyperglycemia and hyperinsulinemia) have been described for heavy veal calves (body weight >100 kg). Replacement of lactose by other dietary substrates can be economically attractive, and may also positively (or negatively) affect the risk of developing problems with glucose metabolism. An experiment was designed to study the effects of replacing one third of the dietary lactose by glucose, fructose, or glycerol on glucose homeostasis and insulin sensitivity in veal calves. Forty male Holstein-Friesian (body weight=114 ± 2.4 kg; age=97 ± 1.4 d) calves were fed an MR containing 462 g of lactose/kg (CON), or an MR in which 150 g of lactose/kg of MR was replaced by glucose (GLU), fructose (FRU), or glycerol (GLY). During the first 10d of the trial, all calves received CON. The CON group remained on this diet and the other groups received their experimental diets for a period of 8 wk. Measurements were conducted during the first (baseline) and last week of the trial. A frequently sampled intravenous glucose tolerance test was performed to assess insulin sensitivity and 24 h of urine was collected to measure glucose excretion. During the last week of the trial, a bolus of 1.5 g of [U-(13)C] substrates was added to their respective meals and plasma glucose, insulin, and (13)C-glucose responses were measured. Insulin sensitivity was low at the start of the trial and remained low [1.2 ± 0.1 and 1.0 ± 0.1 (mU/L)(-1) × min(-1)], and no treatment effect was noted. Glucose excretion was low at the start of the trial (3.4 ± 1.0 g/d), but increased in CON and GLU calves (26.9 ± 3.9 and 43.0 ± 10.6g/d) but not in FRU and GLY calves. Postprandial glucose was higher in GLU, lower in FRU, and similar in GLY compared with CON calves. Postprandial insulin was lower in FRU

  19. A highly sensitive peptide substrate for detecting two Aß-degrading enzymes: neprilysin and insulin-degrading enzyme.

    Science.gov (United States)

    Chen, Po-Ting; Liao, Tai-Yan; Hu, Chaur-Jong; Wu, Shu-Ting; Wang, Steven S-S; Chen, Rita P-Y

    2010-06-30

    Neprilysin has been singled out as the most promising candidate for use in the degradation of Abeta as a therapy for Alzheimer's disease. In this study, a quenched fluorogenic peptide substrate containing the first seven residues of the Abeta peptide plus a C-terminal Cysteine residue was synthesized to detect neprilysin activity. A fluorophore was attached to the C-terminal Cysteine and its fluorescence was quenched by a quencher linked to the N-terminus of the peptide. When this peptide substrate was degraded by an endopeptidase, fluorescence was produced and proved to be a sensitive detection system for endopeptidase activity. Our results showed that this assay system was extremely sensitive to neprilysin and insulin-degrading enzyme, but insensitive, or much less sensitive, to other Abeta-degrading enzymes. As low as 0.1 nM of neprilysin and 0.2 nM of insulin-degrading enzyme can be detected.

  20. Increased glucocorticoid sensitivity in pancreatic beta-cells : Effects on glucose metabolism and insulin release

    OpenAIRE

    Davani, Behrous

    2003-01-01

    Type 2 diabetes mellitus (T2DM) is characterized by three pathological alterations: (1) insulin resistance in peripheral tissues, (2) increased hepatic glucose production and (3) impaired insulin secretion from the pancreatic beta-cells. Glucocorticoids (GCs) exert profound effects on glucose homeostasis. They decrease glucose uptake and increase hepatic glucose production. In addition, they may directly inhibit insulin release. The main aim of this thesis was to investigate...

  1. Insulin sensitizing effects of oligomannuronate-chromium (III complexes in C2C12 skeletal muscle cells.

    Directory of Open Access Journals (Sweden)

    Cui Hao

    Full Text Available BACKGROUND: It was known that the insulin resistance in skeletal muscle is a major pathogenic factor in diabetes mellitus. Therefore prevention of metabolic disorder caused by insulin resistance and improvement of insulin sensitivity are very important for the therapy of type 2 diabetes. In the present study, we investigated the ability of marine oligosaccharides oligomannuronate and its chromium (III complexes from brown alga to enhance insulin sensitivity in C2C12 skeletal muscle cells. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrated that oligomannuronate, especially its chromium (III complexes, enhanced insulin-stimulated glucose uptake and increased the mRNA expression of glucose transporter 4 (GLUT4 and insulin receptor (IR after their internalization into C2C12 skeletal muscle cells. Additionally, oligosaccharides treatment also significantly enhanced the phosphorylation of proteins involved in both AMP activated protein kinase (AMPK/acetyl-CoA carboxylase (ACC and phosphoinositide 3-kinase (PI3K/protein kinase B (Akt signaling pathways in C2C12 cells, indicating that the oligosaccharides activated both the insulin signal pathway and AMPK pathways as their mode of action. Moreover, oligosaccharides distributed to the mitochondria after internalization into C2C12 cells and increased the expression of transcriptional regulator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α, carnitine palmitoyl transferase-1 (CPT-1, and phosphorylated acetyl-CoA carboxylase (p-ACC, which suggested that the actions of these oligosaccharides might be associated with mitochondria through increasing energy expenditure. All of these effects of marine oligosaccharides were comparable to that of the established anti-diabetic drug, metformin. In addition, the treatment with oligosaccharides showed less toxicity than that of metformin. CONCLUSIONS/SIGNIFICANCE: Our findings indicate that oligomannuonate and its chromium (III complexes improved

  2. Plasminogen Activator Inhibitor -1 (PAI-1) Predicts Negative Alterations in Whole Body Insulin Sensitivity in Chronic HIV Infection.

    Science.gov (United States)

    Wirunsawanya, Kamonkiat; Belyea, Loni; Shikuma, Cecilia; Watanabe, Richard; Kohorn, Lindsay; Shiramizu, Bruce; Mitchell, Brooks; Souza, Scott A; Keating, Sheila; Norris, Philip J; Ndhlovu, Lishomwa; Chow, Dominic

    2017-03-21

    Plasminogen activator inhibitor type 1 (PAI-1), a key negative regulator of fibrinolysis, has been investigated to be a potential predictor of the development of insulin resistance and diabetes mellitus. Because chronically stable HIV-infected individuals frequently develop abnormal glucose metabolism including insulin resistance and diabetes mellitus, we postulated PAI-1 could be one of multifactorial pathogenic roles in the development of insulin resistance among chronic HIV-infected individuals. From our longitudinal cohort study, we selectively recruited chronically stable HIV-infected individuals without diagnosis of diabetes mellitus at baseline (N = 62) to analyze the correlation of baseline inflammatory cytokines including PAI-1 and whole body insulin sensitivity with two-year follow-up, as measured by Matsuda Index. We found a negative correlation between baseline PAI-1 and Matsuda Index (r = -.435 , p = .001) and a negative correlation with PAI-1 at baseline and Matsuda Index at two years (r = -.377 , p = .005). In a linear regression model that included age, total body fat mass percentage, serum amyloid A and family history of diabetes mellitus, PAI-1 still remained significantly associated with Matsuda Index at two-year follow-up (β = -.397, p = .002). Our longitudinal study suggests PAI-1 is an independent predictor of insulin resistance among chronic HIV-infected individuals.

  3. Rab14 limits the sorting of Glut4 from endosomes into insulin-sensitive regulated secretory compartments in adipocytes.

    Science.gov (United States)

    Brewer, Paul Duffield; Habtemichael, Estifanos N; Romenskaia, Irina; Coster, Adelle C F; Mastick, Cynthia Corley

    2016-05-15

    Insulin increases glucose uptake by increasing the rate of exocytosis of the facilitative glucose transporter isoform 4 (Glut4) relative to its endocytosis. Insulin also releases Glut4 from highly insulin-regulated secretory compartments (GSVs or Glut4 storage vesicles) into constitutively cycling endosomes. Previously it was shown that both overexpression and knockdown of the small GTP-binding protein Rab14 decreased Glut4 translocation to the plasma membrane (PM). To determine the mechanism of this perturbation, we measured the effects of Rab14 knockdown on the trafficking kinetics of Glut4 relative to two proteins that partially co-localize with Glut4, the transferrin (Tf) receptor and low-density-lipoprotein-receptor-related protein 1 (LRP1). Our data support the hypothesis that Rab14 limits sorting of proteins from sorting (or 'early') endosomes into the specialized GSV pathway, possibly through regulation of endosomal maturation. This hypothesis is consistent with known Rab14 effectors. Interestingly, the insulin-sensitive Rab GTPase-activating protein Akt substrate of 160 kDa (AS160) affects both sorting into and exocytosis from GSVs. It has previously been shown that exocytosis of GSVs is rate-limited by Rab10, and both Rab10 and Rab14 are in vitro substrates of AS160. Regulation of both entry into and exit from GSVs by AS160 through sequential Rab substrates would provide a mechanism for the finely tuned 'quantal' increases in cycling Glut4 observed in response to increasing concentrations of insulin.

  4. Low-Level Fluoride Exposure Increases Insulin Sensitivity in Experimental Diabetes.

    Science.gov (United States)

    Lobo, J G V M; Leite, A L; Pereira, H A B S; Fernandes, M S; Peres-Buzalaf, C; Sumida, D H; Rigalli, A; Buzalaf, M A R

    2015-07-01

    The effect of chronic fluoride (F) exposure from the drinking water on parameters related to glucose homeostasis was investigated. Wistar rats were randomly distributed into 2 groups (diabetic [D] and nondiabetic [ND]; n = 54 each). In D, diabetes was induced with streptozotocin. Each group was further divided into 3 subgroups (0, 10, or 50 mgF/L in drinking water). After 22 days of treatment, plasma and liver samples were collected. No alterations in glycemia, insulinemia, K(ITT), and HOMA2-IR (homeostasis model assessment 2 of insulin resistance) were seen for ND. F-exposure of D rats led to significantly lower insulinemia, without alterations in glycemia (increased %S). Proteomic analysis detected 19, 39, and 16 proteins differentially expressed for the comparisons D0 vs. D10, D0 vs. D50, and D10 vs. D50, respectively. Gene Ontology with the most significant terms in the comparisons D0 vs. D10, D0 vs. D50, and D50 vs. D10 were organic acid metabolic process and carboxylic acid metabolic process, organic acid metabolic process, and cellular ketone metabolic process. Analysis of subnetworks revealed that proteins with fold changes interacted with GLUT4 in comparison D0 vs. D10. Among these proteins, ERj3p was present in D10. Upregulation of this protein in the presence of F might help to explain the higher %S found in these animals. These data suggest that fluoride might enhance glucose homeostasis in diabetes and identify specific biological mechanisms that merit future studies.

  5. Insulin sensitivity is reflected by characteristic metabolic fingerprints--a Fourier transform mass spectrometric non-targeted metabolomics approach.

    Directory of Open Access Journals (Sweden)

    Marianna Lucio

    Full Text Available BACKGROUND: A decline in body insulin sensitivity in apparently healthy individuals indicates a high risk to develop type 2 diabetes. Investigating the metabolic fingerprints of individuals with different whole body insulin sensitivity according to the formula of Matsuda, et al. (ISI(Matsuda by a non-targeted metabolomics approach we aimed a to figure out an unsuspicious and altered metabolic pattern, b to estimate a threshold related to these changes based on the ISI, and c to identify the metabolic pathways responsible for the discrimination of the two patterns. METHODOLOGY AND PRINCIPAL FINDINGS: By applying infusion ion cyclotron resonance Fourier transform mass spectrometry, we analyzed plasma of 46 non-diabetic subjects exhibiting high to low insulin sensitivities. The orthogonal partial least square model revealed a cluster of 28 individuals with alterations in their metabolic fingerprints associated with a decline in insulin sensitivity. This group could be separated from 18 subjects with an unsuspicious metabolite pattern. The orthogonal signal correction score scatter plot suggests a threshold of an ISI(Matsuda of 15 for the discrimination of these two groups. Of note, a potential subgroup represented by eight individuals (ISI(Matsuda value between 8.5 and 15 was identified in different models. This subgroup may indicate a metabolic transition state, since it is already located within the cluster of individuals with declined insulin sensitivity but the metabolic fingerprints still show some similarities with unaffected individuals (ISI >15. Moreover, the highest number of metabolite intensity differences between unsuspicious and altered metabolic fingerprints was detected in lipid metabolic pathways (arachidonic acid metabolism, metabolism of essential fatty acids and biosynthesis of unsaturated fatty acids, steroid hormone biosyntheses and bile acid metabolism, based on data evaluation using the metabolic annotation interface Mass

  6. Diuretics Prevent Thiazolidinedione-Induced Cardiac Hypertrophy without Compromising Insulin-Sensitizing Effects in Mice

    Science.gov (United States)

    Chang, Cherng-Shyang; Tsai, Pei-Jane; Sung, Junne-Ming; Chen, Ju-Yi; Ho, Li-Chun; Pandya, Kumar; Maeda, Nobuyo; Tsai, Yau-Sheng

    2015-01-01

    Much concern has arisen regarding critical adverse effects of thiazolidinediones (TZDs), including rosiglitazone and pioglitazone, on cardiac tissue. Although TZD-induced cardiac hypertrophy (CH) has been attributed to an increase in plasma volume or a change in cardiac nutrient preference, causative roles have not been established. To test the hypothesis that volume expansion directly mediates rosiglitazone-induced CH, mice were fed a high-fat diet with rosiglitazone, and cardiac and metabolic consequences were examined. Rosiglitazone treatment induced volume expansion and CH in wild-type and PPARγ heterozygous knockout (Pparg+/−) mice, but not in mice defective for ligand binding (PpargP465L/+). Cotreatment with the diuretic furosemide in wild-type mice attenuated rosiglitazone-induced CH, hypertrophic gene reprogramming, cardiomyocyte apoptosis, hypertrophy-related signal activation, and left ventricular dysfunction. Similar changes were observed in mice treated with pioglitazone. The diuretics spironolactone and trichlormethiazide, but not amiloride, attenuated rosiglitazone effects on volume expansion and CH. Interestingly, expression of glucose and lipid metabolism genes in the heart was altered by rosiglitazone, but these changes were not attenuated by furosemide cotreatment. Importantly, rosiglitazone-mediated whole-body metabolic improvements were not affected by furosemide cotreatment. We conclude that releasing plasma volume reduces adverse effects of TZD-induced volume expansion and cardiac events without compromising TZD actions in metabolic switch in the heart and whole-body insulin sensitivity. PMID:24287404

  7. Genetic factors modulate the impact of pubertal androgen excess on insulin sensitivity and fertility.

    Directory of Open Access Journals (Sweden)

    Abigail R Dowling

    Full Text Available Polycystic ovary syndrome (PCOS is the most common endocrine disorder of reproductive age women. The syndrome is caused by a combination of environmental influences and genetic predisposition. Despite extensive efforts, the heritable factors contributing to PCOS development are not fully understood. The objective of this study was to test the hypothesis that genetic background contributes to the development of a PCOS-like reproductive and metabolic phenotype in mice exposed to excess DHEA during the pubertal transition. We tested whether the PCOS phenotype would be more pronounced on the diabetes-prone C57BL/6 background than the previously used strain, BALB/cByJ. In addition, we examined strain-dependent upregulation of the expression of ovarian and extra-ovarian candidate genes implicated in human PCOS, genes containing known strain variants, and genes involved with steroidogenesis or insulin sensitivity. These studies show that there are significant strain-related differences in metabolic response to excess androgen exposure during puberty. Additionally, our results suggest the C57BL/6J strain provides a more robust and uniform experimental platform for PCOS research than the BALB/cByJ strain.

  8. Improvements in body composition, cardiometabolic risk factors and insulin sensitivity with trenbolone in normogonadic rats.

    Science.gov (United States)

    Donner, Daniel G; Beck, Belinda R; Bulmer, Andrew C; Lam, Alfred K; Du Toit, Eugene F

    2015-02-01

    Trenbolone (TREN) is used for anabolic growth-promotion in over 20 million cattle annually and continues to be misused for aesthetic purposes in humans. The current study investigated TREN's effects on body composition and cardiometabolic risk factors; and its tissue-selective effects on the cardiovascular system, liver and prostate. Male rats (n=12) were implanted with osmotic infusion pumps delivering either cyclodextrin vehicle (CTRL) or 2mg/kg/day TREN for 6 weeks. Dual-energy X-ray Absorptiometry assessment of body composition; organ wet weights and serum lipid profiles; and insulin sensitivity were assessed. Cardiac ultrasound examinations were performed before in vivo studies assessed myocardial susceptibility to ischemia-reperfusion (I/R) injury. Circulating sex hormones and liver enzyme activities; and prostate and liver histology were examined. In 6 weeks, fat mass increased by 34±7% in CTRLs (pTREN (pTREN rats. Histological examination of the prostates from TREN-treated rats indicated benign hyperplasia associated with an increased prostate mass (149% compared to CTRLs, pTREN treatment without evidence of adverse cardiovascular or hepatic effects that are commonly associated with traditional anabolic steroid misuse. Sex hormone suppression and benign prostate hyperplasia were confirmed as adverse effects of the treatment.

  9. Hypovitaminosis D in obese children and adolescents: relationship with adiposity, insulin sensitivity, ethnicity, and season.

    Science.gov (United States)

    Alemzadeh, Ramin; Kichler, Jessica; Babar, Ghufran; Calhoun, Mariaelena

    2008-02-01

    Low 25-hydroxyvitamin D (25[OH] D) results in hyperparathyroidism and is among the endocrine derangements of adult obesity. There are differing recommendations on defining low 25(OH) D: hypovitaminosis D (serum 25[OH] D concentration hypovitaminosis D ( or =75 nmol/L), vitamin D insufficiency (50-74.9 nmol/L), and vitamin D deficiency (Hypovitaminosis D was present in 74% of the cohort, but was more prevalent in the H (76.9%, P Hypovitaminosis D corresponded to decreased vitamin D intake (P Hypovitaminosis D and vitamin D-deficient groups had higher body mass index, fat mass (FM), and iPTH, but had lower QUICKI than vitamin D-sufficient group (P Hypovitaminosis D was identified in 74% of obese subjects, whereas vitamin D deficiency was observed in 32.3% of our cohort. Vitamin D status was influenced by vitamin D intake, season, ethnicity/race, and adiposity. Interrelationships between 25(OH) D, iPTH, and FM were not influenced by season and race/ethnicity. Furthermore, serum 25(OH) D was positively correlated with insulin sensitivity, which was FM mediated, but negatively correlated with HbA(1c), implying that obese children and adolescents with low vitamin D status may be at increased risk of developing impaired glucose metabolism independent of body adiposity. Additional studies are needed to evaluate the underlying mechanisms.

  10. Improved insulin sensitivity and islet function after PPARdelta activation in diabetic db/db mice.

    Science.gov (United States)

    Winzell, Maria Sörhede; Wulff, Erik Max; Olsen, Grith Skytte; Sauerberg, Per; Gotfredsen, Carsten F; Ahrén, Bo

    2010-01-25

    The peroxisome proliferator-activated receptors (PPARs) are transcription factors belonging to the nuclear receptor superfamily. Several reports have shown that PPARdelta is involved in lipid metabolism, increasing fat oxidation and depleting lipid accumulation. Whether PPARdelta is involved in the regulation of glucose metabolism is not completely understood. In this study, we examined effects of long-term PPARdelta activation on glycemic control, islet function and insulin sensitivity in diabetic db/db mice. Male db/db mice were administered orally once daily with a selective and partial PPARdelta agonist (NNC 61-5920, 30 mg/kg) for eight weeks; control mice received vehicle. Fasting and non-fasting plasma glucose were reduced, reflected in reduced hemoglobinA(1c) (3.6+/-1.6% vs. 5.4+/-1.8 in db/db controls, Pdiabetic db/db mice. This suggests that activation of PPARdelta improves glucose metabolism and may therefore potentially be target for treatment of type 2 diabetes.

  11. Training Does Not Alter Muscle Ceramide and Diacylglycerol in Offsprings of Type 2 Diabetic Patients Despite Improved Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Ditte Søgaard

    2016-01-01

    Full Text Available Ceramide and diacylglycerol (DAG may be involved in the early phase of insulin resistance but data are inconsistent in man. We evaluated if an increase in insulin sensitivity after endurance training was accompanied by changes in these lipids in skeletal muscle. Nineteen first-degree type 2 diabetes Offsprings (Offsprings (age: 33.1±1.4 yrs; BMI: 26.4±0.4 kg/m2 and sixteen matched Controls (age: 31.3±1.5 yrs; BMI: 25.3±0.7 kg/m2 performed 10 weeks of endurance training three times a week at 70% of VO2max on a bicycle ergometer. Before and after the intervention a hyperinsulinemic-euglycemic clamp and VO2max test were performed and muscle biopsies obtained. Insulin sensitivity was significantly lower in Offsprings compared to control subjects (p<0.01 but improved in both groups after 10 weeks of endurance training (Off: 17±6%; Con: 12±9%, p<0.01. The content of muscle ceramide, DAG, and their subspecies were similar between groups and did not change in response to the endurance training except for an overall reduction in C22:0-Cer (p<0.05. Finally, the intervention induced an increase in AKT protein expression (Off: 27±11%; Con: 20±24%, p<0.05. This study showed no relation between insulin sensitivity and ceramide or DAG content suggesting that ceramide and DAG are not major players in the early phase of insulin resistance in human muscle.

  12. Developmental Programming: Insulin Sensitizer Prevents the GnRH-Stimulated LH Hypersecretion in a Sheep Model of PCOS.

    Science.gov (United States)

    Cardoso, Rodolfo C; Burns, Ashleigh; Moeller, Jacob; Skinner, Donal C; Padmanabhan, Vasantha

    2016-12-01

    Prenatal testosterone (T) treatment recapitulates the reproductive and metabolic phenotypes of polycystic ovary syndrome in female sheep. At the neuroendocrine level, prenatal T treatment results in disrupted steroid feedback on gonadotropin release, increased pituitary sensitivity to GnRH, and subsequent LH hypersecretion. Because prenatal T-treated sheep manifest functional hyperandrogenism and hyperinsulinemia, gonadal steroids and/or insulin may play a role in programming and/or maintaining these neuroendocrine defects. Here, we investigated the effects of prenatal and postnatal treatments with an androgen antagonist (flutamide [F]) or an insulin sensitizer (rosiglitazone [R]) on GnRH-stimulated LH secretion in prenatal T-treated sheep. As expected, prenatal T treatment increased the pituitary responsiveness to GnRH leading to LH hypersecretion. Neither prenatal interventions nor postnatal F treatment normalized the GnRH-stimulated LH secretion. Conversely, postnatal R treatment completely normalized the GnRH-stimulated LH secretion. At the tissue level, gestational T increased pituitary LHβ, androgen receptor, and insulin receptor-β, whereas it reduced estrogen receptor (ER)α protein levels. Although postnatal F normalized pituitary androgen receptor and insulin receptor-β, it failed to prevent an increase in LHβ expression. Contrarily, postnatal R treatment restored ERα and partially normalized LHβ pituitary levels. Immunohistochemical findings confirmed changes in pituitary ERα expression to be specific to gonadotropes. In conclusion, these findings indicate that increased pituitary responsiveness to GnRH in prenatal T-treated sheep is likely a function of reduced peripheral insulin sensitivity. Moreover, results suggest that restoration of ERα levels in the pituitary may be one mechanism by which R prevents GnRH-stimulated LH hypersecretion in this sheep model of polycystic ovary syndrome-like phenotype.

  13. Spirulina vesicolor Improves Insulin Sensitivity and Attenuates Hyperglycemia-Mediated Oxidative Stress in Fructose-Fed Rats

    Directory of Open Access Journals (Sweden)

    Walaa Hozayen

    2016-03-01

    Full Text Available Aim: The current study aimed to investigate the anti-hyperglycemic, anti-hyperlipidemic and insulin sensitizing effects of the cyanobacterium Spirulina vesicolor extract in fructose-fed rats. Materials and Methods: Rats were fed 30% fructose solution in drinking water for 4 weeks. Animals exhibited hyperglycemia and hyperinsulinemia were selected for further investigations. Diabetic and control rats were orally supplemented with 50 mg/kg body weight S. vesicolor extract for 4 weeks. Results: At the end of 8 weeks, fructose-fed rats showed significant increase in serum glucose, insulin, cholesterol, triglycerides, cardiovascular risk indices and insulin resistance. Treatment of the fructose-fed rats with S. vesicolor extract improved this metabolic profile. Fructose feeding produced a significant increase in serum tumor necrosis factor alpha (TNF- and #945; and a decrease in adiponectin levels. In addition, fructose-fed rats exhibited a significant increase in liver, kidney and heart lipid peroxidation levels, and declined antioxidant defenses. Supplementation of the fructose-fed rats with S. vesicolor extract reversed these alterations. Conclusion: S. vesicolor attenuates hyperglycemia-mediated oxidative stress and inflammation, and is thus effective in improving insulin sensitivity in fructose-fed rats. [J Intercult Ethnopharmacol 2016; 5(1.000: 57-64

  14. Small Molecule Kaempferol Promotes Insulin Sensitivity and Preserved Pancreatic β -Cell Mass in Middle-Aged Obese Diabetic Mice.

    Science.gov (United States)

    Alkhalidy, Hana; Moore, William; Zhang, Yanling; McMillan, Ryan; Wang, Aihua; Ali, Mostafa; Suh, Kyung-Shin; Zhen, Wei; Cheng, Zhiyong; Jia, Zhenquan; Hulver, Matthew; Liu, Dongmin

    2015-01-01

    Insulin resistance and a progressive decline in functional β-cell mass are hallmarks of developing type 2 diabetes (T2D). Thus, searching for natural, low-cost compounds to target these two defects could be a promising strategy to prevent the pathogenesis of T2D. Here, we show that dietary intake of flavonol kaempferol (0.05% in the diet) significantly ameliorated hyperglycemia, hyperinsulinemia, and circulating lipid profile, which were associated with the improved peripheral insulin sensitivity in middle-aged obese mice fed a high-fat (HF) diet. Kaempferol treatment reversed HF diet impaired glucose transport-4 (Glut4) and AMP-dependent protein kinase (AMPK) expression in both muscle and adipose tissues from obese mice. In vitro, kaempferol increased lipolysis and prevented high fatty acid-impaired glucose uptake, glycogen synthesis, AMPK activity, and Glut4 expression in skeletal muscle cells. Using another mouse model of T2D generated by HF diet feeding and low doses of streptozotocin injection, we found that kaempferol treatment significantly improved hyperglycemia, glucose tolerance, and blood insulin levels in obese diabetic mice, which are associated with the improved islet β-cell mass. These results demonstrate that kaempferol may be a naturally occurring anti-diabetic agent by improving peripheral insulin sensitivity and protecting against pancreatic β-cell dysfunction.

  15. Long-term exposure to abnormal glucose levels alters drug metabolism pathways and insulin sensitivity in primary human hepatocytes

    Science.gov (United States)

    Davidson, Matthew D.; Ballinger, Kimberly R.; Khetani, Salman R.

    2016-06-01

    Hyperglycemia in type 2 diabetes mellitus has been linked to non-alcoholic fatty liver disease, which can progress to inflammation, fibrosis/cirrhosis, and hepatocellular carcinoma. Understanding how chronic hyperglycemia affects primary human hepatocytes (PHHs) can facilitate the development of therapeutics for these diseases. Conversely, elucidating the effects of hypoglycemia on PHHs may provide insights into how the liver adapts to fasting, adverse diabetes drug reactions, and cancer. In contrast to declining PHH monocultures, micropatterned co-cultures (MPCCs) of PHHs and 3T3-J2 murine embryonic fibroblasts maintain insulin-sensitive glucose metabolism for several weeks. Here, we exposed MPCCs to hypo-, normo- and hyperglycemic culture media for ~3 weeks. While albumin and urea secretion were not affected by glucose level, hypoglycemic MPCCs upregulated CYP3A4 enzyme activity as compared to other glycemic states. In contrast, hyperglycemic MPCCs displayed significant hepatic lipid accumulation in the presence of insulin, while also showing decreased sensitivity to insulin-mediated inhibition of glucose output relative to a normoglycemic control. In conclusion, we show for the first time that PHHs exposed to hypo- and hyperglycemia can remain highly functional, but display increased CYP3A4 activity and selective insulin resistance, respectively. In the future, MPCCs under glycemic states can aid in novel drug discovery and mechanistic investigations.

  16. Phytic acid and myo-inositol support adipocyte differentiation and improve insulin sensitivity in 3T3-L1 cells.

    Science.gov (United States)

    Kim, Jin Nam; Han, Sung Nim; Kim, Hye-Kyeong

    2014-08-01

    Phytic acid, also known as myo-inositol hexaphosphate, has been shown to lower blood glucose levels and to improve insulin sensitivity in rodents. We investigated the effects of phytic acid and myo-inositol on differentiation, insulin-stimulated glucose uptake, and lipolysis of adipocytes to test the hypothesis that the antidiabetic properties of phytic acid and myo-inositol are mediated directly through adipocytes. 3T3-L1 cells were treated with 10, 50, or 200 μmol/L of phytic acid or myo-inositol. Oil Red O staining and an intracellular triacylglycerol assay were used to determine lipid accumulation during adipocyte differentiation. Immunoblotting and real-time polymerase chain reaction (PCR) were performed to evaluate expression of transcription factors, a target protein, and insulin signaling molecules. Phytic acid and myo-inositol exposures increased lipid accumulation in a dose-dependent manner (P acid synthase increased upon treatments with phytic acid and myo-inositol (P phytic acid and myo-inositol treatments (P phytic acid and myo-inositol treatments. In fully differentiated adipocytes, phytic acid and myo-inositol reduced basal lipolysis dose dependently (P phytic acid and myo-inositol increase insulin sensitivity in adipocytes by increasing lipid storage capacity, improving glucose uptake, and inhibiting lipolysis.

  17. Correlations between insulin sensitivity and bone mineral density in non-diabetic men

    DEFF Research Database (Denmark)

    Abrahamsen, Bo; Rohold, A; Henriksen, J E;

    2000-01-01

    stimulates osteoblast differentiation and collagen synthesis, with no clear evidence if this response in impaired in insulin resistance. METHODS: Femur and whole body (WB) BMD was measured in 55 male patients with ischaemic heart disease and 40 healthy men, using a Hologic QDR-2000 densitometer. Insulin...

  18. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

    DEFF Research Database (Denmark)

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.;

    2014-01-01

    Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-s...

  19. beta-Cell function and insulin sensitivity in adolescents from an OGTT

    Science.gov (United States)

    Given the increase in the incidence of insulin resistance, obesity, and type 2 diabetes in children and adolescents, it would be of paramount importance to assess quantitative indices of insulin secretion and action during a physiological perturbation, such as a meal or an oral glucose-tolerance tes...

  20. Modest dietary K+ restriction provokes insulin resistance of cellular K+ uptake and phosphorylation of renal outer medulla K+ channel without fall in plasma K+ concentration.

    Science.gov (United States)

    Chen, Pei; Guzman, John P; Leong, Patrick K K; Yang, Li E; Perianayagam, Anjana; Babilonia, Elisa; Ho, Jennifer S; Youn, Jang H; Wang, Wen Hui; McDonough, Alicia A

    2006-05-01

    Extracellular K(+) concentration ([K(+)]) is closely regulated by the concerted regulatory responses of kidney and muscle. In this study, we aimed to define the responses activated when dietary K(+) was moderately reduced from a control diet (1.0% K(+)) to a 0.33% K(+) diet for 15 days. Although body weight and baseline plasma [K(+)] (4.0 mM) were not reduced in the 0.33% K(+) group, regulatory responses to conserve plasma [K(+)] were evident in both muscle and kidney. Insulin-stimulated clearance of K(+) from the plasma was estimated in vivo in conscious rats with the use of tail venous and arterial cannulas. During infusion of insulin.(50 mU.kg(-1).min(-1)), plasma [K(+)] level fell to 3.2 +/- 0.1 mM in the 1.0% K(+) diet group and to only 3.47 +/- 0.07 mM in the 0.33% K(+) diet group (P < 0.01) with no reduction in urinary K(+) excretion, which is evidence of insulin resistance to cellular K(+) uptake. Insulin-stimulated cellular K(+) uptake was quantitated by measuring the K(+) infusion rate necessary to clamp plasma K(+) at baseline (in micromol.kg(-1).min(-1)) during 5 mU of insulin.kg(-1).min(-1) infusion: 9.7 +/- 1.5 in 1% K(+) diet was blunted to 5.2 +/- 1.7 in the 0.33% K(+) diet group (P < 0.001). Muscle [K(+)] and Na(+)-K(+)-ATPase activity and abundance were unchanged during the 0.33% K(+) diet. Renal excretion, which was measured overnight in metabolic cages, was reduced by 80%, from 117.6 +/- 10.5 micromol/h/animal (1% K(+) diet) to 24.2 +/- 1.7 micromol/h/animal (0.33% K(+) diet) (P < 0.001). There was no significant change in total abundance of key renal K(+) transporters, but 50% increases in both renal PTK cSrc abundance and ROMK phosphorylation in the 0.33% K(+) vs. 1% K(+) diet group, previously established to be associated with internalization of ROMK. These results indicate that plasma [K(+)] can be maintained during modest K(+) restriction due to a decrease in insulin-stimulated cellular K(+) uptake as well as renal K(+) conservation

  1. Race differences in the association of oxidative stress with insulin sensitivity in African- and European-American women.

    Science.gov (United States)

    Fisher, Gordon; Alvarez, Jessica A; Ellis, Amy C; Granger, Wesley M; Ovalle, Fernando; Man, Chiara Dalla; Cobelli, Claudio; Gower, Barbara A

    2012-05-01

    Excessive metabolism of glucose and/or fatty acids may impair insulin signaling by increasing oxidative stress. The objective of this study was to examine the association between insulin sensitivity and protein carbonyls, a systemic marker of oxidative stress, in healthy, nondiabetic women, and to determine if the relationship differed with race. Subjects were 25 African-Americans (AA, BMI 28.4 ± 6.2 kg/m(2), range 18.8-42.6 kg/m(2); age 33.1 ± 13.5 years, range 18-58 years) and 28 European-Americans (EA, BMI 26.2 ± 5.9 kg/m(2), range 18.7-48.4 kg/m(2); age 31.6 ± 12.4 years, range 19-58 years). Insulin sensitivity was determined using an intravenous glucose tolerance test incorporating [6,6-(2)H(2)]-glucose, and a two-compartment mathematical model. Multiple linear regression results indicated that insulin sensitivity was inversely associated with protein carbonyls in AA (standardized regression coefficient -0.47, P < 0.05) but not EA (0.01, P = 0.945), after adjusting for %body fat. In contrast, %body fat was significantly and positively associated with insulin sensitivity in EA (-0.54, P < 0.01) but not AA (-0.24, P = 0.196). Protein carbonyls were associated with free fatty acids (FFA) in AA (r = 0.58, P < 0.01) but not EA (r = -0.11, P = 0.59). When subjects were divided based on median levels of fasting glucose and FFA, those with higher glucose/FFA concentrations had a significantly greater concentration of circulating protein carbonyls compared to those with lower glucose/FFA concentrations (P < 0.05). These results suggest that oxidative stress independently contributes to insulin sensitivity among AA women. Further, this association in AA may be mediated by circulating FFA and/or glucose.

  2. Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients

    Institute of Scientific and Technical Information of China (English)

    WU Xue-yan; MAO Jiang-feng; LU Shuang-yu; ZHANG Qian; SHI Yi-fan

    2009-01-01

    Background Many clinical studies suggest the inverse relationship between testosterone levels and insulin sensitivity in men, however the causative relationship of these two events is still not determined. The purpose of this study was to investigate the effects of testosterone replacement therapy (TRT) on insulin sensitivity, body composition, serum lipid profiles and high sensitivity C-reactive protein (hsCRP) in hypogonadotropic hypogonadal (HH) puberty undeveloped male patients.Methods In this prospectively designed study, we compared homeostasis model assessment of insulin resistance (HOMA-IR), insulin areas under the curves (AUC) of 3-hour oral glucose tolerance test (OGTT) and other metabolic parameters between 26 HH patients and 26 healthy men. The patients' HOMA-IR, insulin AUC, body composition, lipid profiles, hsCRP and other parameters were compared before and after nine-month TRT.Results The average levels of total testosterone (TT) in HH and healthy group were (0.9±0.6) nmol/L and (18.8±3.4) nmol/L, respectively. HOMA-IR in HH group was significantly higher than the healthy group (5.14±5.16 vs 2.00±1.38, P<0.005). Insulin AUC in 3-hour OGTT in HH group was significantly higher than the healthy group (698.6±414.7 vs 414.2±267.5, P<0.01). Fasting glucose level in HH group was significantly higher than control group ((5.1±0.6) mmol/L vs (4.7±0.3) mmol/l, P<0.005). Height, weight and grasp strength of the patients were significantly increased after 9-month TRT. Significant reductions in HOMA-IR (from 5.14±5.16 to 2.97±2.16, P<0.01), insulin AUC (from 698.6±414.7 to 511.7±253.9, P<0.01) and hsCRP (from (1.49±1.18) mg/L to (0.70±0.56) mg/L, P<0.05) were found after TRT. Serum total cholesterol, LDL-C, HDL-C and triglyceride were all decreased, albeit with no significant difference compared to the level prior to TRT.Conclusions HOMA-IR, insulin AUC and fasting glucose level in HH young male patients were significantly higher than

  3. Insulin sensitivity is independent of lipid binding protein trafficking at the plasma membrane in human skeletal muscle

    DEFF Research Database (Denmark)

    Jordy, Andreas Børsting; Serup, Annette Karen; Karstoft, Kristian

    2014-01-01

    The aim of the present study was to investigate lipid-induced regulation of lipid binding proteins in human skeletal muscle and the impact hereof on insulin sensitivity. Eleven healthy male subjects underwent a 3-day hyper-caloric and high-fat diet regime. Muscle biopsies were taken before......-regulated by increased fatty acid availability. This suggests a time dependency in the up-regulation of FAT/CD36 and FABPpm protein during high availability of plasma fatty acids. Furthermore, we did not detect FATP1 and FATP4 protein in giant sarcolemmal vesicles obtained from human skeletal muscle. In conclusion......, this study shows that a short-term lipid-load increases mRNA content of key lipid handling proteins in human muscle. However, decreased insulin sensitivity after high-fat diet is not accompanied with relocation of FAT/CD36 or FABPpm protein to the sarcolemma. Finally, FATP1 and FATP4 protein could...

  4. mTOR Inhibition: Reduced Insulin Secretion and Sensitivity in a Rat Model of Metabolic Syndrome

    Science.gov (United States)

    Rovira, Jordi; Ramírez-Bajo, María Jose; Banon-Maneus, Elisenda; Moya-Rull, Daniel; Ventura-Aguiar, Pedro; Hierro-Garcia, Natalia; Lazo-Rodriguez, Marta; Revuelta, Ignacio; Torres, Armando; Oppenheimer, Federico; Campistol, Josep M.; Diekmann, Fritz

    2016-01-01

    Background Sirolimus (SRL) has been associated with new-onset diabetes mellitus after transplantation. The aim was to determine the effect of SRL on development of insulin resistance and β-cell toxicity. Methods Lean Zucker rat (LZR) and obese Zucker rat (OZR) were distributed into groups: vehicle and SRL (0.25, 0.5, or 1.0 mg/kg) during 12 or 28 days. Intraperitoneal glucose tolerance test (IPGTT) was evaluated at days 0, 12, 28, and 45. Islet morphometry, β-cell proliferation, and apoptosis were analyzed at 12 days. Islets were isolated to analyze insulin content, insulin secretion, and gene expression. Results After 12 days, SRL treatment only impaired IPGTT in a dose-dependent manner in OZR. Treatment prolongation induced increase of area under the curve of IPGTT in LZR and OZR; however, in contrast to OZR, LZR normalized glucose levels after 2 hours. The SRL reduced pancreas weight and islet proliferation in LZR and OZR as well as insulin content. Insulin secretion was only affected in OZR. Islets from OZR + SRL rats presented a downregulation of Neurod1, Pax4, and Ins2 gene. Genes related with insulin secretion remained unchanged or upregulated. Conclusions In conditions that require adaptive β-cell proliferation, SRL might reveal harmful effects by blocking β-cell proliferation, insulin production and secretion. These effects disappeared when removing the therapy. PMID:27500257

  5. Influence of glucocorticoids and growth hormone on insulin sensitivity in humans.

    Science.gov (United States)

    Yuen, K C J; Chong, L E; Riddle, M C

    2013-06-01

    The seminal concept proposed by Sir Harold Himsworth more than 75 years ago that a large number of patients with diabetes were 'insulin insensitive', now termed insulin resistance, has now expanded to include several endocrine syndromes, namely those of glucocorticoid excess, and growth hormone excess and deficiency. Synthetic glucocorticoids are increasingly used to treat a wide variety of chronic diseases, whereas the beneficial effects of recombinant growth hormone replacement therapy in children and adults with growth hormone deficiency have now been well-recognized for over 25 years. However, clinical and experimental studies have established that increased circulating levels of glucocorticoids and growth hormone can also lead to worsening of insulin resistance, glucose intolerance, overt diabetes mellitus and cardiovascular disease. Improved understanding of the physiological 24-h rhythmicity of glucocorticoid and growth hormone secretion and its influence on the dawn phenomenon and the Staub-Trauggot effect has therefore led to renewed interest in studies on the mechanisms of insulin resistance induced by exogenous administration of glucocorticoids and growth hormone in humans. In this review, we describe the physiological events that result from the presence of resistance to insulin action at the level of skeletal muscle, adipose tissue, and liver, describe the known mechanisms of glucocorticoid- and growth hormone-mediated insulin resistance, and provide an update of the contributions of glucocorticoids and growth hormone to understanding the pathophysiology of insulin resistance and its effects on several endocrine syndromes.

  6. Specific suppression of insulin sensitivity in growth hormone receptor gene-disrupted (GHR-KO) mice attenuates phenotypic features of slow aging.

    Science.gov (United States)

    Arum, Oge; Boparai, Ravneet K; Saleh, Jamal K; Wang, Feiya; Dirks, Angela L; Turner, Jeremy G; Kopchick, John J; Liu, Jun-Li; Khardori, Romesh K; Bartke, Andrzej

    2014-12-01

    In addition to their extended lifespans, slow-aging growth hormone receptor/binding protein gene-disrupted (knockout) (GHR-KO) mice are hypoinsulinemic and highly sensitive to the action of insulin. It has been proposed that this insulin sensitivity is important for their longevity and increased healthspan. We tested whether this insulin sensitivity of the GHR-KO mouse is necessary for its retarded aging by abrogating that sensitivity with a transgenic alteration that improves development and secretory function of pancreatic β-cells by expressing Igf-1 under the rat insulin promoter 1 (RIP::IGF-1). The RIP::IGF-1 transgene increased circulating insulin content in GHR-KO mice, and thusly fully normalized their insulin sensitivity, without affecting the proliferation of any non-β-cell cell types. Multiple (nonsurvivorship) longevity-associated physiological and endocrinological characteristics of these mice (namely beneficial blood glucose regulatory control, altered metabolism, and preservation of memory capabilities) were partially or completely normalized, thus supporting the causal role of insulin sensitivity for the decelerated senescence of GHR-KO mice. We conclude that a delayed onset and/or decreased pace of aging can be hormonally regulated.

  7. Repeated prolonged whole-body low-intensity exercise: effects on insulin sensitivity and limb muscle adaptations

    DEFF Research Database (Denmark)

    Helge, Jørn Mikael; Overgaard, Kristian; Damsgaard, Rasmus;

    2006-01-01

    . Glycosylated hemoglobin (5.6% ± 0.01%) was not affected by the crossing. The IVGTT data revealed that insulin sensitivity (7.3 ± 0.6 mU · L-1 · min-1) and glucose effectiveness (0.024 ± 0.002 min-1) were not changed after the crossing. Similarly, the IVGTT data, when expressed per kilogram of lean body mass...

  8. Effects of protein intake on blood pressure, insulin sensitivity and blood lipids in children: a systematic review.

    Science.gov (United States)

    Voortman, Trudy; Vitezova, Anna; Bramer, Wichor M; Ars, Charlotte L; Bautista, Paula K; Buitrago-Lopez, Adriana; Felix, Janine F; Leermakers, Elisabeth T M; Sajjad, Ayesha; Sedaghat, Sanaz; Tharner, Anne; Franco, Oscar H; van den Hooven, Edith H

    2015-02-14

    High protein intake in early childhood is associated with obesity, suggesting possible adverse effects on other cardiometabolic outcomes. However, studies in adults have suggested beneficial effects of protein intake on blood pressure (BP) and lipid profile. Whether dietary protein intake is associated with cardiovascular and metabolic health in children is unclear. Therefore, we aimed to systematically review the evidence on the associations of protein intake with BP, insulin sensitivity and blood lipids in children. We searched the databases Medline, Embase, Cochrane Central and PubMed for interventional and observational studies in healthy children up to the age of 18 years, in which associations of total, animal and/or vegetable protein intake with one or more of the following outcomes were reported: BP; measures of insulin sensitivity; cholesterol levels; or TAG levels. In the search, we identified 6636 abstracts, of which fifty-six studies met all selection criteria. In general, the quality of the included studies was low. Most studies were cross-sectional, and many did not control for potential confounders. No overall associations were observed between protein intake and insulin sensitivity or blood lipids. A few studies suggested an inverse association between dietary protein intake and BP, but evidence was inconclusive. Only four studies examined the effects of vegetable or animal protein intake, but with inconsistent results. In conclusion, the literature, to date provides insufficient evidence for effects of protein intake on BP, insulin sensitivity or blood lipids in children. Future studies could be improved by adequately adjusting for key confounders such as energy intake and obesity.

  9. Age-related changes in insulin sensitivity and β-cell function among European American and African American women

    Science.gov (United States)

    Chandler-Laney, P. C.; Phadke, R.; Granger, W. M.; Fernández, J. R.; Muñoz, A. J.; Man, C. Dalla; Cobelli, C.; Ovalle, F.; Gower, B. A.

    2011-01-01

    Type 2 diabetes is more prevalent among African American (AA) than European American (EA) women for reasons that are unknown. Ethnic differences in physiological processes related to insulin sensitivity and secretion, and age-related changes in these processes, may play a role. The purpose of this study was to identify ethnicity- and age-related differences in insulin sensitivity and β-cell responsivity among AA and EA females, and to determine whether these differences are independent of body composition and fat distribution. Healthy, normoglycemic females aged 7–12 yr (n=62), 18–32 yr (n=57), and 40–70 yr (n=49) were recruited for entry into this study. Following an overnight fast, insulin sensitivity (SI), intravenous glucose tolerance (Kg), acute C-peptide secretion (X0), and basal, first-phase, second-phase, and total β-cell responsivity to glucose (PhiB, Phi1, Phi2, and PhiTOT, respectively) were measured by an intravenous glucose tolerance test. Total % body fat was assessed by dual-energy X-ray absorptiometry, and intra-abdominal adiposity (IAAT) by computed tomography. Main effects of age group and ethnicity were measured with ANCOVA, adjusting for %fat, IAAT, and SI as indicated. AA had lower SI, and higher Kg, X0, Phi1, and PhiTOT (P<0.05), which remained after adjustment for %fat and IAAT. Greater X0, Phi1, and PhiTOT among AA were independent of SI. Advancing age was associated with greater Phi2 among both EA and AA. To conclude, inherent ethnic differences in β-cell function exist independently of adiposity and insulin sensitivity. Future research should examine whether ethnic differences in β-cell physiology contribute to disparities in type 2 diabetes risk. PMID:20885386

  10. Cellular mechanism by which estradiol protects female ovariectomized mice from high-fat diet-induced hepatic and muscle insulin resistance.

    Science.gov (United States)

    Camporez, João Paulo G; Jornayvaz, François R; Lee, Hui-Young; Kanda, Shoichi; Guigni, Blas A; Kahn, Mario; Samuel, Varman T; Carvalho, Carla R O; Petersen, Kitt Falk; Jurczak, Michael J; Shulman, Gerald I

    2013-03-01

    Estrogen replacement therapy reduces the incidence of type 2 diabetes in postmenopausal women; however, the mechanism is unknown. Therefore, the aim of this study was to evaluate the metabolic effects of estrogen replacement therapy in an experimental model of menopause. At 8 weeks of age, female mice were ovariectomized (OVX) or sham (SHAM) operated, and OVX mice were treated with vehicle (OVX) or estradiol (E2) (OVX+E2). After 4 weeks of high-fat diet feeding, OVX mice had increased body weight and fat mass compared with SHAM and OVX+E2 mice. OVX mice displayed reduced whole-body energy expenditure, as well as impaired glucose tolerance and whole-body insulin resistance. Differences in whole-body insulin sensitivity in OVX compared with SHAM mice were accounted for by impaired muscle insulin sensitivity, whereas both hepatic and muscle insulin sensitivity were impaired in OVX compared with OVX+E2 mice. Muscle diacylglycerol (DAG), content in OVX mice was increased relative to SHAM and OVX+E2 mice. In contrast, E2 treatment prevented the increase in hepatic DAG content observed in both SHAM and OVX mice. Increases in tissue DAG content were associated with increased protein kinase Cε activation in liver of SHAM and OVX mice compared with OVX+E2 and protein kinase Cθ activation in skeletal muscle of OVX mice compared with SHAM and OVX+E2. Taken together, these data demonstrate that E2 plays a pivotal role in the regulation of whole-body energy homeostasis, increasing O(2) consumption and energy expenditure in OVX mice, and in turn preventing diet-induced ectopic lipid (DAG) deposition and hepatic and muscle insulin resistance.

  11. Acyl CoA synthetase 5 (ACSL5 ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption

    Directory of Open Access Journals (Sweden)

    Thomas A. Bowman

    2016-03-01

    Conclusions: In summary, ACSL5−/− mice have increased hepatic and serum FGF21 levels, reduced adiposity, improved insulin sensitivity, increased energy expenditure and delayed triglyceride absorption. These studies suggest that ACSL5 is an important regulator of whole-body energy metabolism and ablation of ACSL5 may antagonize the development of obesity and insulin resistance.

  12. The effect of the deterioration of insulin sensitivity on beta-cell function in growth-hormone-deficient adults following 4-month growth hormone replacement therapy

    DEFF Research Database (Denmark)

    Rosenfalck, A M; Fisker, S; Hilsted, J;

    1999-01-01

    .07). One patient developed impaired glucose tolerance. Short-term GH replacement therapy in a dose of about 2 IU/m2 daily in GHD adults induces a reduction in insulin sensitivity, despite favourable changes in body composition, and an inadequate enhancement of insulin secretion....

  13. Anti-hyperlipidemic and insulin sensitizing activities of fenofibrate reduces aortic lipid deposition in hyperlipidemic Golden Syrian hamster.

    Science.gov (United States)

    Srivastava, Rai Ajit K; He, Shirley

    2010-12-01

    Cholesterol ester transfer protein (CETP) and apolipoprotein (apo) E are important in peroxisome proliferation activated receptor-α (PPAR-α)-mediated regulation of lipoprotein metabolism. Therefore, popularly used apolipoprotein E knockout mice are not suitable to evaluate PPAR-α agonists. In this study, we aimed to: a) evaluate hamster as a model for insulin resistance, hyperlipidemia and atherosclerosis; and b) investigate the effect of a PPAR-α activator, fenofibrate, in this model. A high fat high cholesterol (HFHC) diet increased serum cholesterol and triglycerides, but inclusion of fenofibrate in the diet decreased cholesterol and proatherogenic lipoproteins, VLDL and LDL, in a time-dependent manner. Concomitantly, serum levels of triglycerides also decreased. These reductions were attributed, in part, to the down-regulation of lipogenic genes and upregulation of lipoprotein lipase. The HFHC diet caused body weight gain and mild insulin resistance, both of which were prevented following the treatments with fenofibrate. Insulin resistance was further investigated in high fructose-fed hamsters. Fenofibrate prevented both hyperinsulinemia and hypertriglyceridemia. The insulin sensitizing activity of fenofibrate appeared to occur via reductions in protein tyrosine phophatase-1B. To determine whether lowering of lipids by fenofibrate treatment contributed to the reduced risks of developing atherosclerosis in hyperlipidemic hamsters, we measured lipid deposition in the aorta. Our results showed that fenofibrate treatment reduced aortic lipid deposition by 70%. These findings suggest that hamster may be an adequate animal model to evaluate the efficacy of lipid lowering, insulin sensitizing and antiatherosclerotic agents. We also show that fenofibrate is an effective antiatherosclerotic agent in hyperlipidemic hamster model.

  14. Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.

    Science.gov (United States)

    Williams, Ian M; Otero, Yolanda F; Bracy, Deanna P; Wasserman, David H; Biaggioni, Italo; Arnold, Amy C

    2016-05-01

    Angiotensin-(1-7) improves glycemic control in animal models of cardiometabolic syndrome. The tissue-specific sites of action and blood pressure dependence of these metabolic effects, however, remain unclear. We hypothesized that Ang-(1-7) improves insulin sensitivity by enhancing peripheral glucose delivery. Adult male C57BL/6J mice were placed on standard chow or 60% high-fat diet for 11 weeks. Ang-(1-7) (400 ng/kg per minute) or saline was infused subcutaneously during the last 3 weeks of diet, and hyperinsulinemic-euglycemic clamps were performed at the end of treatment. High-fat fed mice exhibited modest hypertension (systolic blood pressure: 137 ± 3 high fat versus 123 ± 5 mm Hg chow;P=0.001), which was not altered by Ang-(1-7) (141 ± 4 mm Hg;P=0.574). Ang-(1-7) did not alter body weight or fasting glucose and insulin in chow or high-fat fed mice. Ang-(1-7) increased the steady-state glucose infusion rate needed to maintain euglycemia in high-fat fed mice (31 ± 5 Ang-(1-7) versus 16 ± 1 mg/kg per minute vehicle;P=0.017) reflecting increased whole-body insulin sensitivity, with no effect in chow-fed mice. The improved insulin sensitivity in high-fat fed mice was because of an enhanced rate of glucose disappearance (34 ± 5 Ang-(1-7) versus 20 ± 2 mg/kg per minute vehicle;P=0.049). Ang-(1-7) enhanced glucose uptake specifically into skeletal muscle by increasing translocation of glucose transporter 4 to the sarcolemma. Our data suggest that Ang-(1-7) has direct insulin-sensitizing effects on skeletal muscle, independent of changes in blood pressure. These findings provide new insight into mechanisms by which Ang-(1-7) improves insulin action, and provide further support for targeting this peptide in cardiometabolic disease.

  15. Fgf21 impairs adipocyte insulin sensitivity in mice fed a low-carbohydrate, high-fat ketogenic diet.

    Directory of Open Access Journals (Sweden)

    Yusuke Murata

    Full Text Available BACKGROUND: A low-carbohydrate, high-fat ketogenic diet (KD induces hepatic ketogenesis and is believed to affect energy metabolism in mice. As hepatic Fgf21 expression was markedly induced in mice fed KD, we examined the effects of KD feeding on metabolism and the roles of Fgf21 in metabolism in mice fed KD using Fgf21 knockout mice. METHODOLOGY/PRINCIPAL FINDINGS: We examined C57BL/6 mice fed KD for 6 or 14 days. Blood β-hydroxybutyrate levels were greatly increased at 6 days, indicating that hepatic ketogenesis was induced effectively by KD feeding for 6 days. KD feeding for 6 and 14 days impaired glucose tolerance and insulin sensitivity, although it did not affect body weight, blood NEFA, and triglyceride levels. Hepatic Fgf21 expression and blood Fgf21 levels were markedly increased in mice fed KD for 6 days. Blood β-hydroxybutyrate levels in the knockout mice fed KD for 6 days were comparable to those in wild-type mice fed KD, indicating that Fgf21 is not required for ketogenesis. However, the impaired glucose tolerance and insulin sensitivity caused by KD feeding were improved in the knockout mice. Insulin-stimulated Akt phosphorylation was significantly decreased in the white adipose tissue in wild-type mice fed KD compared with those fed normal chow, but not in the muscle and liver. Its phosphorylation in the white adipose tissue was significantly increased in the knockout mice fed KD compared with wild-type mice fed KD. In contrast, hepatic gluconeogenic gene expression in Fgf21 knockout mice fed KD was comparable to those in the wild-type mice fed KD. CONCLUSIONS/SIGNIFICANCE: The present findings indicate that KD feeding impairs insulin sensitivity in mice due to insulin resistance in white adipose tissue. In addition, our findings indicate that Fgf21 induced to express by KD is a negative regulator of adipocyte insulin sensitivity in adaptation to a low-carbohydrate malnutritional state.

  16. Associations of Adiponectin with Adiposity, Insulin Sensitivity, and Diet in Young, Healthy, Mexican Americans and Non-Latino White Adults

    Directory of Open Access Journals (Sweden)

    Rocio I. Pereira

    2015-12-01

    Full Text Available Low circulating adiponectin levels may contribute to higher diabetes risk among Mexican Americans (MA compared to non-Latino whites (NLW. Our objective was to determine if among young healthy adult MAs have lower adiponectin than NLWs, independent of differences in adiposity. In addition, we explored associations between adiponectin and diet. This was an observational, cross-sectional study of healthy MA and NLW adults living in Colorado (U.S.A.. We measured plasma total adiponectin, adiposity (BMI, and visceral adipose tissue, insulin sensitivity (IVGTT, and self-reported dietary intake in 43 MA and NLW adults. Mean adiponectin levels were 40% lower among MA than NLW (5.8 ± 3.3 vs. 10.7 ± 4.2 µg/mL, p = 0.0003, and this difference persisted after controlling for age, sex, BMI, and visceral adiposity. Lower adiponectin in MA was associated with lower insulin sensitivity (R2 = 0.42, p < 0.01. Lower adiponectin was also associated with higher dietary glycemic index, lower intake of vegetables, higher intake of trans fat, and higher intake of grains. Our findings confirm that ethnic differences in adiponectin reflect differences in insulin sensitivity, but suggest that these are not due to differences in adiposity. Observed associations between adiponectin and diet support the need for future studies exploring the regulation of adiponectin by diet and other environmental factors.

  17. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT--relationship to newly identified mitochondrial pyruvate carrier proteins.

    Directory of Open Access Journals (Sweden)

    Jerry R Colca

    Full Text Available Thiazolidinedione (TZD insulin sensitizers have the potential to effectively treat a number of human diseases, however the currently available agents have dose-limiting side effects that are mediated via activation of the transcription factor PPARγ. We have recently shown PPARγ-independent actions of TZD insulin sensitizers, but the molecular target of these molecules remained to be identified. Here we use a photo-catalyzable drug analog probe and mass spectrometry-based proteomics to identify a previously uncharacterized mitochondrial complex that specifically recognizes TZDs. These studies identify two well-conserved proteins previously known as brain protein 44 (BRP44 and BRP44 Like (BRP44L, which recently have been renamed Mpc2 and Mpc1 to signify their function as a mitochondrial pyruvate carrier complex. Knockdown of Mpc1 or Mpc2 in Drosophila melanogaster or pre-incubation with UK5099, an inhibitor of pyruvate transport, blocks the crosslinking of mitochondrial membranes by the TZD probe. Knockdown of these proteins in Drosophila also led to increased hemolymph glucose and blocked drug action. In isolated brown adipose tissue (BAT cells, MSDC-0602, a PPARγ-sparing TZD, altered the incorporation of (13C-labeled carbon from glucose into acetyl CoA. These results identify Mpc1 and Mpc2 as components of the mitochondrial target of TZDs (mTOT and suggest that understanding the modulation of this complex, which appears to regulate pyruvate entry into the mitochondria, may provide a viable target for insulin sensitizing pharmacology.

  18. The exenatide analogue AC3174 attenuates hypertension, insulin resistance, and renal dysfunction in Dahl salt-sensitive rats

    Directory of Open Access Journals (Sweden)

    Fernandez Rayne

    2010-08-01

    Full Text Available Abstract Background Activation of glucagon-like peptide-1 (GLP-1 receptors improves insulin sensitivity and induces vasodilatation and diuresis. AC3174 is a peptide analogue with pharmacologic properties similar to the GLP-1 receptor agonist, exenatide. Hypothetically, chronic AC3174 treatment could attenuate salt-induced hypertension, cardiac morbidity, insulin resistance, and renal dysfunction in Dahl salt-sensitive (DSS rats. Methods DSS rats were fed low salt (LS, 0.3% NaCl or high salt (HS, 8% NaCl diets. HS rats were treated with vehicle, AC3174 (1.7 pmol/kg/min, or GLP-1 (25 pmol/kg/min for 4 weeks via subcutaneous infusion. Other HS rats received captopril (150 mg/kg/day or AC3174 plus captopril. Results HS rat survival was improved by all treatments except GLP-1. Systolic blood pressure (SBP was lower in LS rats and in GLP-1, AC3174, captopril, or AC3174 plus captopril HS rats than in vehicle HS rats (p Conclusions Thus, AC3174 had antihypertensive, cardioprotective, insulin-sensitizing, and renoprotective effects in the DSS hypertensive rat model. Furthermore, AC3174 improved animal survival, an effect not observed with GLP-1.

  19. Transfer of Intestinal Microbiota From Lean Donors Increases Insulin Sensitivity in Individuals With Metabolic Syndrome

    NARCIS (Netherlands)

    Vrieze, Anne; Van Nood, Els; Holleman, Frits; Salojarvi, Jarkko; Kootte, Ruud S.; Bartelsman, Joep F. W. M.; Dallinga-Thie, Geesje M.; Ackermans, Mariette T.; Serlie, Mireille J.; Oozeer, Raish; Derrien, Muriel; Druesne, Anne; van Hylckama Vlieg, Johan E.T.; Bloks, Vincent W.; Groen, Albert K.; Heilig, Hans G. H. J.; Zoetendal, Erwin G.; Stroes, Erik S.; de Vos, Willem M.; Hoekstra, Joost B. L.; Nieuwdorp, Max

    2012-01-01

    Alterations in intestinal microbiota are associated with obesity and insulin resistance. We studied the effects of infusing intestinal microbiota from lean donors to male recipients with metabolic syndrome on the recipients' microbiota composition and glucose metabolism. Subjects were assigned rando

  20. NAMPT-mediated NAD+ biosynthesis in adipocytes regulates adipose tissue function and multi-organ insulin sensitivity in mice

    Science.gov (United States)

    Stromsdorfer, Kelly L.; Yamaguchi, Shintaro; Yoon, Myeong Jin; Moseley, Anna C.; Franczyk, Michael P.; Kelly, Shannon C.; Qi, Nathan; Imai, Shin-ichiro; Yoshino, Jun

    2016-01-01

    SUMMARY Obesity is associated with adipose tissue dysfunction and multi-organ insulin resistance. However, the mechanisms of such obesity-associated systemic metabolic complications are not clear. Here, we characterized mice with adipocyte-specific deletion of nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting NAD+ biosynthetic enzyme known to decrease in adipose tissue of obese and aged rodents and people. We found that adipocyte-specific Nampt knockout mice had severe insulin resistance in adipose tissue, liver, and skeletal muscle, and adipose tissue dysfunction, manifested by increased plasma free fatty acids concentrations and decreased plasma concentrations of a major insulin-sensitizing adipokine, adiponectin. Loss of Nampt increased phosphorylation of CDK5 and PPARγ (serine-273) and decreased gene expression of obesity-linked phosphorylated PPARγ targets in adipose tissue. Remarkably, these deleterious alterations were normalized by administering rosiglitazone or a key NAD+ intermediate, nicotinamide mononucleotide (NMN). Collectively, our results provide important mechanistic and therapeutic insights into obesity-associated systemic metabolic derangements, particularly multi-organ insulin resistance. PMID:27498863

  1. Hormone-sensitive lipase deficiency suppresses insulin secretion from pancreatic islets of Lep{sup ob/ob} mice

    Energy Technology Data Exchange (ETDEWEB)

    Sekiya, Motohiro [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yahagi, Naoya, E-mail: nyahagi-tky@umin.ac.jp [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Laboratory of Molecular Physiology on Energy Metabolism, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Tamura, Yoshiaki; Okazaki, Hiroaki; Igarashi, Masaki; Ohta, Keisuke; Takanashi, Mikio; Kumagai, Masayoshi; Takase, Satoru; Nishi, Makiko; Takeuchi, Yoshinori; Izumida, Yoshihiko; Kubota, Midori; Ohashi, Ken; Iizuka, Yoko [Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Yagyu, Hiroaki [Division of Endocrinology and Metabolism, Department of Medicine, Jichi Medical University, Tochigi 329-0498 (Japan); Gotoda, Takanari [Department of Nephrology and Endocrinology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Nagai, Ryozo [Department of Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 (Japan); Shimano, Hitoshi; Yamada, Nobuhiro [Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Ibaragi 305-8575 (Japan); and others

    2009-09-25

    It has long been a matter of debate whether the hormone-sensitive lipase (HSL)-mediated lipolysis in pancreatic {beta}-cells can affect insulin secretion through the alteration of lipotoxicity. We generated mice lacking both leptin and HSL (Lep{sup ob/ob}/HSL{sup -/-}) and explored the role of HSL in pancreatic {beta}-cells in the setting of obesity. Lep{sup ob/ob}/HSL{sup -/-} developed elevated blood glucose levels and reduced plasma insulin levels compared with Lep{sup ob/ob}/HSL{sup +/+} in a fed state, while the deficiency of HSL did not affect glucose homeostasis in Lep{sup +/+} background. The deficiency of HSL exacerbated the accumulation of triglycerides in Lep{sup ob/ob} islets, leading to reduced glucose-stimulated insulin secretion. The deficiency of HSL also diminished the islet mass in Lep{sup ob/ob} mice due to decreased cell proliferation. In conclusion, HSL affects insulin secretary capacity especially in the setting of obesity.

  2. Mesoporous materials modified by aptamers and hydrophobic groups assist ultra-sensitive insulin detection in serum.

    Science.gov (United States)

    Lei, Chang; Xu, Chun; Noonan, Owen; Meka, Anand Kumar; Zhang, Long; Nouwens, Amanda; Yu, Chengzhong

    2015-09-14

    A novel mesoporous material modified with both insulin-binding-aptamers and hydrophobic methyl groups is synthesized. With rationally designed pore structures and surface chemistry, this material is applied in sample pre-treatment for ELISA, and enables the quantification (0.25-5 pg ml(-1)) of insulin in serum, 30-fold enhancement of the limit-of-detection compared to the commercial ELISA kit.

  3. Glucose homeostasis and insulin sensitivity in growth hormone-transgenic mice: a cross-sectional analysis

    OpenAIRE

    Boparai, Ravneet K; Arum, Oge; Khardori, Romesh; Bartke, Andrzej

    2010-01-01

    In contrast to its stimulatory effects on musculature, bone, and organ development, and its lipolytic effects, growth hormone (GH) opposes insulin effects on glucose metabolism. Chronic GH overexposure is thought to result in insulin insensitivity and decreased blood glucose homeostatic control. Yet, despite the importance of this concept for basic biology, as well as human conditions of GH excess or deficiency, no systematic assessment of the impact of GH overexpression on glucose homeostasi...

  4. Cellular heterogeneity mediates inherent sensitivity-specificity tradeoff in cancer targeting by synthetic circuits.

    Science.gov (United States)

    Morel, Mathieu; Shtrahman, Roman; Rotter, Varda; Nissim, Lior; Bar-Ziv, Roy H

    2016-07-19

    Synthetic gene circuits are emerging as a versatile means to target cancer with enhanced specificity by combinatorial integration of multiple expression markers. Such circuits must also be tuned to be highly sensitive because escape of even a few cells might be detrimental. However, the error rates of decision-making circuits in light of cellular variability in gene expression have so far remained unexplored. Here, we measure the single-cell response function of a tunable logic AND gate acting on two promoters in heterogeneous cell populations. Our analysis reveals an inherent tradeoff between specificity and sensitivity that is controlled by the AND gate amplification gain and activation threshold. We implement a tumor-mimicking cell-culture model of cancer cells emerging in a background of normal ones, and show that molecular parameters of the synthetic circuits control specificity and sensitivity in a killing assay. This suggests that, beyond the inherent tradeoff, synthetic circuits operating in a heterogeneous environment could be optimized to efficiently target malignant state with minimal loss of specificity.

  5. Growth-Blocking Peptides As Nutrition-Sensitive Signals for Insulin Secretion and Body Size Regulation.

    Directory of Open Access Journals (Sweden)

    Takashi Koyama

    2016-02-01

    Full Text Available In Drosophila, the fat body, functionally equivalent to the mammalian liver and adipocytes, plays a central role in regulating systemic growth in response to nutrition. The fat body senses intracellular amino acids through Target of Rapamycin (TOR signaling, and produces an unidentified humoral factor(s to regulate insulin-like peptide (ILP synthesis and/or secretion in the insulin-producing cells. Here, we find that two peptides, Growth-Blocking Peptide (GBP1 and CG11395 (GBP2, are produced in the fat body in response to amino acids and TOR signaling. Reducing the expression of GBP1 and GBP2 (GBPs specifically in the fat body results in smaller body size due to reduced growth rate. In addition, we found that GBPs stimulate ILP secretion from the insulin-producing cells, either directly or indirectly, thereby increasing insulin and insulin-like growth factor signaling activity throughout the body. Our findings fill an important gap in our understanding of how the fat body transmits nutritional information to the insulin producing cells to control body size.

  6. Acute High-intensity Interval Exercise-induced Redox Signaling is Associated with Enhanced Insulin Sensitivity in Obese Middle-aged Men.

    Directory of Open Access Journals (Sweden)

    Lewan Parker

    2016-09-01

    Full Text Available Background. Obesity and ageing are associated with increased oxidative stress, activation of stress and mitogen activated protein kinases (SAPK, and the development of insulin resistance and metabolic disease. In contrast, acute exercise also increases oxidative stress and SAPK signaling, yet is reported to enhance insulin sensitivity and reduce the risk of metabolic disease. This study explored this paradox by investigating the effect of a single session of high-intensity interval-exercise (HIIE on redox status, muscle SAPK and insulin protein signaling in eleven middle-aged obese men. Methods. Participants completed a 2 hour hyperinsulinaemic-euglycaemic clamp at rest, and 60 minutes after HIIE (4x4 mins at 95% HRpeak; 2 min recovery periods, separated by 1-3 weeks. Results. Irrespective of exercise-induced changes to redox status, insulin stimulation both at rest and after HIIE similarly increased plasma superoxide dismutase activity, plasma catalase activity, and skeletal muscle 4-HNE; and significantly decreased plasma TBARS and hydrogen peroxide. The SAPK signaling pathways of p38 MAPK, NF-κB p65, and JNK, and the distal insulin signaling protein AS160Ser588, were activated with insulin stimulation at rest and to a greater extent with insulin stimulation after a prior bout of HIIE. Higher insulin sensitivity after HIIE was associated with higher insulin-stimulated SAPK phosphorylation (JNK, p38 MAPK and NF-κB and SOD activity (p<0.05. Conclusion. These findings support a role for redox homeostasis and SAPK signaling in insulin-stimulated glucose uptake which may contribute to the enhancement of insulin sensitivity in obese men 3 hours after HIIE.

  7. Effects of anesthesia-induced modest hypothermia on cellular radiation sensitivity

    Institute of Scientific and Technical Information of China (English)

    XIANG; Yingsong(项莺松); TANG; Gusheng(唐古生); XU; Xiongfei(许熊飞); YANG; Rujun(杨如俊); CAI; Jianming(蔡建明); ZHANG; Minghui(张明辉); CAO; Xuetao(曹雪涛)

    2002-01-01

    To assess the mechanisms of modest hypothermia(MH) and its effects on cellular radiation response, a model of anesthesia-induced modest hypothermia(AIMH) in the adult mice and a model of pure MH in the newborn mice were established. The survival rate of lethally irradiated mice was increased to 72% through AIMH before irradiation. Both apoptosis and necrosis of human fetal bone marrow CD34+ hematopoietic stem cells cultured under MH were significantly decreased as detected by MTT and flow cytometry, with three-color labeled by PE-CD34+/ FITC-AnnexinV /7AAD. The survival and proliferation of mouse bone marrow MNC treated with MH after irradiation were also increased. The MH exerted similar protective effects on the leukemia cell lines A20, HL60, K562 to the normal bone marrow cells, but it enhanced the radiation sensitivity of leukemia cell line FBL3 and mouse melanoma B16F10. No effects have been found on the radiation sensitivity of those cells treated with MH before irradiation. The results also showed that MH mediated the effects on radiation sensitivity, in addition to increasing the oxygen tension. These results show different effects of MH on different cells:(i) AIMH exerts a protective effect on the normal hematopoietic stem cells, some leukemia cell lines A20, HL60, K562, and some neoplasma 3LL, LOVO. And MH exhibits a synthetic effect with anesthetic.(ii) MH enhances the radiation sensitivity of another leukemia and neoplasma cell lines FBL3, B16F10 and CT26. Therefore, AIMH has a potential to enhance the effects of radiation-therapy and decrease side effects on some tumors.

  8. Effects of low-dose recombinant human insulin-like growth factor-I on insulin sensitivity, growth hormone and glucagon levels in young adults with insulin-dependent diabetes mellitus.

    Science.gov (United States)

    Acerini, C L; Harris, D A; Matyka, K A; Watts, A P; Umpleby, A M; Russell-Jones, D L; Dunger, D B

    1998-12-01

    Despite recent interest in the therapeutic potential of recombinant human insulin-like growth factor-I (rhIGF-I) in the treatment of diabetes mellitus, its mechanism of action is still not defined. We have studied the effects of low-dose bolus subcutaneous rhIGF-I (40 microg/kg and 20 microg/kg) on insulin sensitivity, growth hormone (GH) and glucagon levels in seven young adults with insulin-dependent diabetes mellitus (IDDM) using a randomized double-blind placebo-controlled crossover study design. Each was subjected to a euglycemic clamp (5 mmol/L) protocol consisting of a variable-rate insulin infusion clamp (6:00 PM to 8:00 AM) followed by a two-dose hyperinsulinemic clamp (insulin infusion of 0.75 mU x kg(-1) x min(-1) from 8 to 10 AM and 1.5 mU x kg(-1) x min(-1) from 10 AM to 12 noon) incorporating [6,6 2H2]glucose tracer for determination of glucose production/utilization rates. Following rhIGF-I administration, the serum IGF-I level (mean +/- SEM) increased (40 microg/kg, 655 +/- 90 ng/mL, P overnight GH level (40 microg/kg, 9.1 +/- 1.4 mU/L, P = .04; 20 microg/kg, 9.6 +/- 2.0 mU/L, P = .12; placebo, 11.3 +/- 1.7 mU/L) and GH pulse amplitude (40 microg/kg, 18.8 +/- 2.9 mU/L, P = .04; 20 microg/kg, 17.0 +/- 3.4 mU/L, P > .05; placebo, 23.0 +/- 3.7 mU/L) were also reduced. No differences in glucagon, IGF binding protein-1 (IGFBP-1), acetoacetate, or beta-hydroxybutyrate levels were found. During the hyperinsulinemic clamp conditions, no differences in glucose utilization were noted, whereas hepatic glucose production was reduced by rhIGF-I 40 microg/kg (P = .05). Our data demonstrate that in subjects with IDDM, low-dose subcutaneous rhIGF-I leads to a dose-dependent reduction in the insulin level for euglycemia overnight that parallels the decrease in overnight GH levels, but glucagon and IGFBP-1 levels remain unchanged. The decreases in hepatic glucose production during the hyperinsulinemic clamp study observed the following day are likely related to GH

  9. Spironolactone in the treatment of polycystic ovary syndrome: effects on clinical features, insulin sensitivity and lipid profile.

    Science.gov (United States)

    Zulian, E; Sartorato, P; Benedini, S; Baro, G; Armanini, D; Mantero, F; Scaroni, C

    2005-01-01

    This prospective clinical trial was designed to assess the effects of a long-term therapy with spironolactone, with and without dietary-induced weight-loss, on clinical features, lipid profile and insulin levels in women with polycystic ovary syndrome (PCOS). Twenty-five patients (range of age 16-32 yr; 13 lean and 12 overweight) fulfilling formal diagnostic criteria for PCOS (oligomenorrhea and/or amenorrhea, biochemical and/or clinical evidence of hyperadrogenism) were studied at baseline and then received oral spironolactone (100 mg/die) for 12 months; association with lifestyle modifications was recommended to all over-weight patients. Clinical, endocrine and metabolic parameters [oral glucose tolerance test (OGTT), lipid profile] were measured at baseline and at the end of the antiandrogen treatment. The therapy was associated with a significant average decline of triglycerides in overweight subjects and with increased HDL-cholesterol levels in lean patients. The insulin levels at 60 min during OGTT, homeostasis model assessment-insulin resistance and area under curve of insulin were significantly lowered in overweight women after 12 months of spironolactone and weight loss and no negative changes in insulin secretion and sensitivity were observed in PCOS women after pharmacological treatment alone. The efficacy of spironolactone on the androgenic clinical aspects of PCOS has been confirmed in this study. Furthermore, our data show that long-term treatment with spironolactone exerts no negative effects on lipoprotein profile and glucose metabolism; more relevant beneficial effects on glucose and lipid metabolism were observed when the antiandrogen was associated with weight loss in overweight PCOS women.

  10. n-3 Fatty acids preserve muscle mass and insulin sensitivity in a rat model of energy restriction.

    Science.gov (United States)

    Galmiche, Guillaume; Huneau, Jean-François; Mathé, Véronique; Mourot, Jacques; Simon, Noémie; Le Guillou, Céline; Hermier, Dominique

    2016-10-01

    In obese subjects, the loss of fat mass during energy restriction is often accompanied by a loss of muscle mass. The hypothesis that n-3 PUFA, which modulate protein homoeostasis via effects on insulin sensitivity, could contribute to maintain muscle mass during energy restriction was tested in rats fed a high-fat diet (4 weeks) rich in 18 : 1 n-9 (oleic acid, OLE-R), 18 : 3 n-3 (α-linolenic acid, ALA-R) or n-3 long-chain (LC-R) fatty acid and then energy restricted (8 weeks). A control group (OLE-ad libitum (AL)) was maintained with AL diet throughout the study. Rats were killed 10 min after an i.v. insulin injection. All energy-restricted rats lost weight and fat mass, but only the OLE-R group showed a significant muscle loss. The Gastrocnemius muscle was enriched with ALA in the ALA-R group and with LC-PUFA in the ALA-R and LC-R groups. The proteolytic ubiquitin-proteasome system was differentially affected by energy restriction, with MAFbx and muscle ring finger-1 mRNA levels being decreased in the LC-R group (-30 and -20 %, respectively). RAC-α serine/threonine-protein kinase and insulin receptor substrate 1 phosphorylation levels increased in the LC-R group (+70 %), together with insulin receptor mRNA (+50 %). The ALA-R group showed the same overall activation pattern as the LC-R group, although to a lesser extent. In conclusion, dietary n-3 PUFA prevent the loss of muscle mass associated with energy restriction, probably by an improvement in the insulin-signalling pathway activation, in relation to enrichment of plasma membranes in n-3 LC-PUFA.

  11. Fatty-acid binding protein 4 gene variants and childhood obesity: potential implications for insulin sensitivity and CRP levels

    Directory of Open Access Journals (Sweden)

    Bhattacharjee Rakesh

    2010-02-01

    Full Text Available Abstract Introduction Obesity increases the risk for insulin resistance and metabolic syndrome in both adults and children. FABP4 is a member of the intracellular lipid-binding protein family that is predominantly expressed in adipose tissue, and plays an important role in maintaining glucose and lipid homeostasis. The purpose of this study was to measure FABP4 plasma levels, assess FABP4 allelic variants, and explore potential associations with fasting glucose and insulin levels in young school-age children with and without obesity. Methods A total of 309 consecutive children ages 5-7 years were recruited. Children were divided based on BMI z score into Obese (OB; BMI z score >1.65 and non-obese (NOB. Fasting plasma glucose, lipids, insulin, hsCRP, and FABP4 levels were measured. HOMA was used as correlate of insulin sensitivity. Four SNPs of the human FABP4 gene (rs1051231, rs2303519, rs16909233 and rs1054135, corresponding to several critical regions of the encoding FABP4 gene sequence were genotyped. Results Compared to NOB, circulating FABP4 levels were increased in OB, as were LDL, hsCRP and HOMA. FABP4 levels correlated with BMI, and also contributed to the variance of HOMA and hsCRP, but not serum lipids. The frequency of rs1054135 allelic variant was increased in OB, and was associated with increased FABP4 levels, while the presence of rs16909233 variant allele, although similar in OB and NOB, was associated with increased HOMA values. Conclusions Childhood obesity is associated with higher FABP4 levels that may promote cardiometabolic risk. The presence of selective SNPs in the FABP4 gene may account for increased risk for insulin resistance or systemic inflammation in the context of obesity.

  12. Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation.

    Directory of Open Access Journals (Sweden)

    Marco van Eijk

    Full Text Available Adipose tissue is a critical mediator in obesity-induced insulin resistance. Previously we have demonstrated that pharmacological lowering of glycosphingolipids and subsequently GM3 by using the iminosugar AMP-DNM, strikingly improves glycemic control. Here we studied the effects of AMP-DNM on adipose tissue function and inflammation in detail to provide an explanation for the observed improved glucose homeostasis. Leptin-deficient obese (Lep(Ob mice were fed AMP-DNM and its effects on insulin signalling, adipogenesis and inflammation were monitored in fat tissue. We show that reduction of glycosphingolipid biosynthesis in adipose tissue of Lep(Ob mice restores insulin signalling in isolated ex vivo insulin-stimulated adipocytes. We observed improved adipogenesis as the number of larger adipocytes was reduced and expression of genes like peroxisome proliferator-activated receptor (PPAR gamma, insulin responsive glucose transporter (GLUT-4 and adipsin increased. In addition, we found that adiponectin gene expression and protein were increased by AMP-DNM. As a consequence of this improved function of fat tissue we observed less inflammation, which was characterized by reduced numbers of adipose tissue macrophages (crown-like structures and reduced levels of the macrophage chemo attractants monocyte-chemoattractant protein-1 (Mcp-1/Ccl2 and osteopontin (OPN. In conclusion, pharmacological lowering of glycosphingolipids by inhibition of glucosylceramide biosynthesis improves adipocyte function and as a consequence reduces inflammation in adipose tissue of obese animals.

  13. Elevation in Tanis expression alters glucose metabolism and insulin sensitivity in H4IIE cells.

    Science.gov (United States)

    Gao, Yuan; Walder, Ken; Sunderland, Terry; Kantham, Lakshmi; Feng, Helen C; Quick, Melissa; Bishara, Natalie; de Silva, Andrea; Augert, Guy; Tenne-Brown, Janette; Collier, Gregory R

    2003-04-01

    Increased hepatic glucose output and decreased glucose utilization are implicated in the development of type 2 diabetes. We previously reported that the expression of a novel gene, Tanis, was upregulated in the liver during fasting in the obese/diabetic animal model Psammomys obesus. Here, we have further studied the protein and its function. Cell fractionation indicated that Tanis was localized in the plasma membrane and microsomes but not in the nucleus, mitochondria, or soluble protein fraction. Consistent with previous gene expression data, hepatic Tanis protein levels increased more significantly in diabetic P. obesus than in nondiabetic controls after fasting. We used a recombinant adenovirus to increase Tanis expression in hepatoma H4IIE cells and investigated its role in metabolism. Tanis overexpression reduced glucose uptake, basal and insulin-stimulated glycogen synthesis, and glycogen content and attenuated the suppression of PEPCK gene expression by insulin, but it did not affect insulin-stimulated insulin receptor phosphorylation or triglyceride synthesis. These results suggest that Tanis may be involved in the regulation of glucose metabolism, and increased expression of Tanis could contribute to insulin resistance in the liver.

  14. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes

    DEFF Research Database (Denmark)

    Vozarova, Barbora; Stefan, Norbert; Lindsay, Robert S

    2002-01-01

    with prospective changes in liver or whole-body insulin sensitivity and/or insulin secretion and whether these elevated enzymes predict the development of type 2 diabetes in Pima Indians. We measured ALT, AST, and GGT in 451 nondiabetic (75-g oral glucose tolerance test) Pima Indians (aged 30 +/- 6 years, body fat......It has been proposed that liver dysfunction may contribute to the development of type 2 diabetes. The aim of the present study was to examine whether elevated hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or gamma -glutamyltranspeptidase [GGT]) are associated...... were available. At baseline, ALT, AST, and GGT were related to percent body fat (r = 0.16, 0.17, and 0.11, respectively), M (r = -0.32, - 0.28, and -0.24), and HGO (r = 0.27, 0.12, and 0.14; all P fat, M, and AIR, higher ALT...

  15. Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes

    DEFF Research Database (Denmark)

    Harder-Lauridsen, Nina Majlund; Krogh-Madsen, R; Holst, J J;

    2014-01-01

    Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would...... increase the insulin-mediated glucose uptake. Men with type 2 diabetes not treated with insulin [n = 9, age 54.9 ± 9.7 (mean ± SD) yr, body mass index 34.8 ± 6.1 kg/m(2), HbA1c 7.0 ± 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h...... in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 (P

  16. PKCδ regulates hepatic insulin sensitivity and hepatosteatosis in mice and humans

    DEFF Research Database (Denmark)

    Bezy, Olivier; Tran, Thien T; Pihlajamäki, Jussi;

    2011-01-01

    PKCδ. Here, we found that PKCδ expression in liver was 2-fold higher in B6 versus 129 mice from birth and was further increased in B6 but not 129 mice in response to a high-fat diet. PRKCD gene expression was also elevated in obese humans and was positively correlated with fasting glucose...... tolerance, and reduced hepatosteatosis with aging. Conversely, mice with liver-specific overexpression of PKCδ developed hepatic insulin resistance characterized by decreased insulin signaling, enhanced lipogenic gene expression, and hepatosteatosis. Therefore, changes in the expression and regulation...... of PKCδ between strains of mice and in obese humans play an important role in the genetic risk of hepatic insulin resistance, glucose intolerance, and hepatosteatosis; and thus PKCδ may be a potential target in the treatment of metabolic syndrome....

  17. 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....

  18. Circulating insulin stimulates fatty acid retention in white adipose tissue via KATP channel activation in the central nervous System only in insulin-sensitive mice

    NARCIS (Netherlands)

    Coomans, C.P.; Geerling, J.J.; Guigas, B.; Hoek, A.M. van den; Parlevliet, E.T.; Ouwens, D.M.; Pijl, H.; Voshol, P.J.; Rensen, P.C.N.; Havekes, L.M.; Romijn, J.A.

    2011-01-01

    Insulin signaling in the central nervous system (CNS) is required for the inhibitory effect of insulin on glucose production. Our aim was to determine whether the CNS is also involved in the stimulatory effect of circulating insulin on the tissue-specific retention of fatty acid (FA) from plasma. In

  19. Effects of combined calcium and vitamin D supplementation on insulin secretion, insulin sensitivity and β-cell function in multi-ethnic vitamin D-deficient adults at risk for type 2 diabetes: a pilot randomized, placebo-controlled trial.

    Directory of Open Access Journals (Sweden)

    Claudia Gagnon

    Full Text Available To examine whether combined vitamin D and calcium supplementation improves insulin sensitivity, insulin secretion, β-cell function, inflammation and metabolic markers.6-month randomized, placebo-controlled trial.Ninety-five adults with serum 25-hydroxyvitamin D [25(OHD] ≤55 nmol/L at risk of type 2 diabetes (with prediabetes or an AUSDRISK score ≥15 were randomized. Analyses included participants who completed the baseline and final visits (treatment n = 35; placebo n = 45.Daily calcium carbonate (1,200 mg and cholecalciferol [2,000-6,000 IU to target 25(OHD >75 nmol/L] or matching placebos for 6 months.Insulin sensitivity (HOMA2%S, Matsuda index, insulin secretion (insulinogenic index, area under the curve (AUC for C-peptide and β-cell function (Matsuda index x AUC for C-peptide derived from a 75 g 2-h OGTT; anthropometry; blood pressure; lipid profile; hs-CRP; TNF-α; IL-6; adiponectin; total and undercarboxylated osteocalcin.Participants were middle-aged adults (mean age 54 years; 69% Europid at risk of type 2 diabetes (48% with prediabetes. Compliance was >80% for calcium and vitamin D. Mean serum 25(OHD concentration increased from 48 to 95 nmol/L in the treatment group (91% achieved >75 nmol/L, but remained unchanged in controls. There were no significant changes in insulin sensitivity, insulin secretion and β-cell function, or in inflammatory and metabolic markers between or within the groups, before or after adjustment for potential confounders including waist circumference and season of recruitment. In a post hoc analysis restricted to participants with prediabetes, a significant beneficial effect of vitamin D and calcium supplementation on insulin sensitivity (HOMA%S and Matsuda was observed.Daily vitamin D and calcium supplementation for 6 months may not change OGTT-derived measures of insulin sensitivity, insulin secretion and β-cell function in multi-ethnic adults with low vitamin D status at risk of type 2 diabetes

  20. Rapamycin has a biphasic effect on insulin sensitivity in C2C12 myotubes due to sequential disruption of mTORC1 and mTORC2

    Directory of Open Access Journals (Sweden)

    Lan eYe

    2012-09-01

    Full Text Available Rapamycin, an inhibitor of mTOR complex 1 (mTORC1, improves insulin sensitivity in acute studies in vitro and in vivo by disrupting a negative feedback loop mediated by S6 kinase. We find that rapamycin has a clear biphasic effect on insulin sensitivity in C2C12 myotubes, with enhanced responsiveness during the first hour that declines to almost complete insulin resistance by 24-48 hours. We and others have recently observed that chronic rapamycin treatment induces insulin resistance in rodents, at least in part due to disruption of mTORC2, an mTOR-containing complex that is not acutely sensitive to the drug. Chronic rapamycin treatment may also impair insulin action via the inhibition of mTORC1-dependent mitochondrial biogenesis and activity, which could result in a buildup of lipid intermediates that are known to trigger insulin resistance. We confirmed that rapamycin inhibits expression of PGC-1α, a key mitochondrial transcription factor, and acutely reduces respiration rate in myotubes. However, rapamycin did not stimulate phosphorylation of PKCθ, a central mediator of lipid-induced insulin resistance. Instead, we found dramatic disruption of mTORC2, which coincided with the onset of insulin resistance. Selective inhibition of mTORC1 or mTORC2 by shRNA-mediated knockdown of specific components (Raptor and Rictor, respectively confirmed that mitochondrial effects of rapamycin are mTORC1-dependent, whereas insulin resistance was recapitulated only by knockdown of mTORC2. Thus, mTORC2 disruption, rather than inhibition of mitochondria, causes insulin resistance in rapamycin-treated myotubes, and this system may serve as a useful model to understand the effects of rapamycin on mTOR signaling in vivo.

  1. Is serum zinc associated with pancreatic beta cell function and insulin sensitivity in pre-diabetic and normal individuals? Findings from the Hunter Community Study.

    Directory of Open Access Journals (Sweden)

    Khanrin P Vashum

    Full Text Available AIM: To determine if there is a difference in serum zinc concentration between normoglycaemic, pre-diabetic and type-2 diabetic groups and if this is associated with pancreatic beta cell function and insulin sensitivity in the former 2 groups. METHOD: Cross sectional study of a random sample of older community-dwelling men and women in Newcastle, New South Wales, Australia. Beta cell function, insulin sensitivity and insulin resistance were calculated for normoglycaemic and prediabetes participants using the Homeostasis Model Assessment (HOMA-2 calculator. RESULT: A total of 452 participants were recruited for this study. Approximately 33% (N = 149 had diabetes, 33% (N = 151 had prediabetes and 34% (N = 152 were normoglycaemic. Homeostasis Model Assessment (HOMA parameters were found to be significantly different between normoglycaemic and prediabetes groups (p<0.001. In adjusted linear regression, higher serum zinc concentration was associated with increased insulin sensitivity (p = 0.01 in the prediabetic group. There was also a significant association between smoking and worse insulin sensitivity. CONCLUSION: Higher serum zinc concentration is associated with increased insulin sensitivity. Longitudinal studies are required to determine if low serum zinc concentration plays a role in progression from pre-diabetes to diabetes.

  2. Activity-sensitive signaling by muscle-derived insulin-like growth factors in the developing and regenerating neuromuscular system.

    Science.gov (United States)

    Caroni, P

    1993-08-27

    In the nervous system, activity-sensitive retrograde signaling pathways couple the status of postsynaptic activation to elimination of collaterals during development and collateral sprouting in the adult. This article presents evidence supporting the hypothesis that in the neuromuscular system, skeletal muscle fiber derived insulin-like growth factors play a central role in such signaling. This evidence includes (1) timing and activity-sensitive expression of IGFs in skeletal muscle fibers, (2) identification of an IGF- and activity-sensitive retrograde signaling pathway from developing muscle to motoneurons in the spinal cord, (3) demonstration that IGFs in the muscle are both sufficient and necessary to induce interstitial cell proliferation and intramuscular nerve sprouting in adult muscle.

  3. Serum Resistin Levels Are Associated with Adiposity and Insulin Sensitivity in Obese Hispanic Subjects

    OpenAIRE

    2014-01-01

    Background and Aims: Resistin is involved in the development of obesity and insulin resistance (IR) in mice and may play a similar role in humans through mechanisms that remain unresolved. The objective of this study was to characterize the relationship between resistin levels in obese subjects with and without IR among Hispanic subjects.

  4. Reducing glycosphingolipid content in adipose tissue of obese mice restores insulin sensitivity, adipogenesis and reduces inflammation

    NARCIS (Netherlands)

    van Eijk, M.; Aten, J.; Bijl, N.; Ottenhoff, R.; van Roomen, C.P.A.A.; Dubbelhuis, P.F.; Seeman, I.; Ghauharali-van der Vlugt, K.; Overkleeft, H.S.; Arbeeny, C.; Groen, A.K.; Aerts, J.F.M.G.

    2009-01-01

    Adipose tissue is a critical mediator in obesity-induced insulin resistance. Previously we have demonstrated that pharmacological lowering of glycosphingolipids and subsequently GM3 by using the iminosugar AMP-DNM, strikingly improves glycemic control. Here we studied the effects of AMP-DNM on adipo

  5. Re-evaluating lipotoxic triggers in skeletal muscle: relating intramyocellular lipid metabolism to insulin sensitivity

    NARCIS (Netherlands)

    Bosma, M.; Kersten, A.H.; Hesselink, M.K.C.; Schrauwen, P.

    2012-01-01

    Ectopic fat accumulation has been linked to lipotoxic events, including the development of insulin resistance in skeletal muscle. Indeed, intramyocellular lipid storage is strongly associated with the development of type 2 diabetes. Research during the last two decades has provided evidence for a ro

  6. 5-HT2CRs expressed by pro-opiomelanocortin neurons regulate insulin sensitivity in liver

    Science.gov (United States)

    Mice lacking 5-HT 2C receptors displayed hepatic insulin resistance, a phenotype normalized by re-expression of 5-HT2CRs only in pro-opiomelanocortin (POMC) neurons. 5-HT2CR deficiency also abolished the anti-diabetic effects of meta-chlorophenylpiperazine (a 5-HT2CR agonist); these effects were re...

  7. Endocrinization of FGF1 produces a neomorphic and potent insulin sensitizer

    NARCIS (Netherlands)

    Suh, Jae Myoung; Jonker, Johan W; Ahmadian, Maryam; Goetz, Regina; Lackey, Denise; Osborn, Olivia; Huang, Zhifeng; Liu, Weilin; Yoshihara, Eiji; van Dijk, Theo H; Havinga, Rick; Fan, Weiwei; Yin, Yun-Qiang; Yu, Ruth T; Liddle, Christopher; Atkins, Annette R; Olefsky, Jerrold M; Mohammadi, Moosa; Downes, Michael; Evans, Ronald M

    2014-01-01

    Fibroblast growth factor 1 (FGF1) is an autocrine/paracrine regulator whose binding to heparan sulphate proteoglycans effectively precludes its circulation. Although FGF1 is known as a mitogenic factor, FGF1 knockout mice develop insulin resistance when stressed by a high-fat diet, suggesting a pote

  8. Partial disruption of lipolysis increases postexercise insulin sensitivity in skeletal muscle despite accumulation of DAG

    DEFF Research Database (Denmark)

    Serup, Annette Karen Lundbeck; Alsted, Thomas Junker; Jordy, Andreas Børsting

    2016-01-01

    Type 2 diabetes and skeletal muscle insulin resistance has been linked to accumulation of the intramyocellular lipid-intermediate diacylglycerol (DAG). However, recent animal and human studies have questioned such an association. Given that DAG appears in different stereoisomers and has different...

  9. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

    DEFF Research Database (Denmark)

    Dyar, Kenneth A; Ciciliot, Stefano; Wright, Lauren E;

    2013-01-01

    -stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase...

  10. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock

    DEFF Research Database (Denmark)

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.

    2014-01-01

    -stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase...

  11. A cross-over study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus.

    Science.gov (United States)

    Krebs, Jeremy D; Parry-Strong, Amber; Weatherall, Mark; Carroll, Richard W; Downie, Michelle

    2012-09-01

    The objective was to determine the effect of a single dose of espresso caffeinated coffee, decaffeinated coffee, or water on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Eighteen participants who were habitual coffee drinkers, were studied using a random-order cross-over design. After a fasting blood sample participants consumed either a double-shot black espresso coffee, decaffeinated coffee, or hot water. The main outcomes were area under the curve (AUC) glucose and insulin, and insulin sensitivity (Matsuda index) during a 75 g oral glucose tolerance test (OGTT) performed one hour later. Other outcomes were change in glucose and insulin and also the insulinogenic index (IGI) and disposition index (DI). AUC glucose was marginally different between beverages (P=.06) being greater following caffeinated coffee than water, mean difference 104 mmol/L/180 min (95% CI 0.1 to 198.1, P=.031), or decaffeinated coffee, mean difference 92.1 mmol/L/180 min (95% CI -1.9 to 186.1, P=.055). There was no difference in AUC insulin (P=.87) or insulin sensitivity (P=.47), nor in change in glucose or insulin over the hour following beverage consumption. There was a marginal difference in IGI between beverages (P=.097) with coffee having a lower incremental increase in insulin/glucose than water (P=.037) though no difference between coffee and decaffeinated coffee (P=.54) and no difference in DI (P=.23). Black espresso coffee in people with type 2 diabetes mellitus results in a marginally greater excursion of glucose during a following OGTT compared with water or decaffeinated coffee. This effect does not appear to be mediated by changes in insulin sensitivity.

  12. Ablation of the transcriptional regulator Id1 enhances energy expenditure, increases insulin sensitivity, and protects against age and diet induced insulin resistance, and hepatosteatosis.

    Science.gov (United States)

    Satyanarayana, Ande; Klarmann, Kimberly D; Gavrilova, Oksana; Keller, Jonathan R

    2012-01-01

    Obesity is a major health concern that contributes to the development of diabetes, hyperlipidemia, coronary artery disease, and cancer. Id proteins are helix-loop-helix transcription factors that regulate the proliferation and differentiation of cells from multiple tissues, including adipocytes. We screened mouse tissues for the expression of Id1 and found that Id1 protein is highly expressed in brown adipose tissue (BAT) and white adipose tissue (WAT), suggesting a role for Id1 in adipogenesis and cell metabolism. Id1(-/-) mice are viable but show a significant reduction in fat mass (P<0.005) over the life of the animal that was not due to decreased number of adipocytes. Analysis of Id1(-/-) mice revealed higher energy expenditure, increased lipolysis, and fatty acid oxidation, resulting in reduced triglyceride accumulation in WAT compared to Id1(+/+) mice. Serum levels of triglycerides (193.9±32.2 vs. 86.5±33.8, P<0.0005), cholesterol (189.4±33.8 vs. 110.6±8.23, P<0.0005) and leptin (1263±835 vs. 222±260, P<0.005) were significantly lower in aged Id1(-/-) mice compared to Id1(+/+) mice. Id1-deficient mice have higher resting (P<0.005) and total (P<0.05) O(2) consumption and lower respiratory exchange ratio (P<0.005), confirming that Id1(-/-) mice use a higher proportion of lipid as an energy source for the increased energy expenditure. The expression of PGC1α and UCP1 were 2- to 3-fold up-regulated in Id1(-/-) BAT, suggesting that loss of Id1 increases thermogenesis. As a consequence of higher energy expenditure and reduced fat mass, Id1(-/-) mice displayed enhanced insulin sensitivity. Id1 deficiency protected mice against age- and high-fat-diet-induced adiposity, insulin resistance, and hepatosteatosis. Our findings suggest that Id1 plays a critical role in the regulation of energy homeostasis and could be a potential target in the treatment of insulin resistance and fatty liver disease.

  13. Cellular basis for the species differences in sensitivity to cardiac glycosides (digitalis).

    Science.gov (United States)

    Gupta, R S; Chopra, A; Stetsko, D K

    1986-05-01

    The relative toxicity of numerous cardiotonic steroids (viz. ouabain, digitoxin, digoxin, convallatoxin, SC4453, bufalin, gitaloxin, digoxigenin, actodigin, oleandrin, digitoxigenin, gitoxin, strophanthidin, gitoxigenin, lanatosides A, B and C, alpha- and beta-acetyl digoxin, alpha- and beta-methyl digoxin) and related compounds towards a number of independent cell lines established from human, monkey, mouse, Syrian hamster, and Chinese hamster have been determined. All cardiac glycosides and their genins, as well as the cardiotonic alkaloid cassaine, exhibited greater than 100-fold higher toxicity towards cultured human and monkey cells in comparison to the cell lines of mouse, Syrian hamster, and Chinese hamster origins. These differences are species-related as all cell lines (both normal as well as transformed) from any one species, as well as cells from the closely related species (e.g., man and monkey or mouse, Chinese hamster, and Syrian hamster), showed similar sensitivity towards these drugs. The failure to see any significant differences in cellular toxicity for a larger number of other compounds which either bear limited structural resemblance to cardiac glycosides (viz. estradiol 17-beta-acetate, testosterone propionate, 21-acetoxy pregnenolone, beta-estradiol, digitonin, tigogenin, and tomatine) or interact with the Na+/K+ ATPase in a different manner (viz. veratridine, sanguinarine nitrate, penicillic acid, vanadium pentoxide, harmaline-HCI,5,5'-diphenyl hydantoin, quindonium bromide, and methyl quinolizinum bromide) provides strong evidence that the observed species-related differences are highly specific for cardiotonic steroids. Studies on the binding of [3H]ouabain show that, in comparison to human and monkey cell lines, no significant binding of the drug is observed in cells derived from the resistant species (i.e., mouse and Chinese hamster). The Na+/K+ ATPase from cells of the resistant species is inhibited at much higher concentrations of

  14. Distal gastrectomy in pancreaticoduodenectomy is associated with accelerated gastric emptying, enhanced postprandial release of GLP-1, and improved insulin sensitivity

    DEFF Research Database (Denmark)

    Harmuth, Stefan; Wewalka, Marlene; Holst, Jens Juul

    2014-01-01

    OBJECTIVE: This study aims to investigate the relationship between gastric emptying, postprandial GLP-1 and insulin sensitivity after pancreaticoduodenectomy (PD). BACKGROUND: Abnormal glucose regulation is highly prevalent in patients with pancreatic neoplasm and resolves in some after PD......, the cause of which is unclear. The procedure is carried out with pylorus preservation (PPPD) or with distal gastrectomy (Whipple procedure). Accelerated gastric emptying and ensuing enhanced release of glucagon-like peptide-1 (GLP-1) conceivably play a role in glucose metabolism after PD. It was the purpose...

  15. The relationship between heat shock protein 72 expression in skeletal muscle and insulin sensitivity is dependent on adiposity

    DEFF Research Database (Denmark)

    Henstridge, Darren C; Forbes, Josephine M; Penfold, Sally A

    2010-01-01

    activity and aerobic fitness did not show any association with HSP72 protein expression in either tissue studied. A lower expression of HSP72 protein in human skeletal muscle was associated with increased adiposity and decreased insulin sensitivity in healthy individuals. These findings are consistent...... healthy human population free of hyperglycemia. Healthy participants (N = 17; age, 30 ± 3 years) underwent measurement of body composition (dual-energy x-ray absorptiometry), a maximum aerobic capacity test (VO(2max)), an oral glucose tolerance test, and a hyperinsulinemic-euglycemic clamp (M) to access...

  16. Are the beneficial cardiovascular effects of simvastatin and metformin also associated with a hormone-dependent mechanism improving insulin sensitivity?

    Directory of Open Access Journals (Sweden)

    C. Bulcão

    Full Text Available In addition to lipid-lowering and cardiovascular protective actions, statins may have beneficial effects on insulin sensitivity. The objective of the present study was to evaluate the effect of simvastatin therapy on insulin resistance and on leptin, adiponectin, and C-reactive protein (CRP levels, as compared to metformin, in overweight pre-diabetic subjects. Forty-one subjects with BMI >25 kg/m² and impaired fasting glucose or impaired glucose tolerance were randomized to take simvastatin, 20 mg/day (N = 20 or metformin, 1.7 g/day (N = 21 for 16 weeks. Blood samples for the determination of metabolic, hormonal, and inflammatory parameters were obtained at baseline and after each treatment. After metformin therapy, significant reductions in mean BMI and waist circumference were observed, and after simvastatin treatment LDL and triglyceride levels were significantly reduced. Insulin resistance determined by the homeostasis model assessment decreased only with metformin. Independently of the type of medication, a significant decrease in CRP levels was detected from baseline to the end of the study. CRP showed a mean reduction of 0.12 ± 0.04 mg/dL (P = 0.002 over time. No change in leptin or adiponectin levels was induced by any therapy. The data suggest that a low dose of simvastatin does not affect insulin resistance in overweight pre-diabetic subjects and has no effect on leptin or adiponectin levels. Further studies including a larger sample size, higher doses of statins, and a placebo control group are necessary to confirm the present data.

  17. Glutamate cysteine ligase – modulatory subunit knockout mouse shows normal insulin sensitivity but reduced liver glycogen storage.

    Directory of Open Access Journals (Sweden)

    Suzie eLavoie

    2016-04-01

    Full Text Available Glutathione (GSH deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO for the modulatory subunit of the glutamate cysteine ligase (GCLM, the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilisation following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage.

  18. Glutamate Cysteine Ligase—Modulatory Subunit Knockout Mouse Shows Normal Insulin Sensitivity but Reduced Liver Glycogen Storage

    KAUST Repository

    Lavoie, Suzie

    2016-04-21

    Glutathione (GSH) deficits have been observed in several mental or degenerative illness, and so has the metabolic syndrome. The impact of a decreased glucose metabolism on the GSH system is well-known, but the effect of decreased GSH levels on the energy metabolism is unclear. The aim of the present study was to investigate the sensitivity to insulin in the mouse knockout (KO) for the modulatory subunit of the glutamate cysteine ligase (GCLM), the rate-limiting enzyme of GSH synthesis. Compared to wildtype (WT) mice, GCLM-KO mice presented with reduced basal plasma glucose and insulin levels. During an insulin tolerance test, GCLM-KO mice showed a normal fall in glycemia, indicating normal insulin secretion. However, during the recovery phase, plasma glucose levels remained lower for longer in KO mice despite normal plasma glucagon levels. This is consistent with a normal counterregulatory hormonal response but impaired mobilization of glucose from endogenous stores. Following a resident-intruder stress, during which stress hormones mobilize glucose from hepatic glycogen stores, KO mice showed a lower hyperglycemic level despite higher plasma cortisol levels when compared to WT mice. The lower hepatic glycogen levels observed in GCLM-KO mice could explain the impaired glycogen mobilization following induced hypoglycemia. Altogether, our results indicate that reduced liver glycogen availability, as observed in GCLM-KO mice, could be at the origin of their lower basal and challenged glycemia. Further studies will be necessary to understand how a GSH deficit, typically observed in GCLM-KO mice, leads to a deficit in liver glycogen storage.

  19. 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.

  20. Pandanus amaryllifolius leaf extract increases insulin sensitivity in high-fat diet-induced obese mice

    Institute of Scientific and Technical Information of China (English)

    Suphaket Saenthaweesuk; Jarinyaporn Naowaboot; Nuntiya Somparn

    2016-01-01

    Objective: To examine the effect of Pandanus amaryllifolius (P. amaryllifolius) leaf extract on the insulin resistance state in obese ICR mice. Methods: Obesity was induced in mice fed with high-fat diet (45%fat) for 12 weeks. After the first six weeks on the diet, the obese mice were administered with the water extract of P. amaryllifolius leaf at 125 and 250 mg/kg/day, respectively for another six weeks. At the 5th week of treatment, oral glucose tolerance test was conducted. After six weeks of treat-ment, the levels of blood glucose, serum insulin, leptin, adiponectin, and lipid profiles were determined. The liver, muscle and epididymal fat tissues were removed for measuring the biochemical parameters and protein expression, as well as histological examination. Results: Six weeks of treatment with P. amaryllifolius led to a significant reduction in the blood glucose level as well as improvement in the insulin resistance. P. amaryllifolius also increased the liver glycogen storage and serum adiponectin and decreased the serum leptin levels. A reduction in the serum and hepatic triglyceride, and non-esterified fatty acid levels was also observed. The histological examination showed that the obese mice treated with P. amaryllifolius reduced the lipid droplet in liver tissue and adipocyte size in epididymal fat tissue. The treatment also increased the protein expression of glucose transporter 4 in the muscle and fat tissues. Conclusions: The treatment with P. amaryllifolius could decrease several parameters of impaired glucose and lipid metabolism. To the best of our knowledge, this is the first report on the role of P. amaryllifolius leaf extract in alleviating the insulin dysfunction in obesity state.

  1. Acrolein decreases endothelial cell migration and insulin sensitivity through induction of let-7a.

    Science.gov (United States)

    O'Toole, Timothy E; Abplanalp, Wesley; Li, Xiaohong; Cooper, Nigel; Conklin, Daniel J; Haberzettl, Petra; Bhatnagar, Aruni

    2014-08-01

    Acrolein is a major reactive component of vehicle exhaust, and cigarette and wood smoke. It is also present in several food substances and is generated endogenously during inflammation and lipid peroxidation. Although previous studies have shown that dietary or inhalation exposure to acrolein results in endothelial activation, platelet activation, and accelerated atherogenesis, the basis for these effects is unknown. Moreover, the effects of acrolein on microRNA (miRNA) have not been studied. Using AGILENT miRNA microarray high-throughput technology, we found that treatment of cultured human umbilical vein endothelial cells with acrolein led to a significant (>1.5-fold) upregulation of 12, and downregulation of 15, miRNAs. Among the miRNAs upregulated were members of the let-7 family and this upregulation was associated with decreased expression of their protein targets, β3 integrin, Cdc34, and K-Ras. Exposure to acrolein attenuated β3 integrin-dependent migration and reduced Akt phosphorylation in response to insulin. These effects of acrolein on endothelial cell migration and insulin signaling were reversed by expression of a let-7a inhibitor. Also, inhalation exposure of mice to acrolein (1 ppm x 6 h/day x 4 days) upregulated let-7a and led to a decrease in insulin-stimulated Akt phosphorylation in the aorta. These results suggest that acrolein exposure has broad effects on endothelial miRNA repertoire and that attenuation of endothelial cell migration and insulin signaling by acrolein is mediated in part by the upregulation of let-7a. This mechanism may be a significant feature of vascular injury caused by inflammation, oxidized lipids, and exposure to environmental pollutants.

  2. The role of skeletal muscle glycogen breakdown for regulation of insulin sensitivity by exercise

    Directory of Open Access Journals (Sweden)

    Jørgen eJensen

    2011-12-01

    Full Text Available Glycogen is the storage form of carbohydrates in mammals. In humans the majority of glycogen is stored in skeletal muscles (~500 g and the liver (~100 g. Food is supplied in larger meals, but the blood glucose concentration has to be kept within narrow limits to survive and stay healthy. Therefore, the body has to cope with periods of excess carbohydrates and periods without supplementation. Healthy persons remove blood glucose rapidly when glucose is in excess, but insulin-stimulated glucose disposal is reduced in insulin resistant and type 2 diabetic subjects. During a hyperinsulinemic euglycaemic clamp, 70-90 % of glucose disposal will be stored as muscle glycogen in healthy subjects. The glycogen stores in skeletal muscles are limited because an efficient feedback-mediated inhibition of glycogen synthase prevents accumulation. De novo lipid synthesis can contribute to glucose disposal when glycogen stores are filled. Exercise physiologists normally consider glycogen’s main function as energy substrate. Glycogen is the main energy substrate during exercise intensity above 70 % of maximal oxygen uptake (VO2max and fatigue develops when the glycogen stores are depleted in the active muscles. After exercise, the rate of glycogen synthesis is increased to replete glycogen stores, and blood glucose is the substrate. Indeed insulin-stimulated glucose uptake and glycogen synthesis is elevated after exercise, which, from an evolutional point of view, will favour glycogen repletion and preparation for new fight or flight events. In the modern society, the reduced glycogen stores in skeletal muscles after exercise allows carbohydrates to be stored as muscle glycogen and prevents that glucose is channelled to de novo lipid synthesis, which over time will causes ectopic fat accumulation and insulin resistance. The reduction of skeletal muscle glycogen after exercise allows a healthy storage of carbohydrates after meals and prevents development of type

  3. Naringenin Inhibits Adipogenesis and Reduces Insulin Sensitivity and Adiponectin Expression in Adipocytes

    Directory of Open Access Journals (Sweden)

    Allison J. Richard

    2013-01-01

    Full Text Available Adipose tissue development and function are widely studied to examine the relationship between obesity and the metabolic syndrome. It is well documented that the inability of adipose tissue to properly increase its lipid storage capacity during the obese state can lead to metabolic dysfunction. In a blind screen of 425 botanicals, we identified naringenin as an inhibitor of adipocyte differentiation. Naringenin is one of the most abundant citrus flavonoids, and recent studies have demonstrated antihyperlipidemic capabilities. These studies have largely focused on the effects of naringenin on the liver. Our biochemical studies clearly demonstrate that naringenin inhibits adipogenesis and impairs mature fat cell function. Naringenin specifically inhibited adipogenesis in a dose-dependent fashion as judged by examining lipid accumulation and induction of adipocyte marker protein expression. In mature 3T3-L1 adipocytes, naringenin reduced the ability of insulin to induce IRS-1 tyrosine phosphorylation and substantially inhibited insulin-stimulated glucose uptake in a dose-dependent manner and over a time frame of 1.5 to 24 hours. Exposure to naringenin also inhibited adiponectin protein expression in mature murine and human adipocytes. Our studies have revealed that naringenin may have a negative impact on adipocyte-related diseases by limiting differentiation of preadipocytes, by significantly inducing insulin resistance, and by decreasing adiponectin expression in mature fat cells.

  4. Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation.

    Science.gov (United States)

    Reno, Candace M; Puente, Erwin C; Sheng, Zhenyu; Daphna-Iken, Dorit; Bree, Adam J; Routh, Vanessa H; Kahn, Barbara B; Fisher, Simon J

    2017-03-01

    GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.

  5. The effect of strength and endurance training on insulin sensitivity and fat distribution in human immunodeficiency virus-infected patients with lipodystrophy

    DEFF Research Database (Denmark)

    Lindegaard, B; Hansen, T; Hvid, T;

    2008-01-01

    CONTEXT: Fat redistribution, insulin resistance, and low-grade inflammation characterize HIV-infected patients with lipodystrophy. Currently, no effective therapies exist for the combined treatment of fat redistribution and insulin resistance. OBJECTIVE: Our objective was to evaluate the effects...... of strength and endurance training on insulin sensitivity and fat distribution in HIV-infected patients with lipodystrophy. SUBJECTS AND METHODS: Twenty sedentary HIV-infected men with lipodystrophy were randomly assigned to supervised strength or endurance training three times a week for 16 wk. The primary...... and increased high-density lipoprotein cholesterol (P lipodystrophy....

  6. Effects of Chronic Consumption of Sugar-Enriched Diets on Brain Metabolism and Insulin Sensitivity in Adult Yucatan Minipigs

    Science.gov (United States)

    Ochoa, Melissa; Malbert, Charles-Henri; Meurice, Paul; Val-Laillet, David

    2016-01-01

    Excessive sugar intake might increase the risk to develop eating disorders via an altered reward circuitry, but it remains unknown whether different sugar sources induce different neural effects and whether these effects are dependent from body weight. Therefore, we compared the effects of three high-fat and isocaloric diets varying only in their carbohydrate sources on brain activity of reward-related regions, and assessed whether brain activity is dependent on insulin sensitivity. Twenty-four minipigs underwent 18FDG PET brain imaging following 7-month intake of high-fat diets of which 20% in dry matter weight (36.3% of metabolisable energy) was provided by starch, glucose or fructose (n = 8 per diet). Animals were then subjected to a euglycemic hyperinsulinemic clamp to determine peripheral insulin sensitivity. After a 7-month diet treatment, all groups had substantial increases in body weight (from 36.02±0.85 to 63.33±0.81 kg; Paddictive-like behavioral correlates of these brain functional characteristics. PMID:27583555

  7. The Hijacking of Cellular Signaling and the Diabetes Epidemic: Mechanisms of Environmental Disruption of Insulin Action and Glucose Homeostasis

    Directory of Open Access Journals (Sweden)

    Robert M. Sargis

    2014-02-01

    Full Text Available The burgeoning epidemic of metabolic disease causes significant societal and individual morbidity and threatens the stability of health care systems around the globe. Efforts to understand the factors that contribute to metabolic derangements are critical for reversing these troubling trends. While excess caloric consumption and physical inactivity superimposed on a susceptible genetic background are central drivers of this crisis, these factors alone fail to fully account for the magnitude and rapidity with which metabolic diseases have increased in prevalence worldwide. Recent epidemiological evidence implicates endocrine disrupting chemicals in the pathogenesis of metabolic diseases. These compounds represent a diverse array of chemicals to which humans are exposed via multiple routes in adulthood and during development. Furthermore, a growing ensemble of animal- and cell-based studies provides preclinical evidence supporting the hypothesis that environmental contaminants contribute to the development of metabolic diseases, including diabetes. Herein are reviewed studies linking specific endocrine disruptors to impairments in glucose homeostasis as well as tying these compounds to disturbances in insulin secretion and impairments in insulin signal transduction. While the data remains somewhat incomplete, the current body of evidence supports the hypothesis that our chemically polluted environment may play a contributing role in the current metabolic crisis.

  8. Trigonella foenum-graecum water extract improves insulin sensitivity and stimulates PPAR and γ gene expression in high fructose-fed insulin-resistant rats

    Directory of Open Access Journals (Sweden)

    Abbas Mohammadi

    2016-01-01

    Conclusion: This study demonstrates the beneficial effects of trigonella foenum-graecum extract on insulin resistance in rats fed on a high-fructose diet. At least three mechanisms are involved, including direct insulin-like effect, increase in adiponectin levels, and PPARγ protein expression.

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

    DEFF Research Database (Denmark)

    Laakso, M; Zilinskaite, J; Hansen, T

    2008-01-01

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

  10. Cellular biomarker responses of limpets (Mollusca as measure of sensitivity to cadmiumcontamination

    Directory of Open Access Journals (Sweden)

    Koot Reinecke

    2008-09-01

    Full Text Available Due to the availability and chemical nature of some heavy metals, sub-lethal toxicant levels may persist in the ocean waters and may cause physiological problems and toxicity in invertebrates and other marine organisms. Although studies of metal concentrations in False Bay showed relatively low mean concentrations of Cd, invertebrates such as molluscs, crustaceans and many other groups are able to accumulate high levels of heavy metals in their tissues and still survive in the heaviest polluted areas. They can accumulate numerous pollutants from natural waters in quantities that are many orders of magnitude higher than background levels. Bioaccumulation ofcadmium in intertidal species could cause stress which may be measurable at the cellular level. A variety of limpet species that may serve as suitable ecotoxicological monitoring species occur in abundance on rocky shores along the South African coastline. The aim of this study was to obtain sensitivity data which could contribute to the selection of a suitable monitoring species and the eventual establishment of a species sensitivity distribution model (SSD with a biomarker responseas endpoint. The limpets Cymbula oculus, Scutellastra longicosta, Cymbula granatina and Scutellastragranularis as well as water samples were collected at two localities in False Bay, South Africa. Analysis of water and biological samples were done by atomic absorption spectrometry. Exposures were done to three different sublethal concentrations of cadmium in the laboratory in static flow tanks over three days. There was a moderate increase in cadmium body concentrations over time. Results obtained at three exposure concentrations showed no significant differences in metal concentrations between the different C. oculus samples. Significant differences were obtained between the control and the exposure groups for each exposure time except between the control and the 1mg/L CdCl2 exposure group after 24 and 72 hours of

  11. A study on lifestyle adjustment and insulin sensitizing treatment in PCOS-IR women

    Institute of Scientific and Technical Information of China (English)

    Ma Liang-kun; Jin Li-na; Yu Qi; Xu Ling

    2008-01-01

    Objective:To compare the efficacy of lifestyle adjustment,metformin and rosiglitazone on women with polycystic ovary syndrome and insulin resistance(PCOS-IR)Methods:A randomized controlled trial(RCT)was carried out in Peking Union Medical College Hospital(PUMCH),One hundred and six women with PCOS were randomly allocated to three intervention groups:lifestyle adjustment,lifestyle adjustment plus metformin,lifestyle adjustment plus rosiglitazone group,patients were treated with lifestyle adjustment(diet and exercise),lifestyle adjustment plus metformin(500mg three times daily),lifestyle adjustment plus rosiglitazone(4mg once daily)for three months.Sixty patients completed treatments,basal body temperature(BBT),total testosterone as well as fasting serum insulin and lipid levels were measured and compared in all patients before and after lifestyle adjustment.Results:No significant differences were found in the baseline characteristics among three groups.In lifestyle adjustment group 51%(22/43)patients completed treatment,23%(5/22)patients resumed ovulation.In lifestyle adjustment plus metformin group 58%(21/36)patients completed treatment,43%(9/21)patients resumed ovulation.In lifestyle adjustment plus rosiglitazone group 63%(17/27)patients completed treatment,59%(10/17)patients resumed ovulation.Ovulation rate was significantly higher in lifestyle adjustment plus rosiglitazone group than that in weight loss group.There was no significant difference among three groups in body mass index(BMI),waist circumference,waist-hip ratio(WHR),sex hormone,serum fasting insulin and lipid levels after treatment.Conclusions:Lifestyle adjustment,metformin and rosiglitazone treatment can improve ovulation each.

  12. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity.

    Science.gov (United States)

    Yasui, Mika; Tamura, Yukinori; Minami, Manabu; Higuchi, Sei; Fujikawa, Risako; Ikedo, Taichi; Nagata, Manabu; Arai, Hidenori; Murayama, Toshinori; Yokode, Masayuki

    2015-01-01

    With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and

  13. The Prostaglandin E2 Receptor EP4 Regulates Obesity-Related Inflammation and Insulin Sensitivity.

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    Mika Yasui

    Full Text Available With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue

  14. Palmitoleic acid reduces intramuscular lipid and restores insulin sensitivity in obese sheep

    OpenAIRE

    Duckett SK; Volpi-Lagreca G; Alende M; Long NM

    2014-01-01

    Susan K Duckett, Gabriela Volpi-Lagreca, Mariano Alende, Nathan M LongAnimal and Veterinary Sciences Department, Clemson University, Clemson, SC, USAAbstract: Obese sheep were used to assess the effects of palmitoleic (C16:1 cis-9) acid infusion on lipogenesis and circulating insulin levels. Infusion of 10 mg/kg body weight (BW)/day C16:1 intravenously in obese sheep reduced (P<0.01) weight gain by 77%. Serum palmitoleic levels increased (P<0.05) in a linear manner with increasi...

  15. Ursolic acid and rosiglitazone combination improves insulin sensitivity by increasing the skeletal muscle insulin-stimulated IRS-1 tyrosine phosphorylation in high-fat diet-fed C57BL/6J mice.

    Science.gov (United States)

    Sundaresan, Arjunan; Radhiga, Thangaiyan; Pugalendi, Kodukkur Viswanathan

    2016-06-01

    The aim of this present study was to investigate the effect of ursolic acid (UA) and rosiglitazone (RSG) on insulin sensitivity and proximal insulin signaling pathways in high-fat diet (HFD)-fed C57/BL/6J mice. Male C57BL/6J mice were fed either normal diet or HFD for 10 weeks, after which animals in each dietary group were divided into the following six groups (normal diet, normal diet plus UA and RSG, HFD alone, HFD plus UA, HFD plus RSG, and HFD plus UA and RSG) for the next 5 weeks. UA (5 mg/kg BW) and RSG (4 mg/kg BW) were administered as suspensions directly into the stomach using a gastric tube. The HFD diet elevated fasting plasma glucose, insulin, and homeostasis model assessment index. The expression of insulin receptor substrate (IRS)-1, phosphoinositide 3-kinase (PI3-kinase), Akt, and glucose transporter (GLUT) 4 were determined by Western blot analyses. The results demonstrated that combination treatment (UA/RSG) ameliorated HFD-induced glucose intolerance and insulin resistance by improving the homeostatic model assessment (HOMA) index. Further, combination treatment (UA/RSG) stimulated the IRS-1, PI3-kinase, Akt, and GLUT 4 translocation. These results strongly suggest that combination treatment (UA/RSG) activates IRS-PI3-kinase-Akt-dependent signaling pathways to induce GLUT 4 translocation and increases the expression of insulin receptor to improve glucose intolerance.

  16. Beneficial role of vitamin K supplementation on insulin sensitivity, glucose metabolism, and the reduced risk of type 2 diabetes: A review.

    Science.gov (United States)

    Manna, Prasenjit; Kalita, Jatin

    2016-01-01

    Micronutrients are gaining acceptance as an important nutritional therapy for the prevention and/or management of diabetes and its associated health risks. Although a very small quantity of micronutrients are required for specific functions in our bodies, moderate deficiencies can lead to serious health issues. Impaired insulin sensitivity and glucose intolerance play a major role in the development of diabetic pathophysiology. Vitamin K is well known for its function in blood coagulation. Moreover, several human studies reported the beneficial role of vitamin K supplementation in improving insulin sensitivity and glucose tolerance, preventing insulin resistance, and reducing the risk of type 2 diabetes (T2 D). Both animal and human studies have suggested that vitamin K-dependent protein (osteocalcin [OC]), regulation of adipokine levels, antiinflammatory properties, and lipid-lowering effects may mediate the beneficial function of vitamin K in insulin sensitivity and glucose tolerance. This review for the first time provides an overview of the currently available preclinical and clinical evidences on the effect of vitamin K supplementation in the management of insulin sensitivity and glucose tolerance. The outcome of this review will increase understanding for the development of a novel adjuvant therapy to achieve better control of glycemia and improve the lives of diabetic patients.

  17. Effect of Probiotic (VSL#3 and Omega-3 on Lipid Profile, Insulin Sensitivity, Inflammatory Markers, and Gut Colonization in Overweight Adults: A Randomized, Controlled Trial

    Directory of Open Access Journals (Sweden)

    Hemalatha Rajkumar

    2014-01-01

    Full Text Available To evaluate the effects of probiotic (VSL#3 and omega-3 fatty acid on insulin sensitivity, blood lipids, and inflammation, we conducted a clinical trial in 60 overweight (BMI>25, healthy adults, aged 40–60 years. After initial screening the subjects were randomized into four groups with 15 per group. The four groups received, respectively, placebo, omega-3 fatty acid, probiotic VSL#3, or both omega-3 and probiotic, for 6 weeks. Blood and fecal samples were collected at baseline and after 6 weeks. The probiotic (VSL#3 supplemented group had significant reduction in total cholesterol, triglyceride, LDL, and VLDL and had increased HDL (P<0.05 value. VSL#3 improved insulin sensitivity (P<0.01, decreased hsCRP, and favorably affected the composition of gut microbiota. Omega-3 had significant effect on insulin sensitivity and hsCRP but had no effect on gut microbiota. Addition of omega-3 fatty acid with VSL#3 had more pronounced effect on HDL, insulin sensitivity and hsCRP. Subjects with low HDL, insulin resistance, and high hsCRP had significantly lower total lactobacilli and bifidobacteria count and higher E. coli and bacteroides count.

  18. High Protein Intake Improves Insulin Sensitivity but Exacerbates Bone Resorption in Immobility (WISE Study)

    Science.gov (United States)

    Heer, Martina; Smith, Scott M.; Frings-Meuthen, Petra; Zwart, Sara R.; Baecker, Natalie

    2012-01-01

    Inactivity, like bed rest (BR), causes insulin resistance (IR) and bone loss even in healthy subjects. High protein intake seems to mitigate this IR but might exacerbate bone loss. We hypothesized that high protein intake (animal:vegetable protein ratio: 60:40), isocaloric, compared to the control group plus high potassium intake would prevent IR without affecting bone turnover. After a 20-day ambulatory adaptation to controlled confinement and diet, 16 women participated in a 60-day, 6 deg head-down-tilt BR and were assigned randomly to one of the two groups. Control subjects (CON, n=8) received 1g/kg body mass/d dietary protein. Nutrition subjects (NUT, n=8) received 1.45g/kg body mass/d dietary protein plus 7.2g branched chain amino acids per day during BR. All subjects received 1670 kcal/d. Bed rest decreased glucose disposal by 35% (pprotein intake prevented insulin resistance, but exacerbated bed rest induced increase in bone resorption markers C-telopeptide (> 30%) and Ntelopeptide (>20%) (both: pprotein intake. We conclude from these results that high protein intake might positively affect glucose tolerance, but might also foster bone loss. Further long-duration studies are mandatory before high protein intake for diabetic patients, who have an increased fracture risk, might be recommended.

  19. Distinct growth hormone receptor signaling modes regulate skeletal muscle development and insulin sensitivity in mice.

    Science.gov (United States)

    Mavalli, Mahendra D; DiGirolamo, Douglas J; Fan, Yong; Riddle, Ryan C; Campbell, Kenneth S; van Groen, Thomas; Frank, Stuart J; Sperling, Mark A; Esser, Karyn A; Bamman, Marcas M; Clemens, Thomas L

    2010-11-01

    Skeletal muscle development, nutrient uptake, and nutrient utilization is largely coordinated by growth hormone (GH) and its downstream effectors, in particular, IGF-1. However, it is not clear which effects of GH on skeletal muscle are direct and which are secondary to GH-induced IGF-1 expression. Thus, we generated mice lacking either GH receptor (GHR) or IGF-1 receptor (IGF-1R) specifically in skeletal muscle. Both exhibited impaired skeletal muscle development characterized by reductions in myofiber number and area as well as accompanying deficiencies in functional performance. Defective skeletal muscle development, in both GHR and IGF-1R mutants, was attributable to diminished myoblast fusion and associated with compromised nuclear factor of activated T cells import and activity. Strikingly, mice lacking GHR developed metabolic features that were not observed in the IGF-1R mutants, including marked peripheral adiposity, insulin resistance, and glucose intolerance. Insulin resistance in GHR-deficient myotubes derived from reduced IR protein abundance and increased inhibitory phosphorylation of IRS-1 on Ser 1101. These results identify distinct signaling pathways through which GHR regulates skeletal muscle development and modulates nutrient metabolism.

  20. Multiple roles for the non-coding RNA SRA in regulation of adipogenesis and insulin sensitivity.

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    Bin Xu

    Full Text Available Peroxisome proliferator-activated receptor-γ (PPARγ is a master transcriptional regulator of adipogenesis. Hence, the identification of PPARγ coactivators should help reveal mechanisms controlling gene expression in adipose tissue development and physiology. We show that the non-coding RNA, Steroid receptor RNA Activator (SRA, associates with PPARγ and coactivates PPARγ-dependent reporter gene expression. Overexpression of SRA in ST2 mesenchymal precursor cells promotes their differentiation into adipocytes. Conversely, knockdown of endogenous SRA inhibits 3T3-L1 preadipocyte differentiation. Microarray analysis reveals hundreds of SRA-responsive genes in adipocytes, including genes involved in the cell cycle, and insulin and TNFα signaling pathways. Some functions of SRA may involve mechanisms other than coactivation of PPARγ. SRA in adipocytes increases both glucose uptake and phosphorylation of Akt and FOXO1 in response to insulin. SRA promotes S-phase entry during mitotic clonal expansion, decreases expression of the cyclin-dependent kinase inhibitors p21Cip1 and p27Kip1, and increases phosphorylation of Cdk1/Cdc2. SRA also inhibits the expression of adipocyte-related inflammatory genes and TNFα-induced phosphorylation of c-Jun NH(2-terminal kinase. In conclusion, SRA enhances adipogenesis and adipocyte function through multiple pathways.

  1. Palmitoleic acid reduces intramuscular lipid and restores insulin sensitivity in obese sheep.

    Science.gov (United States)

    Duckett, Susan K; Volpi-Lagreca, Gabriela; Alende, Mariano; Long, Nathan M

    2014-01-01

    Obese sheep were used to assess the effects of palmitoleic (C16:1 cis-9) acid infusion on lipogenesis and circulating insulin levels. Infusion of 10 mg/kg body weight (BW)/day C16:1 intravenously in obese sheep reduced (Psubcutaneous adipose tissue was not altered. Total lipid content of the liver was also unchanged with C16:1 infusion. Palmitoleic acid infusion upregulated (Psubcutaneous adipose, and ST muscle compared to the controls. However, mRNA expression of glucose transporter type 4 (GLUT4) and carnitine palmitoyltransferase 1b (CPT1B) differed between tissues. In the subcutaneous adipose and liver, C16:1 infusion upregulated (P<0.05) GLUT4 and CPT1B, whereas these genes were downregulated (P<0.05) in ST muscle with C16:1 infusion. These results show that C16:1 infusion for 28 days reduced weight gain, intramuscular adipocyte size and total lipid content, and circulating insulin levels. These changes appear to be mediated through alterations in expression of genes regulating glucose uptake and fatty acid oxidation specifically in the muscles.

  2. The Role of Helicobacter pylori Seropositivity in Insulin Sensitivity, Beta Cell Function, and Abnormal Glucose Tolerance

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    Lou Rose Malamug

    2014-01-01

    Full Text Available Infection, for example, Helicobacter pylori (H. pylori, has been thought to play a role in the pathogenesis of type 2 diabetes mellitus (T2DM. Our aim was to determine the role of H. pylori infection in glucose metabolism in an American cohort. We examined data from 4,136 non-Hispanic white (NHW, non-Hispanic black (NHB, and Mexican Americans (MA aged 18 and over from the NHANES 1999-2000 cohort. We calculated the odds ratios for states of glucose tolerance based on the H. pylori status. We calculated and compared homeostatic model assessment insulin resistance (HOMA-IR and beta cell function (HOMA-B in subjects without diabetes based on the H. pylori status. The results were adjusted for age, body mass index (BMI, poverty index, education, alcohol consumption, tobacco use, and physical activity. The H. pylori status was not a risk factor for abnormal glucose tolerance. After adjustment for age and BMI and also adjustment for all covariates, no difference was found in either HOMA-IR or HOMA-B in all ethnic and gender groups except for a marginally significant difference in HOMA-IR in NHB females. H. pylori infection was not a risk factor for abnormal glucose tolerance, nor plays a major role in insulin resistance or beta cell dysfunction.

  3. Muscle insulin sensitivity and glucose metabolism are controlled by the intrinsic muscle clock★

    Science.gov (United States)

    Dyar, Kenneth A.; Ciciliot, Stefano; Wright, Lauren E.; Biensø, Rasmus S.; Tagliazucchi, Guidantonio M.; Patel, Vishal R.; Forcato, Mattia; Paz, Marcia I.P.; Gudiksen, Anders; Solagna, Francesca; Albiero, Mattia; Moretti, Irene; Eckel-Mahan, Kristin L.; Baldi, Pierre; Sassone-Corsi, Paolo; Rizzuto, Rosario; Bicciato, Silvio; Pilegaard, Henriette; Blaauw, Bert; Schiaffino, Stefano

    2013-01-01

    Circadian rhythms control metabolism and energy homeostasis, but the role of the skeletal muscle clock has never been explored. We generated conditional and inducible mouse lines with muscle-specific ablation of the core clock gene Bmal1. Skeletal muscles from these mice showed impaired insulin-stimulated glucose uptake with reduced protein levels of GLUT4, the insulin-dependent glucose transporter, and TBC1D1, a Rab-GTPase involved in GLUT4 translocation. Pyruvate dehydrogenase (PDH) activity was also reduced due to altered expression of circadian genes Pdk4 and Pdp1, coding for PDH kinase and phosphatase, respectively. PDH inhibition leads to reduced glucose oxidation and diversion of glycolytic intermediates to alternative metabolic pathways, as revealed by metabolome analysis. The impaired glucose metabolism induced by muscle-specific Bmal1 knockout suggests that a major physiological role of the muscle clock is to prepare for the transition from the rest/fasting phase to the active/feeding phase, when glucose becomes the predominant fuel for skeletal muscle. PMID:24567902

  4. Preserved glucagon-like peptide-1 responses to oral glucose, but reduced incretin effect, insulin secretion and sensitivity in young Asians with type 2 diabetes mellitus

    Science.gov (United States)

    Yeow, Toh Peng; Pacini, Giovanni; Tura, Andrea; Lim, Shueh Lin; Tan, Florence Hui Sieng; Tong, Chin Voon; Hong, Janet Yeow Hua; Md Zain, Fuziah; Holst, Jens Juul; Wan Mohamud, Wan Nazaimoon

    2017-01-01

    Objective Youth onset type 2 diabetes mellitus (YT2DM) is a globally rising phenomenon with substantial Asians representation. The understanding of its pathophysiology is derived largely from studies in the obese African-American and Caucasian populations, while studies on incretin effect are scarce. We examined the insulin resistance, β-cell function (BC), glucagon-like peptide (GLP)-1 hormone and incretin effect in Asian YT2DM. Research design and methods This case–control study recruited 25 Asian YT2DM and 15 healthy controls, matched for gender, ethnicity and body mass index. Serum glucose, insulin, C peptide and GLP-1 were sampled during 2-hour oral glucose tolerance tests (OGTTs) and 1-hour intravenous glucose tolerance tests (IVGTTs). Insulin sensitivity was derived from the Quantitative Insulin Sensitivity Check Index (QUICKI), Oral Glucose Insulin Sensitivity Index (OGIS) in OGTT and surrogate index of SI from the minimal model (calculated SI, CSI). Acute insulin response (AIR) was obtained from IVGTT. Total BC was computed as incremental area under the curve of insulin/incremental area under the curve of glucose, during OGTT (BCOG) and IVGTT (BCIV), respectively. Disposition index (DI) was calculated using the product of insulin sensitivity and insulin secretion. GLP-1 response to oral glucose was calculated as incremental area under the curve of GLP-1 (ΔAUCGLP-1). Per cent incretin effect was estimated as 100×(BCOG−BCIV)/BCOG). Results The YT2DM had marked impairment in BC (>80% reduction in AIR and BCOG, p<0.001) and lower QUICKI (p<0.001), OGIS (p<0.001) and CSI (p=0.015) compared with controls. There was no difference in GLP-1 at all time points and ΔAUCGLP-1 but the per cent incretin effect was reduced in the YT2DM compared with controls (12.1±8.93 vs 70.0±4.03, p<0.001). Conclusions Asian YT2DM showed similar GLP-1 response to oral glucose as controls but reduced incretin effect, BC and insulin sensitivity. The lack of compensatory

  5. MsrA Overexpression Targeted to the Mitochondria, but Not Cytosol, Preserves Insulin Sensitivity in Diet-Induced Obese Mice.

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    JennaLynn Hunnicut

    Full Text Available There is growing evidence that oxidative stress plays an integral role in the processes by which obesity causes type 2 diabetes. We previously identified that mice lacking the protein oxidation repair enzyme methionine sulfoxide reductase A (MsrA are particularly prone to obesity-induced insulin resistance suggesting an unrecognized role for this protein in metabolic regulation. The goals of this study were to test whether increasing the expression of MsrA in mice can protect against obesity-induced metabolic dysfunction and to elucidate the potential underlying mechanisms. Mice with increased levels of MsrA in the mitochondria (TgMito MsrA or in the cytosol (TgCyto MsrA were fed a high fat/high sugar diet and parameters of glucose homeostasis were monitored. Mitochondrial content, markers of mitochondrial proteostasis and mitochondrial energy utilization were assessed. TgMito MsrA, but not TgCyto MsrA, mice remain insulin sensitive after high fat feeding, though these mice are not protected from obesity. This metabolically healthy obese phenotype of TgMito MsrA mice is not associated with changes in mitochondrial number or biogenesis or with a reduction of proteostatic stress in the mitochondria. However, our data suggest that increased mitochondrial MsrA can alter metabolic homeostasis under diet-induced obesity by activating AMPK signaling, thereby defining a potential mechanism by which this genetic alteration can prevent insulin resistance without affecting obesity. Our data suggest that identification of targets that maintain and regulate the integrity of the mitochondrial proteome, particular against oxidative damage, may play essential roles in the protection against metabolic disease.

  6. Highly sensitive sensor for picomolar detection of insulin at physiological pH, using GC electrode modified with guanine and electrodeposited nickel oxide nanoparticles.

    Science.gov (United States)

    Salimi, Abdollah; Noorbakhash, Abdollah; Sharifi, Ensieh; Semnani, Abolfazl

    2008-12-01

    The electrochemical behavior of insulin at glassy carbon (GC) electrode modified with nickel oxide nanoparticles and guanine was investigated. Cyclic voltammetry technique has been used for electrodeposition of nickel oxide nanoparticles (NiOx) and immobilization of guanine on the surface GC electrode. In comparison to glassy carbon electrode modified with nickel oxide nanoparticles and bare GC electrode modified with adsorbed guanine, the guanine/nickel oxide nanoparticles/modified GC electrode exhibited excellent catalytic activity for the oxidation of insulin in physiological pH solutions at reduced overpotential. The modified electrode was applied for insulin detection using cyclic voltammetry or hydrodynamic amperometry techniques. It was found that the calibration curve was linear up to 4muM with a detection limit of 22pM and sensitivity of 100.9pA/pM under the optimized condition for hydrodynamic amperometry using a rotating disk modified electrode. In comparison to other electrochemical insulin sensors, this sensor shows many advantages such as simple preparation method without using any special electron transfer mediator or specific reagent, high sensitivity, excellent catalytic activity at physiological pH values, short response time, long-term stability and remarkable antifouling property toward insulin and its oxidation product. Additionally, it is promising for the monitoring of insulin in chromatographic effluents.

  7. Insulin-sensitizing and beneficial lipid-metabolic effects of the water-soluble melanin complex extracted from Inonotus obliquus.

    Science.gov (United States)

    Lee, Jung-Han; Hyun, Chang-Kee

    2014-09-01

    Inonotus obliquus has been traditionally used for treatment of metabolic diseases; however, the mechanism remains to be elucidated. In this study, we found that the water-soluble melanin complex extracted from I. obliquus improved insulin sensitivity and reduced adiposity in high fat (HF)-fed obese mice. When the melanin complex was treated to 3T3-L1 adipocytes, insulin-stimulated glucose uptake was increased significantly, and its phosphoinositide 3-kinase-dependent action was proven with wortmannin treatment. Additionally, dose-dependent increases in Akt phosphorylation and glucose transporter 4 translocation into the plasma membrane were observed in melanin complex-treated cells. Adiponectin gene expression in 3T3-L1 cells incubated with melanin complex increased which was corroborated by increased AMP-activated protein kinase phosphorylation in HepG2 and C2C12 cells treated with conditioned media from the 3T3-L1 culture. Melanin complex-treated 3T3-L1 cells showed no significant change in expression of several lipogenic genes, whereas enhanced expressions of fatty acid oxidative genes were observed. Similarly, the epididymal adipose tissue of melanin complex-treated HF-fed mice had higher expression of fatty acid oxidative genes without significant change in lipogenic gene expression. Together, these results suggest that the water-soluble melanin complex of I. obliquus exerts antihyperglycemic and beneficial lipid-metabolic effects, making it a candidate for promising antidiabetic agent.

  8. The novel ATP-sensitive potassium channel opener iptakalim prevents insulin resistance associated with hypertension via restoring endothelial function

    Institute of Scientific and Technical Information of China (English)

    Yu WANG; Fu-hu ZENG; Chao-liang LONG; Zhi-yuan PAN; Wen-yu CUI; Ru-huan WANG; Guo-shu LIU; Hai WANG

    2011-01-01

    To investigate the effects of iptakalim on endothelial dysfunction induced by insulin resistance (IR) and to determine whether iptakalim improved IR associated with hypertension in fructose-fed rats (FFRs) and spontaneously hypertensive rats (SHRs).Methods:Human umbilical vein endothelial cells (HUVECs) were used for in vitro study.The levels of endothelial vasoactive mediators and eNOS protein expression were determined using radioimmunoassays,ELISAs,colorimetric assays or Western blotting.Sprague-Dawley rats were fed with a high-fructose diet.In both FFRs and SHRs,tail-cuff method was used to measure systolic blood pressure (SBP),and hyperinsulinemic-euglycemic clamp was used to evaluate IR states.Results:(1) Cultured HUVECs incubated with the PI3-kinase inhibitor wortmannin (50 nmol/L) and insulin (100 nmol/L) induced endothelial dysfunction characterized by significantly reduced release of NO and expression of eNOS protein,and significantly increased production of ET-1.Pretreatment with iptakalim (0.1-10 μmol/L) could prevent the endothelial dysfunction.(2) In FFRs,the levels of SBP,fasting plasma glucose and insulin were significantly elevated,whereas the glucose infusion rate (GIR) and insulin sensitive index (ISI) were significantly decreased,and the endothelium-dependent vascular relaxation response to ACh was impaired.These changes could be prevented by oral administration of iptakalim (1,3,or 9 mg-kg-1-d-1,for 4 weeks).The imbalance between serum NO and ET-1 was also ameliorated by iptakalim.(3) In 2-4 month-old SHRs (IR was established at the age of 4 months),oral administration of iptakalim (1,3,or 9 mg.kg-1.d-1,for 8 weeks) significantly ameliorated hypertension and increased the GIR to the normal level.Conclusion:These results demonstrate that iptakalim could protect against IR-induced endothelial dysfunction,and ameliorate IR associated with hypertension,possibly via restoring the balance between NO and ET-1 signaling.

  9. Palmitoleic acid reduces intramuscular lipid and restores insulin sensitivity in obese sheep

    Directory of Open Access Journals (Sweden)

    Duckett SK

    2014-11-01

    Full Text Available Susan K Duckett, Gabriela Volpi-Lagreca, Mariano Alende, Nathan M LongAnimal and Veterinary Sciences Department, Clemson University, Clemson, SC, USAAbstract: Obese sheep were used to assess the effects of palmitoleic (C16:1 cis-9 acid infusion on lipogenesis and circulating insulin levels. Infusion of 10 mg/kg body weight (BW/day C16:1 intravenously in obese sheep reduced (P<0.01 weight gain by 77%. Serum palmitoleic levels increased (P<0.05 in a linear manner with increasing levels of C16:1 infusion. Cis-11 vaccenic (C18:1 cis-11 acid, a known elongation product of palmitoleic acid, was also elevated (P<0.05 in serum after 14 days and 21 days of infusion. Plasma insulin levels were lower (P<0.05 (10 mg/kg BW/day C16:1 than controls (0 mg/kg BW/day C16:1 at 14 days and 28 days of infusion. Infusion of C16:1 resulted in linear increases in tissue concentrations of palmitoleic, cis-11 vaccenic, eicosapentaenoic, and docosapentaenoic acids in a dose-dependent manner. Total lipid content of the semitendinosus (ST muscle and mesenteric adipose tissue was reduced (P<0.01 in both 5 mg/kg and 10 mg/kg BW C16:1 dose levels. Total lipid content and mean adipocyte size in the longissimus muscle was reduced (P<0.05 in the 10 mg/kg BW C16:1 dose level only, whereas total lipid content and adipocyte size of the subcutaneous adipose tissue was not altered. Total lipid content of the liver was also unchanged with C16:1 infusion. Palmitoleic acid infusion upregulated (P<0.05 acetyl-CoA carboxylase (ACC, fatty acid elongase-6 (ELOVL6, and Protein kinase, AMP-activated, alpha 1 catalytic subunit, transcript variant 1 (AMPK mRNA expressions in liver, subcutaneous adipose, and ST muscle compared to the controls. However, mRNA expression of glucose transporter type 4 (GLUT4 and carnitine palmitoyltransferase 1b (CPT1B differed between tissues. In the subcutaneous adipose and liver, C16:1 infusion upregulated (P<0.05 GLUT4 and CPT1B, whereas these genes were

  10. Strength training improves muscle quality and insulin sensitivity in Hispanic older adults with type 2 diabetes

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    Naomi Brooks, Jennifer E. Layne, Patricia L. Gordon , Ronenn Roubenoff , Miriam E. Nelson , Carmen Castaneda-Sceppa

    2007-01-01

    Full Text Available Hispanics are at increased risk of morbidity and mortality due to their high prevalence of diabetes and poor glycemic control. Strength training is the most effective lifestyle intervention to increase muscle mass but limited data is available in older adults with diabetes. We determined the influence of strength training on muscle quality (strength per unit of muscle mass, skeletal muscle fiber hypertrophy, and metabolic control including insulin resistance (Homeostasis Model Assessment –HOMA-IR, C-Reactive Protein (CRP, adiponectin and Free Fatty Acid (FFA levels in Hispanic older adults. Sixty-two community-dwelling Hispanics (>55 y with type 2 diabetes were randomized to 16 weeks of strength training plus standard care (ST group or standard care alone (CON group. Skeletal muscle biopsies and biochemical measures were taken at baseline and 16 weeks. The ST group show improved muscle quality (mean±SE: 28±3 vs CON (-4±2, p2 and type II fiber cross-sectional area (720±285µm2 compared to CON (type I: -164±290µm2, p=0.04; and type II: -130±336µm2, p=0.04. This was accompanied by reduced insulin resistance [ST: median (interquartile range -0.7(3.6 vs CON: 0.8(3.8, p=0.05]; FFA (ST: -84±30µmol/L vs CON: 149±48µmol/L, p=0.02; and CRP [ST: -1.3(2.9mg/L vs CON: 0.4(2.3mg/L, p=0.05]. Serum adiponectin increased with ST [1.0(1.8µg/mL] compared to CON [-1.2(2.2µg/mL, p

  11. Antioxidant treatment normalizes mitochondrial energetics and myocardial insulin sensitivity independently of changes in systemic metabolic homeostasis in a mouse model of the metabolic syndrome.

    Science.gov (United States)

    Ilkun, Olesya; Wilde, Nicole; Tuinei, Joseph; Pires, Karla M P; Zhu, Yi; Bugger, Heiko; Soto, Jamie; Wayment, Benjamin; Olsen, Curtis; Litwin, Sheldon E; Abel, E Dale

    2015-08-01

    Cardiac dysfunction in obesity is associated with mitochondrial dysfunction, oxidative stress and altered insulin sensitivity. Whether oxidative stress directly contributes to myocardial insulin resistance remains to be determined. This study tested the hypothesis that ROS scavenging will improve mitochondrial function and insulin sensitivity in the hearts of rodent models with varying degrees of insulin resistance and hyperglycemia. The catalytic antioxidant MnTBAP was administered to the uncoupling protein-diphtheria toxin A (UCP-DTA) mouse model of insulin resistance (IR) and obesity, at early and late time points in the evolution of IR, and to db/db mice with severe obesity and type-two diabetes. Mitochondrial function was measured in saponin-permeabilized cardiac fibers. Aconitase activity and hydrogen peroxide emission were measured in isolated mitochondria. Insulin-stimulated glucose oxidation, glycolysis and fatty acid oxidation rates were measured in isolated working hearts, and 2-deoxyglucose uptake was measured in isolated cardiomyocytes. Four weeks of MnTBAP attenuated glucose intolerance in 13-week-old UCP-DTA mice but was without effect in 24-week-old UCP-DTA mice and in db/db mice. Despite the absence of improvement in the systemic metabolic milieu, MnTBAP reversed cardiac mitochondrial oxidative stress and improved mitochondrial bioenergetics by increasing ATP generation and reducing mitochondrial uncoupling in all models. MnTBAP also improved myocardial insulin mediated glucose metabolism in 13 and 24-week-old UCP-DTA mice. Pharmacological ROS scavenging improves myocardial energy metabolism and insulin responsiveness in obesity and type 2 diabetes via direct effects that might be independent of changes in systemic metabolism.

  12. 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....

  13. Protective effects of berberine on high fat-induced kidney damage by increasing serum adiponectin and promoting insulin sensitivity.

    Science.gov (United States)

    Wu, Ueyue; Cha, Ying; Huang, Xinmei; Liu, Jun; Chen, Zaoping; Wang, Fang; Xu, Jiong; Sheng, Li; Ding, Heyuan

    2015-01-01

    Berberine (BBR) has been reported in several studies in cell and animal models. However, the mechanism of actions is not fully understood. The present study was therefore aimed to explore the effects of berberine on insulin sensitivity and kidney damage in a high fat diet rat model. Impaired glucose tolerance rats induced by injection of berberine while fed with high fat laboratory chow. After rats were treated for 4 weeks, OGTT and IPITT were determined. Mass and PAS were used to study the kidney tissue. ELISA was used to detect the protein concentration of CRP and TNF-α. Western blot was used to detect the proteins adiponectin, adipoR1, adipoR2 and p-AMPK expression level. These encouraging findings suggest that berberine has excellent pharmacological potential to prevent kidney damage.

  14. Comparison of the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus.

    Science.gov (United States)

    Derosa, Giuseppe; Querci, Fabrizio; Franzetti, Ivano; Dario Ragonesi, Pietro; D'Angelo, Angela; Maffioli, Pamela

    2015-10-01

    The aim of this study was to evaluate the effects of barnidipine+losartan compared with telmisartan+hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. We enrolled 148 normocholesterolemic patients with mild-to-moderate hypertension and type 2 diabetes mellitus. Patients were treated with barnidipine, 20 mg day(-1), in combination with losartan, 100 mg day(-1), or with telmisartan+hydrochlorothiazide, 80/12.5 mg day(-1), for 6 months. We assessed blood pressure (BP) on a monthly basis; additionally, blood samples were collected to assess, at baseline and after 6 months, the following parameters: fasting plasma glucose; glycated hemoglobin; fasting plasma insulin; HOMA index; and some adipocytokines, such as adiponectin (ADN), resistin, leptin, visfatin and vaspin. Patients were also subjected to an euglycemic hyperinsulinemic clamp to assess the M value and glucose infusion rate to ascertain their insulin sensitivity. One hundred and forty-one patients completed the study. The BP was reduced in both groups, although the reduction was greater with barnidipine+losartan (PBarnidipine+losartan increased the M value and glucose infusion rate during the euglycemic hyperinsulinemic clamp (Pbarnidipine+losartan (Pbarnidipine+losartan compared with baseline (Pbarnidipine+losartan were significantly better than those obtained with telmisartan+hydrochlorothiazide (Pbarnidipine+losartan improved the insulin sensitivity, as assessed by an euglycemic hyperinsulinemic clamp, and improved some of the adipocytokines related to insulin resistance.

  15. The C-174G promoter polymorphism of the IL-6 gene affects energy expenditure and insulin sensitivity.

    Science.gov (United States)

    Kubaszek, Agata; Pihlajamäki, Jussi; Punnonen, Kari; Karhapää, Pauli; Vauhkonen, Ilkka; Laakso, Markku

    2003-02-01

    Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 +/- 1.98, CG 14.73 +/- 1.57, GG 14.81 +/- 2.01 kcal x kg(-1) x min(-1); P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 +/- 2.05, CG 16.62 +/- 2.06, GG 16.66 +/- 2.50 kcal x kg(-1) x min(-1); P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 +/- 13.91, CG 59.40 +/- 14.17, GG 59.21 +/- 15.93 micro mol x kg(-1) x min(-1); P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.

  16. Long-term treatment with losartan versus atenolol improves insulin sensitivity in hypertension: ICARUS, a LIFE substudy

    DEFF Research Database (Denmark)

    Olsen, Michael H; Fossum, Eigil; Høieggen, Aud;

    2005-01-01

    Hypertension and insulin resistance might be associated through peripheral vascular hypertrophy/rarefaction which compromises skeletal muscle blood flow and decreases glucose uptake, inducing insulin resistance. We hypothesized that treatment with losartan as compared to atenolol would improve...

  17. Filter paper blood spot enzyme linked immunoassay for adiponectin and application in the evaluation of determinants of child insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Richard M Martin

    Full Text Available BACKGROUND: Adiponectin is an adipocyte-derived hormone that acts as a marker of insulin sensitivity. Bloodspot sampling by fingerstick onto filter paper may increase the feasibility of large-scale studies of the determinants of insulin sensitivity. We first describe the validation of an enzyme-linked immunoassay (ELISA for quantifying adiponectin from dried blood spots and then demonstrate its application in a large trial (PROBIT. METHODS: We quantified adiponectin from 3-mm diameter discs (≈3 µL of blood punched from dried blood spots obtained from: i whole blood standards (validation; and ii PROBIT trial samples (application in which paediatricians collected blood spots from 13,879 children aged 11.5 years from 31 sites across Belarus. We examined the distribution of bloodspot adiponectin by demographic and anthropometric factors, fasting insulin and glucose. RESULTS: In the validation study, mean intra-assay coefficients of variation (n=162 were 15%, 13% and 10% for 'low' (6.78 µg/ml, 'medium' (18.18 µg/ml and 'high' (33.13 µg/ml internal quality control (IQC samples, respectively; the respective inter-assay values (n=40 were 23%, 21% and 14%. The correlation coefficient between 50 paired whole bloodspot versus plasma samples, collected simultaneously, was 0.87 (95% CI: 0.78 to 0.93. Recovery of known quantities of adiponectin (between 4.5 to 36 µg/ml was 100.3-133%. Bloodspot adiponectin was stable for at least 30 months at -80°C. In PROBIT, we successfully quantified fasting adiponectin from dried blood spots in 13,329 of 13,879 (96% children. Mean adiponectin (standard deviation concentrations were 17.34 µg/ml (7.54 in boys and 18.41 µg/ml (7.92 in girls and were inversely associated with body mass index, fat mass, triceps and subscapular skin-fold thickness, waist circumference, height and fasting glucose. CONCLUSIONS: Bloodspot ELISA is suitable for measuring adiponectin in very small volumes of blood collected on filter paper

  18. Redox Sensitivities of Global Cellular Cysteine Residues under Reductive and Oxidative Stress.

    Science.gov (United States)

    Araki, Kazutaka; Kusano, Hidewo; Sasaki, Naoyuki; Tanaka, Riko; Hatta, Tomohisa; Fukui, Kazuhiko; Natsume, Tohru

    2016-08-01

    The protein cysteine residue is one of the amino acids most susceptible to oxidative modifications, frequently caused by oxidative stress. Several applications have enabled cysteine-targeted proteomics analysis with simultaneous detection and quantitation. In this study, we employed a quantitative approach using a set of iodoacetyl-based cysteine reactive isobaric tags (iodoTMT) and evaluated the transient cellular oxidation ratio of free and reversibly modified cysteine thiols under DTT and hydrogen peroxide (H2O2) treatments. DTT treatment (1 mM for 5 min) reduced most cysteine thiols, irrespective of their cellular localizations. It also caused some unique oxidative shifts, including for peroxiredoxin 2 (PRDX2), uroporphyrinogen decarboxylase (UROD), and thioredoxin (TXN), proteins reportedly affected by cellular reactive oxygen species production. Modest H2O2 treatment (50 μM for 5 min) did not cause global oxidations but instead had apparently reductive effects. Moreover, with H2O2, significant oxidative shifts were observed only in redox active proteins, like PRDX2, peroxiredoxin 1 (PRDX1), TXN, and glyceraldehyde 3-phosphate dehydrogenase (GAPDH). Overall, our quantitative data illustrated both H2O2- and reduction-mediated cellular responses, whereby while redox homeostasis is maintained, highly reactive thiols can potentiate the specific, rapid cellular signaling to counteract acute redox stress.

  19. Liuwei Dihuang Lowers Body Weight and Improves Insulin and Leptin Sensitivity in Obese Rats

    Directory of Open Access Journals (Sweden)

    Benjamin Perry

    2012-01-01

    Full Text Available The present study was aimed at investigating the efficacy and mechanism(s of action of a Chinese herbal formulation, Liuwei Dihuang (LWDH, as a prospective natural weight-lowering product. Following a 2-week acclimation period, 48 obesity-prone (OP-CD rats were divided into 4 groups (n=12 each. One group served as a positive control for obesity (OP, while the other 3 were challenged twice daily by oral gavage with total daily dosages of 500, 1500, or 3500 mg/kg BW LWDH, respectively, for 10 weeks. One group (n=12 of obesity-resistant (OR-CD rats served as the normal control group. All rats were fed the same AIN-93G diet modified to contain 60% energy from fat. The highest LWDH dose significantly reduced body weight during the last 4 weeks of treatment. Food intake was reduced beginning in week 2. The high LWDH dose lowered serum triglyceride (TG and nonesterified fatty acid (NEFA levels and body fat. Both the high and medium doses also lowered serum leptin and insulin levels. Liver function testing revealed no adverse side effects under the current experimental conditions. The results of the present study suggest that LWDH has potential as a preventive or therapeutic natural product against overweight and obesity.

  20. Low-Frequency Electroacupuncture Improves Insulin Sensitivity in Obese Diabetic Mice through Activation of SIRT1/PGC-1α in Skeletal Muscle

    Directory of Open Access Journals (Sweden)

    Fengxia Liang

    2011-01-01

    Full Text Available Electroacupuncture (EA has been observed to reduce insulin resistance in obesity and diabetes. However, the biochemical mechanism underlying this effect remains unclear. This study investigated the effects of low-frequency EA on metabolic action in genetically obese and type 2 diabetic db/db mice. Nine-week-old db/m and db/db mice were randomly divided into four groups, namely, db/m, db/m + EA, db/db, and db/db + EA. db/m + EA and db/db + EA mice received 3-Hz electroacupuncture five times weekly for eight consecutive weeks. In db/db mice, EA tempered the increase in fasting blood glucose, food intake, and body mass and maintained insulin levels. In EA-treated db/db mice, improved insulin sensitivity was established through intraperitoneal insulin tolerance test. EA was likewise observed to decrease free fatty acid levels in db/db mice; it increased protein expression in skeletal muscle Sirtuin 1 (SIRT1 and induced gene expression of peroxisome proliferator-activated receptor coactivator (PGC-, nuclear respiratory factor 1 (NRF1, and acyl-CoA oxidase (ACOX. These results indicated that EA offers a beneficial effect on insulin resistance in obese and diabetic db/db mice, at least partly, via stimulation of SIRT1/PGC-, thus resulting in improved insulin signal.

  1. Triglyceride glucose index as a surrogate measure of insulin sensitivity in obese adolescents with normoglycemia, prediabetes, and type 2 diabetes mellitus: Comparison with the hyperinsulinemic–euglycemic clamp

    Science.gov (United States)

    There is a need for simple surrogate estimates of insulin sensitivity in epidemiological studies of obese youth because the hyperinsulinemic-euglycemic clamp is not feasible on a large scale. Objectives: (i) To examine the triglyceride glucose (TyG) index (Ln[fasting triglycerides (mg/dL)'×'fasting ...

  2. Effects of aerobic versus resistance exercise without caloric restriction on abdominal fat, intrahepatic lipid, and insulin sensitivity in obese adolescent boys: a randomized, controlled trial

    Science.gov (United States)

    The optimal exercise modality for reductions of abdominal obesity and risk factors for type 2 diabetes in youth is unknown. We examined the effects of aerobic exercise (AE) versus resistance exercise (RE) without caloric restriction on abdominal adiposity, ectopic fat, and insulin sensitivity and se...

  3. Effect of a high monounsaturated fatty acids diet and a Mediterranean diet on serum lipids and insulin sensitivity in adults with mild abdominal obesity

    NARCIS (Netherlands)

    Bos, M.B.; Vries, de J.H.M.; Feskens, E.J.M.; Dijk, van S.J.; Hoelen, D.; Siebelink, E.; Heijligenberg, R.; Groot, de C.P.G.M.

    2010-01-01

    Background and aims - Diets high in monounsaturated fatty acids (MUFA) such as a Mediterranean diet may reduce the risk of cardiovascular diseases by improving insulin sensitivity and serum lipids. Besides being high in MUFA, a Mediterranean diet also contains abundant plant foods, moderate wine and

  4. The effect of cholecalciferol supplementation on vitamin D levels and insulin sensitivity is dose related in vitamin D-deficient HIV-1-infected patients.

    NARCIS (Netherlands)

    Beukel, CJ van den Bout-va; Bos, M.; Oyen, W.J.G.; Hermus, A.R.M.M.; Sweep, F.C.; Tack, C.J.J.; Bosch, M.E.; Burger, D.M.; Koopmans, P.P.; Ven, A.J.A.M. van der

    2008-01-01

    OBJECTIVE: The aim of this study was to explore the effects of cholecalciferol supplementation on vitamin D levels, bone mineral density (BMD), body fat distribution and insulin sensitivity in vitamin D-deficient HIV-1-infected patients. METHODS: Twenty vitamin D-deficient HIV-1-infected patients we

  5. Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment

    NARCIS (Netherlands)

    R.H. Willemsen (Ruben); A.C.S. Hokken-Koelega (Anita)

    2008-01-01

    textabstractContext: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stoppin

  6. Changes in insulin sensitivity precede changes in body composition during 14 days of step reduction combined with overfeeding in healthy young men

    DEFF Research Database (Denmark)

    Knudsen, Sine Haugaard; Hansen, Louise Seier; Pedersen, Maria

    2012-01-01

    A lifestyle characterized by inactivity and a high-calorie diet is a known risk factor for impaired insulin sensitivity and development of Type 2 diabetes mellitus. To investigate possible links, nine young healthy men (24 ± 3 yr; body mass index of 21.6 ± 2.5 kg/m(2)) completed 14 days of step...

  7. The effect of alcohol consumption on insulin sensitivity and glycemic status: a systematic review and meta-analysis of intervention studies

    NARCIS (Netherlands)

    Schrieks, I.C.; Heil, A.L.; Hendriks, H.F.; Mukamal, K.J.; Beulens, J.W.

    2015-01-01

    OBJECTIVE: Moderate alcohol consumption is associated with a reduced risk of type 2 diabetes. This reduced risk might be explained by improved insulin sensitivity or improved glycemic status, but results of intervention studies on this relation are inconsistent. The purpose of this study was to cond

  8. Chronic reduction of plasma free fatty acid improves mitochondrial function and whole-body insulin sensitivity in obese and type 2 diabetic individuals.

    Science.gov (United States)

    Daniele, Giuseppe; Eldor, Roy; Merovci, Aurora; Clarke, Geoffrey D; Xiong, Juan; Tripathy, Devjit; Taranova, Anna; Abdul-Ghani, Muhammad; DeFronzo, Ralph A

    2014-08-01

    Insulin resistance and dysregulation of free fatty acid (FFA) metabolism are core defects in type 2 diabetic (T2DM) and obese normal glucose tolerant (NGT) individuals. Impaired muscle mitochondrial function (reduced ATP synthesis) also has been described in insulin-resistant T2DM and obese subjects. We examined whether reduction in plasma FFA concentration with acipimox improved ATP synthesis rate and altered reactive oxygen species (ROS) production. Eleven NGT obese and 11 T2DM subjects received 1) OGTT, 2) euglycemic insulin clamp with muscle biopsy, and 3) (1)H-magnetic resonance spectroscopy of tibialis anterior muscle before and after acipimox (250 mg every 6 h for 12 days). ATP synthesis rate and ROS generation were measured in mitochondria isolated from muscle tissue ex vivo with chemoluminescence and fluorescence techniques, respectively. Acipimox 1) markedly reduced the fasting plasma FFA concentration and enhanced suppression of plasma FFA during oral glucose tolerance tests and insulin clamp in obese NGT and T2DM subjects and 2) enhanced insulin-mediated muscle glucose disposal and suppression of hepatic glucose production. The improvement in insulin sensitivity was closely correlated with the decrease in plasma FFA in obese NGT (r = 0.81) and T2DM (r = 0.76) subjects (both P 50% in both obese NGT and T2DM subjects and was strongly correlated with the decrease in plasma FFA and increase in insulin-mediated glucose disposal (both r > 0.70, P < 0.001). Production of ROS did not change after acipimox. Reduction in plasma FFA in obese NGT and T2DM individuals improves mitochondrial ATP synthesis rate, indicating that the mitochondrial defect in insulin-resistant individuals is, at least in part, reversible.

  9. Glycyrrhizic acid improved lipoprotein lipase expression, insulin sensitivity, serum lipid and lipid deposition in high-fat diet-induced obese rats

    Directory of Open Access Journals (Sweden)

    Eu Chia

    2010-07-01

    Full Text Available Abstract Background The metabolic syndrome, known also as the insulin resistance syndrome, refers to the clustering of several risk factors for atherosclerotic cardiovascular disease. Dyslipidaemia is a hallmark of the syndrome and is associated with a whole body reduction in the activity of lipoprotein lipase (LPL, an enzyme under the regulation of the class of nuclear receptors known as peroxisome proliferator-activated receptor (PPAR. Glycyrrhizic acid (GA, a triterpenoid saponin, is the primary bioactive constituent of the roots of the shrub Glycyrrhiza glabra. Studies have indicated that triterpenoids could act as PPAR agonists and GA is therefore postulated to restore LPL expression in the insulin resistant state. Results Oral administration of 100 mg/kg of GA to high-fat diet-induced obese rats for 28 days led to significant reduction in blood glucose concentration and improvement in insulin sensitivity as indicated by the homeostasis model assessment of insulin resistance (HOMA-IR (p Conclusion In conclusion, GA may be a potential compound in improving dyslipidaemia by selectively inducing LPL expression in non-hepatic tissues. Such up-regulation was accompanied by a GA-mediated improvement in insulin sensitivity, which may be associated with a decrease in tissue lipid deposition. The HDL-raising effect of GA suggests the antiatherosclerotic properties of GA.

  10. Overfeeding Dairy Cattle During Late-Pregnancy Alters Hepatic PPARα-Regulated Pathways Including Hepatokines: Impact on Metabolism and Peripheral Insulin Sensitivity

    Science.gov (United States)

    Khan, M Jawad; Jacometo, Carolina B; Graugnard, Daniel E; Corrêa, Marcio N; Schmitt, Eduardo; Cardoso, Felipe; Loor, Juan J

    2014-01-01

    Hepatic metabolic gene networks were studied in dairy cattle fed control (CON, 1.34 Mcal/kg) or higher energy (overfed (OVE), 1.62 Mcal/kg) diets during the last 45 days of pregnancy. A total of 57 target genes encompassing PPARα-targets/co-regulators, hepatokines, growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis, lipogenesis, and lipoprotein metabolism were evaluated on −14, 7, 14, and 30 days around parturition. OVE versus CON cows were in more negative energy balance (NEB) postpartum and had greater serum non-esterified fatty acids (NEFA), β-hydroxybutyrate (BHBA), and liver triacylglycerol (TAG) concentrations. Milk synthesis rate did not differ. Liver from OVE cows responded to postpartal NEB by up-regulating expression of PPARα-targets in the fatty acid oxidation and ketogenesis pathways, along with gluconeogenic genes. Hepatokines (fibroblast growth factor 21 (FGF21), angiopoietin-like 4 (ANGPTL4)) and apolipoprotein A-V (APOA5) were up-regulated postpartum to a greater extent in OVE than CON. OVE led to greater blood insulin prepartum, lower NEFA:insulin, and greater lipogenic gene expression suggesting insulin sensitivity was not impaired. A lack of change in APOB, MTTP, and PNPLA3 coupled with upregulation of PLIN2 postpartum in cows fed OVE contributed to TAG accumulation. Postpartal responses in NEFA and FGF21 with OVE support a role of this hepatokine in diminishing adipose insulin sensitivity. PMID:24737933

  11. Insulin sensitivity and serum TCDD in Air Force veterans occupationally exposed to herbicides during the Vietnam war

    Energy Technology Data Exchange (ETDEWEB)

    Kern, P.; Said, S. [Univ. of Arkansas for Medical Sciences, Little Rock (United States); Jackson, W. Jr; Michalek, J. [Air Force Research Lab., San Antonio (United States)

    2004-09-15

    Between 1961 and 1971, the United States Air Force sprayed 12 million gallons of the defoliant ''Agent Orange'' on 3.6 million acres of Vietnam. Agent Orange was a 1:1 mixture of 2,4-dichlorophenoxyacetic acid and 2,4,5- trichlorophenoxyacetic acid, and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) was a contaminant of the defoliant, from less than 0.05 to almost 50 parts per million. Numerous Vietnam veterans were exposed to TCDD when Agent Orange and other TCDD-contaminated herbicides were sprayed in large quantities in Vietnam and TCDD has been found at many toxic waste disposal sites in the United States. Some of the highest exposure to TCDD occurred in members of Operation Ranch Hand, the Air Force unit responsible for spraying herbicides from fix-wing aircraft in Vietnam. The Air Force Health Study (AFHS), an epidemiological study of Ranch Hand veterans, was launched in 1980 to address veteran concerns regarding Agent Orange exposure. A link between TCDD and diabetes has been demonstrated in several studies. Among the Ranch Hand veterans with high blood levels of TCDD, there was a significant increase in the prevalence of diabetes and a decrease in the age at which diabetes was diagnosed. In a study from Seveso, Italy, where 45,000 people had varying levels of exposure to TCDD, there were significant increases in mortality from coronary artery disease and diabetes. Several studies have demonstrated a relationship between blood TCDD levels and hyperinsulinemia. The data suggest that non-diabetic individuals exposed to TCDD have an increased risk of insulin-resistance, being able to maintain normal blood glucose levels but only because of very high concentrations of insulin. As a result of available evidence, public policy decisions have been made, such as a decision by the Veterans Administration that diabetes is a service-connected condition in Agent Orange-exposed Vietnam veterans. Here we study the relation between TCDD insulin sensitivity

  12. Effects of combined dietary chromium(III) propionate complex and thiamine supplementation on insulin sensitivity, blood biochemical indices, and mineral levels in high-fructose-fed rats.

    Science.gov (United States)

    Król, Ewelina; Krejpcio, Zbigniew; Michalak, Sławomir; Wójciak, Rafał W; Bogdański, Paweł

    2012-12-01

    Insulin resistance is the first step in glucose intolerance and the development of type 2 diabetes mellitus, thus effective prevention strategies should also include dietary interventions to enhance insulin sensitivity. Nutrients, such as microelement chromium(III) and thiamine, play regulatory roles in carbohydrate metabolism. The objective of this study was to evaluate the insulin-sensitizing potential of the combined supplementary chromium(III) propionate complex (CrProp) and thiamine in insulin resistance animal model (rats fed a high-fructose diet). The experiment was carried out on 40 nine-week-old male Wistar rats divided into five groups (eight animals each). Animals were fed ad libitum: the control diet (AIN-93 M) and high-fructose diets with and without a combination of two levels of CrProp (0.1 and 1 mg Cr/kg body mass/day) and two levels of thiamine (0.5 and 10 mg/kg body mass/day) for 8 weeks. At the end of the experiment rats were sacrificed to collect blood and internal organs for analyses of blood biochemical and hematologic indices as well as tissular microelement levels that were measured using appropriate methods. It was found that both supplementary CrProp and thiamine (given alone) have significant insulin-sensitizing and moderate blood-lipid-lowering properties, while the combined supplementation with these agents does not give synergistic effects in insulin-resistant rats. CrProp given separately increased kidney Cu and Cr levels, while thiamine alone increased hepatic Cu contents and decreased renal Zn and Cu contents.

  13. Pancreatic beta-cell function is a stronger predictor of changes in glycemic control after an aerobic exercise intervention than insulin sensitivity

    DEFF Research Database (Denmark)

    Solomon, Thomas; Malin, Steven K; Karstoft, Kristian;

    2013-01-01

    glucose-stimulated insulin secretion (GSIS), and disposition index (DI) were measured following 12-16-weeks of aerobic exercise training. Regression analyses were used to identify relationships between variables.ResultsFollowing training, 86% of subjects increased VO2max and lost weight. HbA1c, fasting......ContextUnderstanding inter-subject variability in glycemic control following exercise training will help individualize treatment.ObjectiveTo determine whether this variability is related to training-induced changes in insulin sensitivity or pancreatic beta-cell function.Design, Setting...

  14. NEU-P11, a novel melatonin agonist, inhibits weight gain and improves insulin sensitivity in high-fat/high-sucrose-fed rats.

    Science.gov (United States)

    She, Meihua; Deng, Xiaojian; Guo, Zhenyu; Laudon, Moshe; Hu, Zhuowei; Liao, Duanfang; Hu, Xiaobo; Luo, Yi; Shen, Qingyun; Su, Zehong; Yin, Weidong

    2009-04-01

    Evidences indicate that a complex relationship exists among sleep disorders, obesity and insulin resistance. NEU-P11 is a novel melatonin agonist used in treatment of psychophysiological insomnia, and in animal studies NEU-P11 showed sleep-promoting effect. In this study, we applied NEU-P11 on obese rats to assess its potential melatoninergic effects in vivo. Obese models were established using high-fat/high-sucrose-fed for 5 months. NEU-P11 (10mg/kg)/melatonin (4mg/kg)/vehicle were administered by a daily intraperitoneal injection respectively for 8 weeks. Our results showed that NEU-P11 or melatonin inhibited both body weight gain and deposit of abdominal fat with no influence on food intake. The impaired insulin sensitivity and antioxidative potency were improved and the levels of plasma glucose, total cholesterol (TC), triglycerides (TG) decreased with an increased in HDL-cholesterol (HDL-c) after NEU-P11 or melatonin administration. These data suggest that NEU-P11, like melatonin, decreased body weight gain and improved insulin sensitivity and metabolic profiles in obese rats. We conclude that NEU-P11 has a melatoninergic effect on regulating body weight in obese rats and also improving metabolic profiles and efficiently enhancing insulin sensitivity.

  15. Relationship of adipokine to insulin sensitivity and glycemic regulation in obese women: The effect of body weight reduction by caloric restriction

    Directory of Open Access Journals (Sweden)

    Velojić-Golubović Milena

    2013-01-01

    Full Text Available Bacground/Aim. Visceral fat is highly active metabolic and endocrine tissue which secretes many adipokines that act both on local and systemic level. It is believed that adipokines and "low-grade inflammatory state" represent a potential link between obesity, metabolic syndrome, insulin resistance and cardiovascular disease. Leptin and adiponectin are considered to be the most important adipokines with the potential metabolic and cardiovascular effects. Body weight loss improves insulin sensitivity and decreases risk for most complications associated with obesity. The aim of this study was to determine the effects of moderate loss of body weight on the level of leptin and adiponectin, insulin sensitivity and abnormalities of glycoregulation in obese women, to determine whether and to what extent the secretory products of adipose tissue, leptin and adiponectin contribute to insulin sensitivity, as well as to assess their relationship and influence on glycemia and insulinemia during the period of losing body weight using a calorie restricted diet. Methods. The study involved 90 obese female subjects (BMI

  16. Di-(2-ethylhexyl phthalate metabolites in urine show age-related changes and associations with adiposity and parameters of insulin sensitivity in childhood.

    Directory of Open Access Journals (Sweden)

    Arianna Smerieri

    Full Text Available Phthalates might be implicated with obesity and insulin sensitivity. We evaluated the levels of primary and secondary metabolites of Di-(2-ethylhexyl phthalate (DEHP in urine in obese and normal-weight subjects both before and during puberty, and investigated their relationships with auxological parameters and indexes of insulin sensitivity.DEHP metabolites (MEHP, 6-OH-MEHP, 5-oxo-MEHP, 5-OH-MEHP, and 5-CX-MEHP, were measured in urine by RP-HPLC-ESI-MS. Traditional statistical analysis and a data mining analysis using the Auto-CM analysis were able to offer an insight into the complex biological connections between the studied variables.The data showed changes in DEHP metabolites in urine related with obesity, puberty, and presence of insulin resistance. Changes in urine metabolites were related with age, height and weight, waist circumference and waist to height ratio, thus to fat distribution. In addition, clear relationships in both obese and normal-weight subjects were detected among MEHP, its products of oxidation and measurements of insulin sensitivity.It remains to be elucidated whether exposure to phthalates per se is actually the risk factor or if the ability of the body to metabolize phthalates is actually the key point. Further studies that span from conception to elderly subjects besides further understanding of DEHP metabolism are warranted to clarify these aspects.

  17. Dissociation of GLP-1 and insulin association with food processing in the brain: GLP-1 sensitivity despite insulin resistance in obese humans

    Directory of Open Access Journals (Sweden)

    Martin Heni

    2015-12-01

    Conclusions: The postprandial release of GLP-1 might alter reward processes in the orbitofrontal cortex and might thereby support the termination of food intake and reduce hunger. While obese persons showed brain insulin resistance, no GLP-1 resistance was observed. Our study provides novel insight into the central regulation of food intake by the incretin hormone GLP-1.

  18. Human skeletal muscle perilipin 2 and 3 expression varies with insulin sensitivity

    DEFF Research Database (Denmark)

    Vigelsø Hansen, Andreas; Prats Gavalda, Clara; Ploug, Thorkil;

    2013-01-01

    was obtained from vastus lateralis, and a two-step sequential euglycaemic-hy- perinsulinaemic clamp was performed. Muscle sam- ples were analyzed by Western blot for expression of perilipin 2, 3, 5, adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), endothelial lipase (EL) and lipoprotein...... lipase (LPL). Results: Perilipin 3 expression was higher in T2D compared to CON. Perilipin 2 expression was higher in CON than T2D. We observed no difference in expression of perilipin 5, ATGL, HSL, EL or LPL between the groups. Con- clusions: In the present study the muscle perilipin 3 expression...

  19. Regulation of serum potassium during insulin-induced hypoglycemia.

    Science.gov (United States)

    Petersen, K G; Schlüter, K J; Kerp, L

    1982-07-01

    Counterregulatory secretion of epinephrine occurs during severe insulin-induced hypoglycemia. Under these conditions (minimal plasma glucose 27.4 +/- 1 mg/dl) the decrease of serum potassium concentration (0.9 mVal/L) is mediated by two mechanisms: insulin-induced (0.48 mVal/L) and epinephrine-induced (0.42 mVal/L) cellular uptake of potassium. Epinephrine-induced serum potassium uptake appears to be more sensitive to beta-adrenoceptor blockade than glucose production. The intensification of insulin-induced hypokalemia by epinephrine is of clinical significance.

  20. The effects of diet- and RYGB-induced weight loss on insulin sensitivity in obese patients with and without type 2 diabetes

    DEFF Research Database (Denmark)

    Hansen, Merethe; Lund, Michael Taulo; Jørgensen, Anne Line Kjærholm

    2016-01-01

    AIMS: The impact of diet-induced weight loss and weight loss due to RYGB in patients with (T2DM, N = 16) and without (OB, N = 27) type 2 diabetes was studied. METHODS: At inclusion (A), after diet-induced weight loss (B), 4 months post-surgery (C) and 18 months post-surgery (D) body composition......, and approximately one-third of the total improvement in GIR in T2DM was observed after the diet-induced weight loss of only ~6 kg (B). Insulin clearance, visceral fat and fasting plasma insulin also improved significantly after the diet (P ... not change significantly, but IMTG decreased significantly consistent with significant increases in GIR. Metabolic flexibility and hepatic insulin sensitivity improved after RYGB. CONCLUSIONS: Metabolic improvements of RYGB are present already after the diet-induced weight loss prior to surgery. GLUT4...

  1. Roles of TP53 in determining therapeutic sensitivity, growth, cellular senescence, invasion and metastasis.

    Science.gov (United States)

    McCubrey, James A; Lertpiriyapong, Kvin; Fitzgerald, Timothy L; Martelli, Alberto M; Cocco, Lucio; Rakus, Dariusz; Gizak, Agnieszka; Libra, Massimo; Cervello, Melchiorre; Montalto, Guiseppe; Yang, Li V; Abrams, Stephen L; Steelman, Linda S

    2017-01-01

    TP53 is a critical tumor suppressor gene that regulates cell cycle progression, apoptosis, cellular senescence and many other properties critical for control of normal cellular growth and death. Due to the pleiotropic effects that TP53 has on gene expression and cellular physiology, mutations at this tumor suppressor gene result in diverse physiological effects. T53 mutations are frequently detected in numerous cancers. The expression of TP53 can be induced by various agents used to treat cancer patients such as chemotherapeutic drugs and ionizing radiation. Radiation will induce Ataxia telangiectasia mutated (ATM) and other kinases that results in the phosphorylation and activation of TP53. TP53 is also negatively regulated by other mechanisms, such as ubiquitination by ligases such as MDM2. While TP53 has been documented to control the expression of many "classical" genes (e.g., p21(Cip-1), PUMA, Bax) by transcriptional mechanisms for quite some time, more recently TP53 has been shown to regulate microRNA (miR) gene expression. Different miRs can promote oncogenesis (oncomiR) whereas others act to inhibit tumor progression (tumor suppressor miRs). Targeted therapies to stabilize TP53 have been developed by various approaches, MDM2/MDM4 inhibitors have been developed to stabilize TP53 in TP53-wild type (WT) tumors. In addition, small molecules have been isolated that will reactivate certain mutant TP53s. Both of these types of inhibitors are in clinical trials. Understanding the actions of TP53 may yield novel approaches to suppress cancer, aging and other health problems.

  2. Effect of fruit juice on glucose control and insulin sensitivity in adults: a meta-analysis of 12 randomized controlled trials.

    Directory of Open Access Journals (Sweden)

    Bin Wang

    Full Text Available BACKGROUND: Diabetes mellitus has become a worldwide health problem. Whether fruit juice is beneficial in glycemic control is still inconclusive. This study aimed to synthesize evidence from randomized controlled trials on fruit juice in relationship to glucose control and insulin sensitivity. METHODS: A strategic literature search of PubMed, EMBASE, and the Cochrane Library (updated to March, 2014 was performed to retrieve the randomized controlled trials that evaluated the effects of fruit juice on glucose control and insulin sensitivity. Study quality was assessed using the Jadad scale. Weighted mean differences were calculated for net changes in the levels of fasting glucose, fasting insulin, hemoglobin A1c (HbA1c, and homeostatic model assessment of insulin resistance (HOMA-IR using fixed- or random-effects model. Prespecified subgroup and sensitivity analyses were performed to explore the potential heterogeneity. RESULTS: Twelve trials comprising a total of 412 subjects were included in the current meta-analysis. The numbers of these studies that reported the data on fasting glucose, fasting insulin, HbA1c and HOMA-IR were 12, 5, 3 and 3, respectively. Fruit juice consumption did not show a significant effect on fasting glucose and insulin concentrations. The net change was 0.79 mg/dL (95% CI: -1.44, 3.02 mg/dL; P = 0.49 for fasting glucose concentrations and -0.74 µIU/ml (95% CI: -2.62, 1.14 µIU/ml; P = 0.44 for fasting insulin concentrations in the fixed-effects model. Subgroup analyses further suggested that the effect of fruit juice on fasting glucose concentrations was not influenced by population region, baseline glucose concentration, duration, type of fruit juice, glycemic index of fruit juice, fruit juice nutrient constitution, total polyphenols dose and Jadad score. CONCLUSION: This meta-analysis showed that fruit juice may have no overall effect on fasting glucose and insulin concentrations. More RCTs are warranted to

  3. Changes in plasma melanocyte-stimulating hormone, ACTH, prolactin, GH, LH, FSH, and thyroid-stimulating hormone in response to injection of sulpiride, thyrotropin-releasing hormone, or vehicle in insulin-sensitive and -insensitive mares.

    Science.gov (United States)

    Valencia, N Arana; Thompson, D L; Mitcham, P B

    2013-05-01

    Six insulin-sensitive and 6 insulin-insensitive mares were used in a replicated 3 by 3 Latin square design to determine the pituitary hormonal responses (compared with vehicle) to sulpiride and thyrotropin-releasing hormone (TRH), 2 compounds commonly used to diagnose pituitary pars intermedia dysfunction (PPID) in horses. Mares were classified as insulin sensitive or insensitive by their previous glucose responses to direct injection of human recombinant insulin. Treatment days were February 25, 2012, and March 10 and 24, 2012. Treatments were sulpiride (racemic mixture, 0.01 mg/kg BW), TRH (0.002 mg/kg BW), and vehicle (saline, 0.01 mL/kg BW) administered intravenously. Blood samples were collected via jugular catheters at -10, 0, 5, 10, 20, 30, 45, 60, 90, and 120 min relative to treatment injection. Plasma ACTH concentrations were variable and were not affected by treatment or insulin sensitivity category. Plasma melanocyte-stimulating hormone (MSH) concentrations responded (P sulpiride and TRH injection and were greater (P sulpiride and TRH injection, and the response was greater (P sulpiride; no effect of insulin sensitivity was observed. Plasma thyroid-stimulating hormone (TSH) concentrations responded (P sulpiride and TRH in insulin-insensitive mares were similar to, but not as exaggerated as, those observed by others for PPID horses. In addition, the reduced TSH concentrations in insulin-insensitive mares are consistent with our previous observation of elevated plasma triiodothyronine concentrations in hyperleptinemic horses (later shown to be insulin insensitive as well).

  4. Effects of GLP-1 receptor agonists on insulin sensitivity%GLP-1受体激动剂的胰岛素增敏效应

    Institute of Scientific and Technical Information of China (English)

    郑仁东; 刘超

    2012-01-01

    Insulin resistance and lack of insulin secretion is the main pathogenesis of type 2 diabetes.Researches have shown that glucagon-like peptide-1 ( GLP-1 ) receptor agonists could effectively improve the function of pancreatic β cell,and promote the secretion of insulin.Moreover,GLP-1 receptor agonists could regulate signal transduction,increase adipocytes differentiation and glucose uptake,decrease expression of inflammation factors,reduce weight and so on.Therefore,it can improve insulin resistance,increase insulin sensitivity.%2型糖尿病的发病机制主要涉及胰岛素抵抗张胰岛素分泌缺乏.研究表明,胰高血糖素样肽-1受体激动剂在有效改善胰岛β细胞功能,促进胰岛素分泌的同时,还能够作用于细胞信号转导,促进脂肪细胞分化和葡萄糖摄取,并通过减轻相关炎性反应因子表达,降低体重等,改善胰岛素抵抗,增加胰岛素敏感性.

  5. State of the Art Review: Emerging Therapies: The Use of Insulin Sensitizers in the Treatment of Adolescents with Polycystic Ovary Syndrome (PCOS

    Directory of Open Access Journals (Sweden)

    Gordon Catherine M

    2011-08-01

    Full Text Available Abstract PCOS, a heterogeneous disorder characterized by cystic ovarian morphology, androgen excess, and/or irregular periods, emerges during or shortly after puberty. Peri- and post-pubertal obesity, insulin resistance and consequent hyperinsulinemia are highly prevalent co-morbidities of PCOS and promote an ongoing state of excess androgen. Given the relationship of insulin to androgen excess, reduction of insulin secretion and/or improvement of its action at target tissues offer the possibility of improving the physical stigmata of androgen excess by correction of the reproductive dysfunction and preventing metabolic derangements from becoming entrenched. While lifestyle changes that concentrate on behavioral, dietary and exercise regimens should be considered as first line therapy for weight reduction and normalization of insulin levels in adolescents with PCOS, several therapeutic options are available and in wide use, including oral contraceptives, metformin, thiazolidenediones and spironolactone. Overwhelmingly, the data on the safety and efficacy of these medications derive from the adult PCOS literature. Despite the paucity of randomized control trials to adequately evaluate these modalities in adolescents, their use, particularly that of metformin, has gained popularity in the pediatric endocrine community. In this article, we present an overview of the use of insulin sensitizing medications in PCOS and review both the adult and (where available adolescent literature, focusing specifically on the use of metformin in both mono- and combination therapy.

  6. Cellular entry of nanoparticles via serum sensitive clathrin-mediated endocytosis, and plasma membrane permeabilization

    Directory of Open Access Journals (Sweden)

    Smith PJ

    2012-04-01

    Full Text Available Philip J Smith1, Maude Giroud2, Helen L Wiggins2, Florence Gower2, Jennifer A Thorley2, Bjorn Stolpe3, Julie Mazzolini2, Rosemary J Dyson4, Joshua Z Rappoport21Physical Sciences of Imaging for the Biomedical Sciences (PSIBS Doctoral Training Center, School of Chemistry, 2School of Biosciences, 3School of Geography, Earth, and Environmental Sciences, 4School of Mathematics, University of Birmingham, Edgbaston, Birmingham, United KingdomAbstract: Increasing production and application of nanomaterials raises significant questions regarding the potential for cellular entry and toxicity of nanoparticles. It was observed that the presence of serum reduces the cellular association of 20 nm carboxylate-modified fluorescent polystyrene beads up to 20-fold, relative to cells incubated in serum-free media. Analysis by confocal microscopy demonstrated that the presence of serum greatly reduces the cell surface association of nanoparticles, as well as the potential for internalization. However, both in the presence and absence of serum, nanoparticle entry depends upon clathrin-mediated endocytosis. Finally, experiments performed with cells cooled to 4°C suggest that a proportion of the accumulation of nanoparticles in cells was likely due to direct permeabilization of the plasma membrane.Keywords: nanoparticles, polystyrene beads, serum, endocytosis, dynamin, clathrin, permeabilization

  7. Postprandial improvement in insulin sensitivity after a single exercise session in adolescents with low aerobic fitness and physical activity.

    Science.gov (United States)

    Short, Kevin R; Pratt, Lauren V; Teague, April M; Man, Chiara Dalla; Cobelli, Claudio

    2013-03-01

    The purpose of this study was to determine the acute and residual impact of a single exercise bout on meal glucose control in adolescents with habitually low physical activity. Twelve adolescents (seven females/five males, 14 ± 2 yr) completed three trials. One trial [No Exercise (No Ex)] was completed after refraining from vigorous activity for ≥ 3 d. On the other two trials, a 45-min aerobic exercise bout at 75% peak heart rate was performed either 17-h Prior Day Exercise (Prior Day Ex) trial or 1-h Same Day Exercise (Same Day Ex) trial before consuming the test meal (2803 kJ, 45/40/15% energy as carbohydrate/fat/protein, respectively). Compared to No Ex, insulin sensitivity (SI) (minimal model analysis) was increased by 45% (p postprandial suppression of fatty acids. These results show that SI is improved with a single bout of moderate intensity exercise in adolescents with habitually low physical activity and that the residual beneficial effect of exercise lasts at least 17 h. This finding highlights the plasticity of exercise responses in youth and the importance of daily exercise for metabolic health.

  8. Comparative Effect of Insulin Sensitizers and Statin on Metabolic Profile and Ultrasonographical Score in Non Alcoholic Fatty Liver Disease

    Science.gov (United States)

    Yadav, Suraj Singh; Reddy, Himanshu D.; Singhal, Shubham; Singh, Dinesh Kumar; Usman, Kauser

    2016-01-01

    Introduction Non Alcoholic Fatty Liver Disease (NAFLD) is a metabolic disorder involving fat accumulation in the liver. The initial management for patients with NAFLD includes lifestyle modification and weight loss in overweight or obese patients. Aim The present study was conducted to compare the efficacy of insulin sensitizers and statin in the patients of NAFLD. Materials and Methods The study included 98 patients diagnosed with NAFLD on USG (Ultrasonography) abdomen, divided into three Groups randomly and administered Metformin (Group I), Rosuvastatin (Group II) or Pioglitazone (Group III) along with dietary intervention and lifestyle modification. Their Body Mass Index (BMI), liver function tests, fasting lipid profile, USG scores for fatty liver were done and followed up at 4 weeks, 12 weeks and 24 week for change in above parameters. Results Out of the three Groups, Group II showed a maximum improvements in usg scores for NAFLD (p<0.001) and fasting lipid profile. Group II also showed maximum derangement of liver enzymes at 24 weeks though none of the subjects had more than three times elevation of liver enzymes. Conclusion Rosuvastatin may be an effective therapy as add on treatment to dietary and lifestyle intervention in patients of NAFLD. As an add-on treatment Rosuvastatin was superior to Pioglitazone or Metformin and acute decompensation is unlikely with this drug. Metformin was not effective as add on therapy for NAFLD, rather rapid weight loss in short period of time resulted in worsening of hepatic steatosis. PMID:27656480

  9. Cockayne's syndrome: correlation of clinical features with cellular sensitivity of RNA synthesis to UV irradiation

    Energy Technology Data Exchange (ETDEWEB)

    Lehmann, A.R.; Thompson, A.F.; Harcourt, S.A. (Medical Research Council, Brighton (United Kingdom). Cell Mutation Unit); Stefanini, Miria (Consiglio Nazionale delle Ricerche, Pavia (Italy). Ist. di Genetica Biochimica ed Evoluzionistica); Norris, P.G. (Addenbrooke' s Hospital, Cambridge (United Kingdom))

    1993-08-01

    Cockayne's syndrome (CS) is a rare autosomal recessive disorder with dwarfism, mental retardation, and otherwise clinically heterogeneous features. In cultured CS fibroblasts, the failure of RNA synthesis to recover to normal rates after UV-C irradiation provides a useful and relatively simple diagnostic test. We have measured post-UV-C RNA synthesis in 52 patients for whom a clinical diagnosis of CS was considered a possibility. Twenty-nine patients showed the defect characteristic of CS cells, and 23 had a normal response. We have attempted to correlate the cellular diagnosis with the different clinical features of the disorder. Clinical details of the patients were obtained from referring clinicians in the form of a questionnaire. Our results show that, apart from the cardinal features of dwarfism and mental retardation, sun sensitivity correlated best with a positive cellular diagnosis. Pigmentary retinopathy, gait defects, and dental caries were also good positive indicators, although several patients with a positive cellular diagnosis did not have these features. (Author).

  10. Swertiamarin: An Active Lead from Enicostemma littorale Regulates Hepatic and Adipose Tissue Gene Expression by Targeting PPAR-γ and Improves Insulin Sensitivity in Experimental NIDDM Rat Model

    Directory of Open Access Journals (Sweden)

    Tushar P. Patel

    2013-01-01

    Full Text Available Enicostemma littorale (EL Blume is one of the herbs widely used for treating and alleviating the effects of both type I and type II diabetes. However, lack of understanding of mechanism precludes the use of the herb and its molecules. In this study, we attempt to unravel the molecular mechanism of action of swertiamarin, a compound isolated form EL, by comparing its molecular effects with those of aqueous EL extract in alleviating the insulin resistance in type II diabetes. We further investigated hypolipidemic and insulin sensitizing effect of swertiamarin in experimentally induced noninsulin dependent diabetes mellitus (NIDDM in rats. Swertiamarin (50 mg/kg and aqueous extract (15 grams dried plant equivalent extract/kg were administered to rats orally for 40 days and tight regulation of serum glucose, insulin, and lipid profile was found in both groups. Their mode of action was by restoring G6Pase and HMG-CoA reductase activities to normal levels and restoring normal transcriptional levels of PEPCK, GK, Glut 2, PPAR-γ, leptin, adiponectin, LPL, SREBP-1c, and Glut 4 genes. This suggests that both treatments increased insulin sensitivity and regulated carbohydrate and fat metabolism. This is the first report on the role of SM in regulating the PPARγ-mediated regulation of candidate genes involved in metabolism in peripheral tissues in vivo.

  11. Effect of Opuntia humifusa Supplementation and Acute Exercise on Insulin Sensitivity and Associations with PPAR-γ and PGC-1α Protein Expression in Skeletal Muscle of Rats

    Directory of Open Access Journals (Sweden)

    Youngju Song

    2013-03-01

    Full Text Available This study examined whether Opuntia humifusa (O. humifusa, which is a member of the Cactaceae family, supplementation and acute swimming exercise affect insulin sensitivity and associations with PPAR-γ and PGC-1α protein expression in rats. Thirty-two rats were randomly divided into four groups (HS: high fat diet sedentary group, n = 8; HE: high fat diet acute exercise group, n = 8; OS: 5% O. humifusa supplemented high fat diet sedentary group, n = 8; OE: 5% O. humifusa supplemented high fat diet acute exercise group, n = 8. Rats in the HE and OE swam for 120 min. before being sacrificed. Our results indicated that serum glucose level, fasting insulin level and homeostasis model assessment of insulin resistance (HOMA-IR in OS were significantly lower compared to those of the HS (p < 0.01, p < 0.05, p < 0.05. In addition, PPAR-γ protein expression in the OS and OE was significantly higher than that of the HS and HE, respectively (p < 0.05, p < 0.01. PGC-1α and GLUT-4 protein expressions in the OS were significantly higher compared to those of the HS (p < 0.05, p < 0.05. From these results, O. humifusa supplementation might play an important role for improving insulin sensitivity through elevation of PPAR-γ, PGC-1α, and GLUT-4 protein expression in rat skeletal muscle.

  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. Insulin-like growth factor I, growth hormone, and insulin sensitivity: the effects of a one-year cholecalciferol supplementation in middle-aged overweight and obese subjects.

    Science.gov (United States)

    Kamycheva, Elena; Berg, Vivian; Jorde, Rolf

    2013-04-01

    Both altered GH-IGF-I axis and low serum levels of 25-hydroxyvitamin D (25(OH)D) are linked to measures of metabolic syndrome. Our hypothesis was that there is a relation between GH, IGF-I, and 25(OH)D; and that vitamin D supplementation may have an effect on the levels of GH, IGF-I, and IGF-I/IGFBP-3 ratio. 318 overweight and obese subjects completed a one-year randomized intervention with either 40,000 or 20,000 IU cholecalciferol per week or placebo. GH, IGF-I, IGFBP-3 and measures of insulin resistance were evaluated at baseline and at the end of study. There was a significant relation between entities of GH-IGF-I axis and insulin resistance. Subjects with severe obesity had significantly lower serum 25(OH)D and had a significant linear decline in IGF-I/IGFBP-3 ratio with increasing serum 25(OH)D quartiles. Vitamin D status was an independent predictor of GH-IGF-I axis and supplementation with vitamin D decreased IGF-I/IGFBP-3 ratio in subjects without severe obesity. No corresponding effect of vitamin D supplementation on BMI or insulin resistance was observed. Adverse effects of GH-IGF-I axis on glucose metabolism and the development of metabolic syndrome may be in part associated with the changes in vitamin D status.

  14. Involvement of capsaicin-sensitive nerves in regulation of insulin secretion and glucose tolerance in conscious mice

    NARCIS (Netherlands)

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

    1994-01-01

    The impact of sensory nerves in glucose-stimulated insulin secretion and glucose tolerance was investigated in conscious mice treated neonatally with either capsaicin (Cap) or vehicle (Veh). At 10-12 wk after Cap, both the early (1 min) insulin secretory response to intravenous glucose (2.8 mmol/kg)

  15. Insulin sensitivity and clustering of coronary heart disease risk factors in young adults. The Northern Ireland Young Hearts Study

    DEFF Research Database (Denmark)

    Andersen, Lars Bo; Boreham, Colin A.G.; Young, Ian S.;

    2006-01-01

    Background. Coronary heart disease (CHD) is usually associated with "clustering" of risk factors. Insulin resistance may cause deleterious changes in several CHD risk factors and is of potential interest in the aetiology of clustered risk. We analyzed how glucose and insulin variables were associ...

  16. Cinnamon improves insulin sensitivity, prevents mesenteric fat accumulation, and increases glycogen synthesis in an animal model of the metabolic syndrome

    Science.gov (United States)

    In Western countries, over consumption of fat and/or refined carbohydrates are leading causes of insulin resistance, obesity, and the metabolic syndrome. Some nutritional factors, including many polyphenols, may be beneficial in counteracting insulin resistance associated with the metabolic syndrom...

  17. Identification of cellular targets of a series of boron heterocycles using TIPA II-A sensitive target identification platform.

    Science.gov (United States)

    Ward, Matthew S; Silva, Isba; Martinez, Walfre; Jefferson, Jameka; Rahman, Shakila; Garcia, Jeanie M; Kanichar, Divya; Roppiyakuda, Lance; Kosmowska, Ewa; Faust, Michelle A; Tran, Kim P; Chow, Felicia; Buglo, Elena; Zhou, Feimeng; Groziak, Michael P; Xu, H Howard

    2016-08-01

    One of the hurdles in the discovery of antibiotics is the difficulty of linking antibacterial compounds to their cellular targets. Our laboratory has employed a genome-wide approach of over-expressing essential genes in order to identify cellular targets of antibacterial inhibitors. Our objective in this project was to develop and validate a more sensitive disk diffusion based platform of target identification (Target Identification Platform for Antibacterials version 2; TIPA II) using a collection of cell clones in an Escherichia coli mutant (AS19) host with increased outer membrane permeability. Five known antibiotics/inhibitors and 28 boron heterocycles were tested by TIPA II assay, in conjunction with the original assay TIPA. The TIPA II was more sensitive than TIPA because eight boron heterocycles previously found to be inactive to AG1 cells in TIPA assays exhibited activity to AS19 cells. For 15 boron heterocycles, resistant colonies were observed within the zones of inhibition only on the inducing plates in TIPA II assays. DNA sequencing confirmed that resistant clones harbor plasmids with fabI gene as insert, indicating that these boron heterocycles all target enoyl ACP reductase. Additionally, cell-based assays and dose response curved obtained indicated that for two boron heterocycle inhibitors, the fabI cell clone in AG1 (wild-type) host cells exhibited at least 11 fold more resistance under induced conditions than under non-induced conditions. Moreover, TIPA II also identified cellular targets of known antibacterial inhibitors triclosan, phosphomycin, trimethoprim, diazaborine and thiolactomycin, further validating the utility of the new system.

  18. Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in skeletal muscle membrane phospholipids of obese subjects. Implications for insulin sensitivity

    DEFF Research Database (Denmark)

    Haugaard, S.B.; Madsbad, S.; Høy, Carl-Erik;

    2006-01-01

    Objective Cross-sectional studies suggest that the fatty acid (FA) composition of phospholipids in skeletal muscle cell membrane may modulate insulin sensitivity in humans. We examined the impact of a hypocaloric low-fat dietary intervention on membrane FA composition and insulin sensitivity...... analysis that included changes in weight, fat mass, waist circumference, plasma lipids, PUFA, SFA and long-chain PUFAn-3 indicated that SFA and long-chain PUFAn-3 were independent predictors of HOMA-IR (R-2 = 0.33, P dietary intervention programme increased....... Design Muscle membrane FA profiles were determined in muscle (vastus lateralis) biopsies from 21 obese subjects before and after 6 months of dietary restriction. Diet instructions emphasized low intake of FA of marine origin by recommending lean fish and prohibiting fatty fish and fish oil supplements...

  19. Dietary intervention increases n-3 long-chain polyunsaturated fatty acids in sceletal muscle membrane phospholipids of obese subjects. Inplications for insulin sensitivity

    DEFF Research Database (Denmark)

    Haugaard, Steen B; Madsbad, Sten; Høy, C-E;

    2006-01-01

    OBJECTIVE: Cross-sectional studies suggest that the fatty acid (FA) composition of phospholipids in skeletal muscle cell membrane may modulate insulin sensitivity in humans. We examined the impact of a hypocaloric low-fat dietary intervention on membrane FA composition and insulin sensitivity...... that included changes in weight, fat mass, waist circumference, plasma lipids, PUFA, SFA and long-chain PUFAn-3 indicated that SFA and long-chain PUFAn-3 were independent predictors of HOMA-IR (R(2)=0.33, Pdietary intervention programme increased incorporation of long....... DESIGN Muscle membrane FA profiles were determined in muscle (vastus lateralis) biopsies from 21 obese subjects before and after 6 months of dietary restriction. Diet instructions emphasized low intake of FA of marine origin by recommending lean fish and prohibiting fatty fish and fish oil supplements...

  20. Hepatic VLDL production in ob/ob mice is not stimulated by massive de novo lipogenesis but is less sensitive to the suppressive effects of insulin.

    Science.gov (United States)

    Wiegman, Coen H; Bandsma, Robert H J; Ouwens, Margriet; van der Sluijs, Fjodor H; Havinga, Rick; Boer, Theo; Reijngoud, Dirk-Jan; Romijn, Johannes A; Kuipers, Folkert

    2003-05-01

    Type 2 diabetes in humans is associated with increased de novo lipogenesis (DNL), increased fatty acid (FA) fluxes, decreased FA oxidation, and hepatic steatosis. In this condition, VLDL production is increased and resistant to suppressive effects of insulin. The relationships between hepatic FA metabolism, steatosis, and VLDL production are incompletely understood. We investigated VLDL-triglyceride and -apolipoprotein (apo)-B production in relation to DNL and insulin sensitivity in female ob/ob mice. Hepatic triglyceride (5-fold) and cholesteryl ester (15-fold) contents were increased in ob/ob mice compared with lean controls. Hepatic DNL was increased approximately 10-fold in ob/ob mice, whereas hepatic cholesterol synthesis was not affected. Basal rates of hepatic VLDL-triglyceride and -apoB100 production were similar between the groups. Hyperinsulinemic clamping reduced VLDL-triglyceride and -apoB100 production rates by approximately 60% and approximately 75%, respectively, in lean mice but only by approximately 20% and approximately 20%, respectively, in ob/ob mice. No differences in hepatic expression of genes encoding apoB and microsomal triglyceride transfer protein were found. Hepatic expression and protein phosphorylation of insulin receptor and insulin receptor substrate isoforms were reduced in ob/ob mice. Thus, strongly induced hepatic DNL is not associated with increased VLDL production in ob/ob mice, possibly related to differential hepatic zonation of apoB synthesis (periportal) and lipid accumulation (perivenous) and/or relatively low rates of cholesterogenesis. Insulin is unable to effectively suppress VLDL-triglyceride production in ob/ob mice, presumably because of impaired insulin signaling.

  1. Increased postexercise insulin sensitivity is accompanied by increased AS160 phosphorylation in slow-twitch soleus muscle.

    Science.gov (United States)

    Iwabe, Maiko; Kawamoto, Emi; Koshinaka, Keiichi; Kawanaka, Kentaro

    2014-12-01

    A single bout of exercise can enhance insulin-stimulated glucose uptake in both fast-twitch (type II) and slow-twitch (type I) skeletal muscle for several hours postexercise. Akt substrate of 160 kDa (AS160) is most distal insulin signaling proteins that have been proposed to contribute to the postexercise enhancement of insulin action in fast-twitch muscle. In this study, we examined whether the postexercise increase in insulin action of glucose uptake in slow-twitch muscle is accompanied by increased phosphorylation of AS160 and its paralog TBC1D1. Male Wistar rats (~1-month-old) were exercised on a treadmill for 180 min (9 m/min). Insulin (50 μU/mL)-stimulated glucose uptake was increased at 2 h after cessation of exercise in soleus muscle composed of predominantly slow-twitch fibers. This postexercise increase in insulin action of glucose uptake was accompanied by increased phosphorylation of AS160 (detected by phospho-Thr642 and phospho-Ser588 antibody). On the other hand, prior exercise did not increase phosphorylation of TBC1D1 (detected by phospho-Thr590) at 2 h postexercise. These results suggest the possibility that an enhancement in AS160 phosphorylation but not TBC1D1 phosphorylation is involved with increased postexercise insulin action of glucose uptake in slow-twitch muscle.

  2. A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance.

    LENUS (Irish Health Repository)

    O'Sullivan, Eoin P

    2013-01-01

    Insulin resistance (IR) is associated with low adiponectin and elevated high sensitivity C-reactive protein (hsCRP). Osteoprotegerin (OPG) has been shown to be elevated in type 2 diabetes, but whether it reflects underlying IR is unclear. We aimed to compare the ability of serum OPG with adiponectin and hsCRP to act as a marker for IR in individuals with normal and abnormal glucose tolerance.

  3. N-3 fatty acids in glucose metabolism and insulin sensitivity Ácidos grasos n-3 en el metabolismo de la glucosa y la sensibilidad a la insulina

    OpenAIRE

    L. Martín de Santa Olalla; F. J. Sánchez Muniz; Vaquero, M. P.

    2009-01-01

    Polyunsaturated fatty acids (PUFA) of the n-3 series are essential for normal growth and development. The health effects of these fatty acids include reduction of cardiovascular risk due to antiarrhythmic, antiinflammatory, anti-thrombotic and lipid lowering actions. An increase in unsaturation of the muscle membrane fatty acids is associated with improved insulin sensitivity. Higher proportion of n-3 fatty acids may have beneficial roles, such as antiobesity effects and protection against th...

  4. Heroin Dependence Duration Influences the Metabolic Parameters Mechanisms and Consequences of Impaired Insulin Sensitivity in Hepatitis C Virus Seronegative Heroin Dependents

    OpenAIRE

    Pereska, Zanina; Bozinovska, Cvetanka; Dimitrovski, Chedo; Cakalarovski, Koco; Chibishev, Andon; Zdravkovska, Milka; Babulovska, Aleksandra; Janikevik Ivanovska, Danijela

    2012-01-01

    Objective: Carbohydrate metabolism disorder in heroin dependence is an issue with long history and contradicting results. The aim of the study was to evaluate basal insulin sensitivity in hepatitis C virus seronegative heroin dependents with normal body mass index, taking into consideration the duration of heroin dependence. Method: 78 heroin dependents and 32 healthy controls were enrolled in the cross-sectional, prospective study. The dependents were observed in 2 groups: group 1 with de...

  5. Longitudinal changes in insulin sensitivity and body composition of small-for-gestational-age adolescents after cessation of growth hormone treatment

    OpenAIRE

    Willemsen, Ruben; Hokken-Koelega, Anita

    2008-01-01

    textabstractContext: GH treatment reduces insulin sensitivity (Si). For small-for-gestational-age (SGA) subjects, who might have an increased risk to develop cardiovascular disease and type 2 diabetes, it is still uncertain how Si, β-cell function, and body composition change over time after stopping GH treatment. Objective: Our objective was to investigate longitudinal changes in Si, β-cell function, and body composition after cessation of long-term GH treatment. Design and Patients: We cond...

  6. Dietary modulation of body composition and insulin sensitivity during catch-up growth in rats: effects of oils rich in n-6 or n-3 PUFA.

    Science.gov (United States)

    Yepuri, Gayathri; Marcelino, Helena; Shahkhalili, Yasaman; Aprikian, Olivier; Macé, Katherine; Seydoux, Josiane; Miles, Jennifer L; Montani, Jean-Pierre; Dulloo, Abdul G

    2011-06-28

    The present study investigates whether excessive fat accumulation and hyperinsulinaemia during catch-up growth on high-fat diets are altered by n-6 and n-3 PUFA derived from oils rich in either linoleic acid (LA), α-linolenic acid (ALA), arachidonic acid (AA) or DHA. It has been shown that, compared with food-restricted rats refed a high-fat (lard) diet low in PUFA, those refed isoenergetically on diets enriched in LA or ALA, independently of the n-6:n-3 ratio, show improved insulin sensitivity, lower fat mass and higher lean mass, the magnitude of which is related to the proportion of total PUFA precursors (LA+ALA) consumed. These relationships are best fitted by quadratic regression models (r2>0·8, P diets enriched in AA or DHA also led to improved body composition, with increases in lean mass as predicted by the quadratic model for PUFA precursors, but decreases in fat mass, which are disproportionately greater than predicted values; insulin sensitivity, however, was not improved. These findings pertaining to the impact of dietary intake of PUFA precursors (LA and ALA) and their elongated-desaturated products (AA and DHA), on body composition and insulin sensitivity, provide important insights into the search for diets aimed at counteracting the pathophysiological consequences of catch-up growth. In particular, diets enriched in essential fatty acids (LA and/or ALA) markedly improve insulin sensitivity and composition of weight regained, independently of the n-6:n-3 fatty acid ratio.

  7. Modification of the cellular heat sensitivity of cucumber by growth under supplemental ultraviolet-B radiation

    Energy Technology Data Exchange (ETDEWEB)

    Caldwell, C.R. [Department of Agriculture, Beltsville, MD (United States)

    1994-02-01

    The effect of ultraviolet B (UV-B) radiation on the thermal sensitivity of cucumber (Cucumis sativus L.) was studied using UV-B-sensitive cv Poinsett 76 and UV-B-resistant cv Ashley grown under control and elevated (300 mW m{sup -2}) UV-B radiation levels. Using both cotyledon and leaf discs, the ability of the tissue to reduce triphenyl tetrazolium chloride (TTC) was determined after treatment at 50{degrees}C for various times. Semilogarithmic plots of TTC reduction as a function of time at 50{degrees}were curvilinear. They were monophasic for the control cucumber and biphasic for cucumber grown in the presence of elevated UV-B. Treatment of cucumber plants at 37{degrees}C for 24 h or of tissue discs at acute UV-B levels for 1 h further modified their response to elevated temperature. These results suggest that growth of cucumber under enhanced UV-B radiation levels increased its ability to withstand elevated temperatures. 19 refs., 2 figs., 2 tabs.

  8. Increased postexercise insulin sensitivity is accompanied by increased AS160 phosphorylation in slow‐twitch soleus muscle

    OpenAIRE

    Iwabe, Maiko; Kawamoto, Emi; Koshinaka, Keiichi; Kawanaka, Kentaro

    2014-01-01

    Abstract A single bout of exercise can enhance insulin‐stimulated glucose uptake in both fast‐twitch (type II) and slow‐twitch (type I) skeletal muscle for several hours postexercise. Akt substrate of 160 kDa (AS160) is most distal insulin signaling proteins that have been proposed to contribute to the postexercise enhancement of insulin action in fast‐twitch muscle. In this study, we examined whether the postexercise increase in insulin action of glucose uptake in slow‐twitch muscle is accom...

  9. Ectopic UCP1 Overexpression in White Adipose Tissue Improves Insulin Sensitivity in Lou/C Rats, a Model of Obesity Resistance.

    Science.gov (United States)

    Poher, Anne-Laure; Veyrat-Durebex, Christelle; Altirriba, Jordi; Montet, Xavier; Colin, Didier J; Caillon, Aurélie; Lyautey, Jacqueline; Rohner-Jeanrenaud, Françoise

    2015-11-01

    Brown adipose tissue (BAT), characterized by the presence of uncoupling protein 1 (UCP1), has been described as metabolically active in humans. Lou/C rats, originating from the Wistar strain, are resistant to obesity. We previously demonstrated that Lou/C animals express UCP1 in beige adipocytes in inguinal white adipose tissue (iWAT), suggesting a role of this protein in processes such as the control of body weight and the observed improved insulin sensitivity. A β3 adrenergic agonist was administered for 2 weeks in Wistar and Lou/C rats to activate UCP1 and delineate its metabolic impact. The treatment brought about decreases in fat mass and improvements in insulin sensitivity in both groups. In BAT, UCP1 expression increased similarly in response to the treatment in the two groups. However, the intervention induced the appearance of beige cells in iWAT, associated with a marked increase in UCP1 expression, in Lou/C rats only. This increase was correlated with a markedly enhanced glucose uptake measured during euglycemic-hyperinsulinemic clamps, suggesting a role of beige cells in this process. Activation of UCP1 in ectopic tissues, such as beige cells in iWAT, may be an interesting therapeutic approach to prevent body weight gain, decrease fat mass, and improve insulin sensitivity.

  10. Exercise increases insulin signaling in the hippocampus: physiological effects and pharmacological impact of intracerebroventricular insulin administration in mice.

    Science.gov (United States)

    Muller, Alexandre P; Gnoatto, Jussânia; Moreira, Julia D; Zimmer, Eduardo R; Haas, Clarissa B; Lulhier, Francisco; Perry, Marcos L S; Souza, Diogo O; Torres-Aleman, Ignácio; Portela, Luis V

    2011-10-01

    Increasing evidence indicates that physical exercise induces adaptations at the cellular, molecular, and systemic levels that positively affect the brain. Insulin plays important functional roles within the brain that are mediated by insulin-receptor (IR) signaling. In the hippocampus, insulin improves synaptic plasticity, memory formation, and learning via direct modulation of GABAergic and glutamatergic receptors. Separately, physical exercise and central insulin administration exert relevant roles in cognitive function. We here use CF1 mice to investigate (i) the effects of voluntary exercise on hippocampal insulin signaling and memory performance and (ii) whether central insulin administration alters the effects of exercise on hippocampal insulin signaling and memory performance. Adult mice performed 30 days of voluntary exercise on running wheel and afterward both, sedentary and exercised groups, received intracerebroventricular (icv) injection of saline or insulin (0.5-5 mU). Memory performance was assessed using the inhibitory avoidance and water maze tasks. Hippocampal tissue was measured for [U-(14)C] glucose oxidation and the immunocontent of insulin receptor/signaling (IR, pTyr, pAktser473). Additionally, the phosphorylation of the glutamate NMDA receptor NR2B subunit and the capacity of glutamate uptake were measured, and immunohistochemistry was used to determine glial reactivity. Exercise significantly increased insulin peripheral sensitivity, spatial learning, and hippocampal IR/pTyrIR/pAktser473 immunocontent. Glucose oxidation, glutamate uptake, and astrocyte number also increased relative to the sedentary group. In both memory tasks, 5 mU icv insulin produced amnesia but only in exercised animals. This amnesia was associated a rapid (15 min) and persistent (24 h) increase in hippocampal pNR2B immunocontent that paralleled the increase in glial reactivity. In conclusion, physical exercise thus increased hippocampal insulin signaling and improved

  11. Relationships between fat deposition in the liver and skeletal muscle and insulin sensitivity in Japanese individuals: a pilot study

    Directory of Open Access Journals (Sweden)

    Eiichi Yoshimura

    2011-01-01

    Full Text Available Eiichi Yoshimura1,2, Hideaki Kumahara3, Takuro Tobina4, Sakiko Matono1, Akira Kiyonaga4, Miyuki Kimura5, Hiroshi Tsukikawa6, Shinya Kono6, Takashi Etou5, Shin Irie5, Keizo Anzai7, Hiroaki Tanaka41Graduate School of Sports and Health Science, Fukuoka University, Fukuoka, Japan; 2Faculty of Medicine, Fukuoka University, Fukuoka, Japan; 3Faculty of Nutrition Sciences, Nakamura Gakuen University, Fukuoka, Japan; 4Faculty of Sports and Health Science, Fukuoka University, Fukuoka, Japan; 5Kyushu Clinical Pharmacology Research Clinic, Fukuoka, Japan; 6PS Clinic, Fukuoka, Japan; 7Saga University Hospital, Saga, JapanPurpose: To evaluate the relationships between insulin sensitivity (IS, body fat accumulation, and aerobic capacity in middle- to older-aged Japanese participants with visceral adiposity.Participants and methods: Aerobic capacity was measured during an incremental ramp exercise test. Computed tomography was used to measure visceral (VFA and subcutaneous (SFA fat area, the fat in liver-to-spleen ratio (L/S, and low-density skeletal muscle area (LDMA. IS was assessed using euglycemic-hyperinsulinemic clamps.Results: A total of 11 males and 9 females, age 58 ± 9 years (mean ± standard deviation, body mass index 29 ± 4.1 kg/m2, and VFA 190 ± 53 cm2 participated in this study. In unadjusted models, VFA, LDMA, and L/S were significantly correlated with IS, which remained in adjusted models for LDMA and L/S, but not for VFA. In multiple stepwise regression analysis including sex, age, body fat, VFA, SFA, alcohol consumption, and aerobic capacity (oxygen uptake at the lactate threshold, L/S, and LDMA accounted for 70% of the total variance in IS. Percentage body fat and SFA, but not VFA, were significantly correlated with high molecular-weight adiponectin levels (r = 0.58, P < 0.01 and r = 0.54, P < 0.05, respectively. IS and L/S were significantly and negatively correlated with tumor necrosis factor-α (r = -0.67 and -0.63, respectively; both P

  12. Is individual nasal sensitivity related to cellular metabolism of formaldehyde and susceptibility towards formaldehyde-induced genotoxicity?

    Science.gov (United States)

    Zeller, Jasmin; Ulrich, Alexandra; Mueller, Joerg U; Riegert, Clarissa; Neuss, Simone; Bruckner, Thomas; Triebig, Gerhard; Speit, Günter

    2011-07-14

    Forty-one volunteers (male non-smokers, aged 32 ± 9.6yrs) were tested for susceptibility towards unspecific nasal irritation (sensitivity towards CO(2)) in order to define subgroups of hypersensitive and hyposensitive subjects. Blood samples were taken and the expression (mRNA level) of the GSH-dependent formaldehyde dehydrogenase gene (FDH, identical to alcohol dehydrogenase 5, ADH5; EC 1.2.1.46) was measured in leukocytes by quantitative real-time RT-PCR with TaqMan probes. FDH is the most important enzyme for the metabolic inactivation of FA. Blood samples were exposed to 150μM formaldehyde (FA) for 2h and the induction of DNA-protein crosslinks (DPX) in leukocytes was measured by means of a modification of the alkaline comet assay (i.e., by assessing the reduction of DNA migration induced by γ-radiation). Removal of DPX was determined by the abolition of FA-induced reduction in DNA migration within 4h after the end of the exposure. Furthermore, the induction of sister chromatid exchange (SCE) in cultured lymphocytes was studied after treatment of whole blood cultures with FA (150μM). A correlation analysis was performed for all parameters tested for the whole study group and for hypersensitive and hyposensitive subgroups. The results indicate that despite large differences in CO(2)-sensitivity, the susceptibility towards nasal irritation was not related to the induction of genotoxic effects (DPX, SCE) in peripheral blood or to the protection of blood cells against FA-induced effects (expression of FDH, repair capacity for FA-induced DPX). There was no correlation between CO(2)-sensitivity and the expression of FDH. There was also no close correlation between the various indicators of cellular sensitivity towards FA-induced genotoxic effects and no subgroups were identified with particular mutagen sensitivity towards FA.

  13. 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

    .989, FAI (AUC = 0.932; CI: 0.895–0.993, SHBG (AUC = 0.924; CI: 0.87–0.978, and LH/FSH ratios (AUC = 0.906; CI: 0.821–0.965.Conclusion: For insulin and LH/FSH ratios, FAI, and SHBG seemed the best predictors and markers for insulin resistance, inappropriate gonadotrophin secretion, and hyperandrogenemia, respectively, with high sensitivity and specificity for identifying Bahraini women with and without PCOS.Keywords: polycystic ovary syndrome, insulin resistance, gonadotrophin, hyperandrogenemia, diagnostic markers

  14. Association of β3 Adrenergic Receptor and Peroxisome Proliferator-activated Receptor Gamma 2 Polymorphisms With Insulin Sensitivity: A Twin Study

    Institute of Scientific and Technical Information of China (English)

    TIAN-JIAO CHEN; CHENG-YE JI; XIAO-YING ZHENG; YONG-HUA HU

    2007-01-01

    Objective To study the effect of β3 adrenergic receptor (β3AR) Trp64Arg and peroxisome proliferator activated receptor gamma 2 (PPARγ2) Pro12Ala polymorphisms on insulin resistance. Methods One hundred and eight dizygotic twin pairs were enrolled in this study. Microsatellite polymorphism was used to diagnose zygosity of twins. Insulin sensitivity was estimated with logarithm transformed homeostasis model assessment (HOMA). PCR-RFLP analysis was performed to detect the variants. As a supplement to the sib-pair method, identity by state (IBS) was used to analyze the association of polymorphisms with insulin sensitivity. Results The genotype frequencies of Trp64Trg, Trp64Arg, and Arg64Arg were 72.3%, 23.8%, and 3.9%, respectively, while the genotype frequencies of Pro12Pro, Pro12Ala, and Ala12Ala were 89.9%, 9.6%,and 0.5%, respectively. For β3AR Trp64Arg the interclass co-twin correlations of Waist-to-hip ratio (WHR), blood glucose (GLU), and insulin (INS), homeostasis model assessment insulin resistance index (HOMA-IR) of the twin pairs sharing 2alleles of IBS were greater than those sharing 0-1 allele of IBS, and HOMA-IR had statistic significance. For PPARγ2 Pro12Ala most traits of twin pairs sharing 2 alleles of IBS had greater correlations and statistic significance in body mass index (BMI),WHR, percent of body fat (PBF) and GLU, but there were low correlations of either insulin or HOMA-IR of twin pairs sharing 1 or 2 alleles of IBS. The combined effects of the two variations showed less squared significant twin-pair differences of INS and HOMA-IR among twins sharing 4 alleles of IBS. Conclusions β3AR Trp64Arg and PPARγ2 Pro12Ala polymorphisms might be associated with insulin resistance and obesity, and there might be slight synergistic effects between this two gene loci,and further studies are necessary to confirm this finding.

  15. Bixin regulates mRNA expression involved in adipogenesis and enhances insulin sensitivity in 3T3-L1 adipocytes through PPAR{gamma} activation

    Energy Technology Data Exchange (ETDEWEB)

    Takahashi, Nobuyuki; Goto, Tsuyoshi; Taimatsu, Aki; Egawa, Kahori; Katoh, Sota; Kusudo, Tatsuya; Sakamoto, Tomoya; Ohyane, Chie; Lee, Joo-Young; Kim, Young-il; Uemura, Taku; Hirai, Shizuka [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011 (Japan); Kawada, Teruo, E-mail: fat@kais.kyoto-u.ac.jp [Laboratory of Molecular Function of Food, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Uji 611-0011 (Japan)

    2009-12-25

    Insulin resistance is partly due to suppression of insulin-induced glucose uptake into adipocytes. T