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Sample records for quantitative insulin-sensitivity check

  1. Compositional and Quantitative Model Checking

    DEFF Research Database (Denmark)

    Larsen, Kim Guldstrand

    2010-01-01

    This paper gives a survey of a composition model checking methodology and its succesfull instantiation to the model checking of networks of finite-state, timed, hybrid and probabilistic systems with respect; to suitable quantitative versions of the modal mu-calculus [Koz82]. The method is based...

  2. Quantitative estimation of insulin sensitivity in type 1 diabetic subjects wearing a sensor-augmented insulin pump.

    Science.gov (United States)

    Schiavon, Michele; Dalla Man, Chiara; Kudva, Yogish C; Basu, Ananda; Cobelli, Claudio

    2014-01-01

    The goal was to develop a new index of insulin sensitivity in patients with type 1 diabetes estimated from continuous glucose monitoring (CGM) and subcutaneous insulin delivery data under carefully controlled conditions. The database consists of 12 subjects with type 1 diabetes, studied during breakfast, lunch, and dinner, in a clinical research unit, wearing both subcutaneous insulin pump and CGM device. Frequent blood samples were drawn for measurements of plasma glucose and insulin concentrations in order to estimate insulin sensitivity with the oral minimal model (SI(MM)). The new index of insulin sensitivity (SI(SP)) was calculated with a simple algebraic formula for each meal, using only CGM and insulin pump data and compared with SI(MM). SI(SP) was well correlated with SI(MM) (r = 0.825; P insulin sensitivity in subjects with type 1 diabetes on sensor-augmented insulin pump therapy has been presented. This new index correlates well with the reference oral minimal model estimate of insulin sensitivity. The knowledge of patient-specific insulin sensitivity and its diurnal variation can help in optimizing insulin therapy in type 1 diabetes and could also inform next-generation closed-loop control systems.

  3. Compositional and Quantitative Model Checking

    DEFF Research Database (Denmark)

    Larsen, Kim Guldstrand

    2010-01-01

    on the existence of a quotient construction, allowing a property phi of a parallel system phi/A to be transformed into a sufficient and necessary quotient-property yolA to be satisfied by the component 13. Given a model checking problem involving a network Pi I and a property yo, the method gradually move (by...

  4. Insulin sensitivity and albuminuria

    DEFF Research Database (Denmark)

    Pilz, Stefan; Rutters, Femke; Nijpels, Giel

    2014-01-01

    OBJECTIVE: Accumulating evidence suggests an association between insulin sensitivity and albuminuria, which, even in the normal range, is a risk factor for cardiovascular diseases. We evaluated whether insulin sensitivity is associated with albuminuria in healthy subjects. RESEARCH DESIGN...... 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...... 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...

  5. Fitness, Insulin Sensitivity and Frontal Lobe Integrity in Overweight and Obese Adults

    Science.gov (United States)

    Castro, Mary Grace; Venutolo, Christopher; Yau, Po Lai; Convit, Antonio

    2016-01-01

    Objective To formally test whether insulin sensitivity mediates the relationship between fitness and brain integrity. Methods Eighty-four non-diabetic, middle-aged participants received a 6-minute walk test from which maximal oxygen uptake (VO2 max) was derived, a structural MR scan, and a medical evaluation including fasting glucose and insulin levels. Results We showed significant associations between fitness, abdominal obesity, and insulin sensitivity and anterior cingulate cortex (ACC) volume as well as between ACC thickness and quantitative insulin-sensitivity check index (QUICKI). We showed that the relationship between ACC volume and VO2 max was completely mediated through QUICKI, see Figure 3. Further, this strong association was confirmed by a single and very significant cluster on the ACC linking gray matter volume and QUICKI in a voxel-based morphometry analysis. Conclusions As expected, increased abdominal obesity was associated with reductions in fitness, ACC volumes, and insulin sensitivity. Importantly, we demonstrate a significant mediation of the relationship between VO2 max and ACC volume by QUICKI. This suggests that the links between impaired insulin sensitivity and brain abnormalities in adults carrying excess weight could be alleviated through increased physical activity and fitness. PMID:27123868

  6. Quantification of adipose tissue insulin sensitivity.

    Science.gov (United States)

    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. Copyright © 2016 American Federation for Medical Research.

  7. 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.

  8. 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.

  9. 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...... that Prazosin was cleared from the blood stream. Whole-body insulin sensitivity was measured in conscious, unrestrained rats by hyperinsulinemic euglycemic clamp. Tissue specific insulin sensitivity was assessed by administration of 2-deoxy-[(3)H]-Glucose during the plateau phase of the clamp. Whole...

  10. How to Measure Adipose Tissue Insulin Sensitivity?

    DEFF Research Database (Denmark)

    Søndergaard, Esben; Espinosa De Ycaza, Ana Elena; Morgan-Bathke, Maria

    2017-01-01

    Background: Adipose tissue insulin resistance may be a proximate cause of hepatic and skeletal muscle insulin resistance by releasing excess FFA. However, no consensus exists on how to quantify adipose tissue insulin sensitivity. We compared three methods for measuring adipose tissue insulin...... sensitivity ranging from the complex multistep pancreatic clamp technique to the simple adipose tissue insulin resistance index (Adipo-IR). Methods: We completed studies of 25 adults with a wide range of insulin sensitivity. The insulin dose resulting in a 50% suppression of palmitate flux (IC50) was measured...... using both a multistep pancreatic clamp and a one-step hyperinsulinemic-euglycemic clamp. Palmitate kinetics were measured using a continuous infusion of [U-13C]palmitate. Adipo-IR was calculated from fasting insulin and fasting FFA concentrations. Results: Adipo-IR was reproducible [sample CV=10...

  11. How to Measure Adipose Tissue Insulin Sensitivity.

    Science.gov (United States)

    Søndergaard, Esben; Espinosa De Ycaza, Ana Elena; Morgan-Bathke, Maria; Jensen, Michael D

    2017-04-01

    Adipose tissue insulin resistance may cause hepatic and skeletal muscle insulin resistance by releasing excess free fatty acids (FFAs). Because no consensus exists on how to quantify adipose tissue insulin sensitivity we compared three methods for measuring adipose tissue insulin sensitivity: the single step insulin clamp, the multistep pancreatic clamp, and the adipose tissue insulin resistance index (Adipo-IR). We studied insulin sensitivity in 25 adults by measuring the insulin concentration resulting in 50% suppression of palmitate flux (IC50) using both a multistep pancreatic clamp and a one-step hyperinsulinemic-euglycemic clamp. Palmitate kinetics were measured using a continuous infusion of [U-13C]palmitate. Adipo-IR was calculated from fasting insulin and fasting FFA concentrations. Adipo-IR was reproducible (sample coefficient of variability, 10.0%) and correlated with the IC50 measured by the multistep pancreatic clamp technique (r, 0.86; P adipose tissue insulin sensitivity. However, age and physical fitness systematically affect the predictive values. Although Adipo-IR is suitable for larger population studies, the multistep pancreatic clamp technique is probably needed for mechanistic studies of adipose tissue insulin action.

  12. 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

  13. 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

  14. 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

  15. 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.

  16. 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......-1 kg-1, not significant). Basal plasma concentrations of free fatty acids were similar, but at the end of the clamp free fatty acids were lower in the post-obese women than in the control women (139 +/- 19 and 276 +/- 48 mumol/l, P = 0.02). 3. We conclude that the insulin sensitivity of glucose...... 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)...

  17. The quantitative check-measure of the bend strain parameters of the rotating components

    Institute of Scientific and Technical Information of China (English)

    李文华; 乔中涛

    2002-01-01

    Based on the principle of the electric-magnetic check-measure, this paper puts forward a new technology and method that use the magnetic marks to check and measure the dynamic physical parameters such as angle speed, bending strain,stress and bending moment. The principles of the check-measure and the dealing and exchanging technology about signals have been demonstrated and the rotating components have been made up. The timely and quantitative check-measure of the dynamic physical parameters during the component in working has been realized by using computer control.

  18. PVeStA: A Parallel Statistical Model Checking and Quantitative Analysis Tool

    KAUST Repository

    AlTurki, Musab

    2011-01-01

    Statistical model checking is an attractive formal analysis method for probabilistic systems such as, for example, cyber-physical systems which are often probabilistic in nature. This paper is about drastically increasing the scalability of statistical model checking, and making such scalability of analysis available to tools like Maude, where probabilistic systems can be specified at a high level as probabilistic rewrite theories. It presents PVeStA, an extension and parallelization of the VeStA statistical model checking tool [10]. PVeStA supports statistical model checking of probabilistic real-time systems specified as either: (i) discrete or continuous Markov Chains; or (ii) probabilistic rewrite theories in Maude. Furthermore, the properties that it can model check can be expressed in either: (i) PCTL/CSL, or (ii) the QuaTEx quantitative temporal logic. As our experiments show, the performance gains obtained from parallelization can be very high. © 2011 Springer-Verlag.

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

    NARCIS (Netherlands)

    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

  20. Quantitative Safety: Linking Proof-Based Verification with Model Checking for Probabilistic Systems

    CERN Document Server

    Ndukwu, Ukachukwu

    2009-01-01

    This paper presents a novel approach for augmenting proof-based verification with performance-style analysis of the kind employed in state-of-the-art model checking tools for probabilistic systems. Quantitative safety properties usually specified as probabilistic system invariants and modeled in proof-based environments are evaluated using bounded model checking techniques. Our specific contributions include the statement of a theorem that is central to model checking safety properties of proof-based systems, the establishment of a procedure; and its full implementation in a prototype system (YAGA) which readily transforms a probabilistic model specified in a proof-based environment to its equivalent verifiable PRISM model equipped with reward structures. The reward structures capture the exact interpretation of the probabilistic invariants and can reveal succinct information about the model during experimental investigations. Finally, we demonstrate the novelty of the technique on a probabilistic library cas...

  1. Euglycemic clamp insulin sensitivity and longitudinal systolic blood pressure

    DEFF Research Database (Denmark)

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

    2013-01-01

    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...... 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...

  2. Insulin sensitivity in clinically healthy individuals with microalbuminuria

    DEFF Research Database (Denmark)

    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....

  3. 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

  4. 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...

  5. 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.

  6. Discovery of Novel Insulin Sensitizers: Promising Approaches and Targets.

    Science.gov (United States)

    Chen, Yadan; Ma, Haiming; Zhu, Dasheng; Zhao, Guowei; Wang, Lili; Fu, Xiujuan; Chen, Wei

    2017-01-01

    Insulin resistance is the undisputed root cause of type 2 diabetes mellitus (T2DM). There is currently an unmet demand for safe and effective insulin sensitizers, owing to the restricted prescription or removal from market of certain approved insulin sensitizers, such as thiazolidinediones (TZDs), because of safety concerns. Effective insulin sensitizers without TZD-like side effects will therefore be invaluable to diabetic patients. The specific focus on peroxisome proliferator-activated receptor γ- (PPARγ-) based agents in the past decades may have impeded the search for novel and safer insulin sensitizers. This review discusses possible directions and promising strategies for future research and development of novel insulin sensitizers and describes the potential targets of these agents. Direct PPARγ agonists, selective PPARγ modulators (sPPARγMs), PPARγ-sparing compounds (including ligands of the mitochondrial target of TZDs), agents that target the downstream effectors of PPARγ, along with agents, such as heat shock protein (HSP) inducers, 5'-adenosine monophosphate-activated protein kinase (AMPK) activators, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) selective inhibitors, biguanides, and chloroquines, which may be safer than traditional TZDs, have been described. This minireview thus aims to provide fresh perspectives for the development of a new generation of safe insulin sensitizers.

  7. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity.

    Science.gov (United States)

    Carrasco-Benso, Maria P; Rivero-Gutierrez, Belen; Lopez-Minguez, Jesus; Anzola, Andrea; Diez-Noguera, Antoni; Madrid, Juan A; Lujan, Juan A; Martínez-Augustin, Olga; Scheer, Frank A J L; Garaulet, Marta

    2016-09-01

    In humans, insulin sensitivity varies according to time of day, with decreased values in the evening and at night. Mechanisms responsible for the diurnal variation in insulin sensitivity are unclear. We investigated whether human adipose tissue (AT) expresses intrinsic circadian rhythms in insulin sensitivity that could contribute to this phenomenon. Subcutaneous and visceral AT biopsies were obtained from extremely obese participants (body mass index, 41.8 ± 6.3 kg/m(2); 46 ± 11 y) during gastric-bypass surgery. To assess the rhythm in insulin signaling, AKT phosphorylation was determined every 4 h over 24 h in vitro in response to different insulin concentrations (0, 1, 10, and 100 nM). Data revealed that subcutaneous AT exhibited robust circadian rhythms in insulin signaling (P Insulin sensitivity reached its maximum (acrophase) around noon, being 54% higher than during midnight (P = 0.009). The amplitude of the rhythm was positively correlated with in vivo sleep duration (r = 0.53; P = 0.023) and negatively correlated with in vivo bedtime (r = -0.54; P = 0.020). No circadian rhythms were detected in visceral AT (P = 0.643). Here, we demonstrate the relevance of the time of the day for how sensitive AT is to the effects of insulin. Subcutaneous AT shows an endogenous circadian rhythm in insulin sensitivity that could provide an underlying mechanism for the daily rhythm in systemic insulin sensitivity.-Carrasco-Benso, M. P., Rivero-Gutierrez, B., Lopez-Minguez, J., Anzola, A., Diez-Noguera, A., Madrid, J. A., Lujan, J. A., Martínez-Augustin, O., Scheer, F. A. J. L., Garaulet, M. Human adipose tissue expresses intrinsic circadian rhythm in insulin sensitivity. © FASEB.

  8. Quantitative Analysis of Probabilistic Models of Software Product Lines with Statistical Model Checking

    DEFF Research Database (Denmark)

    ter Beek, Maurice H.; Legay, Axel; Lluch Lafuente, Alberto

    2015-01-01

    We investigate the suitability of statistical model checking techniques for analysing quantitative properties of software product line models with probabilistic aspects. For this purpose, we enrich the feature-oriented language FLAN with action rates, which specify the likelihood of exhibiting...... particular behaviour or of installing features at a specific moment or in a specific order. The enriched language (called PFLAN) allows us to specify models of software product lines with probabilistic configurations and behaviour, e.g. by considering a PFLAN semantics based on discrete-time Markov chains....... The Maude implementation of PFLAN is combined with the distributed statistical model checker MultiVeStA to perform quantitative analyses of a simple product line case study. The presented analyses include the likelihood of certain behaviour of interest (e.g. product malfunctioning) and the expected average...

  9. 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.

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

    Science.gov (United States)

    Yang, Dong-jie; Zhang, Sheng; He, Wei-ling; Chen, Hua-yun; Cai, Shi-rong; Chen, Chuang-qi; Song, Xin-ming; Cui, Ji; Ma, Jin-Ping; Zhang, Chang-Hua; He, Yu-Long

    2012-09-01

    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. 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. 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. Fast track surgery accelerates the recovery of postoperative insulin sensitivity in elective surgery for colorectal carcinoma with a shorter length of postoperative hospital stay.

  11. 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....

  12. 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...

  13. Dietary Fat – Insulin Sensitivity and Molecular Substrate Metabolism

    DEFF Research Database (Denmark)

    Lundsgaard, Annemarie

    to be an important mechanism in the handling of the high dietary FA load. The capacity for trans-sarcolemmal FA uptake into skeletal muscle was increased via an increased content of lipid binding proteins as FAT/CD36, FATP1 and FATP4 in skeletal muscle after both high-fat diets, potentially assisted by lower TBC1D1......Increased lipid availability is proposed to reduce insulin sensitivity, a proposal which is primarily derived from studies in rodents and muscle cells, and from lipid infusion studies in humans. Though it is well documented that lipid infusion reduces whole-body insulin sensitivity by 30...... that are induced by high fat intake are still unexplored. Compared to lipid infusion, a more physiological way to increase fatty acid (FA) availability is by dietary manipulation. Therefore, a short period of increased dietary FA intake was applied to investigate the impact on insulin sensitivity and molecular...

  14. Morning Circadian Misalignment during Short Sleep Duration Impacts Insulin Sensitivity.

    Science.gov (United States)

    Eckel, Robert H; Depner, Christopher M; Perreault, Leigh; Markwald, Rachel R; Smith, Mark R; McHill, Andrew W; Higgins, Janine; Melanson, Edward L; Wright, Kenneth P

    2015-11-16

    Short sleep duration and circadian misalignment are hypothesized to causally contribute to health problems including obesity, diabetes, metabolic syndrome, heart disease, mood disorders, cognitive impairment, and accidents. Here, we investigated the influence of morning circadian misalignment induced by an imposed short nighttime sleep schedule on impaired insulin sensitivity, a precursor to diabetes. Imposed short sleep duration resulted in morning wakefulness occurring during the biological night (i.e., circadian misalignment)-a time when endogenous melatonin levels were still high indicating the internal circadian clock was still promoting sleep and related functions. We show the longer melatonin levels remained high after wake time, insulin sensitivity worsened. Overall, we find a simulated 5-day work week of 5-hr-per-night sleep opportunities and ad libitum food intake resulted in ∼20% reduced oral and intravenous insulin sensitivity in otherwise healthy men and women. Reduced insulin sensitivity was compensated by an increased insulin response to glucose, which may reflect an initial physiological adaptation to maintain normal blood sugar levels during sleep loss. Furthermore, we find that transitioning from the imposed short sleep schedule to 9-hr sleep opportunities for 3 days restored oral insulin sensitivity to baseline, but 5 days with 9-hr sleep opportunities was insufficient to restore intravenous insulin sensitivity to baseline. These findings indicate morning wakefulness and eating during the biological night is a novel mechanism by which short sleep duration contributes to metabolic dysregulation and suggests food intake during the biological night may contribute to other health problems associated with short sleep duration. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. 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

  16. 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...

  17. 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].

  18. PACAP stimulates insulin secretion but inhibits insulin sensitivity in mice

    NARCIS (Netherlands)

    Filipsson, K; Pacini, G; Scheurink, AJW; Ahren, B

    Although pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates insulin secretion, its net influence on glucose homeostasis in vivo has not been established. We therefore examined the action of PACAP-27 and PACAP-38 on insulin secretion, insulin sensitivity, and glucose disposal as

  19. 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

  20. 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

  1. 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.

  2. 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...

  3. 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.

  4. Insulin sensitivity in long-living Ames dwarf mice

    OpenAIRE

    Wiesenborn, Denise S.; Ayala, Julio E.; King, Emily; Masternak, Michal M.

    2014-01-01

    Long-living Ames dwarf mice (df/df) characterized by growth hormone (GH) deficiency are widely used in aging research because of their 40–60 % lifespan extension compared to normal (N) littermates. Importantly, these mice not only live longer but are also protected from age-related diseases including insulin resistance. Several studies demonstrate that df/df mice have enhanced insulin signaling in different insulin-sensitive tissues and suggest that this is a mechanism for extended lifespan. ...

  5. 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....

  6. Effects of ginger (Zingiber officinale) on plasma glucose level, HbA1c and insulin sensitivity in type 2 diabetic patients.

    Science.gov (United States)

    Mahluji, Sepide; Attari, Vahide Ebrahimzade; Mobasseri, Majid; Payahoo, Laleh; Ostadrahimi, Alireza; Golzari, Samad E J

    2013-09-01

    The present study was aimed to evaluate the effects of Zingiber officinale on some biochemical parameters in type 2 diabetic (DM2) patients. In a randomized double-blind placebo controlled trial, 64 patients with DM2 were assigned to ginger or placebo groups (receiving 2 g/d of each). A 3 d diet record, anthropometric measurements and concentrations of fasting blood glucose (FPG), HbA1c, lipid profile (including total cholesterol, triglyceride, low density lipoprotein and high density lipoprotein) and also the homeostasis model assessment (HOMA) and quantitative insulin-sensitivity check index (QUICKI) were determined before and after 2 months of intervention. Ginger supplementation significantly lowered the levels of insulin (11.0 ± 2.3 versus 12.1 ± 3.3; p = 0.001), LDL-C (67.8 ± 27.2 versus 89.2 ± 24.9; p = 0.04), TG (127.7 ± 43.7 versus 128.2 ± 37.7; p = 0.03) and the HOMA index (3.9 ± 1.09 versus 4.5 ± 1.8; p = 0.002) and increased the QUICKI index (0.313 ± 0.012 versus 0.308 ± 0.012; p = 0.005) in comparison to the control group; while, there were no significant changes in FPG, TC, HDL-C and HbA1c (p > 0.05). In summary, ginger supplementation improved insulin sensitivity and some fractions of lipid profile in DM2 patients. Therefore it may be considered as a useful remedy to reduce the secondary complications of DM2.

  7. 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.

  8. 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

  9. Autonomic Blockade Improves Insulin Sensitivity in Obese Subjects

    Science.gov (United States)

    Gamboa, Alfredo; Okamoto, Luis E.; Arnold, Amy C.; Figueroa, Rocio A.; Diedrich, André; Raj, Satish R.; Paranjape, Sachin Y.; Farley, Ginnie; Abumrad, Naji; Biaggioni, Italo

    2014-01-01

    Obesity is an important risk factor for the development of insulin resistance. Initial compensatory mechanisms include an increase in insulin levels, which are thought to induce sympathetic activation in an attempt to restore energy balance. We have previously shown, however, that sympathetic activity has no beneficial effect on resting energy expenditure in obesity. On the contrary, we hypothesize that sympathetic activation contributes to insulin resistance. To test this hypothesis, we determined insulin sensitivity using a standard hyperinsulinemic euglycemic clamp protocol in obese subjects randomly assigned in a crossover design one month apart to receive saline (intact day) or trimetaphan (4 mg/min IV, autonomic blocked day). Whole body glucose uptake (MBW in mg/kg/min) was used as index of maximal muscle glucose utilization. During autonomic blockade we clamped blood pressure with a concomitant titrated IV infusion of the nitric oxide synthase inhibitor L-NMMA. Of the 21 obese subjects (43±2 years of age, 35±2 kg/m2 BMI) studied fourteen were insulin resistant; they were more obese, had higher plasma glucose and insulin, and higher muscle sympathetic nerve activity (23.3±1.5 vs. 17.2±2.1 burst/min, p=0.03) compared to insulin sensitive subjects. Glucose utilization improved during autonomic blockade in insulin resistant subjects (MBW 3.8±0.3 blocked vs. 3.1±0.3 mg/kg/min intact; p=0.025), with no effect in the insulin sensitive group. These findings support the concept that sympathetic activation contributes to insulin resistance in obesity and may result in a feedback loop whereby the compensatory increase in insulin levels contributes to greater sympathetic activation. PMID:25001269

  10. The Effects of Telmisartan and Losartan on Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Okan Bakıner

    2013-12-01

    Full Text Available Purpose: Telmisartan has been reported to increase insulin sensitivity by acting as a partial PPAR-gamma agonist, regardless of its renin-angiotensin system inhibition, but losartan has no such activity. In this study, we compared the effects of telmisartan and losartan on insulin sensitivity among type 2 diabetic patients. Material and Method: Age-, sex- and weight-matched patients, who had been on telmisartan or losartan treatment for at least 3 months, were included. Their anthropometric measurements were performed, blood pressures were recorded. Fasting venous blood samples were obtained for analyzing the levels of glucose, HbA1C, insulin and adiponectin. HOMA-IR was calculated. An euglycemic hyperinsulinemic clamp procedure was performed in each subject and M index was calculated. Thereafter, telmisartan and losartan were withdrawn in both groups. A cross-over design was planned; following a wash-out period of 15 days, losartan group (Group 1 was given telmisartan 80 mg/day, telmisartan group (Group 2 was administered losartan 50 mg/day. After 12 weeks of therapy, all measurements, calculations and the euglycemic hyperinsulinemic clamp test were re-performed. Results: General characteristics of the patients at inclusion were similar. Nine cases in group 1 and 8 cases in Group 2 concluded the follow-up. In Group 1, among all follow-up parameters, only weight exhibited a significant decrease at final evaluation (p=0,034. In Group 2, only M value was found to increase (p=0,028. Discussion: Our findings indicated that losartan improved insulin sensitivity in patients with concomitant hypertension and type 2 diabetes, and telmisartan use resulted in more weight loss. Turk Jem 2013; 17: 92-7

  11. 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.

  12. 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...

  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. Role of AMPK in Regulating Muscle Insulin Sensitivity

    DEFF Research Database (Denmark)

    Kjøbsted, Rasmus

    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...... prevail in healthy lean subjects. In the present thesis, experimental results from the three studies as well as unpublished observations are placed in the context of existing literature in order to provide a general overview of the current understandings within this field of research....

  15. 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 known...... to affect carotid wall (diabetes mellitus, hypertension, and dyslipidemia). All subjects received an oral glucose tolerance test, a euglycemic hyperinsulinemic clamp (M/I as a measure of insulin sensitivity), and B-mode carotid ultrasound. In 833 participants (380 men), the carotid ultrasound was repeated...

  16. 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.

  17. Reproductive tissues maintain insulin sensitivity in diet-induced obesity.

    Science.gov (United States)

    Wu, Sheng; Divall, Sara; Wondisford, Fredric; Wolfe, Andrew

    2012-01-01

    Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet-induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH(2)-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.

  18. 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.

  19. 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.

  20. 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...

  1. 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.

  2. 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.

  3. Role of PKCδ in Insulin Sensitivity and Skeletal Muscle Metabolism

    DEFF Research Database (Denmark)

    Li, Mengyao; Vienberg, Sara G; Bezy, Olivier

    2015-01-01

    levels of insulin. Likewise, in young mice, muscle-specific deletion of PKCδ did not rescue high-fat diet-induced insulin resistance or glucose intolerance. However, with an increase in age, PKCδ levels in muscle increased, and by 6 to 7 months of age, muscle-specific deletion of PKCδ improved whole......Protein kinase C (PKC)δ has been shown to be increased in liver in obesity and plays an important role in the development of hepatic insulin resistance in both mice and humans. In the current study, we explored the role of PKCδ in skeletal muscle in the control of insulin sensitivity and glucose...... metabolism by generating mice in which PKCδ was deleted specifically in muscle using Cre-lox recombination. Deletion of PKCδ in muscle improved insulin signaling in young mice, especially at low insulin doses; however, this did not change glucose tolerance or insulin tolerance tests done with pharmacological...

  4. 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

  5. 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....

  6. 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....

  7. 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

  8. 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.

  9. 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.

    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

  10. Central GLP-2 enhances hepatic insulin sensitivity via activating PI3K signaling in POMC neurons

    Science.gov (United States)

    Glucagon-like peptides (GLP-1/GLP-2) are coproduced and highlighted as key modulators to improve glucose homeostasis and insulin sensitivity after bariatric surgery. However, it is unknown if CNS GLP-2 plays any physiological role in the control of glucose homeostasis and insulin sensitivity. We sho...

  11. 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...

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

    Science.gov (United States)

    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.

  13. Quantitative modelling and analysis of a Chinese smart grid: a stochastic model checking case study

    DEFF Research Database (Denmark)

    Yuksel, Ender; Nielson, Hanne Riis; Nielson, Flemming

    2014-01-01

    Cyber-physical systems integrate information and communication technology with the physical elements of a system, mainly for monitoring and controlling purposes. The conversion of traditional power grid into a smart grid, a fundamental example of a cyber-physical system, raises a number of issues...... that require novel methods and applications. One of the important issues in this context is the verification of certain quantitative properties of the system. In this paper, we consider a specific Chinese smart grid implementation as a case study and address the verification problem for performance and energy...

  14. 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.

  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

    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...... 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...

  16. 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

    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...... 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....

  17. 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.

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

    DEFF Research Database (Denmark)

    Stallknecht, B; 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......-time: T, 44 +/- 9 min (n = 7); S, 102 +/- 23 min (n = 5); P insulin sensitivity of glucose uptake in subcutaneous adipose tissue and in skeletal muscle. Furthermore, interstitial glycerol data suggest that training also increases insulin sensitivity of lipolysis...

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

    DEFF Research Database (Denmark)

    Abrahamsen, B.; Rohold, A.; Henriksen, Jan Erik

    2000-01-01

    AIMS: To investigate relationships between bone mineral density (BMD), insulin secretion and insulin sensitivity, controlling for body composition, in view of data suggesting that hyperglycaemia [corrected] leads to decreased osteoblast proliferation and a negative calcium balance and that insulin...

  20. 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

  1. 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.

  2. Relationships of generalized and regional adiposity to insulin sensitivity in men.

    OpenAIRE

    Abate, N.; Garg, A.; Peshock, R M; Stray-Gundersen, J; Grundy, S M

    1995-01-01

    The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H]glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) a...

  3. 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....

  4. Down-regulation of Risa improves insulin sensitivity by enhancing autophagy.

    Science.gov (United States)

    Wang, Yuangao; Hu, Yanan; Sun, Chenxia; Zhuo, Shu; He, Zhishui; Wang, Hui; Yan, Menghong; Liu, Jun; Luan, Yi; Dai, Changgui; Yang, Yonggang; Huang, Rui; Zhou, Ben; Zhang, Fang; Zhai, Qiwei

    2016-09-01

    It has been reported that some small noncoding RNAs are involved in the regulation of insulin sensitivity. However, whether long noncoding RNAs also participate in the regulation of insulin sensitivity is still largely unknown. We identified and characterized a long noncoding RNA, regulator of insulin sensitivity and autophagy (Risa), which is a poly(A)(+) cytoplasmic RNA. Overexpression of Risa in mouse primary hepatocytes or C2C12 myotubes attenuated insulin-stimulated phosphorylation of insulin receptor, Akt, and Gsk3β, and knockdown of Risa alleviated insulin resistance. Further studies showed that overexpression of Risa in hepatocytes or myotubes decreased autophagy, and knockdown of Risa up-regulated autophagy. Moreover, knockdown of Atg7 or -5 significantly inhibited the effect of knockdown of Risa on insulin resistance, suggesting that knockdown of Risa alleviated insulin resistance via enhancing autophagy. In addition, tail vein injection of adenovirus to knock down Risa enhanced insulin sensitivity and hepatic autophagy in both C57BL/6 and ob/ob mice. Taken together, the data demonstrate that Risa regulates insulin sensitivity by affecting autophagy and suggest that Risa is a potential target for treating insulin-resistance-related diseases.-Wang, Y., Hu, Y., Sun, C., Zhuo, S., He, Z., Wang, H., Yan, M., Liu, J., Luan, Y., Dai, C., Yang, Y., Huang, R., Zhou, B., Zhang, F., Zhai, Q. Down-regulation of Risa improves insulin sensitivity by enhancing autophagy. © FASEB.

  5. 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.

  6. Statin Intake Is Associated With Decreased Insulin Sensitivity During Cardiac Surgery

    Science.gov (United States)

    Sato, Hiroaki; Carvalho, George; Sato, Tamaki; Hatzakorzian, Roupen; Lattermann, Ralph; Codere-Maruyama, Takumi; Matsukawa, Takashi; Schricker, Thomas

    2012-01-01

    OBJECTIVE Surgical trauma impairs intraoperative insulin sensitivity and is associated with postoperative adverse events. Recently, preprocedural statin therapy is recommended for patients with coronary artery disease. However, statin therapy is reported to increase insulin resistance and the risk of new-onset diabetes. Thus, we investigated the association between preoperative statin therapy and intraoperative insulin sensitivity in nondiabetic, dyslipidemic patients undergoing coronary artery bypass grafting. RESEARCH DESIGN AND METHODS In this prospective, nonrandomized trial, patients taking lipophilic statins were assigned to the statin group and hypercholesterolemic patients not receiving any statins were allocated to the control group. Insulin sensitivity was assessed by the hyperinsulinemic-normoglycemic clamp technique during surgery. The mean, SD of blood glucose, and the coefficient of variation (CV) after surgery were calculated for each patient. The association between statin use and intraoperative insulin sensitivity was tested by multiple regression analysis. RESULTS We studied 120 patients. In both groups, insulin sensitivity gradually decreased during surgery with values being on average ∼20% lower in the statin than in the control group. In the statin group, the mean blood glucose in the intensive care unit was higher than in the control group (153 ± 20 vs. 140 ± 20 mg/dL; P statin group (SD, P statin use was independently associated with intraoperative insulin sensitivity (β = −0.16; P = 0.03). CONCLUSIONS Preoperative use of lipophilic statins is associated with increased insulin resistance during cardiac surgery in nondiabetic, dyslipidemic patients. PMID:22829524

  7. Changes in subcutaneous fat cell volume and insulin sensitivity after weight loss.

    Science.gov (United States)

    Andersson, Daniel P; Eriksson Hogling, Daniel; Thorell, Anders; Toft, Eva; Qvisth, Veronica; Näslund, Erik; Thörne, Anders; Wirén, Mikael; Löfgren, Patrik; Hoffstedt, Johan; Dahlman, Ingrid; Mejhert, Niklas; Rydén, Mikael; Arner, Erik; Arner, Peter

    2014-07-01

    Large subcutaneous fat cells associate with insulin resistance and high risk of developing type 2 diabetes. We investigated if changes in fat cell volume and fat mass correlate with improvements in the metabolic risk profile after bariatric surgery in obese patients. Fat cell volume and number were measured in abdominal subcutaneous adipose tissue in 62 obese women before and 2 years after Roux-en-Y gastric bypass (RYGB). Regional body fat mass by dual-energy X-ray absorptiometry; insulin sensitivity by hyperinsulinemic-euglycemic clamp; and plasma glucose, insulin, and lipid profile were assessed. RYGB decreased body weight by 33%, which was accompanied by decreased adipocyte volume but not number. Fat mass in the measured regions decreased and all metabolic parameters were improved after RYGB (P fat cell size correlated strongly with improved insulin sensitivity (P = 0.0057), regional changes in fat mass did not, except for a weak correlation between changes in visceral fat mass and insulin sensitivity and triglycerides. The curve-linear relationship between fat cell size and fat mass was altered after weight loss (P = 0.03). After bariatric surgery in obese women, a reduction in subcutaneous fat cell volume associates more strongly with improvement of insulin sensitivity than fat mass reduction per se. An altered relationship between adipocyte size and fat mass may be important for improving insulin sensitivity after weight loss. Fat cell size reduction could constitute a target to improve insulin sensitivity. © 2014 by the American Diabetes Association.

  8. Contraction-induced increase in muscle insulin sensitivity: requirement for a serum factor.

    Science.gov (United States)

    Gao, J; Gulve, E A; Holloszy, J O

    1994-02-01

    The insulin sensitivity of glucose transport is enhanced in skeletal muscle after a bout of exercise. In a previous study, stimulation of washed muscles to contract in vitro, in contrast to exercise, did not result in an increase in insulin sensitivity. The purpose of the present study was to explain this apparent discrepancy. We found that, although rat epitrochlearis muscles stimulated to contract in vitro after 15 min of incubation in Krebs-Henseleit buffer did not develop increased insulin sensitivity, muscles stimulated to contract immediately after being dissected showed a small but significant enhancement of the stimulation of 3-O-methyl-D-glucose transport by 30 microU/ml insulin. Furthermore, muscles stimulated to contract in situ and then allowed to recover in vitro showed as large an increase in insulin sensitivity as that which occurs after a bout of swimming. To follow up these findings suggesting involvement of a humoral factor, we incubated epitrochlearis muscles in serum before and during contractile activity in vitro. Epitrochlearis muscle insulin sensitivity was enhanced to as great an extent after in vitro contractile activity in serum as after swimming. Experiments involving charcoal treatment, ultrafiltration, or trypsin digestion provided evidence that the serum factor that interacts with contractions to enhance insulin sensitivity is a protein.

  9. Enhanced insulin sensitivity in prepubertal children with constitutional delay of growth and development.

    Science.gov (United States)

    Wilson, Dyanne A; Hofman, Paul L; Miles, Harriet L; Sato, Tim A; Billett, Nathalie E; Robinson, Elizabeth M; Cutfield, Wayne S

    2010-02-01

    To test the hypothesis that prepubertal children with presumed constitutional delay of growth and development (CDGD) have enhanced insulin sensitivity and, therefore, insulin sensitivity is associated with later onset of puberty. Twenty-one prepubertal children with presumed CDGD and 23 prepubertal control children, underwent a frequently sampled intravenous glucose tolerance test to evaluate insulin sensitivity and other markers of insulin, glucose, and growth regulation. Children in the CDGD group were shorter and leaner than control subjects. Children with presumed CDGD were 40% more insulin sensitive (17.0 x 10(-4) min(-1)/[mU/L] versus 12.1 x 10(-4) min(-1)/[mU/L]; P = .0006) and had reduced acute insulin response, thus maintaining euglycemia (216 mU/L versus 330 mU/L; P = .02) compared with control subjects. In addition, the CDGD group had lower serum insulin-like growth factor binding protein 3 levels (3333 ng/mL versus 3775 ng/mL; P = .0004) and a trend toward lower serum insulin-like growth factor-II levels (794 ng/mL versus 911 ng/mL; P = .06). Prepubertal children with presumed CDGD have enhanced insulin sensitivity, supporting the hypothesis that insulin sensitivity is associated with timing of puberty. It may signify long-term biological advantages with lower risk of metabolic syndrome and malignancy. Copyright 2010 Mosby, Inc. All rights reserved.

  10. c-Abl inhibition mitigates diet-induced obesity through improving insulin sensitivity of subcutaneous fat in mice.

    Science.gov (United States)

    Wu, Rong; Sun, Jian-Guang; Wang, Ji-Qiu; Li, Binhua; Liu, Qingsong; Ning, Guang; Jin, Wanzhu; Yuan, Zengqiang

    2017-05-01

    High-energy diets are among the main causes of the global epidemic of metabolic disorders, including obesity and type 2 diabetes. The mechanisms of high-energy-diet-induced metabolic disorders are complex and largely unknown. The non-receptor tyrosine kinase c-Abl plays an important role in adipogenesis in vitro but its role in vivo in the regulation of metabolism is still elusive. Hence, we sought to address the role of c-Abl in diet-induced obesity and obesity-associated insulin resistance. The expression of c-Abl in different fat tissues from obese humans or mice fed a high-fat diet (HFD) were first analysed by western blotting and quantitative PCR. We employed conditional deletion of the c-Abl gene (also known as Abl1) in adipose tissue using Fabp4-Cre and 6-week-old mice were fed with either a chow diet (CD) or an HFD. Age-matched wild-type mice were treated with the c-Abl inhibitor nilotinib or with vehicle and exposed to either CD or HFD, followed by analysis of body mass, fat mass, glucose and insulin tolerance. Histological staining, ELISA and biochemical analysis were used to clarify details of changes in physiology and molecular signalling. c-Abl was highly expressed in subcutaneous fat from obese humans and HFD-induced obese mice. Conditional knockout of c-Abl in adipose tissue improved insulin sensitivity and mitigated HFD-induced body mass gain, hyperglycaemia and hyperinsulinaemia. Consistently, treatment with nilotinib significantly reduced fat mass and improved insulin sensitivity in HFD-fed mice. Further biochemical analyses suggested that c-Abl inhibition improved whole-body insulin sensitivity by reducing HFD-triggered insulin resistance and increasing adiponectin in subcutaneous fat. Our findings define a new biological role for c-Abl in the regulation of diet-induced obesity through improving insulin sensitivity of subcutaneous fat. This suggests it may become a novel therapeutic target in the treatment of metabolic disorders.

  11. Oligonucleotide microarray analysis reveals dysregulation of energy-related metabolism in insulin-sensitive tissues of type 2 diabetes patients.

    Science.gov (United States)

    Wang, M; Wang, X C; Zhao, L; Zhang, Y; Yao, L L; Lin, Y; Peng, Y D; Hu, R M

    2014-06-17

    Impaired insulin action within skeletal muscle, adipose tissue, and the liver is an important characteristic of type 2 diabetes (T2D). In order to identify common underlying defects in insulin-sensitive tissues that may be involved in the pathogenesis of T2D, the gene expression profiles of skeletal muscle, visceral adipose tissue, and liver from autopsy donors with or without T2D were examined using oligonucleotide microarrays and quantitative reverse transcriptase-PCR. Compared with controls, 691 genes were commonly dysregulated in these three insulin-sensitive tissues of humans with T2D. These co-expressed genes were enriched within the mitochondrion, with suggested involvement in energy metabolic processes such as glycolysis and gluconeogenesis, fatty acid beta oxidative, tricarboxylic acid cycle, and electron transport. Genes related to energy metabolism were mostly downregulated in diabetic skeletal muscle and visceral adipose tissue, while they were upregulated in the diabetic liver. This observed dysregulation in energy-related metabolism may be the underlying factor leading to the molecular mechanisms responsible for the insulin resistance of patients with T2D.

  12. Genome-Wide Association Study of the Modified Stumvoll Insulin Sensitivity Index Identifies BCL2 and FAM19A2 as Novel Insulin Sensitivity Loci.

    Science.gov (United States)

    Walford, Geoffrey A; Gustafsson, Stefan; Rybin, Denis; Stančáková, Alena; Chen, Han; Liu, Ching-Ti; Hong, Jaeyoung; Jensen, Richard A; Rice, Ken; Morris, Andrew P; Mägi, Reedik; Tönjes, Anke; Prokopenko, Inga; Kleber, Marcus E; Delgado, Graciela; Silbernagel, Günther; Jackson, Anne U; Appel, Emil V; Grarup, Niels; Lewis, Joshua P; Montasser, May E; Landenvall, Claes; Staiger, Harald; Luan, Jian'an; Frayling, Timothy M; Weedon, Michael N; Xie, Weijia; Morcillo, Sonsoles; Martínez-Larrad, María Teresa; Biggs, Mary L; Chen, Yii-Der Ida; Corbaton-Anchuelo, Arturo; Færch, Kristine; Gómez-Zumaquero, Juan Miguel; Goodarzi, Mark O; Kizer, Jorge R; Koistinen, Heikki A; Leong, Aaron; Lind, Lars; Lindgren, Cecilia; Machicao, Fausto; Manning, Alisa K; Martín-Núñez, Gracia María; Rojo-Martínez, Gemma; Rotter, Jerome I; Siscovick, David S; Zmuda, Joseph M; Zhang, Zhongyang; Serrano-Rios, Manuel; Smith, Ulf; Soriguer, Federico; Hansen, Torben; Jørgensen, Torben J; Linnenberg, Allan; Pedersen, Oluf; Walker, Mark; Langenberg, Claudia; Scott, Robert A; Wareham, Nicholas J; Fritsche, Andreas; Häring, Hans-Ulrich; Stefan, Norbert; Groop, Leif; O'Connell, Jeff R; Boehnke, Michael; Bergman, Richard N; Collins, Francis S; Mohlke, Karen L; Tuomilehto, Jaakko; März, Winfried; Kovacs, Peter; Stumvoll, Michael; Psaty, Bruce M; Kuusisto, Johanna; Laakso, Markku; Meigs, James B; Dupuis, Josée; Ingelsson, Erik; Florez, Jose C

    2016-10-01

    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 a GWAS of the modified Stumvoll Insulin Sensitivity Index (ISI) within the Meta-Analyses of Glucose and Insulin-Related Traits Consortium. Discovery for genetic association was performed in 16,753 individuals, and replication was attempted for the 23 most significant novel loci in 13,354 independent individuals. Association with ISI was tested in models adjusted for age, sex, and BMI and in a model analyzing the combined influence of the genotype effect adjusted for BMI and the interaction effect between the genotype and BMI on ISI (model 3). In model 3, three variants reached genome-wide significance: rs13422522 (NYAP2; P = 8.87 × 10(-11)), rs12454712 (BCL2; P = 2.7 × 10(-8)), and rs10506418 (FAM19A2; P = 1.9 × 10(-8)). The association at NYAP2 was eliminated by conditioning on the known IRS1 insulin sensitivity locus; the BCL2 and FAM19A2 associations were independent of known cardiometabolic loci. In conclusion, we identified two novel loci and replicated known variants associated with insulin sensitivity. Further studies are needed to clarify the causal variant and function at the BCL2 and FAM19A2 loci. © 2016 by the American Diabetes Association.

  13. Differential effects of hypercaloric choice diets on insulin sensitivity in rats.

    Science.gov (United States)

    Diepenbroek, Charlene; Eggels, Leslie; Ackermans, Mariëtte T; Fliers, Eric; Kalsbeek, Andries; Serlie, Mireille J; la Fleur, Susanne E

    2017-01-01

    We showed previously that rats on a free-choice high-fat, high-sugar (fcHFHS) diet become rapidly obese and develop glucose intolerance within a week. Interestingly, neither rats on a free-choice high-fat diet (fcHF), although equally obese and hyperphagic, nor rats on a free-choice high-sugar (fcHS) diet consuming more sugar water, develop glucose intolerance. Here, we investigate whether changes in insulin sensitivity contribute to the observed glucose intolerance and whether this is related to consumption of saturated fat and/or sugar water. Rats received either a fcHFHS, fcHF, fcHS or chow diet for one week. We performed a hyperinsulinemic-euglycemic clamp with stable isotope dilution to measure endogenous glucose production (EGP; hepatic insulin sensitivity) and glucose disappearance (Rd; peripheral insulin sensitivity). Rats on all free-choice diets were hyperphagic, but only fcHFHS-fed rats showed significantly increased adiposity. EGP suppression by hyperinsulinemia in fcHF-fed and fcHFHS-fed rats was significantly decreased compared with chow-fed rats. One week fcHFHS diet also significantly decreased Rd. Neither EGP suppression nor Rd was affected in fcHS-fed rats. Our results imply that, short-term fat feeding impaired hepatic insulin sensitivity, whereas short-term consumption of both saturated fat and sugar water impaired hepatic and peripheral insulin sensitivity. The latter likely contributed to glucose intolerance observed previously. In contrast, overconsumption of only sugar water affected insulin sensitivity slightly, but not significantly, in spite of similar adiposity as fcHF-fed rats and higher sugar intake compared with fcHFHS-fed rats. These data imply that the palatable component consumed plays a role in the development of site-specific insulin sensitivity. © 2017 Society for Endocrinology.

  14. Sexual dimorphism in hepatic, adipose tissue and peripheral tissue insulin sensitivity in obese humans

    Directory of Open Access Journals (Sweden)

    Kasper W. ter Horst

    2015-11-01

    Full Text Available Glucose and lipid metabolism differ between men and women, and women tend to have better whole-body or muscle insulin sensitivity. This may be explained, in part, by differences in sex hormones and adipose tissue distribution. Few studies have investigated gender differences in hepatic, adipose tissue and whole-body insulin sensitivity between severely obese men and women. In this study, we aimed to determine the differences in glucose metabolism between severely obese men and women using tissue-specific measurements of insulin sensitivity. Insulin sensitivity was compared between age and body mass index (BMI-matched obese men and women by a two-step euglycemic hyperinsulinemic clamp with infusion of [6,6-2H2]glucose. Basal endogenous glucose production and insulin sensitivity of the liver, adipose tissue and peripheral tissues were assessed. Liver fat content was assessed by proton magnetic resonance spectroscopy in a subset of included subjects. We included 46 obese men and women (age, 48±2 vs 46±2 years, p=0.591; BMI, 41±1 vs 41±1 kg/m2, p=0.832. There was no difference in basal endogenous glucose production (14.4±1.0 vs 15.3±0.5 µmol•kg fat-free mass-1•min-1, p=0.410, adipose tissue insulin sensitivity (insulin-mediated suppression of free fatty acids, 71.6±3.6 vs 76.1±2.6%, p=0.314 or peripheral insulin sensitivity (insulin-stimulated rate of disappearance of glucose, 26.2±2.1 vs 22.7±1.7 µmol•kg-1•min-1, p=0.211. Obese men were characterized by lower hepatic insulin sensitivity (insulin-mediated suppression of endogenous glucose production, 61.7±4.1 vs 72.8±2.5% in men vs women, resp., p=0.028. Finally, these observations could not be explained by differences in liver fat content (men vs women, 16.5±3.1 vs 16.0±2.5%, p=0.913, n=27.We conclude that obese men have lower hepatic, but comparable adipose tissue and peripheral tissue, insulin sensitivity compared to similarly obese women. Hepatic insulin resistance may

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

    Science.gov (United States)

    McLean, Carrie S; Mielke, Clinton; Cordova, Jeanine M; Langlais, Paul R; Bowen, Benjamin; Miranda, Danielle; Coletta, Dawn K; Mandarino, Lawrence J

    2015-01-01

    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 Pinsulin 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. 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...

  18. Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids

    DEFF Research Database (Denmark)

    Rasmussen, Jon Jarløv; Schou, Morten; Selmer, Christian

    2017-01-01

    OBJECTIVE: Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current...... tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy X-ray absorptiometry. RESULTS: Current and former AAS abusers displayed lower Matsuda index than controls...... predicted lower Matsuda index among former AAS abusers. CONCLUSIONS: Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively....

  19. 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....

  20. Effects of prepartum 2,4-thiazolidinedione on insulin sensitivity, plasma concentrations of tumor necrosis factor-α and leptin, and adipose tissue gene expression.

    Science.gov (United States)

    Schoenberg, K M; Perfield, K L; Farney, J K; Bradford, B J; Boisclair, Y R; Overton, T R

    2011-11-01

    Administration of peroxisome proliferator-activated receptor gamma (PPARγ) ligands, thiazolidinediones (TZD), to prepartum dairy cattle has been shown to improve dry matter intake and decrease circulating nonesterified fatty acids (NEFA) around the time of calving. The objective of this work was to elucidate mechanisms of TZD action in transition dairy cattle by investigating changes in plasma leptin, tumor necrosis factor-α (TNFα), the revised quantitative insulin sensitivity check index (RQUICKI), and adipose tissue gene expression of leptin, PPARγ, lipoprotein lipase (LPL), and fatty acid synthase (FAS). Multiparous Holstein cows (n=40) were administered 0, 2.0, or 4.0 mg of TZD/kg of body weight (BW) by intrajugular infusion once daily from 21 d before expected parturition until parturition. Plasma samples collected daily from 22 d before expected parturition through 21 d postpartum were analyzed for glucose, NEFA, and insulin. Plasma samples collected on d -14, -3, -1, 1, 3, 7, 14, and 49 relative to parturition were also analyzed for leptin and TNFα. Adipose tissue was collected on d 7 before expected parturition from a subset of cows, and gene expression was examined via quantitative real-time PCR. A tendency for a treatment by time effect on plasma leptin prepartum was observed such that values were similar on d -14 but cows receiving 2.0 mg/kg of BW of TZD tended to have lower circulating leptin as calving approached. Postpartum leptin tended to be increased linearly (2.3, 2.4, and 2.5±0.1 ng/mL for 0, 2.0, and 4.0 mg/kg treatments, respectively) in cows that received TZD prepartum. Plasma TNFα increased linearly (2.6, 3.7, and 4.0±0.1 pg/mL) in response to TZD treatment and decreased through the first week postpartum. Calculation of RQUICKI 1/[log(glucose)+log(insulin)+log(NEFA)] suggested altered insulin sensitivity in cows administered TZD that may depend on day relative to calving. Administration of TZD increased adipose tissue expression of

  1. 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.

  2. Fish oil supplementation and insulin sensitivity: a systematic review and meta-analysis.

    Science.gov (United States)

    Gao, Huanqing; Geng, Tingting; Huang, Tao; Zhao, Qinghua

    2017-07-03

    Fish oil supplementation has been shown to be associated with a lower risk of metabolic syndrome and benefit a wide range of chronic diseases, such as cardiovascular disease, type 2 diabetes and several types of cancers. However, the evidence of fish oil supplementation on glucose metabolism and insulin sensitivity is still controversial. This meta-analysis summarized the exist evidence of the relationship between fish oil supplementation and insulin sensitivity and aimed to evaluate whether fish oil supplementation could improve insulin sensitivity. We searched the Cochrane Library, PubMed, Embase database for the relevant studies update to Dec 2016. Two researchers screened the literature independently by the selection and exclusion criteria. Studies were pooled using random effect models to estimate a pooled SMD and corresponding 95% CI. This meta-analysis was performed by Stata 13.1 software. A total of 17 studies with 672 participants were included in this meta-analysis study after screening from 498 published articles found after the initial search. In a pooled analysis, fish oil supplementation had no effects on insulin sensitivity compared with the placebo (SMD 0.17, 95%CI -0.15 to 0.48, p = 0.292). In subgroup analysis, fish oil supplementation could benefit insulin sensitivity among people who were experiencing at least one symptom of metabolic disorders (SMD 0.53, 95% CI 0.17 to 0.88, p oil supplementation or duration of the intervention. The sensitivity analysis indicated that the results were robust. Short-term fish oil supplementation is associated with increasing the insulin sensitivity among those people with metabolic disorders.

  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. 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

  5. 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.

  6. 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

  7. 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...

  8. 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.

  9. 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.

  10. Insulin sensitivity in relation to fat distribution and plasma adipocytokines among abusers of anabolic androgenic steroids.

    Science.gov (United States)

    Rasmussen, Jon Jarløv; Schou, Morten; Selmer, Christian; Johansen, Marie Louise; Gustafsson, Finn; Frystyk, Jan; Dela, Flemming; Faber, Jens; Kistorp, Caroline

    2017-09-01

    Abuse of anabolic androgenic steroids (AAS) is prevalent among young men, but information regarding effects on insulin sensitivity and fat distribution is limited. The objective was to investigate insulin sensitivity in relation to fat distribution and adipocytokines among current and former AAS abusers compared with controls. Cross-sectional study among men involved in recreational strength training. Current and former AAS abusers (n=37 and n=33) and controls (n=30) volunteered from the community. We assessed insulin sensitivity by Matsuda index (oral glucose tolerance test). Using overnight fasting blood samples, adiponectin and leptin were measured. Body composition and fat distribution, including visceral adipose tissue (VAT), were assessed by dual energy X-ray absorptiometry. Current and former AAS abusers displayed lower Matsuda index than controls (%-difference (95%CI) from controls, -26% (-45; -1) and -39% (-55; -18)). Testosterone was markedly higher among current AAS abusers and subnormal among former AAS abusers compared with controls. Current AAS abusers displayed higher mean VAT than controls (388 (17) vs 293 (12) cm(3) , Pfat %, adiponectin and leptin concentrations were lower. In contrast, former AAS abusers showed highest leptin concentrations and body fat %. Multivariate linear regressions identified VAT as independent predictor of lower Matsuda index among current AAS abusers compared with controls; while body fat % independently predicted lower Matsuda index among former AAS abusers. Both current and former AAS abusers displayed lower insulin sensitivity which could be mediated by higher VAT and total body fat %, respectively. © 2017 John Wiley & Sons Ltd.

  11. 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...

  12. 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

  13. 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 ...

  14. 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.

  15. 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.

  16. Effect of exercise on insulin sensitivity in healthy postmenopausal women : The SHAPE study

    NARCIS (Netherlands)

    Van Gemert, Willemijn A.; Monninkhof, Evelyn M.; May, Anne M.; Peeters, Petra H.; Schuit, Albertine J.

    2015-01-01

    Background: An inactive lifestyle is a risk factor for several types of cancer. A proposed pathway through which exercise influences cancer risk is via insulin. We aim to investigate the effect of a oneyear exercise intervention on insulin sensitivity, and the role of body fat in this association,

  17. 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.

  18. Effect of training intensity on insulin sensitivity evaluated by insulin tolerance test

    NARCIS (Netherlands)

    K. Backx; H.A. Keizer; M.F. Mensink; dr. Lars B. Borghouts

    1999-01-01

    This research article shows that a high intensity exercise program compared to a low intensity exercise program of the same session duration and frequency, increases insulin sensitivity to a larger extend in healthy subjects. It also shows that the short insulin tolerance test can be used to detect

  19. The inflammasome-mediated caspase-1 activation controls adipocyte differentiation and insulin sensitivity

    NARCIS (Netherlands)

    Stienstra, R.; Joosten, L.A.; Koenen, T.; Tits, van B.; Diepen, van J.A.; Berg, van den S.A.A.; Rensen, P.C.; Voshol, P.J.; Fantuzzi, G.; Hijmans, A.; Kersten, A.H.; Müller, M.R.; Berg, van den W.B.; Rooijen, van N.; Wabitsch, M.; Kullberg, B.J.; Meer, van der J.W.; Kanneganti, T.; Tack, C.J.; Netea, M.G.

    2010-01-01

    Obesity-induced inflammation originating from expanding adipose tissue interferes with insulin sensitivity. Important metabolic effects have been recently attributed to IL-1ß and IL-18, two members of the IL-1 family of cytokines. Processing of IL-1ß and IL-18 requires cleavage by caspase-1, a

  20. 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

  1. PUFAs acutely affect triacylglycerol-derived skeletal muscle fatty acid uptake and increase postprandial insulin sensitivity

    NARCIS (Netherlands)

    Jans, A.; Konings, E.; Goossens, G.H.; Bouwman, F.G.; Moors, C.C.; Boekschoten, M.V.; Afman, L.A.; Muller, M.R.; Mariman, E.C.; Blaak, E.E.

    2012-01-01

    Background: Dietary fat quality may influence skeletal muscle lipid processing and fat accumulation, thereby modulating insulin sensitivity. Objective: The objective was to examine the acute effects of meals with various fatty acid (FA) compositions on skeletal muscle FA processing and postprandial

  2. 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

  3. 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...

  4. 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

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

    DEFF Research Database (Denmark)

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

    2015-01-01

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

  6. High levels of dietary stearate promote adiposity and deteriorate hepatic insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Havekes Louis M

    2010-03-01

    Full Text Available Abstract Background Relatively little is known about the role of specific saturated fatty acids in the development of high fat diet induced obesity and insulin resistance. Here, we have studied the effect of stearate in high fat diets (45% energy as fat on whole body energy metabolism and tissue specific insulin sensitivity. Methods C57Bl/6 mice were fed a low stearate diet based on palm oil or one of two stearate rich diets, one diet based on lard and one diet based on palm oil supplemented with tristearin (to the stearate level of the lard based diet, for a period of 5 weeks. Ad libitum fed Oxidative metabolism was assessed by indirect calorimetry at week 5. Changes in body mass and composition was assessed by DEXA scan analysis. Tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp analysis and Western blot at the end of week 5. Results Indirect calorimetry analysis revealed that high levels of dietary stearate resulted in lower caloric energy expenditure characterized by lower oxidation of fatty acids. In agreement with this metabolic phenotype, mice on the stearate rich diets gained more adipose tissue mass. Whole body and tissue specific insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp and analysis of insulin induced PKBser473 phosphorylation. Whole body insulin sensitivity was decreased by all high fat diets. However, while insulin-stimulated glucose uptake by peripheral tissues was impaired by all high fat diets, hepatic insulin sensitivity was affected only by the stearate rich diets. This tissue-specific pattern of reduced insulin sensitivity was confirmed by similar impairment in insulin-induced phosphorylation of PKBser473 in both liver and skeletal muscle. Conclusion In C57Bl/6 mice, 5 weeks of a high fat diet rich in stearate induces a metabolic state favoring low oxidative metabolism, increased adiposity and whole body insulin resistance characterized by severe hepatic insulin

  7. 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

  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. 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

  10. 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....

  11. 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

    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...... haemoglobin rose during both diet intervention periods (P = 0.18), with no difference between the two diets. CONCLUSIONS: Change to an isocaloric, low-fat diet in Type 1 diabetic patients during a 3-month period resulted in significant improvement in insulin sensitivity without improvement in glycaemic...

  12. 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...

  13. 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....

  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

    CONTEXT: Pegvisomant is a specific GH receptor antagonist that is able to normalize serum IGF-I concentrations in most patients with acromegaly. The impact of pegvisomant on insulin sensitivity and substrate metabolism is less well described. PATIENTS AND METHODS: We assessed basal and insulin......-stimulated (euglycemic clamp) substrate metabolism in seven patients with active acromegaly before and after 4-wk pegvisomant treatment (15 mg/d) in an open design. RESULTS: After pegvisomant, IGF-I decreased, whereas GH increased (IGF-I, 621 +/- 82 vs. 247 +/- 33 microg/liter, P = 0.02; GH, 5.3 +/- 1.5 vs. 10.8 +/- 3...... 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...

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

    DEFF Research Database (Denmark)

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

    2013-01-01

    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...

  16. 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...

  17. 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.

  18. 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.

  19. 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.

  20. 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

  1. 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

  2. Ethnic Differences in the Role of Adipocytokines Linking Abdominal Adiposity and Insulin Sensitivity Among Asians.

    Science.gov (United States)

    Parvaresh Rizi, Ehsan; Teo, Yvonne; Leow, Melvin Khee-Shing; Khoo, Eric Yin Hao; Yeo, Chia Rou; Chan, Edmund; Song, Tammy; Sadananthan, Suresh Anand; Velan, S Sendhil; Gluckman, Peter D; Lee, Yung Seng; Chong, Yap Seng; Tai, E Shyong; Toh, Sue-Anne; Khoo, Chin Meng

    2015-11-01

    Among Asian ethnic groups, Chinese or Malays are more insulin sensitive than South Asians, in particular in lean individuals. We have further reported that body fat partitioning did not explain this ethnic difference in insulin sensitivity. We examined whether adipocytokines might explain the ethnic differences in the relationship between obesity and insulin resistance among the three major ethnic groups in Singapore. This was a cross-sectional study of 101 Chinese, 82 Malays, and 81 South Asian men. Insulin sensitivity index (ISI) was measured using hyperinsulinemic euglycemic clamp. Visceral (VAT) and subcutaneous adipose tissue (SAT) volumes were quantified using magnetic resonance imaging. Plasma total and high-molecular-weight adiponectin, leptin, visfatin, apelin, IL-6, fibroblast growth factor 21 (FGF21), retinol binding protein-4 (RBP 4), and resistin were measured using enzyme-linked immunoassays. Principle component (PC) analysis on the adipocytokines identified three PCs, which explained 49.5% of the total variance. Adiponectin loaded negatively, and leptin and FGF21 loaded positively onto PC1. Visfatin, resistin, and apelin all loaded positively onto PC2. IL-6 loaded positively and RBP-4 negatively onto PC3. Only PC1 was negatively associated with ISI in all ethnic groups. In the path analysis, SAT and VAT were negatively associated with ISI in Chinese and Malays without significant mediatory role of PC1. In South Asians, the relationship between VAT and ISI was mediated partly through PC1, whereas the relationship between SAT and ISI was mediated mainly through PC1. The relationships between abdominal obesity, adipocytokines and insulin sensitivity differ between ethnic groups. Adiponectin, leptin, and FGF21 play a mediating role in the relationship between abdominal adiposity and insulin resistance in South Asians, but not in Malays or Chinese.

  3. 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.

  4. Reduced access to insulin-sensitive tissues in dogs with obesity secondary to increased fat intake.

    Science.gov (United States)

    Ellmerer, Martin; Hamilton-Wessler, Marianthe; Kim, Stella P; Huecking, Katrin; Kirkman, Erlinda; Chiu, Jenny; Richey, Joyce; Bergman, Richard N

    2006-06-01

    Physiological hyperinsulinemia provokes hemodynamic actions and augments access of macromolecules to insulin-sensitive tissues. We investigated whether induction of insulin resistance by a hypercaloric high-fat diet has an effect on the extracellular distribution of macromolecules to insulin-sensitive tissues. Male mongrel dogs were randomly selected into two groups: seven dogs were fed an isocaloric control diet ( approximately 3,900 kcal, 35% from fat), and six dogs were fed a hypercaloric high-fat diet ( approximately 5,300 kcal, 54% from fat) for a period of 12 weeks. During hyperinsulinemic-euglycemic clamps, we determined transport parameters and distribution volumes of [(14)C]inulin by applying a three-compartment model to the plasma clearance data of intravenously injected [(14)C]inulin (0.8 microCi/kg). In another study with direct cannulation of the hindlimb skeletal muscle lymphatics, we investigated the effect of physiological hyperinsulinemia on the appearance of intravenously injected [(14)C]inulin in skeletal muscle interstitial fluid and compared the effect of insulin between control and high-fat diet groups. The hypercaloric high-fat diet resulted in significant weight gain (18%; Pfat depots, as well as peripheral insulin resistance, measured as a significant reduction of insulin-stimulated glucose uptake during clamps (-35%; Pinsulin action to stimulate access of macromolecules to insulin-sensitive tissues (control diet 32%, Pfat diet 18%, NS). The present results indicate that access of macromolecules to insulin-sensitive tissues is impaired during diet-induced insulin resistance and suggest that the ability of insulin itself to stimulate tissue access is diminished. We speculate that the observed diet-induced defects in stimulation of tissue perfusion contribute to the development of peripheral insulin resistance.

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

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    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.

  6. Adipose tissue monomethyl branched chain fatty acids and insulin sensitivity: effects of obesity and weight loss

    Science.gov (United States)

    Su, Xiong; Magkos, Faidon; Zhou, Dequan; Eagon, J. Christopher; Fabbrini, Elisa; Okunade, Adewole L.; Klein, Samuel

    2014-01-01

    Objective An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. We evaluated whether monomethyl branched chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity. Design and Methods Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion, in 9 lean and 9 obese subjects, and in a separate group of 9 obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state. Results Total adipose tissue mmBCFA content was ~30% lower in obese than lean subjects (P = 0.02), and increased by ~65% after weight loss in the RYGB group (P = 0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R2 = 35%, P = 0.01, n = 18). Conclusions These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association. PMID:25328153

  7. Circulating natriuretic peptide concentrations reflect changes in insulin sensitivity over time in the Diabetes Prevention Program.

    Science.gov (United States)

    Walford, Geoffrey A; Ma, Yong; Christophi, Costas A; Goldberg, Ronald B; Jarolim, Petr; Horton, Edward; Mather, Kieren J; Barrett-Connor, Elizabeth; Davis, Jaclyn; Florez, Jose C; Wang, Thomas J

    2014-05-01

    We aimed to study the relationship between measures of adiposity, insulin sensitivity and N-terminal pro-B-type natriuretic peptide (NT-proBNP) in the Diabetes Prevention Program (DPP). The DPP is a completed clinical trial. Using stored samples from this resource, we measured BMI, waist circumference (WC), an insulin sensitivity index (ISI; [1/HOMA-IR]) and NT-proBNP at baseline and at 2 years of follow-up in participants randomised to placebo (n = 692), intensive lifestyle intervention (n = 832) or metformin (n = 887). At baseline, log NT-proBNP did not differ between treatment arms and was correlated with baseline log ISI (p  0.05 for both). In regression models, the change in log NT-proBNP was positively associated with the change in log ISI (p < 0.005) in all three study groups after adjusting for changes in BMI and WC, but was not associated with the change in BMI or WC after adjusting for changes in log ISI. Circulating NT-proBNP was associated with a measure of insulin sensitivity before and during preventive interventions for type 2 diabetes in the DPP. This relationship persisted after adjustment for measures of adiposity and was consistent regardless of whether a participant was treated with placebo, intensive lifestyle intervention or metformin.

  8. 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.

  9. 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.

  10. The TZD insulin sensitizer clue provides a new route into diabetes drug discovery.

    Science.gov (United States)

    Colca, Jerry R

    2015-12-01

    Thiazolidinedione (TZD) insulin sensitizers have a pleotropic pharmacology including reduction of insulin resistance, a root cause of diabetes. Importantly, these agents also preserve pancreatic beta cell function. TZDs are not widely used, especially early on in disease progression when they might have the greatest benefit, because of side effects, principally volume expansion, weight gain, and increased bone reabsorption. Incomplete understanding of their mechanism of action has prevented the development of new agents. Recent studies suggest that these compounds modify mitochondrial metabolism and metabolic signals that coordinate downstream cell function. The author provides a brief history of the development of the first generation insulin sensitizer TZDs, which coincided with the expansion of the concept of insulin resistance in disease. Furthermore, the article summarizes ideas as to how a newly identified mitochondrial target might explain the activity of new clinical candidates. Recognition of the pyruvate carrier complex as a mitochondrial target of the TZDs provides a new direction for discovery and development of anti-diabetic agents. Recent clinical studies have suggested that reduction of direct agonism of PPARγ may prove to be useful therapeutically by reducing dose-limiting side effects. The study of the mechanism of insulin resistance produced by metabolic signals (metabolic inflammation) and the counterbalance of these signals by insulin sensitizers is likely to be useful in providing more target and discovery approaches to metabolic diseases.

  11. 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.

  12. 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.

  13. Gynostemma pentaphyllum Tea Improves Insulin Sensitivity in Type 2 Diabetic Patients

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    V. T. T. Huyen

    2013-01-01

    Full Text Available Aims. To evaluate the effect of the traditional Vietnamese herb Gynostemma pentaphyllum tea on insulin sensitivity in drug-naïve type 2 diabetic patients. Methods. Patients received GP or placebo tea 6 g daily for four weeks and vice versa with a 2-week wash-out period. At the end of each period, a somatostatin-insulin-glucose infusion test (SIGIT was performed to evaluate the insulin sensitivity. Fasting plasma glucose (FPG, HbA1C, and oral glucose tolerance tests and insulin levels were measured before, during, and after the treatment. Results. FPG and steady-state plasma glucose (SIGIT mean were lower after GP treatment compared to placebo treatment (P<0.001. The levels of FPG in the control group were slightly reduced to 0.2±1.5 versus 1.9±1.0 mmol/L in GP group (P<0.001, and the effect on FPG was reversed after exchanging treatments. The glycometabolic improvements were achieved without any major change of circulating insulin levels. There were no changes in lipids, body measurements, blood pressure, and no reported hypoglycemias or acute adverse effects regarding kidney and liver parameters. Conclusion. The results of this study suggested that the GP tea exerted antidiabetic effect by improving insulin sensitivity.

  14. Gynostemma pentaphyllum Tea Improves Insulin Sensitivity in Type 2 Diabetic Patients

    Science.gov (United States)

    Huyen, V. T. T.; Phan, D. V.; Thang, P.; Hoa, N. K.; Östenson, C. G.

    2013-01-01

    Aims. To evaluate the effect of the traditional Vietnamese herb Gynostemma pentaphyllum tea on insulin sensitivity in drug-naïve type 2 diabetic patients. Methods. Patients received GP or placebo tea 6 g daily for four weeks and vice versa with a 2-week wash-out period. At the end of each period, a somatostatin-insulin-glucose infusion test (SIGIT) was performed to evaluate the insulin sensitivity. Fasting plasma glucose (FPG), HbA1C, and oral glucose tolerance tests and insulin levels were measured before, during, and after the treatment. Results. FPG and steady-state plasma glucose (SIGIT mean) were lower after GP treatment compared to placebo treatment (P < 0.001). The levels of FPG in the control group were slightly reduced to 0.2 ± 1.5 versus 1.9 ± 1.0 mmol/L in GP group (P < 0.001), and the effect on FPG was reversed after exchanging treatments. The glycometabolic improvements were achieved without any major change of circulating insulin levels. There were no changes in lipids, body measurements, blood pressure, and no reported hypoglycemias or acute adverse effects regarding kidney and liver parameters. Conclusion. The results of this study suggested that the GP tea exerted antidiabetic effect by improving insulin sensitivity. PMID:23431428

  15. 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...

  16. 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...

  17. 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.

  18. 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

  19. 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.

  20. 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.

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

    Directory of Open Access Journals (Sweden)

    Jessica A. Alvarez

    2010-01-01

    Full Text Available 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(OHD is inversely associated with insulin resistance, although direct measurements of insulin sensitivity are required for confirmation. Reported associations with insulin secretion, however, are contradictory. Available prospective studies support a protective influence of high 25(OHD concentrations on type 2 diabetes mellitus risk. There is a general lack of consistency in vitamin D intervention outcomes on insulin secretion and sensitivity, likely due to differences in subject populations, length of interventions, and forms of vitamin D supplementation. Vitamin D receptor gene polymorphisms and vitamin D interactions with the insulin like growth factor system may further influence glucose homeostasis. The ambiguity of optimal vitamin D dosing regimens and optimal therapeutic concentrations of serum 25(OHD limit available intervention studies. Future studies, including cross-sectional and prospective, should be performed in populations at high risk for both vitamin D deficiency and type 2 diabetes mellitus. Well-designed, placebo-controlled, randomized intervention studies are required to establish a true protective influence of vitamin D on glucose homeostasis.

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

    Science.gov (United States)

    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.

  3. 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.

  4. 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

  5. Trajectories of glycaemia, insulin sensitivity and insulin secretion in South Asian and white individuals before diagnosis of type 2 diabetes

    DEFF Research Database (Denmark)

    Hulman, Adam; Simmons, Rebecca K; Brunner, Eric J

    2017-01-01

    PG trajectories. CONCLUSIONS/INTERPRETATION: We observed different trajectories of plasma glucose, insulin sensitivity and secretion prior to diabetes diagnosis in South Asian and white individuals. This might be due to ethnic differences in the natural history of diabetes. South Asian individuals experienced......AIMS/HYPOTHESIS: South Asian individuals have reduced insulin sensitivity and increased risk of type 2 diabetes compared with white individuals. Temporal changes in glycaemic traits during middle age suggest that impaired insulin secretion is a particular feature of diabetes development among South...... (FPG), 2 h post-load plasma glucose (2hPG), fasting serum insulin (FSI), 2 h post-load serum insulin (2hSI), HOMA of insulin sensitivity (HOMA2-S) and secretion (HOMA2-B), and the Gutt insulin sensitivity index (ISI0,120) among 120 South Asian and 867 white participants who developed diabetes during...

  6. 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...

  7. 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

  8. 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.

  9. 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

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

    Directory of Open Access Journals (Sweden)

    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.

  11. Effects of acarbose treatment on markers of insulin sensitivity and systemic inflammation.

    Science.gov (United States)

    Rudovich, Natalia N; Weickert, Martin O; Pivovarova, Olga; Bernigau, Wolfgang; Pfeiffer, Andreas F H

    2011-06-01

    This study assessed the effect of postprandial glucose reduction by acarbose on insulin sensitivity and biomarkers of systemic inflammation. This was a single-center, double-blind, randomized, placebo-controlled, crossover study <40 weeks in duration, involving 66 subjects with varying degrees of glucose tolerance. Eligible patients completed a 3-week run-in period and were randomized to receive either 100 mg of acarbose three times daily followed by placebo, or vice versa, lasting 12 weeks each with a 12-week washout between interventions. Liquid meal challenges and hyperinsulinemic-euglycemic glucose clamp were performed at weeks 0, 12, 24, and 36. Fasting proinsulin levels and proinsulin-to-adiponectin ratios but not fasting adiponectin levels were significantly lower during acarbose versus placebo treatment. Clamp-derived insulin sensitivity index and body weight were unchanged by the intervention. Levels of fasting insulin, fasting glucose, monocyte chemoattractant protein-1, interleukin-6, and interleukin-1β were comparable between treatments. In the liquid meal challenge tests, postprandial glucose and insulin responses were significantly lower during acarbose versus placebo treatment. The effects of acarbose on the reduction of fasting proinsulin was most pronounced in subjects with impaired fasting glucose/impaired glucose tolerance (n = 24). Reduction of the glycemic load by acarbose decreased fasting levels of proinsulin but had no effect on adiponectin and whole-body insulin sensitivity as well as biomarkers reflecting inflammation. The preventive effects of acarbose on type 2 diabetes mellitus and cardiovascular risk need further investigation and cannot be explained by changes of insulin resistance and inflammatory biomarkers.

  12. Adiponectin in mice with altered growth hormone action: links to insulin sensitivity and longevity?

    Science.gov (United States)

    Lubbers, Ellen R.; List, Edward O.; Jara, Adam; Sackman-Sala, Lucila; Cordoba-Chacon, Jose; Gahete, Manuel D.; Kineman, Rhonda D.; Boparai, Ravneet; Bartke, Andrzej; Kopchick, John J.; Berryman, Darlene E.

    2013-01-01

    Adiponectin is positively correlated with longevity and negatively correlated with many obesity-related diseases. While there are several circulating forms of adiponectin, the high molecular weight (HMW) version has been suggested to have the predominant bioactivity. Adiponectin gene expression and cognate serum protein levels are of particular interest in mice with altered growth hormone (GH) signaling as these mice exhibit extremes in obesity that are positively associated with insulin sensitivity and lifespan as opposed to the typical negative association of these factors. While a few studies have reported total adiponectin levels in young adult mice with altered GH signaling, much remains unresolved, including changes in adiponectin levels with advancing age, proportion of total adiponectin in the HMW form, adipose depot of origin, and differential effects of GH versus IGF1. Therefore, the purpose of this study was to address these issues using assorted mouse lines with altered GH signaling. Our results show that adiponectin is generally negatively associated with GH activity, regardless of age. Further, the amount of HMW adiponectin is consistently linked with the level of total adiponectin and not necessarily with previously reported lifespan or insulin sensitivity of these mice. Interestingly, circulating adiponectin levels correlated strongly with inguinal fat mass, implying the effects of GH on adiponectin are depot-specific. Interestingly rbGH, but not IGF1, decreased circulating total and HMW adiponectin levels. Taken together, these results fill important gaps in the literature related to GH and adiponectin and question the frequently reported associations of total and HMW adiponectin with insulin sensitivity and longevity. PMID:23261955

  13. 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

  14. Increased activin bioavailability enhances hepatic insulin sensitivity while inducing hepatic steatosis in male mice.

    Science.gov (United States)

    Ungerleider, Nathan A; Bonomi, Lara M; Brown, Melissa L; Schneyer, Alan L

    2013-06-01

    The development of insulin resistance is tightly linked to fatty liver disease and is considered a major health concern worldwide, although their mechanistic relationship remains controversial. Activin has emerging roles in nutrient homeostasis, but its metabolic effects on hepatocytes remain unknown. In this study, we investigated the effects of increased endogenous activin bioactivity on hepatic nutrient homeostasis by creating mice with inactivating mutations that deplete the circulating activin antagonists follistatin-like-3 (FSTL3) or the follistatin 315 isoform (FST315; FST288-only mice). We investigated liver histology and lipid content, hepatic insulin sensitivity, and metabolic gene expression including the HepG2 cell and primary hepatocyte response to activin treatment. Both FSTL3-knockout and FST288-only mice had extensive hepatic steatosis and elevated hepatic triglyceride content. Unexpectedly, insulin signaling, as assessed by phospho-Akt (a.k.a. protein kinase B), was enhanced in both mouse models. Pretreatment of HepG2 cells with activin A increased their response to subsequent insulin challenge. Gene expression analysis suggests that increased lipid uptake, enhanced de novo lipid synthesis, decreased lipolysis, and/or enhanced glucose uptake contribute to increased hepatic triglyceride content in these models. However, activin treatment recapitulated only some of these gene changes, suggesting that increased activin bioactivity may be only partially responsible for this phenotype. Nevertheless, our results indicate that activin enhances hepatocyte insulin response, which ultimately leads to hepatic steatosis despite the increased insulin sensitivity. Thus, regulation of activin bioactivity is critical for maintaining normal liver lipid homeostasis and response to insulin, whereas activin agonists may be useful for increasing liver insulin sensitivity.

  15. 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.

  16. 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.

  17. 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

  18. 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

    of calcineurin inhibitors (CNIs) ciclosporin (CsA) and tacrolimus (Tac) has improved the outcome of organ transplants, but complications such as new onset diabetes mellitus after transplantation (NODAT) cause impairment of survival rates. The relative contribution of each CNI to the pathogenesis and development.......047), whereas first phase and pulsatile insulin secretion were unaffected. Coinciding with the CNI induced improved insulin sensitivity, glucose oxidation rates increased, while insulin clearance rates decreased, only non-significantly. Tac singularly lowered hsCRP concentrations, otherwise no changes were...

  19. 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

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

    Directory of Open Access Journals (Sweden)

    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

  1. 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...

  2. 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 ...

  3. Body weight, not insulin sensitivity or secretion, may predict spontaneous weight changes in nondiabetic and prediabetic subjects: the RISC study.

    Science.gov (United States)

    Rebelos, Eleni; Muscelli, Elza; Natali, Andrea; Balkau, Beverley; Mingrone, Geltrude; Piatti, Piermarco; Konrad, Thomas; Mari, Andrea; Ferrannini, Ele

    2011-07-01

    Previous studies have found that high insulin sensitivity predicts weight gain; this association has not been confirmed. Our aim was to systematically analyze metabolic predictors of spontaneous weight changes. In 561 women and 467 men from the Relationship Between Insulin Sensitivity and Cardiovascular Disease (RISC) cohort (mean age 44 years, BMI range 19-44 kg/m(2), 9% impaired glucose tolerance) followed up for 3 years, we measured insulin sensitivity (by a euglycemic clamp) and β-cell function (by modeling of the C-peptide response to oral glucose and by acute insulin response to intravenous glucose). Insulin sensitivity was similar in weight gainers (top 20% of the distribution of BMI changes), weight losers (bottom 20%), and weight stable subjects across quartiles of baseline BMI. By multiple logistic or linear regression analyses controlling for center, age, sex, and baseline BMI, neither insulin sensitivity nor any β-cell function parameter showed an independent association with weight gain; this was true in normal glucose tolerance, impaired glucose tolerance, and whether subjects progressed to dysglycemia or not. Baseline BMI was significantly higher in gainers (26.1 ± 4.1 kg/m(2)) and losers (26.6 ± 3.7 kg/m(2)) than in weight stable subjects (24.8 ± 3.8 kg/m(2), Pweight) was a positive, independent predictor of both weight gain and weight loss (odds ratio 1.48 [95% CI 1.12-1.97]) in men and (1.67 [1.28-2.12]) in women. In men only, better insulin sensitivity was an additional independent predictor of weight loss. Neither insulin sensitivity nor insulin secretion predicts spontaneous weight gain. Individuals who have attained a higher weight are prone to either gaining or losing weight regardless of their glucose tolerance. © 2011 by the American Diabetes Association.

  4. Calibration plot for proteomics: A graphical tool to visually check the assumptions underlying FDR control in quantitative experiments.

    Science.gov (United States)

    Giai Gianetto, Quentin; Combes, Florence; Ramus, Claire; Bruley, Christophe; Couté, Yohann; Burger, Thomas

    2016-01-01

    In MS-based quantitative proteomics, the FDR control (i.e. the limitation of the number of proteins that are wrongly claimed as differentially abundant between several conditions) is a major postanalysis step. It is classically achieved thanks to a specific statistical procedure that computes the adjusted p-values of the putative differentially abundant proteins. Unfortunately, such adjustment is conservative only if the p-values are well-calibrated; the false discovery control being spuriously underestimated otherwise. However, well-calibration is a property that can be violated in some practical cases. To overcome this limitation, we propose a graphical method to straightforwardly and visually assess the p-value well-calibration, as well as the R codes to embed it in any pipeline. All MS data have been deposited in the ProteomeXchange with identifier PXD002370 (http://proteomecentral.proteomexchange.org/dataset/PXD002370).

  5. 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.

  6. Exercise increases human skeletal muscle insulin sensitivity via coordinated increases in microvascular perfusion and molecular signaling

    DEFF Research Database (Denmark)

    Sjøberg, Kim Anker; Frøsig, Christian; Kjøbsted, Rasmus

    2017-01-01

    Insulin resistance is a major health risk and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic hyperinsulinemic clamp four hours after single-legged exercise in humans increased microvascular perfusion...... and glycogen synthase in muscle. This secures improved glucose delivery on the one hand and increased ability to take up and dispose of the delivered glucose on the other hand.......Insulin resistance is a major health risk and although exercise clearly improves skeletal muscle insulin sensitivity, the mechanisms are unclear. Here we show that initiation of a euglycemic hyperinsulinemic clamp four hours after single-legged exercise in humans increased microvascular perfusion...... the insulin stimulated increase in microvascular perfusion in both legs and abrogated the greater glucose uptake in the exercised compared with the rested leg. Skeletal muscle phosphorylation of TBC1D4 Ser(318) and Ser(704) and glycogen synthase activity were greater in the exercised leg before insulin...

  7. 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.

  8. Brown adipose tissue triglyceride content is associated with decreased insulin sensitivity, independently of age and obesity.

    Science.gov (United States)

    Raiko, J; Holstila, M; Virtanen, K A; Orava, J; Saunavaara, V; Niemi, T; Laine, J; Taittonen, M; Borra, R J H; Nuutila, P; Parkkola, R

    2015-05-01

    The aim of the present study was to determine whether single-voxel proton magnetic resonance spectroscopy ((1)H-MRS) can non-invasively assess triglyceride content in both supraclavicular fat depots and subcutaneous white adipose tissue (WAT) to determine whether these measurements correlate to metabolic variables. A total of 25 healthy volunteers were studied using (18)F-fluorodeoxyglucose positron emission tomography (PET) and (15)O-H2O PET perfusion during cold exposure, and (1)H-MRS at ambient temperature. Image-guided biopsies were collected from nine volunteers. The supraclavicular triglyceride content determined by (1)H-MRS varied between 60 and 91% [mean ± standard deviation (s.d.) 77 ± 10%]. It correlated positively with body mass index, waist circumference, subcutaneous and visceral fat masses and 8-year diabetes risk based on the Framingham risk score and inversely with HDL cholesterol and insulin sensitivity (M-value; euglycaemic-hyperinsulinaemic clamp). Subcutaneous WAT had a significantly higher triglyceride content, 76-95% (mean ± s.d. 87 ± 5%; p = 0.0002). In conclusion, the triglyceride content in supraclavicular fat deposits measured by (1)H-MRS may be an independent marker of whole-body insulin sensitivity, independent of brown adipose tissue metabolic activation. © 2015 John Wiley & Sons Ltd.

  9. 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.

  10. 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.

  11. Relationships of generalized and regional adiposity to insulin sensitivity in men.

    Science.gov (United States)

    Abate, N; Garg, A; Peshock, R M; Stray-Gundersen, J; Grundy, S M

    1995-01-01

    The relative impacts of regional and generalized adiposity on insulin sensitivity have not been fully defined. Therefore, we investigated the relationship of insulin sensitivity (measured using hyperinsulinemic, euglycemic clamp technique with [3-3H]glucose turnover) to total body adiposity (determined by hydrodensitometry) and regional adiposity. The latter was assessed by determining subcutaneous abdominal, intraperitoneal, and retroperitoneal fat masses (using magnetic resonance imaging) and the sum of truncal and peripheral skinfold thicknesses. 39 healthy middle-aged men with a wide range of adiposity were studied. Overall, the intraperitoneal and retroperitoneal fat constituted only 11 and 7% of the total body fat. Glucose disposal rate (Rd) and residual hepatic glucose output (rHGO) values during the 40 mU/m2.min insulin infusion correlated significantly with total body fat (r = -0.61 and 0.50, respectively), subcutaneous abdominal fat (r = -0.62 and 0.50, respectively), sum of truncal skinfold thickness (r = -0.72 and 0.57, respectively), and intraperitoneal fat (r = -0.51 and 0.44, respectively) but not to retroperitoneal fat. After adjusting for total body fat, the Rd and rHGO values showed the highest correlation with the sum of truncal skinfold thickness (partial r = -0.40 and 0.33, respectively). We conclude that subcutaneous truncal fat plays a major role in obesity-related insulin resistance in men, whereas intraperitoneal fat and retroperitoneal fat have a lesser role. PMID:7615840

  12. MicroRNA-26a regulates insulin sensitivity and metabolism of glucose and lipids.

    Science.gov (United States)

    Fu, Xianghui; Dong, Bingning; Tian, Yan; Lefebvre, Philippe; Meng, Zhipeng; Wang, Xichun; Pattou, François; Han, Weidong; Wang, Xiaoqiong; Lou, Fang; Jove, Richard; Staels, Bart; Moore, David D; Huang, Wendong

    2015-06-01

    Type 2 diabetes (T2D) is characterized by insulin resistance and increased hepatic glucose production, yet the molecular mechanisms underlying these abnormalities are poorly understood. MicroRNAs (miRs) are a class of small, noncoding RNAs that have been implicated in the regulation of human diseases, including T2D. miR-26a is known to play a critical role in tumorigenesis; however, its function in cellular metabolism remains unknown. Here, we determined that miR-26a regulates insulin signaling and metabolism of glucose and lipids. Compared with lean individuals, overweight humans had decreased expression of miR-26a in the liver. Moreover, miR-26 was downregulated in 2 obese mouse models compared with control animals. Global or liver-specific overexpression of miR-26a in mice fed a high-fat diet improved insulin sensitivity, decreased hepatic glucose production, and decreased fatty acid synthesis, thereby preventing obesity-induced metabolic complications. Conversely, silencing of endogenous miR-26a in conventional diet-fed mice impaired insulin sensitivity, enhanced glucose production, and increased fatty acid synthesis. miR-26a targeted several key regulators of hepatic metabolism and insulin signaling. These findings reveal miR-26a as a regulator of liver metabolism and suggest miR-26a should be further explored as a potential target for the treatment of T2D.

  13. Chronic Eccentric Exercise and Antioxidant Supplementation: Effects on Lipid Profile and Insulin Sensitivity.

    Science.gov (United States)

    Yfanti, Christina; Tsiokanos, Athanasios; Fatouros, Ioannis G; Theodorou, Anastasios A; Deli, Chariklia K; Koutedakis, Yiannis; Jamurtas, Athanasios Z

    2017-09-01

    Eccentric exercise has been shown to exert beneficial effects in both lipid profile and insulin sensitivity. Antioxidant supplementation during chronic exercise is controversial as it may prevent the physiological training-induced adaptations. The aim of this study was to investigate: 1) the minimum duration of the eccentric exercise training required before changes on metabolic parameters are observed and 2) whether antioxidant supplementation during training would interfere with these adaptations. Sixteen young healthy men were randomized into the Vit group (1 g of vitamin C and 400 IU vitamin E daily) and the placebo (PL) group. Subjects received the supplementation for 9 weeks. During weeks 5-9 all participants went through an eccentric exercise training protocol consisting of two exercise sessions (5 sets of 15 eccentric maximal voluntary contractions) per week. Plasma triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low density lipoprotein (LDL), apolipoproteins (Apo A1, Apo B and Lpa) and insulin sensitivity (HOMA) were assessed before the supplementation (week 0), at weeks 5, 6, 7, 8 and 9. TG, TC and LDL were significantly lower compared to pre supplementation at both weeks 8 and 9 (Peccentric exercise training is required before beneficial effects in lipid profile can be observed in healthy young men. Concomitant antioxidant supplementation does not interfere with the training-induced adaptations.

  14. 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.

  15. 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.

  16. 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.

  17. Peroxisome proliferator-activated receptor gamma agonists as insulin sensitizers: from the discovery to recent progress.

    Science.gov (United States)

    Cho, Nobuo; Momose, Yu

    2008-01-01

    An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes.

  18. 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.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. 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.

  4. Inducing Muscle Heat Shock Protein 70 Improves Insulin Sensitivity and Muscular Performance in Aged Mice.

    Science.gov (United States)

    Silverstein, Marnie G; Ordanes, Diane; Wylie, Ashley T; Files, D Clark; Milligan, Carol; Presley, Tennille D; Kavanagh, Kylie

    2015-07-01

    Heat shock proteins (HSPs) are molecular chaperones with roles in longevity and muscular preservation. We aimed to show elevating HSP70 improves indices of health span. Aged C57/BL6 mice acclimated to a western diet were randomized into: geranylgeranylacetone (GGA)-treated (100 mg/kg/d), biweekly heat therapy (HT), or control. The GGA and HT are well-known pharmacological and environmental inducers of HSP70, respectively. Assessments before and after 8 weeks of treatment included glycemic endpoints, body composition, and muscular endurance, power, and perfusion. An HT mice had more than threefold, and GGA mice had a twofold greater HSP70 compared with control. Despite comparable body compositions, both treatment groups had significantly better insulin sensitivity and insulin signaling capacity. Compared with baseline, HT mice ran 23% longer than at study start, which was significantly more than GGA or control. Hanging ability (muscular endurance) also tended to be best preserved in HT mice. Muscle power, contractile force, capillary perfusion, and innervation were not different. Heat treatment has a clear benefit on muscular endurance, whereas HT and GGA both improved insulin sensitivity. Different effects may relate to muscle HSP70 levels. An HSP induction could be a promising approach for improving health span in the aged mice. © The Author 2014. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  5. 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.

  6. 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

    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...... in adults with IFG, IGT or IFG+IGT is unknown. Twenty-four older (66.7±0.8yr) obese (34.2±0.9kg/m(2)) adults were categorized as IFG (n=8), IGT (n=8), or IFG+IGT (n=8) according to a 75-gram oral glucose tolerance test (OGTT). Subjects underwent 12-weeks of exercise (60 min/d for 5 d/wk at ~85% HRmax......) and were instructed to maintain a eucaloric diet. A euglycemic-hyperinsulinemic clamp (40 mU/m(2)/min) with [6,6-(2)H]-glucose was used to determine peripheral and hepatic insulin sensitivity. Non-oxidative glucose disposal and metabolic flexibility (insulin-stimulated respiratory quotient [RQ] minus...

  7. NASH Therapy: omega 3 supplementation, vitamin E, insulin sensitizers and statin drugs

    Directory of Open Access Journals (Sweden)

    Stephen Caldwell

    2017-06-01

    Full Text Available Non-alcoholic steatohepatitis (NASH is the more aggressive form of non-alcoholic fatty liver disease (NAFLD. NASH can progress to hepatic fibrosis, cirrhosis, portal hypertension and primary liver cancer. Therapy is evolving with a substantial number of trials of promising new agents now in progress. In this article however, we will examine data for several older forms of therapy which have been fairly extensively studied over the years: Polyunsaturated Fatty Acid (PUFA supplements, vitamin E, insulin sensitizing agents with a focus on pioglitazone and statin agents. Early interest in PUFA derived from their potential benefit in cardio-metabolic disease and the close association of NAFLD/NASH with Metabolic Syndrome. Results have been variable although most studies show reduction of liver fat without other major effects and their effects are influenced by concomitant weight loss and underlying genetic factors. Vitamin E has had some efficacy in pediatric NASH but questionable efficacy in even mild NASH among adults. Pioglitazone has shown significant histological benefit in a number of trials but concern over side-effects (especially weight gain have dampened enthusiasm. A newer insulin sensitizer, liraglutide, has also shown promise in a small randomized, controlled trial. Very limited data exists regarding the histological effects of the statins in NASH and these agents appear to be fairly neutral with neither clear cut benefit nor detriment. Their use is best guided by cardiovascular risks rather than liver histology.

  8. Maternal periodontal disease in rats decreases insulin sensitivity and insulin signaling in adult offspring.

    Science.gov (United States)

    Shirakashi, Daisy J; Leal, Rosana P; Colombo, Natalia H; Chiba, Fernando Y; Garbin, Cléa A S; Jardim, Elerson G; Antoniali, Cristina; Sumida, Doris H

    2013-03-01

    Periodontal disease during pregnancy has been recognized as one of the causes of preterm and low-birth-weight (PLBW) babies. Several studies have demonstrated that PLBW babies are prone to developing insulin resistance as adults. Although there is controversy over the association between periodontal disease and PLBW, the phenomenon known as programming can translate any stimulus or aggression experienced during intrauterine growth into physiologic and metabolic alterations in adulthood. The purpose of the present study is to investigate whether the offspring of rats with periodontal disease develop insulin resistance in adulthood. Ten female Wistar rats were divided into periodontal disease (PED) and control (CN) groups. All rats were mated at 7 days after induction of periodontal disease. Male offspring were divided into two groups: 1) periodontal disease offspring (PEDO; n = 24); and 2) control offspring (CNO; n = 24). Offspring body weight was measured from birth until 75 days. When the offspring reached 75 days old, the following parameters were measured: 1) plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and tumor necrosis factor-α (TNF-α); 2) insulin sensitivity (IS); and 3) insulin signal transduction (IST) in insulin-sensitive tissues. Low birth weight was not detected in the PEDO group. However, plasma concentrations of glucose, insulin, fructosamine, lipase, amylase, and TNF-α were increased and IS and IST were reduced (P PEDO group compared with the CNO group. Maternal periodontal disease may induce insulin resistance and reduce IST in adult offspring, but such alterations are not attributable to low birth weight.

  9. Metabolic phenotype in obese children and adolescents with preserved insulin sensitivity

    Directory of Open Access Journals (Sweden)

    Zdravković Dragan

    2012-01-01

    Full Text Available Rising prevalence of childhood obesity is accompanied by the increased risk of associated metabolic complications and other comorbidities. Nevertheless, a distinct subgroup of the obese appear to have a normal metabolic phenotype, and these individuals are referred to as the metabolically healthy obese. Prevalence of metabolically healthy individuals within the population of the obese is estimated up to 44%. Metabolically healthy obese are at lesser risk for impaired glucose regulation, dyslipidemia, non-alcoholic fatty liver disease and hypertension, and the preserved insulin sensitivity is the most frequently used criterion in identification of these individuals. Results of the research conducted in Institute for Mother and Child Health Care of Serbia 'Dr Vukan Čupić' indicate that a subgroup with low prevalence of metabolic complications of obesity is also present within population of obese children and adolescents in Serbia. A significant association of preserved insulin sensitivity with favorable metabolic phenotype is also supported by the results. Known data suggest the need for a different approach in the treatment of obesity in the subpopulation of the metabolically healthy obese. Due to differences in terms of complications and treatment, these individuals should also be regarded as a separate entity in further research.

  10. 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.

  11. 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.

  12. A Single Day of Excessive Dietary Fat Intake Reduces Whole-Body Insulin Sensitivity: The Metabolic Consequence of Binge Eating

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    Siôn A. Parry

    2017-07-01

    Full Text Available Consuming excessive amounts of energy as dietary fat for several days or weeks can impair glycemic control and reduce insulin sensitivity in healthy adults. However, individuals who demonstrate binge eating behavior overconsume for much shorter periods of time; the metabolic consequences of such behavior remain unknown. The aim of this study was to determine the effect of a single day of high-fat overfeeding on whole-body insulin sensitivity. Fifteen young, healthy adults underwent an oral glucose tolerance test before and after consuming a high-fat (68% of total energy, high-energy (78% greater than daily requirements diet for one day. Fasting and postprandial plasma concentrations of glucose, insulin, non-esterified fatty acids, and triglyceride were measured and the Matsuda insulin sensitivity index was calculated. One day of high-fat overfeeding increased postprandial glucose area under the curve (AUC by 17.1% (p < 0.0001 and insulin AUC by 16.4% (p = 0.007. Whole-body insulin sensitivity decreased by 28% (p = 0.001. In conclusion, a single day of high-fat, overfeeding impaired whole-body insulin sensitivity in young, healthy adults. This highlights the rapidity with which excessive consumption of calories through high-fat food can impair glucose metabolism, and suggests that acute binge eating may have immediate metabolic health consequences for the individual.

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

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    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

  14. Fibrinolysis and insulin sensitivity in imidapril and candesartan (FISIC study) recipients with hypertension.

    Science.gov (United States)

    Fogari, Roberto; Zoppi, Annalisa; Salvadeo, Sibilla A T; Mugellini, Amedeo; Lazzari, Pierangelo; Santoro, Tara; Derosa, Giuseppe

    2011-04-01

    The aim of this study was to evaluate the effects of imidapril and candesartan on fibrinolysis and insulin sensitivity in normoweight hypertensive patients. After a 2-week wash-out period, 61 patients with mild-to-moderate hypertension were randomized to imidapril or candesartan for 12 weeks. Blood pressure (BP), plasma tissue plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) antigen activities were evaluated at baseline and during treatment. The patients underwent a euglycemic-hyperinsulinemic clamp (insulin sensitivity was evaluated as glucose infusion rate during the last 30 min) and a desmopressin test (with desmopressin infusion in the brachial artery) to evaluate endothelial ability to release t-PA. Imidapril and candesartan induced similar systolic/diastolic BP reductions (-16/12.6 and -16.1/12.2 mm Hg, respectively, P<0.001 vs. baseline). Imidapril increased glucose infusion rate (+1.1 mg min(-1) per kg, P<0.02), whereas candesartan did not change it. Both drugs decreased PAI-1 antigen activity after 4 weeks of treatment; subsequently, only the decreasing effect of imidapril was sustained throughout the 12 weeks, whereas candesartan increased PAI-1 activity at week 12 (P<0.05 vs. baseline, P<0.01 vs. imidapril). Activity of t-PA decreased with candesartan (from 0.48±0.16 to 0.43±0.14 IU ml(-1), P<0.05) but not with imidapril. Activity of t-PA in response to desmopressin was increased more by imidapril (+4.45 IU ml(-1)) than by candesartan (+2.73 IU ml(-1), P<0.01 vs. imidapril). These results indicate that in normoweight hypertensive patients, despite similar BP reduction, imidapril but not candesartan improved the fibrinolytic balance, suggesting that mechanisms other than Ang II inhibition, possibly including bradykinin-mediated effects on insulin sensitivity and endothelial function, may be responsible for these different effects.

  15. 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

  16. 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

  17. 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.

  18. 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

  19. 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.

  20. 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....

  1. 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.

  2. [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.

  3. 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

  4. 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.

  5. Sleep architecture when sleeping at an unusual circadian time and associations with insulin sensitivity.

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    Hanne K J Gonnissen

    Full Text Available Circadian misalignment affects total sleep time, but it may also affect sleep architecture. The objectives of this study were to examine intra-individual effects of circadian misalignment on sleep architecture and inter-individual relationships between sleep stages, cortisol levels and insulin sensitivity. Thirteen subjects (7 men, 6 women, age: 24.3±2.5 y; BMI: 23.6±1.7 kg/m² stayed in a time blinded respiration chamber during three light-entrained circadian cycles (3x21h and 3x27h resulting in a phase advance and a phase delay. Sleep was polysomnographically recorded. Blood and salivary samples were collected to determine glucose, insulin and cortisol concentrations. Intra-individually, a phase advance decreased rapid eye movement (REM sleep and slow-wave sleep (SWS, increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. A phase delay increased REM sleep, decreased stage 2 sleep, increased time awake, decreased sleep and REM sleep latency compared to the 24h cycle. Moreover, circadian misalignment changed REM sleep distribution with a relatively shorter REM sleep during the second part of the night. Inter-individually, REM sleep was inversely associated with cortisol levels and HOMA-IR index. Circadian misalignment, both a phase advance and a phase delay, significantly changed sleep architecture and resulted in a shift in rem sleep. Inter-individually, shorter REM sleep during the second part of the night was associated with dysregulation of the HPA-axis and reduced insulin sensitivity.International Clinical Trials Registry Platform NTR2926 http://apps.who.int/trialsearch/

  6. Effect of exercise intensity and volume on persistence of insulin sensitivity during training cessation.

    Science.gov (United States)

    Bajpeyi, Sudip; Tanner, Charles J; Slentz, Cris A; Duscha, Brian D; McCartney, Jennifer S; Hickner, Robert C; Kraus, William E; Houmard, Joseph A

    2009-04-01

    The purpose of this study was to determine whether exercise prescriptions differing in volume or intensity also differ in their ability to retain insulin sensitivity during an ensuing period of training cessation. Sedentary, overweight/obese subjects were assigned to one of three 8-mo exercise programs: 1) low volume/moderate intensity [equivalent of approximately 12 miles/wk, 1,200 kcal/wk at 40-55% peak O(2) consumption (Vo(2peak)), 200 min exercise/wk], 2) low volume/vigorous intensity ( approximately 12 miles/wk, 1,200 kcal/wk at 65-80% Vo(2peak), 125 min/wk), and 3) high volume/vigorous intensity ( approximately 20 miles/wk, 2,000 kcal/wk at 65-80% Vo(2peak), 200 min/wk). Insulin sensitivity (intravenous glucose tolerance test, S(I)) was measured when subjects were sedentary and at 16-24 h and 15 days after the final training bout. S(I) increased with training compared with the sedentary condition (P sedentary, pretraining values after 15 days of training cessation in the low-volume/vigorous-intensity group. In contrast, at 15 days S(I) was significantly elevated compared with sedentary (P intensity, high volume/vigorous intensity). In the high-volume/vigorous-intensity group, indexes of muscle mitochondrial density followed a pattern paralleling insulin action by being elevated at 15 days compared with pretraining; this trend was not evident in the low-volume/moderate-intensity group. These findings suggest that in overweight/obese subjects a relatively chronic persistence of enhanced insulin action may be obtained with endurance-oriented exercise training; this persistence, however, is dependent on the characteristics of the exercise training performed.

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

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    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.

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

    Science.gov (United States)

    Kawaguchi, Takumi; Sata, Michio

    2010-01-01

    Insulin resistance is one of the pathological features in patients with hepatitis C virus (HCV) infection. Generally, persistence of insulin resistance leads to an increase in the risk of life-threatening complications such as cardiovascular diseases. However, these complications are not major causes of death in patients with HCV-associated insulin resistance. Indeed, insulin resistance plays a crucial role in the development of various complications and events associated with HCV infection. Mounting evidence indicates that HCV-associated insulin resistance may cause (1) hepatic steatosis; (2) resistance to anti-viral treatment; (3) hepatic fibrosis and esophageal varices; (4) hepatocarcinogenesis and proliferation of hepatocellular carcinoma; and (5) extrahepatic manifestations. Thus, HCV-associated insulin resistance is a therapeutic target at any stage of HCV infection. Although the risk of insulin resistance in HCV-infected patients has been documented, therapeutic guidelines for preventing the distinctive complications of HCV-associated insulin resistance have not yet been established. In addition, mechanisms for the development of HCV-associated insulin resistance differ from lifestyle-associated insulin resistance. In order to ameliorate HCV-associated insulin resistance and its complications, the efficacy of the following interventions is discussed: a late evening snack, coffee consumption, dietary iron restriction, phlebotomy, and zinc supplements. Little is known regarding the effect of anti-diabetic agents on HCV infection, however, a possible association between use of exogenous insulin or a sulfonylurea agent and the development of HCC has recently been reported. On the other hand, insulin-sensitizing agents are reported to improve sustained virologic response rates. In this review, we summarize distinctive complications of, and therapeutic strategies for, HCV-associated insulin resistance. Furthermore, we discuss supplementation with branched

  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. 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.

  11. ANP system activity predicts variability of fat mass reduction and insulin sensitivity during weight loss.

    Science.gov (United States)

    Brachs, Maria; Wiegand, Susanna; Leupelt, Verena; Ernert, Andrea; Kintscher, Ulrich; Jumpertz von Schwarzenberg, Reiner; Decker, Anne-Marie; Bobbert, Thomas; Hübner, Norbert; Chen, Wei; Krude, Heiko; Spranger, Joachim; Mai, Knut

    2016-06-01

    In weight loss trials, a considerable inter-individual variability in reduction of fat mass and changes of insulin resistance is observed, even under standardized study conditions. The underlying mechanisms are not well understood. Given the metabolic properties of the atrial natriuretic peptide (ANP) system, we hypothesized that ANP signaling might be involved in this phenomenon by changes of ANP secretion or receptor balance. Therefore, we investigated the impact of systemic, adipose and myocellular ANP system on metabolic and anthropometric improvements during weight loss. We comprehensively investigated 143 subjects (31 male, 112 female) before and after a 3 month-standardized weight loss program. The time course of BMI, fat mass, insulin sensitivity, circulating mid-regional proANP (MR-proANP) levels as well as adipose and myocellular natriuretic receptor A (NPR-A) and C (NPR-C) mRNA expression were investigated. BMI decreased by -12.6±3.7%. This was accompanied by a remarkable decrease of adipose NPR-C expression (1005.0±488.4 vs. 556.7±465.6; ploss induced changes in NPR-C (ΔNPR-C) was linked to relative reduction of total fat mass (ΔFM) (r=0.281; ploss induced ΔNPR-C independently explained 22.7% of ΔFM. In addition, ΔMR-proANP was independently associated with improvement of insulin sensitivity (standardized ß=0.246, ploss induced fat mass reduction. Our comprehensive human data support that peripheral ANP signalling is involved in control of adipose tissue plasticity and function during weight loss. (Funded by the Deutsche Forschungsgemeinschaft (KFO281/2), the Berlin Institute of Health (BIH) and the German Centre for Cardiovascular Research (DZHK/BMBF); ClinicalTrials.gov number: NCT00850629). Copyright © 2016 Elsevier Inc. All rights reserved.

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

    Directory of Open Access Journals (Sweden)

    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.

  13. Adipose tissue (P)RR regulates insulin sensitivity, fat mass and body weight.

    Science.gov (United States)

    Shamansurova, Zulaykho; Tan, Paul; Ahmed, Basma; Pepin, Emilie; Seda, Ondrej; Lavoie, Julie L

    2016-10-01

    We previously demonstrated that the handle-region peptide, a prorenin/renin receptor [(P)RR] blocker, reduces body weight and fat mass and may improve insulin sensitivity in high-fat fed mice. We hypothesized that knocking out the adipose tissue (P)RR gene would prevent weight gain and insulin resistance. An adipose tissue-specific (P)RR knockout (KO) mouse was created by Cre-loxP technology using AP2-Cre recombinase mice. Because the (P)RR gene is located on the X chromosome, hemizygous males were complete KO and had a more pronounced phenotype on a normal diet (ND) diet compared to heterozygous KO females. Therefore, we challenged the female mice with a high-fat diet (HFD) to uncover certain phenotypes. Mice were maintained on either diet for 9 weeks. KO mice had lower body weights compared to wild-types (WT). Only hemizygous male KO mice presented with lower total fat mass, higher total lean mass as well as smaller adipocytes compared to WT mice. Although food intake was similar between genotypes, locomotor activity during the active period was increased in both male and female KO mice. Interestingly, only male KO mice had increased O2 consumption and CO2 production during the entire 24-hour period, suggesting an increased basal metabolic rate. Although glycemia during a glucose tolerance test was similar, KO males as well as HFD-fed females had lower plasma insulin and C-peptide levels compared to WT mice, suggesting improved insulin sensitivity. Remarkably, all KO animals exhibited higher circulating adiponectin levels, suggesting that this phenotype can occur even in the absence of a significant reduction in adipose tissue weight, as observed in females and, thus, may be a specific effect related to the (P)RR. (P)RR may be an important therapeutic target for the treatment of obesity and its associated complications such as type 2 diabetes.

  14. 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.

  15. 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

    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.

  16. 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...

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

    Directory of Open Access Journals (Sweden)

    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

  18. 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

  19. The suppression of hepatic glucose production improves metabolism and insulin sensitivity in subcutaneous adipose tissue in mice.

    Science.gov (United States)

    Casteras, Sylvie; Abdul-Wahed, Aya; Soty, Maud; Vulin, Fanny; Guillou, Hervé; Campana, Mélanie; Le Stunff, Hervé; Pirola, Luciano; Rajas, Fabienne; Mithieux, Gilles; Gautier-Stein, Amandine

    2016-12-01

    Despite the strong correlation between non-alcoholic fatty liver disease and insulin resistance, hepatic steatosis is associated with greater whole-body insulin sensitivity in several models. We previously reported that the inhibition of hepatic glucose production (HGP) protects against the development of obesity and diabetes despite severe steatosis, thanks to the secretion of specific hepatokines such as fibroblast growth factor 21 (FGF21) and angiopoietin-related growth factor. In this work, we focused on adipose tissue to assess whether liver metabolic fluxes might, by interorgan communication, control insulin signalling in lean animals. Insulin signalling was studied in the adipose tissue of mice lacking the catalytic subunit of glucose 6-phosphatase, the key enzyme in endogenous glucose production, in the liver (L-G6pc (-/-) mice). Morphological and metabolic changes in the adipose tissues were characterised by histological analyses, gene expression and protein content. Mice lacking HGP exhibited improved insulin sensitivity of the phosphoinositide 3-kinase/Akt pathway in the subcutaneous adipose tissue associated with a browning of adipocytes. The suppression of HGP increased FGF21 levels in lean animals, and increased FGF21 was responsible for the metabolic changes in the subcutaneous adipose tissue but not for its greater insulin sensitivity. The latter might be linked to an increase in the ratio of monounsaturated to saturated fatty acids released by the liver. Our work provides evidence that HGP controls subcutaneous adipose tissue browning and insulin sensitivity through two pathways: the release of beneficial hepatokines and changes in hepatic fatty acids profile.

  20. Liver enzymes but not free fatty acid levels predict markers of insulin sensitivity in overweight and obese, nondiabetic adults.

    Science.gov (United States)

    Gray, Belinda; Muhlhausler, Beverly Sara; Davies, Peter Stephen Wynford; Vitetta, Luis

    2013-10-01

    Although obesity is a key predisposing risk factor in the development of insulin resistance (IR) and type 2 diabetes mellitus, not all obese individuals develop IR. This study aimed to identify key anthropometric and biochemical parameters that predict insulin sensitivity in overweight and obese adults. Based on previous literature, we hypothesized that markers of insulin sensitivity would be negatively correlated with plasma concentrations of free fatty acids and liver enzymes. Forty nondiabetic adult participants (body mass index ≥ 25.0 kg/m²) were recruited. Data collection included anthropometric measurements and fasting plasma samples for the quantification of liver enzymes (alanine transaminase, aspartate transaminase, γ-glutamyl transpeptidase), blood lipid profile, and markers of insulin sensitivity. Questionnaires relating to dietary intake, physical activity, and fatigue were also completed. Insulin and Homeostasis Model of Assessment (HOMA) scores were significantly correlated with indirect measures of central obesity (P fatty acids (P = .04) and ratio of n-3/n-6 fatty acids (P fatty acids (P = .03). No significant correlations were found between markers of insulin sensitivity and cholesterol levels, physical activity, or self-reported fatigue. These results have reinforced the integral role of liver function in the development of IR. Despite previous data linking elevations in free fatty acid to the development of IR, we found no relationship between these variables in this study. © 2013 Elsevier Inc. All rights reserved.

  1. 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

  2. Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with higher ghrelin levels

    Science.gov (United States)

    Tamboli, Robyn A.; Breitman, Igal; Marks-Shulman, Pam A.; Jabbour, Kareem; Melvin, Willie; Williams, Brandon; Clements, Ronald H.; Feurer, Irene D.; Abumrad, Naji N.

    2014-01-01

    Objectives We sought to determine: 1) if early weight regain between one and two years after RYGB is associated with worsened hepatic and peripheral insulin sensitivity, and 2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB. Design and Methods Hepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at one month, six months, one year, and two years post operatively. Weight regain was defined as ≥ 5% increase in body weight between one and two years after RYGB. Results Weight regain occurred in 33% of subjects, with an average increase in body weight of 10 ± 5 % (8.5 ± 3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups. Conclusions Early weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB. PMID:24777992

  3. Early weight regain after gastric bypass does not affect insulin sensitivity but is associated with elevated ghrelin.

    Science.gov (United States)

    Tamboli, Robyn A; Breitman, Igal; Marks-Shulman, Pam A; Jabbour, Kareem; Melvin, Willie; Williams, Brandon; Clements, Ronald H; Feurer, Irene D; Abumrad, Naji N

    2014-07-01

    We sought to determine: (1) if early weight regain between 1 and 2 years after Roux-en-Y gastric bypass (RYGB) is associated with worsened hepatic and peripheral insulin sensitivity, and (2) if preoperative levels of ghrelin and leptin are associated with early weight regain after RYGB. Hepatic and peripheral insulin sensitivity and ghrelin and leptin plasma levels were assessed longitudinally in 45 subjects before RYGB and at 1 month, 6 months, 1 year, and 2 years postoperatively. Weight regain was defined as ≥5% increase in body weight between 1 and 2 years after RYGB. Weight regain occurred in 33% of subjects, with an average increase in body weight of 10 ± 5% (8.5 ± 3.3 kg). Weight regain was not associated with worsening of peripheral or hepatic insulin sensitivity. Subjects with weight regain after RYGB had higher preoperative and postoperative levels of ghrelin compared to those who maintained or lost weight during this time. Conversely, the trajectories of leptin levels corresponded with the trajectories of fat mass in both groups. Early weight regain after RYGB is not associated with a reversal of improvements in insulin sensitivity. Higher preoperative ghrelin levels might identify patients that are more susceptible to weight regain after RYGB. Copyright © 2014 The Obesity Society.

  4. Hemin Improves Insulin Sensitivity and Lipid Metabolism in Cultured Hepatocytes and Mice Fed a High-Fat Diet

    Directory of Open Access Journals (Sweden)

    Yi Luan

    2017-07-01

    Full Text Available Hemin is a breakdown product of hemoglobin. It has been reported that the injection of hemin improves lipid metabolism and insulin sensitivity in various genetic models. However, the effect of hemin supplementation in food on lipid metabolism and insulin sensitivity is still unclear, and whether hemin directly affects cellular insulin sensitivity is yet to be elucidated. Here we show that hemin enhances insulin-induced phosphorylation of insulin receptors, Akt, Gsk3β, FoxO1 and cytoplasmic translocation of FoxO1 in cultured primary hepatocytes under insulin-resistant conditions. Furthermore, hemin diminishes the accumulation of triglyceride and increases in free fatty acid content in primary hepatocytes induced by palmitate. Oral administration of hemin decreases body weight, energy intake, blood glucose and triglyceride levels, and improves insulin and glucose tolerance as well as hepatic insulin signaling and hepatic steatosis in male mice fed a high-fat diet. In addition, hemin treatment decreases the mRNA and protein levels of some hepatic genes involved in lipogenic regulation, fatty acid synthesis and storage, and increases the mRNA level and enzyme activity of CPT1 involved in fatty acid oxidation. These data demonstrate that hemin can improve lipid metabolism and insulin sensitivity in both cultured hepatocytes and mice fed a high-fat diet, and show the potential beneficial effects of hemin from food on lipid and glucose metabolism.

  5. 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.

  6. 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...

  7. 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

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

    NARCIS (Netherlands)

    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.

    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

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

    Science.gov (United States)

    Hvid, Thine; Winding, Kamilla; Rinnov, Anders; Dejgaard, Thomas; Thomsen, Carsten; Iversen, Peter; Brasso, Klaus; Mikines, Kari J; van Hall, Gerrit; Lindegaard, Birgitte; Solomon, Thomas P J; Pedersen, Bente K

    2013-10-01

    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 undergoing ADT for prostate cancer and ten healthy men with normal testosterone levels underwent 12 weeks of endurance training. Primary endpoints were insulin sensitivity (euglycemic-hyperinsulinemic clamps with concomitant glucose-tracer infusion) and body composition (dual-energy X-ray absorptiometry 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 (Phepatic insulin sensitivity (P=0.32). Muscle protein content of GLUT4 (SLC2A4) and total AKT (AKT1) was also increased in response to the training (Pfat mass (FM) (Pvisceral (Pcancer patients exhibited improved insulin sensitivity and body composition to a similar degree as eugonadal men.

  10. 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.

  11. 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...

  12. Insulin sensitivity across the lifespan from obese adolescents to obese adults with impaired glucose tolerance: Who is worse off?

    Science.gov (United States)

    Youth type 2 diabetes mellitus (T2DM) occurs decades earlier than adult T2DM and is characterized by high therapeutic failure rates and decreased response to insulin sensitizers suggesting a more severe disease process than in adults. To explain these observations, we hypothesized that insulin resis...

  13. 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...

  14. 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....

  15. 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

  16. 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

  17. 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...

  18. Does bicarbonated mineral water rich in sodium change insulin sensitivity of postmenopausal women? ¿Modifica el agua mineral bicarbonatada rica en sodio la sensibilidad a la insulina de las mujeres postmenopáusicas?

    Directory of Open Access Journals (Sweden)

    S. Schoppen

    2007-10-01

    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 Objetivo: Estudiar los efectos de la ingesta de 0.5L de dos aguas minerales bicarbonatadas ricas en sodio (BMW-1 y 2, junto con una comida estándar, sobre los cambios en la insulina y la glucosa postprandial; y determinar si los posibles efectos varían en función de la resistencia a la insulina evaluada a través del modelo homeostático (HOMA. Métodos: 18 mujeres postmenopáusicas sanas participaron en un estudio triple cruzado aleatorizado, en el que bebieron 2 aguas minerales bicarbonatadas ricas en sodio (BMW-1 y 2 y un agua mineral débil (LMW junto con una comida estándar rica en grasa. Se tomaron muestras de sangre en ayunas y postprandiales a los 30, 60 y 120 min. Se determinó glucosa, insulina, colesterol y triglicéridos en suero. La resistencia a la insulina fue estimada a través del HOMA y la sensibilidad a la insulina se calculó mediante el índice de sensibilidad cuantitativa a la insulina (QUICKY. Resultados: Los niveles de glucosa no presentaron cambios. Los valores de HOMA y QUICKY presentaron una fuerte correlación inversa (r = -1,000; p < 0,0001. Las concentraciones de insulina

  19. 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, Annemarie

    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...

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

    Directory of Open Access Journals (Sweden)

    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.

  1. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  3. 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.

  4. Model Checking Algorithms for CTMDPs

    DEFF Research Database (Denmark)

    Buchholz, Peter; Hahn, Ernst Moritz; Hermanns, Holger

    2011-01-01

    Continuous Stochastic Logic (CSL) can be interpreted over continuoustime Markov decision processes (CTMDPs) to specify quantitative properties of stochastic systems that allow some external control. Model checking CSL formulae over CTMDPs requires then the computation of optimal control strategie...

  5. Model Checking Algorithms for CTMDPs

    DEFF Research Database (Denmark)

    Buchholz, Peter; Hahn, Ernst Moritz; Hermanns, Holger

    2011-01-01

    Continuous Stochastic Logic (CSL) can be interpreted over continuoustime Markov decision processes (CTMDPs) to specify quantitative properties of stochastic systems that allow some external control. Model checking CSL formulae over CTMDPs requires then the computation of optimal control strategie...

  6. 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...

  7. 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.

  8. Opposite regulation of insulin sensitivity by dietary lipid versus carbohydrate excess

    DEFF Research Database (Denmark)

    Lundsgaard, Annemarie; Sjøberg, Kim Anker; Høeg, Louise Dalgas

    2017-01-01

    To understand the mechanisms in lipid-induced insulin resistance, a more physiologic approach is to enhance FA availability through the diet. Nine healthy men ingested two hypercaloric diets (+75 E%) for three days, enriched in unsaturated FA (78 E% fat; UNSAT) or carbohydrates (80 E% carbohydrat......-CoA, are suggested to impact on insulin-stimulated glucose uptake. Taken together, the oxidative metabolic fluxes of glucose and FA are powerful and opposite regulators of insulin action in muscle....... not to activate PKC, and insulin signaling was intact. UNSAT decreased PDH-E1α protein content, and increased inhibitory PDH-E1α Ser(300) phosphorylation and FA oxidation. CHO increased whole body and leg insulin sensitivity, while increasing hepatic glucose production. After CHO, muscle PDH-E1α Ser(300......To understand the mechanisms in lipid-induced insulin resistance, a more physiologic approach is to enhance FA availability through the diet. Nine healthy men ingested two hypercaloric diets (+75 E%) for three days, enriched in unsaturated FA (78 E% fat; UNSAT) or carbohydrates (80 E% carbohydrate...

  9. The AMP-activated protein kinase α2 catalytic subunit controls whole-body insulin sensitivity

    Science.gov (United States)

    Viollet, Benoit; Andreelli, Fabrizio; Jørgensen, Sebastian B.; Perrin, Christophe; Geloen, Alain; Flamez, Daisy; Mu, James; Lenzner, Claudia; Baud, Olivier; Bennoun, Myriam; Gomas, Emmanuel; Nicolas, Gaël; Wojtaszewski, Jørgen F.P.; Kahn, Axel; Carling, David; Schuit, Frans C.; Birnbaum, Morris J.; Richter, Erik A.; Burcelin, Rémy; Vaulont, Sophie

    2003-01-01

    AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKα2 catalytic subunit gene was inactivated. AMPKα2–/– mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKα2–/– pancreatic islets, glucose- and L-arginine–stimulated insulin secretion were not affected. AMPKα2–/– mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKα2–/– muscles. These data indicate that AMPKα2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKα2–/– mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKα2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity. PMID:12511592

  10. The AMP-activated protein kinase alpha2 catalytic subunit controls whole-body insulin sensitivity.

    Science.gov (United States)

    Viollet, Benoit; Andreelli, Fabrizio; Jørgensen, Sebastian B; Perrin, Christophe; Geloen, Alain; Flamez, Daisy; Mu, James; Lenzner, Claudia; Baud, Olivier; Bennoun, Myriam; Gomas, Emmanuel; Nicolas, Gaël; Wojtaszewski, Jørgen F P; Kahn, Axel; Carling, David; Schuit, Frans C; Birnbaum, Morris J; Richter, Erik A; Burcelin, Rémy; Vaulont, Sophie

    2003-01-01

    AMP-activated protein kinase (AMPK) is viewed as a fuel sensor for glucose and lipid metabolism. To better understand the physiological role of AMPK, we generated a knockout mouse model in which the AMPKalpha2 catalytic subunit gene was inactivated. AMPKalpha2(-/-) mice presented high glucose levels in the fed period and during an oral glucose challenge associated with low insulin plasma levels. However, in isolated AMPKalpha2(-/-) pancreatic islets, glucose- and L-arginine-stimulated insulin secretion were not affected. AMPKalpha2(-/-) mice have reduced insulin-stimulated whole-body glucose utilization and muscle glycogen synthesis rates assessed in vivo by the hyperinsulinemic euglycemic clamp technique. Surprisingly, both parameters were not altered in mice expressing a dominant-negative mutant of AMPK in skeletal muscle. Furthermore, glucose transport was normal in incubated isolated AMPKalpha2(-/-) muscles. These data indicate that AMPKalpha2 in tissues other than skeletal muscles regulates insulin action. Concordantly, we found an increased daily urinary catecholamine excretion in AMPKalpha2(-/-) mice, suggesting altered function of the autonomic nervous system that could explain both the impaired insulin secretion and insulin sensitivity observed in vivo. Therefore, extramuscular AMPKalpha2 catalytic subunit is important for whole-body insulin action in vivo, probably through modulation of sympathetic nervous activity.

  11. 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.

  12. 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. © 2016 by the American Diabetes Association.

  13. 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.

  14. 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.

  15. Discovery of p1736, a novel antidiabetic compound that improves peripheral insulin sensitivity in mice models.

    Science.gov (United States)

    Anthony, Jessy; Kelkar, Aditya; Wilankar, Chandan; Ranjith, Vijayalakshmi; Bhumra, Sujit Kaur; Mutt, Shivaprakash Jagalur; Mutt, Shivaprakash; Deka, Nabajyoti; Sivaramakrishnan, Hariharan; Sharma, Somesh; Marita, Adaikalasamy Rosalind

    2013-01-01

    Insulin resistance is a characteristic feature of Type 2 diabetes. Insulin resistance has also been implicated in the pathogenesis of cardiovascular disease. Currently used thiazolidinedione (TZD) insulin sensitizers although effective, have adverse side effects of weight gain, fluid retention and heart failure. Using fat cell-based phenotypic drug discovery approach we identified P1736, a novel antidiabetic molecule that has completed Phase II clinical trials. The present study evaluated the in vitro and in vivo pharmacological properties of P1736. P1736 is a non-TZD and it did not activate human PPAR(Peroxisome Proliferator Activated Receptor Gamma )receptors. P1736 caused dose dependent increase in glucose uptake (EC50-400 nM) in the insulin resistant 3T3 adipocytes. The compound (10 µM) induced translocation of GLUT-4 (Glucose Transporter type 4) transporters in these adipocytes while metformin (1.0mM) was inactive. In diabetic db/db mice, P1736 (150 mg/kg) was more efficacious than metformin in lowering plasma glucose (35% vs 25%) and triglyceride levels (38% vs 31%). P1736 tested at 5mg/kg, twice daily doses, reduced glucose by 41% and triglycerides by 32%, in db/db mice. These effects were not associated with adverse effects on body weight or liver function. Rosiglitazone (5mg/kg, twice daily) caused 60% and 40 % decreases in glucose and triglyceride levels, respectively. However, rosiglitazone induced 13% weight gain (pinsulin resistant Type 2 diabetic patients.

  16. 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.

  17. 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.

  18. Substrate Metabolism and Insulin Sensitivity During Fasting in Obese Human Subjects: Impact of GH Blockade.

    Science.gov (United States)

    Pedersen, Morten Høgild; Svart, Mads Vandsted; Lebeck, Janne; Bidlingmaier, Martin; Stødkilde-Jørgensen, Hans; Pedersen, Steen Bønløkke; Møller, Niels; Jessen, Niels; Jørgensen, Jens O L

    2017-04-01

    Insulin resistance and metabolic inflexibility are features of obesity and are amplified by fasting. Growth hormone (GH) secretion increases during fasting and GH causes insulin resistance. To study the metabolic effects of GH blockade during fasting in obese subjects. Nine obese males were studied thrice in a randomized design: (1) after an overnight fast (control), (2) after 72 hour fasting (fasting), and (3) after 72 hour fasting with GH blockade (pegvisomant) [fasting plus GH antagonist (GHA)]. Each study day consisted of a 4-hour basal period followed by a 2-hour hyperinsulinemic, euglycemic clamp combined with indirect calorimetry, assessment of glucose and palmitate turnover, and muscle and fat biopsies. GH levels increased with fasting (P fasting-induced reduction of serum insulin-like growth factor I was enhanced by GHA (P Fasting increased lipolysis and lipid oxidation independent of GHA, but fasting plus GHA caused a more pronounced suppression of lipid intermediates in response to hyperinsulinemic, euglycemic clamp. Fasting-induced insulin resistance was abrogated by GHA (P Fasting plus GHA also caused elevated glycerol levels and reduced levels of counterregulatory hormones. Fasting significantly reduced the expression of antilipolytic signals in adipose tissue independent of GHA. Suppression of GH activity during fasting in obese subjects reverses insulin resistance and amplifies insulin-stimulated suppression of lipid intermediates, indicating that GH is an important regulator of substrate metabolism, insulin sensitivity, and metabolic flexibility also in obese subjects.

  19. Physical activity and weight loss are independent predictors of improved insulin sensitivity following energy restriction.

    Science.gov (United States)

    Camps, Stefan G J A; Verhoef, Sanne P M; Westerterp, Klaas R

    2016-02-01

    The role of physical activity and the joint effect with sleep duration on insulin sensitivity (IS) during energy restriction followed by weight maintenance were determined. One hundred and two subjects (28 males) (mean ± SD age: 40 ± 9 years; BMI: 31.9 ± 3.0 kg/m(2) ) followed a very-low-energy diet for 8 weeks, followed by a 44-week period of weight maintenance. Body composition (three-compartment model based on body weight, total body water, and body volume), physical activity (accelerometry), sleep (questionnaire, Epworth Sleepiness Scale), and fasting plasma insulin and glucose concentrations were assessed before the diet and at 8, 20, and 52 weeks after the start. Compared to baseline, IS was improved significantly after 8 weeks (P physical activity counts. Maintaining daily physical activity during energy restriction is as important as weight loss itself in the improvement of IS; there was no additional effect of change in sleep duration. During weight maintenance, improved IS is maintained better if physical activity returns to baseline or higher. © 2016 The Obesity Society.

  20. 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

  1. Adipocyte SIRT1 controls systemic insulin sensitivity by modulating macrophages in adipose tissue.

    Science.gov (United States)

    Hui, Xiaoyan; Zhang, Mingliang; Gu, Ping; Li, Kuai; Gao, Yuan; Wu, Donghai; Wang, Yu; Xu, Aimin

    2017-04-01

    Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD(+)-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the Il4 gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages. © 2017 The Authors.

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

    Science.gov (United States)

    Noebauer, Britta; Jais, Alexander; Todoric, Jelena; Gossens, Klaus; Sutterlüty-Fall, Hedwig; Einwallner, Elisa

    2017-01-01

    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.

  3. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  5. Effects of menopause and high-intensity training on insulin sensitivity and muscle metabolism

    DEFF Research Database (Denmark)

    Mandrup, Camilla Maria; Egelund, Jon; Nyberg, Michael Permin

    2017-01-01

    was observed in body composition. Training increased lean body mass (estimate [95% confidence interval] 0.5 [0.2-0.9] kg, P muscle mass (0.2 [-0.1 to 0.6] kg, P decreased fat percentage (1.0 [0.5-1.5]%, P ...MR in vastus lateralis muscle than the premenopausal women (-14.0 [-26.0 to -2.0] μmol/min/kg, P = 0.02), and tended to have lower eMR in femoral muscles (-11.2 [-22.7 to 0.4] μmol/min/kg, P = 0.06), and also GDR (-59.3 [-124.8 to 6.3] mg/min, P = 0.08), but increased similarly in both groups with training (e......MR vastus lateralis muscle: 27.8 [19.6-36.0] μmol/min/kg, P muscle: 20.0 [13.1-26.7] μmol/min/kg, P increases in insulin sensitivity included increased expression...

  6. Hemin improves insulin sensitivity in skeletal muscle in high fat-fed mice.

    Science.gov (United States)

    Ju, Tae-Jin; Kwon, Woo-Young; Kim, Yong-Woon; Kim, Jong-Yeon; Kim, Yong-Dae; Lee, In-Kyu; Park, So-Young

    2014-01-01

    The present study examined whether hemin could prevent the development of high-fat diet-induced insulin resistance in the liver and skeletal muscle using a hyperinsulinemic-euglycemic clamp. A four-week high-fat feeding to mice increased the body weight, fat mass, and plasma levels of insulin and lipid, which were reduced by hemin. High-fat diet reduced whole body glucose uptake, which were increased by hemin. Insulin-stimulated hepatic glucose production (HGP) was increased by high-fat diet, but hemin had no significant effect on HGP. Skeletal muscle glucose uptake was reduced by high-fat diet, and hemin normalized the glucose uptake. High-fat diet increased triglyceride levels and mRNA levels of lipogenic enzymes, and decreased mRNA levels of enzymes involved in lipid β-oxidation, which was reversed by hemin. Phosphorylated AMP-activated protein kinase levels were increased in the skeletal muscle of high fat-fed hemin-injected mice. High-fat diet reduced mRNA levels of antioxidant enzymes and increased mRNA levels of inflammatory cytokines and nitrotyrosine levels, which was normalized by hemin in the skeletal muscle. However, hemin had no significant effect on these factors in the liver. These results suggest that hemin prevents the development of high-fat diet-induced insulin resistance by increased insulin sensitivity in the skeletal muscle.

  7. 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.

  8. 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.

  9. Anti-inflammatory effect of pioglitazone on insulin sensitivity and vascular endothelial cell function of patients with metabolic syndrome%吡格列酮抗炎作用对代谢综合征患者胰岛素敏感性、血管内皮细胞功能的影响

    Institute of Scientific and Technical Information of China (English)

    卢辉和; 黎叶飞; 盛臻强; 王毅

    2012-01-01

    目的 研究吡格列酮对伴糖耐量减低(IGT)的代谢综合征(MS)患者血管内皮细胞功能的影响.方法 对30例伴IGT的MS患者采用吡格列酮45 mg/d治疗8周.在治疗前后分别测定胰岛素敏感度检测指数(QU ICKI)、肱动脉内皮依赖性舒张功能(FMD)和硝酸甘油诱导的非内皮依赖性舒张功能(NID),高敏C反应蛋白(hs-CRP)改变.结果 治疗后FMD明显改善(P<0.01),QUICKI指数升高(P<0.05); hs-CRP水平降低(P<0.01).结论 吡格列酮能明显改善IGT的MS患者的血管内皮细胞功能,其机制可能与改善体内胰岛素抵抗,抑制慢性炎症反应有关.%Objective To explore the beneficial effects of pioglitazone on endothelial function in metabolic syndrome (MS) patients with impaired glucose tolerance (IGT). Methods Thirty MS patients with IGT were administrated pioglitazone (45 mg/d) for eight weeks. The quantitative insulin sensitivity check index (QUICKI), endotheliurrrdependent vasodilation (flow-mediated vasodilation, FMD) and endothelium-independent vasodilation (nitroglycerineinduced vasodilation, NID) were measured in the brachial artery by high resolution ultrasound technique were measured before and after treatment respectively. The changes of hsCRP were assessed as well. Results After treatment, the levels of FMD, QUICKI and hsCRP were improved significantly (P<0. 05, P<0. 01). Conclusion Pioglitazone treatment improves endothelial vasodilator function in MS patients via enhancing insulin sensitivity and inhibition of chronic inflammation.

  10. 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

  11. 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

  12. 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

  13. 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...

  14. 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

    resulted in improvements in insulin action in the absence of weight loss. Glucose disposal rates during the euglycemic clamp were significantly increased at both hyperinsulinemic stages after training (40 mU: 1.84 +/- 0.32 to 2.67 +/- 0.37 mg.kg(-1).min(-1), P ...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...

  15. 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 

  16. 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

  17. 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...

  18. 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.

  19. Low-versus high-glycemic index diets in women: effects on caloric requirement, substrate utilization and insulin sensitivity.

    Science.gov (United States)

    Clapp, James F; Lopez, Beth

    2007-09-01

    Lowering dietary glycemic index appears to have positive health effects in obese and/or insulin resistant individuals. However, detailed studies in lean young men show no effect. This study was designed to test the null hypothesis that a diet rich in low-glycemic carbohydrate has no effect on lipid profile, caloric requirements, fat oxidation, or insulin sensitivity in adult women when compared to one rich in high-glycemic carbohydrate. The metabolic feeding protocol used was conducted in both a free-living and in-patient setting using a randomized crossover design. Seven women were studied on each of 2 diets in which 60% of the calories were from either high- or low-glycemic carbohydrate sources. Each diet lasted 20 days with measurements of caloric requirement, resting metabolic rate, glucose and insulin responses to diet and activity, insulin sensitivity, and lipid profile over the last 7 days. Caloric requirement was determined by bomb calorimetry. Other techniques included indirect calorimetry, hydrodensitometry, stable isotope tracers, and the euglycemic clamp. On the low-glycemic index diet the women's caloric requirements were 11% +/- 1% higher, fat oxidation at fasted rest supplied an average of 45% +/- 4% versus 28% +/- 5% of oxidative requirements, average glucose and insulin levels were approximately 40% lower, low density lipoproteins (LDL) and leptin concentrations were lower, and various indices of insulin sensitivity were > 20% higher. In this group of adult women, a diet that lowered glycemic index well below that typically found in western diets increased both daily caloric requirement and fat oxidation, decreased insulin and glucose concentrations and increased insulin sensitivity.

  20. 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...

  1. The importance of palmitoleic acid to adipocyte insulin resistance and whole-body insulin sensitivity in type 1 diabetes.

    Science.gov (United States)

    Bergman, Bryan C; Howard, David; Schauer, Irene E; Maahs, David M; Snell-Bergeon, Janet K; Clement, Timothy W; Eckel, Robert H; Perreault, Leigh; Rewers, Marian

    2013-01-01

    Type 1 diabetes is an insulin-resistant state, but it is less clear which tissues are affected. Our previous report implicated skeletal muscle and liver insulin resistance in people with type 1 diabetes, but this occurred independently of generalized, visceral, or ectopic fat. The aim of the study was to measure adipose tissue insulin sensitivity and plasma triglyceride composition in individuals with type 1 diabetes after overnight insulin infusion to lower fasting glucose. Fifty subjects (25 individuals with type 1 diabetes and 25 controls without) were studied. After 3 d of dietary control and overnight insulin infusion, we performed a three-stage hyperinsulinemic/euglycemic clamp infusing insulin at 4, 8, and 40 mU/m(2) · min. Infusions of [1,1,2,3,3-(2)H(2)]glycerol and [1-(13)C]palmitate were used to quantify lipid metabolism. Basal glycerol and palmitate rates of appearance were similar between groups, decreased more in control subjects during the first two stages of the clamp, and similarly suppressed during the highest insulin dose. The concentration of insulin required for 50% inhibition of lipolysis was twice as high in individuals with type 1 diabetes. Plasma triglyceride saturation was similar between groups, but palmitoleic acid in plasma triglyceride was inversely related to adipocyte insulin sensitivity. Unesterified palmitoleic acid in plasma was positively related to insulin sensitivity in controls, but not in individuals with type 1 diabetes. Adipose tissue insulin resistance is a significant feature of type 1 diabetes. Palmitoleic acid is not related to insulin sensitivity in type 1 diabetes, as it was in controls, suggesting a novel mechanism for insulin resistance in this population.

  2. "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."

  3. Neuronal Androgen Receptor Regulates Insulin Sensitivity via Suppression of Hypothalamic NF-κB–Mediated PTP1B Expression

    OpenAIRE

    Yu, I-Chen; Lin, Hung-Yun; Liu, Ning-Chun; Sparks, Janet D.; Yeh, Shuyuan; Fang, Lei-Ya; Chen, Lumin; Chang, Chawnshang

    2013-01-01

    Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes ...

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

    Science.gov (United States)

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

    2017-08-01

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

  5. 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

  6. 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

  7. 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.

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

    Directory of Open Access Journals (Sweden)

    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

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

    Directory of Open Access Journals (Sweden)

    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.

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

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    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.

  11. 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

  12. Deleterious effects of omitting breakfast on insulin sensitivity and fasting lipid profiles in healthy lean women.

    Science.gov (United States)

    Farshchi, Hamid R; Taylor, Moira A; Macdonald, Ian A

    2005-02-01

    Breakfast consumption is recommended, despite inconclusive evidence of health benefits. The study's aim was to ascertain whether eating breakfast (EB) or omitting breakfast (OB) affects energy intake, energy expenditure, and circulating insulin, glucose, and lipid concentrations in healthy women. In a randomized crossover trial, 10 women [x+/-SD body mass index (BMI; in kg/m2): 23.2+/-1.4] underwent two 14-d EB or OB interventions separated by a 2-wk interval. In the EB period, subjects consumed breakfast cereal with 2%-fat milk before 0800 and a chocolate-covered cookie between 1030 and 1100. In the OB period, subjects consumed the cookie between 1030 and 1100 and the cereal and milk between 1200 and 1330. Subjects then consumed 4 additional meals with content similar to usual at predetermined times later in the day and recorded food intake on 3 d during each period. Fasting and posttest meal glucose, lipid, and insulin concentrations and resting energy expenditure were measured before and after each period. Reported energy intake was significantly lower in the EB period (P=0.001), and resting energy expenditure did not differ significantly between the 2 periods. OB was associated with significantly higher fasting total and LDL cholesterol than was EB (3.14 and 3.43 mmol/L and 1.55 and 1.82 mmol/L, respectively; P=0.001). The area under the curve of insulin response to the test meal was significantly lower after EB than after OB (P<0.01). OB impairs fasting lipids and postprandial insulin sensitivity and could lead to weight gain if the observed higher energy intake was sustained.

  13. 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.

  14. UP780, a chromone-enriched aloe composition improves insulin sensitivity.

    Science.gov (United States)

    Yimam, Mesfin; Zhao, Jifu; Corneliusen, Brandon; Pantier, Mandee; Brownell, Lidia Alfaro; Jia, Qi

    2013-08-01

    Diabetic individuals experience elevated fasting glucose, glycosylated hemoglobin (HbA1c), and plasma insulin and impaired glucose tolerance. Adiponectin is a hormone inversely correlated with insulin resistance. Here we describe the activity of aloesin, an aloe chromone that increases adiponectin production and, when formulated with an aloe polysaccharide composition, improves the insulin sensitivity in db/db and diet-induced obese-diabetic mice. Two aloe chromones, aloesin and aloesinol, were tested in vitro for adiponectin production. Following confirmation of glucose-lowering activity in a high-fat diet (HFD)-induced mouse model, aloesin was formulated with an Aloe vera inner leaf gel powder polysaccharide preparation to yield a composition designated UP780. Efficacy of UP780 was evaluated in HDF-induced and db/db mouse models. GW1929, a synthetic peroxisome proliferator-activated receptor-γ (PPARγ) agonist, was used as a positive control. After 3 weeks of treatment of HDF-induced mice, plasma insulin levels were decreased 37.9% and 46.7% by aloesin and aloesinol, respectively. In db/db mice, the chromone- (2% chromone:98% aloe polysaccharide) enriched UP780 aloe composition showed a 33.7% and 46.0% decrease in fasting triglyceride and plasma glucose levels after 10 weeks of oral treatment, respectively. Diabetic mice gavaged with 200 mg/kg of UP780 for 10 weeks showed a 30.3% decrease in fasting blood glucose levels and a 32.2% reduction in plasma insulin. In both animal models, UP780 showed a statistically significant improvement in blood glucose clearance. These findings indicate that UP780, a chromone-standardized, aloe-based composition, could potentially be used as a natural product option to facilitate the maintenance of healthy blood glucose levels.

  15. 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.

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

    Directory of Open Access Journals (Sweden)

    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.

  17. Free fatty acids link metabolism and regulation of the insulin-sensitizing fibroblast growth factor-21.

    Science.gov (United States)

    Mai, Knut; Andres, Janin; Biedasek, Katrin; Weicht, Jessica; Bobbert, Thomas; Sabath, Markus; Meinus, Sabine; Reinecke, Franziska; Möhlig, Matthias; Weickert, Martin O; Clemenz, Markus; Pfeiffer, Andreas F H; Kintscher, Ulrich; Spuler, Simone; Spranger, Joachim

    2009-07-01

    Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator-activator receptor (PPAR) alpha-dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARalpha, might modify FGF-21 levels. The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARgamma activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. Oleate and linoleate increased FGF-21 expression and secretion in a PPARalpha-dependent fashion, as demonstrated by small-interfering RNA-induced PPARalpha knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.

  18. 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.

  19. Artemisia extracts activate PPARγ, promote adipogenesis, and enhance insulin sensitivity in adipose tissue of obese mice.

    Science.gov (United States)

    Richard, Allison J; Burris, Thomas P; Sanchez-Infantes, David; Wang, Yongjun; Ribnicky, David M; Stephens, Jacqueline M

    2014-01-01

    Studies have shown that the inability of adipose tissue to properly expand during the obese state or respond to insulin can lead to metabolic dysfunction. Artemisia is a diverse group of plants that has a history of medicinal use. The aim of this study was to examine the ability of ethanolic extracts of Artemisia scoparia (SCO) and Artemisia santolinifolia (SAN) to modulate adipocyte development in cultured adipocytes and white adipose tissue (WAT) function in vivo using a mouse model of diet-induced obesity. Adipogenesis was assessed using Oil Red O staining and immunoblotting. A nuclear receptor specificity assay was used to examine the specificity of SCO- and SAN-induced PPARγ activation. C57BL/6J mice, fed a high-fat diet, were gavaged with saline, SCO, or SAN for 2 wk. Whole-body insulin sensitivity was examined using insulin tolerance tests. WAT depots were assessed via immunoblotting for markers of insulin action and adipokine production. We established that SCO and SAN were highly specific activators of PPARγ and did not activate other nuclear receptors. After a 1-wk daily gavage, SCO- and SAN-treated mice had lower insulin-induced glucose disposal rates than control mice. At the end of the 2-wk treatment period, SCO- and SAN-treated mice had enhanced insulin-responsive Akt serine-473 phosphorylation and significantly decreased monocyte chemotactic protein-1 levels in visceral WAT compared with control mice; these differences were depot specific. Moreover, plasma adiponectin levels were increased following SCO treatment. Overall, these studies demonstrate that extracts from two Artemisia species can have metabolically favorable effects on adipocytes and WAT. Copyright © 2014 Elsevier Inc. All rights reserved.

  20. Identification of a mitochondrial target of thiazolidinedione insulin sensitizers (mTOT--relationship to newly identified mitochondrial pyruvate carrier proteins.

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    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.

  1. 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.

  2. Synthesis of cytochrome c oxidase 1 (SCO1) inhibits insulin sensitivity by decreasing copper levels in adipocytes.

    Science.gov (United States)

    Wei, Xiang-Bo; Guo, Liang; Liu, Yang; Zhou, Shui-Rong; Liu, Yuan; Dou, Xin; Du, Shao-Yue; Ding, Meng; Peng, Wan-Qiu; Qian, Shu-Wen; Huang, Hai-Yan; Tang, Qi-Qun

    2017-09-23

    Dysregulation of insulin signaling leads to type 2 diabetes mellitus (T2DM) and other metabolic disorders. Obesity is an important contributor to insulin resistance, and although the understanding of this relationship has improved in recent years, the mechanism of obesity-induced insulin resistance is not completely understood. Disorders of copper metabolism tend to accompany the development of obesity, which increases the risk of insulin resistance. Synthesis of cytochrome c oxidase 1 (SCO1) functions in the assembly of cytochrome c oxidase (COX) and cellular copper homeostasis. However, the role of SCO1 in the regulation of metabolism remains unknown. Here, we found that obese mice had higher expression of SCO1 and lower levels of copper in white adipose tissue (WAT) than did the control mice. Overexpression of SCO1 in adipocytes was associated with copper deficiency. Copper increased insulin sensitivity by decreasing the level of phosphatase and tensin homolog (PTEN) protein. Ectopic expression of SCO1 led to insulin resistance and was accompanied by a decrease in intracellular copper level, and addition of copper abolished the inhibitory effect of SCO1 on insulin sensitivity. Our results demonstrated a novel role of SCO1 in modulating insulin sensitivity via the regulation of copper concentration in WAT and suggested a potential therapeutic target for T2DM. Copyright © 2017. Published by Elsevier Inc.

  3. Inducible Deletion of Protein Kinase Map4k4 in Obese Mice Improves Insulin Sensitivity in Liver and Adipose Tissues.

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    Danai, Laura V; Flach, Rachel J Roth; Virbasius, Joseph V; Menendez, Lorena Garcia; Jung, Dae Young; Kim, Jong Hun; Kim, Jason K; Czech, Michael P

    2015-07-01

    Studies in vitro suggest that mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) attenuates insulin signaling, but confirmation in vivo is lacking since Map4k4 knockout is lethal during embryogenesis. We thus generated mice with floxed Map4k4 alleles and a tamoxifen-inducible Cre/ERT2 recombinase under the control of the ubiquitin C promoter to induce whole-body Map4k4 deletion after these animals reached maturity. Tamoxifen administration to these mice induced Map4k4 deletion in all tissues examined, causing decreased fasting blood glucose concentrations and enhanced insulin signaling to AKT in adipose tissue and liver but not in skeletal muscle. Surprisingly, however, mice generated with a conditional Map4k4 deletion in adiponectin-positive adipocytes or in albumin-positive hepatocytes displayed no detectable metabolic phenotypes. Instead, mice with Map4k4 deleted in Myf5-positive tissues, including all skeletal muscles tested, were protected from obesity-induced glucose intolerance and insulin resistance. Remarkably, these mice also showed increased insulin sensitivity in adipose tissue but not skeletal muscle, similar to the metabolic phenotypes observed in inducible whole-body knockout mice. Taken together, these results indicate that (i) Map4k4 controls a pathway in Myf5-positive cells that suppresses whole-body insulin sensitivity and (ii) Map4k4 is a potential therapeutic target for improving glucose tolerance and insulin sensitivity in type 2 diabetes.

  4. Adipose tissue monomethyl branched-chain fatty acids and insulin sensitivity: Effects of obesity and weight loss.

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    Su, Xiong; Magkos, Faidon; Zhou, Dequan; Eagon, J Christopher; Fabbrini, Elisa; Okunade, Adewole L; Klein, Samuel

    2015-02-01

    An increase in circulating branched-chain amino acids (BCAA) is associated with insulin resistance. Adipose tissue is a potentially important site for BCAA metabolism. It was evaluated whether monomethyl branched-chain fatty acids (mmBCFA) in adipose tissue, which are likely derived from BCAA catabolism, are associated with insulin sensitivity. Insulin-stimulated glucose disposal was determined by using the hyperinsulinemic-euglycemic clamp procedure with stable isotope glucose tracer infusion in nine lean and nine obese subjects, and in a separate group of nine obese subjects before and 1 year after Roux-en-Y gastric bypass (RYGB) surgery (38% weight loss). Adipose tissue mmBCFA content was measured in tissue biopsies taken in the basal state. Total adipose tissue mmBCFA content was ∼30% lower in obese than lean subjects (P=0.02) and increased by ∼65% after weight loss in the RYGB group (P=0.01). Adipose tissue mmBCFA content correlated positively with skeletal muscle insulin sensitivity (R(2) =35%, P=0.01, n=18). These results demonstrate a novel association between adipose tissue mmBCFA content and obesity-related insulin resistance. Additional studies are needed to determine whether the association between adipose tissue mmBCFA and muscle insulin sensitivity is causal or a simple association. © 2014 The Obesity Society.

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

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    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.

  6. Loss-of-function myostatin mutation increases insulin sensitivity and browning of white fat in Meishan pigs.

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    Cai, Chunbo; Qian, Lili; Jiang, Shengwang; Sun, Youde; Wang, Qingqing; Ma, Dezun; Xiao, Gaojun; Li, Biao; Xie, Shanshan; Gao, Ting; Chen, Yaoxing; Liu, Jie; An, Xiaorong; Cui, Wentao; Li, Kui

    2017-05-23

    Myostatin-deficient mice showed a remarkable hypertrophy of skeletal muscle, with a decreased fat mass and enhanced insulin sensitivity. Currently, it is unclear if the inhibition of myostatin could be used as an approach to treat human obesity and insulin resistance. In this study, we investigated if the inhibition of porcine myostatin has any effect on fat deposition and insulin sensitivity using genetically engineered Meishan pigs containing a myostatin loss-of-function mutation (Mstn -/- ). Our results indicated that, when compared with wild-type pigs, the amount of subcutaneous fat and leaf fat of Mstn -/- pigs were significantly decreased mainly due to the browning of subcutaneous adipose tissue. Additionally, the serum insulin level decreased and the insulin sensitivity increased significantly in Mstn -/- pigs. Moreover, we found a significant increase in levels of insulin receptor and insulin receptor substrate proteins in skeletal muscle of Mstn -/- pigs, which then activating the insulin signaling pathway. Irisin-mediated regulation is not the only pathway for the activation of insulin signal in Mstn -/- skeletal muscle. This study provides valuable insight for the treatment of human obesity and diabetes mellitus.

  7. Associations of Adiponectin with Adiposity, Insulin Sensitivity, and Diet in Young, Healthy, Mexican Americans and Non-Latino White Adults

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    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.

  8. High-fat diet feeding induces sex-dependent changes in inflammatory and insulin sensitivity profiles of rat adipose tissue.

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    Estrany, Maria E; Proenza, Ana M; Gianotti, Magdalena; Lladó, Isabel

    2013-08-01

    The aim of the study was to determine, in rats of both sexes, the effect of HF diet feeding on the expression of adipokines involved in inflammatory status and insulin sensitivity and on the levels of proteins involved in lipid handling of retroperitoneal adipose tissue. Eight-week-old Wistar rats of both sexes were fed a control diet (2.9% w/w fat) or an HF diet (30% w/w fat) for 14 weeks. Adiponectin, peroxisome proliferator-activated receptor γ and inflammatory marker mRNA levels were analyzed by real-time polymerase chain reaction. Levels of insulin receptor, glucose transporter 4, carnitine palmitoyltransferase 1, fatty acid synthase, hormone-sensitive lipase and lipoprotein lipase were determined by Western blot. HF diet feeding did not induce hyperphagia or body weight gain but did promote an increase in adiposity although only in male rats. HF diet impaired glucose tolerance and the expression of inflammatory and insulin sensitivity markers in adipose tissue of male rats, but not in female rats. Male rats seem to be more prone to disorders associated with an unbalanced composition of the diet, even in the absence of hyperphagia. In contrast, female rats counteract excessive fat intake by improving their ability to use lipid fuels, which limits adiposity and maintains insulin sensitivity. Copyright © 2012 John Wiley & Sons, Ltd.

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

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    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.

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

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    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.

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

    Science.gov (United States)

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

    2017-05-03

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

  12. 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

  13. Race differences in the association of oxidative stress with insulin sensitivity in African- and European-American women.

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    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.

  14. Restoration of Muscle Mitochondrial Function and Metabolic Flexibility in Type 2 Diabetes by Exercise Training Is Paralleled by Increased Myocellular Fat Storage and Improved Insulin Sensitivity

    NARCIS (Netherlands)

    Meex, R.C.R.; Schrauwen-Hinderling, V.B.; Moonen-Kornips, E.; Schaart, G.; Mensink, M.R.; Phielix, E.; Weijer, van de T.; Sels, J.P.; Schrauwen, P.; Hesselink, M.K.C.

    2010-01-01

    OBJECTIVE-Mitochondrial dysfunction and fat accumulation in skeletal muscle (increased intramyocellular lipid [IMCL]) have been linked to development of type 2 diabetes. We examined whether exercise training could restore mitochondrial function and insulin sensitivity in patients with type 2

  15. 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

  16. 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

  17. Higher insulin sensitivity in vegans is not associated with higher mitochondrial density.

    Science.gov (United States)

    Gojda, J; Patková, J; Jaček, M; Potočková, J; Trnka, J; Kraml, P; Anděl, M

    2013-12-01

    Vegans have a lower incidence of insulin resistance (IR)-associated diseases and a higher insulin sensitivity (IS) compared with omnivores. The aim of this study was to examine whether the higher IS in vegans relates to markers of mitochondrial biogenesis and to intramyocellular lipid (IMCL) content. Eleven vegans and 10 matched (race, age, sex, body mass index, physical activity and energy intake) omnivorous controls were enrolled in a case-control study. Anthropometry, bioimpedance (BIA), ultrasound measurement of visceral and subcutaneous fat layer, parameters of glucose and lipid homeostasis, hyperinsulinemic euglycemic clamp and muscle biopsies were performed. Citrate synthase (CS) activity, mitochondrial DNA (mtDNA) and IMCL content were assessed in skeletal muscle samples. Both groups were comparable in anthropometric and BIA parameters, physical activity and protein-energy intake. Vegans had significantly higher glucose disposal (M-value, vegans 8.11±1.51 vs controls 6.31±1.57 mg/kg/min, 95% confidence interval: 0.402 to 3.212, P=0.014), slightly lower IMCL content (vegans 13.91 (7.8 to 44.0) vs controls 17.36 (12.4 to 78.5) mg/g of muscle, 95% confidence interval: -7.594 to 24.550, P=0.193) and slightly higher relative muscle mtDNA amount (vegans 1.36±0.31 vs controls 1.13±0.36, 95% confidence interval:-0.078 to 0.537, P=0.135). No significant differences were found in CS activity (vegans 18.43±5.05 vs controls 18.16±5.41 μmol/g/min, 95% confidence interval: -4.503 to 5.050, P=0.906). Vegans have a higher IS, but comparable mitochondrial density and IMCL content with omnivores. This suggests that a decrease in whole-body glucose disposal may precede muscle lipid accumulation and mitochondrial dysfunction in IR development.

  18. Association of Sleep Deprivation With Reduction in Insulin Sensitivity as Assessed by the Hyperglycemic Clamp Technique in Adolescents.

    Science.gov (United States)

    De Bernardi Rodrigues, Ana Maria; da Silva, Cleliani de Cassia; Vasques, Ana Carolina Junqueira; Camilo, Daniella Fernandes; Barreiro, Francieli; Cassani, Roberta Soares Lara; Zambon, Mariana Porto; Antonio, Maria Ângela Reis de Góes Monteiro; Geloneze, Bruno

    2016-05-01

    The association between short sleep duration and decreased insulin sensitivity in adolescents has been described. However, to our knowledge, no studies have investigated this association measuring insulin sensitivity by the hyperglycemic clamp technique. To compare the distributions of parameters of insulin resistance in adolescents with sleep deprivation vs adequate sleep, and to investigate the association between sleep deprivation and insulin sensitivity. Cross-sectional multicenter study using data from the Brazilian Metabolic Syndrome Study conducted from June 29, 2011, to December 3, 2014, at an obesity outpatient clinic at the University of Campinas and public schools, with a convenience sample of 615 adolescents aged 10 to 19.9 years with a body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) for age and sex at the fifth percentile or higher. A subsample of 81 adolescents underwent the hyperglycemic clamp technique. The self-reported sleep duration was used to classify the population into 2 groups: adolescents with sleep deprivation (sleep (≥8 hours/night). Insulin sensitivity was assessed using the hyperglycemic clamp technique. Among the 615 adolescents (56.3% female; median age, 15.9 years [interquartile range, 12.9-17.8 years]) included in the sample, the mean (SD) sleep duration was 7.9 (1.7) hours/night. The adolescents with sleep deprivation (n = 257) compared with those with adequate sleep (n = 358) had a higher median (interquartile range) age (17.0 [15.4-18.3] vs 14.1 [11.8-16.9] years), BMI (25.0 [21.2-29.3] vs 23.1 [19.5-27.6]), waist circumference (83.0 [73.5-95.4] vs 79.0 [68.5-91.0] cm), sagittal abdominal diameter (17.9 [15.8-20.8] vs 17.0 [15.0-19.8] cm), neck circumference (35.2 [33.0-38.0] vs 33.0 [30.0-35.5] cm), uric acid level (4.9 [4.0-5.8] vs 4.5 [3.7-5.5] mg/dL), and white blood cell count (7000 [5900-8200] vs 6600 [5600-7800] cells/μL) (all P sleep deprivation had a lower median

  19. Effect of 8 weeks of overfeeding on ectopic fat deposition and insulin sensitivity: testing the "adipose tissue expandability" hypothesis.

    Science.gov (United States)

    Johannsen, Darcy L; Tchoukalova, Yourka; Tam, Charmaine S; Covington, Jeffrey D; Xie, Wenting; Schwarz, Jean-Marc; Bajpeyi, Sudip; Ravussin, Eric

    2014-10-01

    The presence of large subcutaneous adipocytes in obesity has been proposed to be linked with insulin resistance and type 2 diabetes through the "adipose tissue expandability" hypothesis, which holds that large adipocytes have a limited capacity for expansion, forcing lipids to be stored in nonadipose ectopic depots (skeletal muscle, liver), where they interfere with insulin signaling. This hypothesis has, however, been largely formulated by cross-sectional findings and to date has not been prospectively demonstrated in the development of insulin resistance in humans. Twenty-nine men (26.8 ± 5.4 years old; BMI 25.5 ± 2.3 kg/m(2)) were fed 40% more than their baseline requirement for 8 weeks. Before and after overfeeding, insulin sensitivity was determined using a two-step hyperinsulinemic-euglycemic clamp. Intrahepatic lipid (IHL) and intramyocellular lipid (IMCL) were measured by (1)H-MRS and abdominal fat by MRI. Subcutaneous abdominal adipose and skeletal muscle tissues were collected to measure adipocyte size and markers of tissue inflammation. Subjects gained 7.6 ± 2.1 kg (55% fat) and insulin sensitivity decreased 18% (P insulin sensitivity, which was linked with upregulated skeletal muscle tissue inflammation. In experimental substantial weight gain, the presence of larger adipocytes did not promote ectopic lipid accumulation. In contrast, smaller fat cells were associated with a worsened metabolic response to overfeeding. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.

  20. Integrative mRNA-microRNA analyses reveal novel interactions related to insulin sensitivity in human adipose tissue.

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    Kirby, Tyler J; Walton, R Grace; Finlin, Brian; Zhu, Beibei; Unal, Resat; Rasouli, Neda; Peterson, Charlotte A; Kern, Philip A

    2016-02-01

    Adipose tissue has profound effects on whole-body insulin sensitivity. However, the underlying biological processes are quite complex and likely multifactorial. For instance, the adipose transcriptome is posttranscriptionally modulated by microRNAs, but the relationship between microRNAs and insulin sensitivity in humans remains to be determined. To this end, we utilized an integrative mRNA-microRNA microarray approach to identify putative molecular interactions that regulate the transcriptome in subcutaneous adipose tissue of insulin-sensitive (IS) and insulin-resistant (IR) individuals. Using the NanoString nCounter Human v1 microRNA Expression Assay, we show that 17 microRNAs are differentially expressed in IR vs. IS. Of these, 16 microRNAs (94%) are downregulated in IR vs. IS, including miR-26b, miR-30b, and miR-145. Using Agilent Human Whole Genome arrays, we identified genes that were predicted targets of miR-26b, miR-30b, and miR-145 and were upregulated in IR subjects. This analysis produced ADAM22, MYO5A, LOX, and GM2A as predicted gene targets of these microRNAs. We then validated that miR-145 and miR-30b regulate these mRNAs in differentiated human adipose stem cells. We suggest that use of bioinformatic integration of mRNA and microRNA arrays yields verifiable mRNA-microRNA pairs that are associated with insulin resistance and can be validated in vitro. Copyright © 2016 the American Physiological Society.

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

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    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.

  2. 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.

  3. Insulin sensitizers prevent fine particulate matter-induced vascular insulin resistance and changes in endothelial progenitor cell homeostasis.

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    Haberzettl, Petra; McCracken, James P; Bhatnagar, Aruni; Conklin, Daniel J

    2016-06-01

    Exposure to fine particular matter (PM2.5) increases the risk of developing cardiovascular disease and Type 2 diabetes. Because blood vessels are sensitive targets of air pollutant exposure, we examined the effects of concentrated ambient PM2.5 (CAP) on vascular insulin sensitivity and circulating levels of endothelial progenitor cells (EPCs), which reflect cardiovascular health. We found that CAP exposure for 9 days decreased insulin-stimulated Akt phosphorylation in the aorta of mice maintained on control diet. This change was accompanied by the induction of IL-1β and increases in the abundance of cleaved IL-18 and p10 subunit of Casp-1, consistent with the activation of the inflammasome pathway. CAP exposure also suppressed circulating levels of EPCs (Flk-1(+)/Sca-1(+) cells), while enhancing the bone marrow abundance of these cells. Although similar changes in vascular insulin signaling and EPC levels were observed in mice fed high-fat diet, CAP exposure did not exacerbate diet-induced changes in vascular insulin resistance or EPC homeostasis. Treatment with an insulin sensitizer, metformin or rosiglitazone, prevented CAP-induced vascular insulin resistance and NF-κB and inflammasome activation and restored peripheral blood and bone marrow EPC levels. These findings suggest that PM2.5 exposure induces diet-independent vascular insulin resistance and inflammation and prevents EPC mobilization, and that this EPC mobilization defect could be mediated by vascular insulin resistance. Impaired vascular insulin sensitivity may be an important mechanism underlying PM2.5-induced vascular injury, and pharmacological sensitization to insulin action could potentially prevent deficits in vascular repair and mitigate vascular inflammation due to exposure to elevated levels of ambient air pollution. Copyright © 2016 the American Physiological Society.

  4. Neuronal androgen receptor regulates insulin sensitivity via suppression of hypothalamic NF-κB-mediated PTP1B expression.

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    Yu, I-Chen; Lin, Hung-Yun; Liu, Ning-Chun; Sparks, Janet D; Yeh, Shuyuan; Fang, Lei-Ya; Chen, Lumin; Chang, Chawnshang

    2013-02-01

    Clinical investigations highlight the increased incidence of metabolic syndrome in prostate cancer (PCa) patients receiving androgen deprivation therapy (ADT). Studies using global androgen receptor (AR) knockout mice demonstrate that AR deficiency results in the development of insulin resistance in males. However, mechanisms by which AR in individual organs coordinately regulates insulin sensitivity remain unexplored. Here we tested the hypothesis that functional AR in the brain contributes to whole-body insulin sensitivity regulation and to the metabolic abnormalities developed in AR-deficient male mice. The mouse model selectively lacking AR in the central nervous system and AR-expressing GT1-7 neuronal cells were established and used to delineate molecular mechanisms in insulin signaling modulated by AR. Neuronal AR deficiency leads to reduced insulin sensitivity in middle-aged mice. Neuronal AR regulates hypothalamic insulin signaling by repressing nuclear factor-κB (NF-κB)-mediated induction of protein-tyrosine phosphatase 1B (PTP1B). Hypothalamic insulin resistance leads to hepatic insulin resistance, lipid accumulation, and visceral obesity. The functional deficiency of AR in the hypothalamus leads to male mice being more susceptible to the effects of high-fat diet consumption on PTP1B expression and NF-κB activation. These findings suggest that in men with PCa undergoing ADT, reduction of AR function in the brain may contribute to insulin resistance and visceral obesity. Pharmacotherapies targeting neuronal AR and NF-κB may be developed to combat the metabolic syndrome in men receiving ADT and in elderly men with age-associated hypogonadism.

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

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    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.

  6. Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells.

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    Hammarstedt, Ann; Graham, Timothy E; Kahn, Barbara B

    2012-09-19

    Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals. 32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements. Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R = 0.49, p = 0.011) and protein (R = 0.51, p = 0.004) expression, as well as with circulating adiponectin levels (R = 0.46, 0 = 0.009). In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R = -0.61, 0 = 0.003) and adipocyte cell size (R = -0.40, p = 0.022). Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found between the hypertrophy-associated adipocyte

  7. Adipose tissue dysregulation and reduced insulin sensitivity in non-obese individuals with enlarged abdominal adipose cells

    Directory of Open Access Journals (Sweden)

    Hammarstedt Ann

    2012-09-01

    Full Text Available Abstract Background Obesity contributes to Type 2 diabetes by promoting systemic insulin resistance. Obesity causes features of metabolic dysfunction in the adipose tissue that may contribute to later impairments of insulin action in skeletal muscle and liver; these include reduced insulin-stimulated glucose transport, reduced expression of GLUT4, altered expression of adipokines, and adipocyte hypertrophy. Animal studies have shown that expansion of adipose tissue alone is not sufficient to cause systemic insulin resistance in the absence of adipose tissue metabolic dysfunction. To determine if this holds true for humans, we studied the relationship between insulin resistance and markers of adipose tissue dysfunction in non-obese individuals. Method 32 non-obese first-degree relatives of Type 2 diabetic patients were recruited. Glucose tolerance was determined by an oral glucose tolerance test and insulin sensitivity was measured with the hyperinsulinaemic-euglycaemic clamp. Blood samples were collected and subcutaneous abdominal adipose tissue biopsies obtained for gene/protein expression and adipocyte cell size measurements. Results Our findings show that also in non-obese individuals low insulin sensitivity is associated with signs of adipose tissue metabolic dysfunction characterized by low expression of GLUT4, altered adipokine profile and enlarged adipocyte cell size. In this group, insulin sensitivity is positively correlated to GLUT4 mRNA (R = 0.49, p = 0.011 and protein (R = 0.51, p = 0.004 expression, as well as with circulating adiponectin levels (R = 0.46, 0 = 0.009. In addition, insulin sensitivity is inversely correlated to circulating RBP4 (R = −0.61, 0 = 0.003 and adipocyte cell size (R = −0.40, p = 0.022. Furthermore, these features are inter-correlated and also associated with other clinical features of the metabolic syndrome in the absence of obesity. No association could be found

  8. Chronic Angiotensin-(1-7) Improves Insulin Sensitivity in High-Fat Fed Mice Independent of Blood Pressure.

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    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.

  9. High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes.

    Science.gov (United States)

    Vozarova, Barbora; Stefan, Norbert; Lindsay, Robert S; Saremi, Aramesh; Pratley, Richard E; Bogardus, Clifton; Tataranni, P Antonio

    2002-06-01

    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 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 33 +/- 8%, ALT 45 +/- 29 units/l, AST 34 +/- 18 units/l, and GGT 56 +/- 40 units/l [mean +/- SD]) who were characterized for body composition (hydrodensitometry or dual-energy X-ray absorptiometry), whole-body insulin sensitivity (M), and hepatic insulin sensitivity (hepatic glucose output [HGO] during the low-dose insulin infusion of a hyperinsulinemic clamp) and acute insulin response (AIR) (25-g intravenous glucose challenge). Sixty-three subjects developed diabetes over an average follow-up of 6.9 +/- 4.9 years. In 224 subjects, who remained nondiabetic, follow-up measurements of M and AIR 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 < 0.01). In a proportional hazard analysis with adjustment for age, sex, body fat, M, and AIR, higher ALT [relative hazard 90th vs. 10th centiles (95% CI): 1.9 (1.1-3.3), P = 0.02], but not AST or GGT, predicted diabetes. Elevated ALT at baseline was associated prospectively with an increase in HGO (r = 0.21, P = 0.001) but not with changes in M or AIR (both P = 0.1). Higher ALT concentrations were cross-sectionally associated with obesity and whole-body and hepatic insulin resistance and prospectively associated with a decline in hepatic insulin sensitivity and the development of

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

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    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

  11. 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...

  12. Fgf21 impairs adipocyte insulin sensitivity in mice fed a low-carbohydrate, high-fat ketogenic diet.

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    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.

  13. 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...

  14. 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.

  15. Lack of CUL4B in Adipocytes Promotes PPARγ-Mediated Adipose Tissue Expansion and Insulin Sensitivity.

    Science.gov (United States)

    Li, Peishan; Song, Yu; Zan, Wenying; Qin, Liping; Han, Shuang; Jiang, Baichun; Dou, Hao; Shao, Changshun; Gong, Yaoqin

    2017-02-01

    Obesity and obesity-associated diseases are linked to dysregulation of the peroxisome proliferator-activated receptor γ (PPARγ) signaling pathway. Identification of the factors that regulate PPARγ expression and activity is crucial for combating obesity. However, the ubiquitin E3 ligases that target PPARγ for proteasomal degradation have been rarely identified, and their functions in vivo have not been characterized. Here we report that CUL4B-RING E3 ligase (CRL4B) negatively regulates PPARγ by promoting its polyubiquitination and proteasomal degradation. Depletion of CUL4B led to upregulation of PPARγ-regulated genes and facilitated adipogenesis. Adipocyte-specific Cul4b knockout (AKO) mice being fed a high-fat diet exhibited increased body fat accumulation that was mediated by increased adipogenesis. However, AKO mice showed improved metabolic phenotypes, including increased insulin sensitivity and glucose tolerance. Correspondingly, there was a decreased inflammatory response in adipose tissues of AKO mice. Genetic inhibition of CUL4B thus appears to phenocopy the beneficial effects of PPARγ agonists. Collectively, this study establishes a critical role of CRL4B in the regulation of PPARγ stability and insulin sensitivity and suggests that CUL4B could be a potential therapeutic target for combating obesity and metabolic syndromes. © 2017 by the American Diabetes Association.

  16. [Rosuvastatin improves insulin sensitivity in overweight rats induced by high fat diet. Role of SIRT1 in adipose tissue].

    Science.gov (United States)

    Valero-Muñoz, María; Martín-Fernández, Beatriz; Ballesteros, Sandra; Cachofeiro, Victoria; Lahera, Vicente; de Las Heras, Natalia

    2014-01-01

    To study the effects of rosuvastatin on insulin resistance in overweight rats induced by high fat diet, as well as potential mediators. We used male Wistar rats fed with a standard diet (CT) or high fat diet (33.5% fat) (HFD); half of the animals HFD were treated with rosuvastatin (15mg/kg/day) (HFD+Rosu) for 7 weeks. HFD rats showed increased body, epididymal and lumbar adipose tissue weights. Treatment with Rosu did not modify body weight or the weight of the adipose packages in HFD rat. Plasma glucose and insulin levels and HOMA index were higher in HFD rats, and rosuvastatin treatment reduced them. Leptin/adiponectin ratio in plasma and lumbar adipose tissue were higher in HDF rats, and were reduced by rosuvastatin. SIRT-1, PPAR-γ and GLUT-4 protein expression in lumbar adipose tissue were lower in HFD rats and Rosu normalized expression of the three mediators. Rosuvastatin ameliorates insulin sensitivity induced by HFD in rats. This effect is mediated by several mechanisms including reduction of leptin and enhancement of SIRT-1, PPAR-γ and GLUT-4 expression in white adipose tissue. SIRT1 could be considered a major mediator of the beneficial effects of rosuvastatin on insulin sensitivity in overweight rats induced by diet. Copyright © 2013 Sociedad Española de Arteriosclerosis. Published by Elsevier España. All rights reserved.

  17. 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.

  18. 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

  19. 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.

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

    Science.gov (United States)

    Franko, Andras; Neschen, Susanne; Rozman, Jan; Rathkolb, Birgit; Aichler, Michaela; Feuchtinger, Annette; Brachthäuser, Laura; Neff, Frauke; Kovarova, Marketa; Wolf, Eckhard; Fuchs, Helmut; Häring, Hans-Ulrich; Peter, Andreas; Hrabě de Angelis, Martin

    2017-03-01

    Recently, we have shown that Bezafibrate (BEZ), the pan-PPAR (peroxisome proliferator-activated receptor) activator, ameliorated diabetes in insulin deficient streptozotocin treated diabetic mice. In order to study whether BEZ can also improve glucose metabolism in a mouse model for fatty liver and type 2 diabetes, the drug was applied to TallyHo mice. TallyHo mice were divided into an early (ED) and late (LD) diabetes progression group and both groups were treated with 0.5% BEZ (BEZ group) or standard diet (SD group) for 8 weeks. We analyzed plasma parameters, pancreatic beta-cell morphology, and mass as well as glucose metabolism of the BEZ-treated and control mice. Furthermore, liver fat content and composition as well as hepatic gluconeogenesis and mitochondrial mass were determined. Plasma lipid and glucose levels were markedly reduced upon BEZ treatment, which was accompanied by elevated insulin sensitivity index as well as glucose tolerance, respectively. BEZ increased islet area in the pancreas. Furthermore, BEZ treatment improved energy expenditure and metabolic flexibility. In the liver, BEZ ameliorated steatosis, modified lipid composition and increased mitochondrial mass, which was accompanied by reduced hepatic gluconeogenesis. 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.

  1. Longitudinal changes in insulin sensitivity and beta cell function between women with and without a history of gestational diabetes mellitus.

    Science.gov (United States)

    Xiang, Anny H; Takayanagi, Miwa; Black, Mary Helen; Trigo, Enrique; Lawrence, Jean M; Watanabe, Richard M; Buchanan, Thomas A

    2013-12-01

    The aim of the study was to compare longitudinal changes in insulin sensitivity (SI) and beta cell function between women with and without a history of gestational diabetes mellitus (GDM). The prospective follow-up cohort included 235 parous non-diabetic Mexican-American women, 93 with and 142 without a history of GDM. The participants underwent dual-energy x-ray absorptiometry, OGTTs and IVGTTs at baseline and at a median of 4.1 years follow-up. The baseline values and rates of change of metabolic measures were compared between groups. At baseline, women with prior GDM (mean age 36.3 years) had similar values of SI but higher percentages of body fat and trunk fat (p ≤ 0.02), a lower acute insulin response and poorer beta cell compensation (disposition index [DI]) (p  0.50). Adjustment for baseline age, adiposity, calorie intake, physical activity, age at first pregnancy, additional pregnancies and changes in adiposity during follow-up increased the between-group differences in the rates of change of SI and DI (p ≤ 0.003). Mexican-American women with recent GDM had a faster deterioration in insulin sensitivity and beta cell compensation than their parous counterparts without GDM. The differences were not explained by differences in adiposity, suggesting more deleterious effects of existing fat and/or reduced beta cell robustness in women with GDM.

  2. 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.

  3. Insulin sensitizers in 2013: new insights for the development of novel therapeutic agents to treat metabolic diseases.

    Science.gov (United States)

    Colca, Jerry R; Tanis, Steven P; McDonald, William G; Kletzien, Rolf F

    2014-01-01

    Insulin-sensitizing thiazolidinediones (TZDs) correct a root cause of type 2 diabetes and potentially other diseases of metabolic dysfunction, including conditions ranging from oncologic, inflammatory, and neurodegenerative diseases. Importantly, compounds with this mode of action can modify disease progression, as opposed to simply mitigating symptoms. However, side effects have limited the use of marketed agents. Moreover, the same and additional issues have prevented development of newer agents, and no new compounds with this mode of action have been approved since 1999. Here we briefly review the drug discovery track record of compounds in the TZD class as well as several classes of compounds that have been designed with substitutes for the TZD ring, while maintaining and/or expanding the ability to directly activate peroxisome proliferator-activated receptor (PPAR) transcription factors. A key discovery that could change the course of drug discovery in this area is a newly identified mitochondrial target for the insulin sensitizers. This has allowed new drug discovery into molecules designed to maintain this mitochondrial interaction while specifically avoiding significant interactions with PPAR receptors. This commentary suggests that a fresh approach could pave the way for a new directed group of therapeutic agents with potential for disease modification of common metabolic disorders.

  4. 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

  5. Lipid metabolism disturbances contribute to insulin resistance and decrease insulin sensitivity by malathion exposure in Wistar rat.

    Science.gov (United States)

    Lasram, Mohamed Montassar; Bouzid, Kahena; Douib, Ines Bini; Annabi, Alya; El Elj, Naziha; El Fazaa, Saloua; Abdelmoula, Jaouida; Gharbi, Najoua

    2015-04-01

    Several studies showed that organophosphorus pesticides disturb glucose homeostasis and can increase incidence of metabolic disorders and diabetes via insulin resistance. The current study investigates the influence of malathion on glucose metabolism regulation, in vivo, during subchronic exposure. Malathion was administered orally (200 mg/kg), once a day for 28 consecutive days. Plasma glucose, insulin and Glycated hemoglobin levels were significantly increased while hepatic glycogen content was decreased in intoxicated animals compared with the control group. Furthermore, there was a significant disturbance of lipid content in subchronic treated and post-treated rats deprived of malathion for one month. In addition, we used the homeostasis model assessment (HOMA) to assess insulin resistance (HOMA-IR) and pancreatic β-cell function (HOMA-β). Our results show that malathion increases insulin resistance biomarkers and decreases insulin sensitivity indices. Statistical analysis demonstrates that there was a positive and strong significant correlation between insulin level and insulin resistance indices, HOMA-IR, HOMA-β. Similarly, a negative and significant correlation was also found between insulin level and insulin sensitivity indices. For the first time, we demonstrate that malathion induces insulin resistance in vivo using homeostasis model assessment and these changes were detectable one month after the end of exposure. To explain insulin resistance induced by malathion we focus on lipid metabolism disturbances and their interaction with many proteins involved in insulin signaling pathways.

  6. Variable Hepatic Insulin Clearance with Attendant Insulinemia is the Primary Determinant of Insulin Sensitivity in the Normal Dog

    Science.gov (United States)

    Ader, Marilyn; Stefanovski, Darko; Kim, Stella P.; Richey, Joyce M.; Ionut, Viorica; Catalano, Karyn J.; Hucking, Katrin; Ellmerer, Martin; Van Citters, Gregg; Hsu, Isabel R.; Chiu, Jenny D.; Woolcott, Orison O.; Harrison, Lisa N.; Zheng, Dan; Lottati, Maya; Kolka, Cathryn M.; Mooradian, Vahe; Dittmann, Justin; Yae, Sophia; Liu, Huiwen; Castro, Ana Valeria B.; Kabir, Morvarid; Bergman, Richard N.

    2013-01-01

    OBJECTIVE Insulin resistance is a powerful risk factor for Type 2 diabetes and a constellation of chronic diseases, and is most commonly associated with obesity. We examined if factors other than obesity are more substantial predictors of insulin sensitivity under baseline, non-stimulated conditions. DESIGN AND METHODS Metabolic assessment was performed in healthy dogs (n=90). Whole-body sensitivity from euglycemic clamps (SICLAMP) was the primary outcome variable, and was measured independently by IVGTT (n=36). Adiposity was measured by MRI (n=90), and glucose-stimulated insulin response was measured from hyperglycemic clamp or IVGTT (n=86 and 36, respectively). RESULTS SICLAMP was highly variable (5.9 to 75.9 dl/min per kg per μU/ml). Despite narrow range of body weight (mean, 28.7±0.3 kg), adiposity varied ∼8-fold and was inversely correlated with SICLAMP (pinsulin, but most strongly associated with insulin clearance. Clearance was the dominant factor associated with sensitivity (r=0.53, pinsulin clearance contributes substantially to insulin sensitivity, and may be pivotal in understanding the pathogenesis of insulin resistance. We propose that hyperinsulinemia due to reduction in insulin clearance is responsible for insulin resistance secondary to changes in body weight. PMID:24123967

  7. Altered Fetal Skeletal Muscle Nutrient Metabolism Following an Adverse In Utero Environment and the Modulation of Later Life Insulin Sensitivity

    Directory of Open Access Journals (Sweden)

    Kristyn Dunlop

    2015-02-01

    Full Text Available The importance of the in utero environment as a contributor to later life metabolic disease has been demonstrated in both human and animal studies. In this review, we consider how disruption of normal fetal growth may impact skeletal muscle metabolic development, ultimately leading to insulin resistance and decreased insulin sensitivity, a key precursor to later life metabolic disease. In cases of intrauterine growth restriction (IUGR associated with hypoxia, where the fetus fails to reach its full growth potential, low birth weight (LBW is often the outcome, and early in postnatal life, LBW individuals display modifications in the insulin-signaling pathway, a critical precursor to insulin resistance. In this review, we will present literature detailing the classical development of insulin resistance in IUGR, but also discuss how this impaired development, when challenged with a postnatal Western diet, may potentially contribute to the development of later life insulin resistance. Considering the important role of the skeletal muscle in insulin resistance pathogenesis, understanding the in utero programmed origins of skeletal muscle deficiencies in insulin sensitivity and how they may interact with an adverse postnatal environment, is an important step in highlighting potential therapeutic options for LBW offspring born of pregnancies characterized by placental insufficiency.

  8. 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.

  9. Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

    Science.gov (United States)

    Hashimoto, Takeshi; Igarashi, Junsuke; Hasan, Arif U; Ohmori, Koji; Kohno, Masakazu; Nagai, Yukiko; Yamashita, Tetsuo; Kosaka, Hiroaki

    2013-01-01

    The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed mifepristone, they exhibited a marked improvement in insulin sensitivity, attenuated hepatic injury, and decreased adipocyte size, compared with mice that received only the high-fat diet. Intriguingly, mifepristone-treated mice showed significantly elevated plasma adiponectin levels. Second, we tested the effects of mifepristone on differentiated 3T3-L1 adipocytes in vitro. When differentiated adipocytes were treated with mifepristone for 48 h, adiponectin was upregulated at both mRNA and protein levels. Collectively, these results reveal novel actions of mifepristone on metabolic functions, in vivo and in vitro, in which the drug exerts antidiabetic effects associated with an upregulation in adiponectin-secretion.

  10. Mifepristone promotes adiponectin production and improves insulin sensitivity in a mouse model of diet-induced-obesity.

    Directory of Open Access Journals (Sweden)

    Takeshi Hashimoto

    Full Text Available The steroid receptor antagonist mifepristone is used as an anti-cancer agent, eliciting both cytostatic and cytotoxic effects on malignant cells. However, the metabolic effects of long-term treatment with mifepristone have remained unclear. The effects of mifepristone on insulin sensitivity and adiponectin secretion were evaluated both in in vivo and in vitro. First, we explored the effects of mifepristone, on metabolic functions in obese mice receiving a high-fat diet. When these mice were fed mifepristone, they exhibited a marked improvement in insulin sensitivity, attenuated hepatic injury, and decreased adipocyte size, compared with mice that received only the high-fat diet. Intriguingly, mifepristone-treated mice showed significantly elevated plasma adiponectin levels. Second, we tested the effects of mifepristone on differentiated 3T3-L1 adipocytes in vitro. When differentiated adipocytes were treated with mifepristone for 48 h, adiponectin was upregulated at both mRNA and protein levels. Collectively, these results reveal novel actions of mifepristone on metabolic functions, in vivo and in vitro, in which the drug exerts antidiabetic effects associated with an upregulation in adiponectin-secretion.

  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. 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.

  13. 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.

  14. 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.

  15. Cinnamon Extract Improves Insulin Sensitivity in the Brain and Lowers Liver Fat in Mouse Models of Obesity

    Science.gov (United States)

    Sartorius, Tina; Peter, Andreas; Schulz, Nadja; Drescher, Andrea; Bergheim, Ina; Machann, Jürgen; Schick, Fritz; Siegel-Axel, Dorothea; Schürmann, Annette; Weigert, Cora; Häring, Hans-Ulrich; Hennige, Anita M.

    2014-01-01

    Objectives Treatment of diabetic subjects with cinnamon demonstrated an improvement in blood glucose concentrations and insulin sensitivity but the underlying mechanisms remained unclear. This work intends to elucidate the impact of cinnamon effects on the brain by using isolated astrocytes, and an obese and diabetic mouse model. Methods Cinnamon components (eugenol, cinnamaldehyde) were added to astrocytes and liver cells to measure insulin signaling and glycogen synthesis. Ob/ob mice were supplemented with extract from cinnamomum zeylanicum for 6 weeks and cortical brain activity, locomotion and energy expenditure were evaluated. Insulin action was determined in brain and liver tissues. Results Treatment of primary astrocytes with eugenol promoted glycogen synthesis, whereas the effect of cinnamaldehyde was attenuated. In terms of brain function in vivo, cinnamon extract improved insulin sensitivity and brain activity in ob/ob mice, and the insulin-stimulated locomotor activity was improved. In addition, fasting blood glucose levels and glucose tolerance were greatly improved in ob/ob mice due to cinnamon extracts, while insulin secretion was unaltered. This corresponded with lower triglyceride and increased liver glycogen content and improved insulin action in liver tissues. In vitro, Fao cells exposed to cinnamon exhibited no change in insulin action. Conclusions Together, cinnamon extract improved insulin action in the brain as well as brain activity and locomotion. This specific effect may represent an important central feature of cinnamon in improving insulin action in the brain, and mediates metabolic alterations in the periphery to decrease liver fat and improve glucose homeostasis. PMID:24643026

  16. Egr-1 decreases adipocyte insulin sensitivity by tilting PI3K/Akt and MAPK signal balance in mice

    Science.gov (United States)

    Yu, Xiao; Shen, Ning; Zhang, Ming-Liang; Pan, Fei-Yan; Wang, Chen; Jia, Wei-Ping; Liu, Chang; Gao, Qian; Gao, Xiang; Xue, Bin; Li, Chao-Jun

    2011-01-01

    It is well known that insulin can activate both PI3K/Akt pathway, which is responsible for glucose uptake, and MAPK pathway, which is crucial for insulin resistance formation. But, it is unclear exactly how the two pathways coordinate to regulate insulin sensitivity upon hyperinsulinism stress of type 2 diabetes mellitus (T2DM). Here, we show that an early response transcription factor Egr-1 could tilt the signalling balance by blocking PI3K/Akt signalling through PTEN and augmenting Erk/MAPK signalling through GGPPS, resulting in insulin resistance in adipocytes. Egr-1, PTEN and GGPPS are upregulated in the fat tissue of T2DM patients and db/db mice. Egr-1 overexpression in epididymal fat induced systematic insulin resistance in wild-type mice, and loss of Egr-1 function improved whole-body insulin sensitivity in diabetic mice, which is mediated by Egr-1 controlled PI3K/Akt and Erk/MAPK signalling balance. Therefore, we have revealed, for the first time, the mechanism by which Egr-1 induces insulin resistance under hyperinsulinism stress, which provides an ideal pharmacological target since inhibiting Egr-1 can simultaneously block MAPK and augment PI3K/Akt activation during insulin stimulation. PMID:21829168

  17. 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.

  18. 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.

  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. Get Your Cholesterol Checked

    Science.gov (United States)

    ... Checked Print This Topic En español Get Your Cholesterol Checked Browse Sections The Basics Overview Cholesterol Test ... How often do I need to get my cholesterol checked? The general recommendation is to get your ...

  1. Associations of Dietary Glucose, Fructose, and Sucrose with β-Cell Function, Insulin Sensitivity, and Type 2 Diabetes in the Maastricht Study.

    Science.gov (United States)

    Biggelaar, Louise J C J den; Eussen, Simone J P M; Sep, Simone J S; Mari, Andrea; Ferrannini, Ele; Dongen, Martien C J M van; Denissen, Karlijn F M; Wijckmans, Nicole E G; Schram, Miranda T; Kallen, Carla J van der; Koster, Annemarie; Schaper, Nicolaas; Henry, Ronald M A; Stehouwer, Coen D A; Dagnelie, Pieter C

    2017-04-13

    The associations of glucose, fructose, and sucrose intake with type 2 diabetes mellitus (T2DM) have been inconsistent. Furthermore, there is a lack of studies focusing on early markers of T2DM that provide insight into the process of T2DM progression: impaired pancreatic β-cell function (BCF) and insulin sensitivity. This study evaluated associations cross-sectionally in a population-based cohort consisting of 2818 individuals (mean ± SD age 59.7 ± 8.18, 49.5% male, n = 120 newly diagnosed T2DM). Glucose, fructose, and sucrose intake were assessed by a food frequency questionnaire. Glucose metabolism status, insulin sensitivity, and BCF were measured by a seven-points oral glucose tolerance test. Linear regression analysis revealed a positive association of glucose intake with insulin sensitivity in the fully adjusted model (standardized beta (95% CI) 0.07 (0.05, 0.14) SD for ≥23 g vs. glucose). Fructose and sucrose intake were not associated with insulin sensitivity after full adjustments. In addition, no associations of dietary glucose, fructose, and sucrose with BCF were detected. In conclusion, higher intake of glucose, not fructose and sucrose, was associated with higher insulin sensitivity, independent of dietary fibre. No convincing evidence was found for associations of dietary glucose, fructose, and sucrose with BCF in this middle-aged population.

  2. 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.

  3. 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.

  4. Chronic leucine supplementation increases body weight and insulin sensitivity in rats on high-fat diet likely by promoting insulin signaling in insulin-target tissues.

    Science.gov (United States)

    Li, Xiang; Wang, Xiaolei; Liu, Rui; Ma, Yan; Guo, Huailan; Hao, Liping; Yao, Ping; Liu, Liegang; Sun, Xiufa; He, Ka; Cao, Wenhong; Yang, Xuefeng

    2013-06-01

    This study investigated the effect of chronic leucine supplementation on insulin sensitivity and the associated mechanisms in rats on high-fat diet (HFD). Male Sprague-Dawley rats were fed either normal chow diet or HFD supplemented with 0, 1.5, 3.0, and 4.5% leucine for 24 weeks. We found that chronic leucine supplementation increased insulin sensitivity together with increased body weight in rats on HFD, but had no effect on insulin sensitivity in rats on normal chow diet. The increased insulin sensitivity by leucine supplementation was not associated with altered ectopic fat accumulation in liver and muscle, plasma levels of lipids and cytokines, but is associated with reduced oxidative stress and improved insulin signaling. Chronic leucine supplementation did not enhance insulin receptor substract-1 (IRS-1) phosphorylation on serine 302, but elevated basal IRS-1 phosphorylation on tyrosine 632 and improved insulin-stimulated protein kinase B (Akt) and mammalian target of rapamycin (mTOR) phosphorylation in liver, skeletal muscle, and adipose tissue of rats on HFD rats, indicating leucine supplementation prevented HFD-induced insulin resistance in insulin-target tissues. Chronic leucine supplementation can increase insulin sensitivity and body weight likely by reducing oxidative stress and improving insulin signaling pathway in rats on HFD. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  5. 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

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

    DEFF Research Database (Denmark)

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

    2008-01-01

    OBJECTIVE: The aim of this study was to describe the natural history of insulin secretion and insulin sensitivity in the development of isolated impaired fasting glycemia (i-IFG), isolated impaired glucose tolerance (i-IGT), and combined IFG/IGT. RESEARCH DESIGN AND METHODS: Baseline and 5-year...... of insulin sensitivity (HOMA-IS), early-phase insulin release (EPIR), and insulin secretion relative to insulin action (disposition index) were estimated. RESULTS: Five years before the pre-diabetes diagnoses (i-IFG, i-IGT, and IFG/IGT), ISI, HOMA-IS, EPIR, and disposition index were lower than...... follow-up data from the Inter99 study were used. Individuals with normal glucose tolerance (NGT) at baseline and i-IFG, i-IGT, combined IFG/IGT, or NGT at the 5-year follow-up were examined with an oral glucose tolerance test (n = 3,145). Insulin sensitivity index (ISI), homeostasis model assessment...

  7. 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...

  8. Global Gene Expression Profiles of Subcutaneous Adipose and Muscle From Glucose-Tolerant, Insulin-Sensitive, and Insulin-Resistant Individuals Matched for BMI

    Science.gov (United States)

    Elbein, Steven C.; Kern, Philip A.; Rasouli, Neda; Yao-Borengasser, Aiwei; Sharma, Neeraj K.; Das, Swapan K.

    2011-01-01

    OBJECTIVE To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic, insulin-resistant individuals compared with insulin-sensitive individuals matched for BMI. RESEARCH DESIGN AND METHODS A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity (31 insulin-resistant and 31 insulin-sensitive subjects; 40 were European American and 22 were African American) and matched for age and obesity measures. Global gene expression profiles were determined and compared between ethnic groups and between insulin-resistant and insulin-sensitive participants individually and using gene-set enrichment analysis. RESULTS African American and European American subjects differed in 58 muscle and 140 adipose genes, including many inflammatory and metabolically important genes. Peroxisome proliferator–activated receptor γ cofactor 1A (PPARGC1A) was 1.75-fold reduced with insulin resistance in muscle, and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated. Unexpected categories included ubiquitination, citrullination, and protein degradation. In adipose, highly represented categories included lipid and fatty acid metabolism, insulin action, and cell-cycle regulation. Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene-set enrichment analysis. FADS1, VEGFA, PTPN3, KLF15, PER3, STEAP4, and AGTR1 were among genes expressed differentially in both adipose and muscle. CONCLUSIONS Adipose tissue gene expression showed more differences between insulin-resistant versus insulin-sensitive groups than the expression of genes in muscle. We confirm the role of PPARGC1A in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues. PMID:21266331

  9. A fasting insulin-raising allele at IGF1 locus is associated with circulating levels of IGF-1 and insulin sensitivity.

    Directory of Open Access Journals (Sweden)

    Gaia Chiara Mannino

    Full Text Available BACKGROUND: A meta-analysis of genome-wide data reported the discovery of the rs35767 polymorphism near IGF1 with genome-wide significant association with fasting insulin levels. However, it is unclear whether the effects of this polymorphism on fasting insulin are mediated by a reduced insulin sensitivity or impaired insulin clearance. We investigated the effects of the rs35767 polymorphism on circulating IGF-1 levels, insulin sensitivity, and insulin clearance. METHODOLOGY/PRINCIPAL FINDINGS: Two samples of adult nondiabetic white Europeans were studied. In sample 1 (n=569, IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (190±77 vs. 218±97 ng/ml, respectively; P=0.007 after adjusting for age, gender, and BMI. Insulin sensitivity assessed by euglycaemic-hyperinsulinemic clamp was lower in GG genotype carriers compared with A allele carriers (8.9±4.1 vs. 10.1±5.1 mg x Kg(-1 free fat mass x min(-1, respectively; P=0.03 after adjusting for age, gender, and BMI. The rs35767 polymorphism did not show significant association with insulin clearance. In sample 2 (n=859, IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (155±60 vs. 164±63 ng/ml, respectively; P=0.02 after adjusting for age, gender, and BMI. Insulin sensitivity, as estimated by the HOMA index, was lower in GG genotype carriers compared with A allele carriers (2.8±2.2 vs. 2.5±1.3, respectively; P=0.03 after adjusting for age, gender, and BMI. CONCLUSION/SIGNIFICANCE: The rs35767 polymorphism near IGF1 was associated with circulating IGF-1 levels, and insulin sensitivity with carriers of the GG genotype exhibiting lower IGF-1 concentrations and insulin sensitivity as compared with subjects carrying the A allele.

  10. A fasting insulin-raising allele at IGF1 locus is associated with circulating levels of IGF-1 and insulin sensitivity.

    Science.gov (United States)

    Mannino, Gaia Chiara; Greco, Annalisa; De Lorenzo, Carlo; Andreozzi, Francesco; Marini, Maria A; Perticone, Francesco; Sesti, Giorgio

    2013-01-01

    A meta-analysis of genome-wide data reported the discovery of the rs35767 polymorphism near IGF1 with genome-wide significant association with fasting insulin levels. However, it is unclear whether the effects of this polymorphism on fasting insulin are mediated by a reduced insulin sensitivity or impaired insulin clearance. We investigated the effects of the rs35767 polymorphism on circulating IGF-1 levels, insulin sensitivity, and insulin clearance. Two samples of adult nondiabetic white Europeans were studied. In sample 1 (n=569), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (190±77 vs. 218±97 ng/ml, respectively; P=0.007 after adjusting for age, gender, and BMI). Insulin sensitivity assessed by euglycaemic-hyperinsulinemic clamp was lower in GG genotype carriers compared with A allele carriers (8.9±4.1 vs. 10.1±5.1 mg x Kg(-1) free fat mass x min(-1), respectively; P=0.03 after adjusting for age, gender, and BMI). The rs35767 polymorphism did not show significant association with insulin clearance. In sample 2 (n=859), IGF-1 levels were lower in GG genotype carriers compared with A allele carriers (155±60 vs. 164±63 ng/ml, respectively; P=0.02 after adjusting for age, gender, and BMI). Insulin sensitivity, as estimated by the HOMA index, was lower in GG genotype carriers compared with A allele carriers (2.8±2.2 vs. 2.5±1.3, respectively; P=0.03 after adjusting for age, gender, and BMI). The rs35767 polymorphism near IGF1 was associated with circulating IGF-1 levels, and insulin sensitivity with carriers of the GG genotype exhibiting lower IGF-1 concentrations and insulin sensitivity as compared with subjects carrying the A allele.

  11. (-)-Epigallocatechin gallate enhances the expression of genes related to insulin sensitivity and adipocyte differentiation in 3T3-L1 adipocytes at an early stage of differentiation.

    Science.gov (United States)

    Sakurai, Naoko; Mochizuki, Kazuki; Kameji, Hiroyuki; Shimada, Masaya; Goda, Toshinao

    2009-10-01

    (-)-Epigallocatechin gallate (EGCG) is thought to enhance insulin sensitivity in adipocytes, although doses used in in vitro experiments have been shown to promote apoptosis. To explore the effects of EGCG on insulin sensitivity in adipocytes, the expression of genes related to insulin sensitivity and adipocyte differentiation in 3T3-L1 adipocytes were measured in response to low doses of EGCG. Increasing concentrations of low-dose EGCG were administered for 8 d to differentiating 3T3 adipocytes, either at days 0-8 (early stage) or at days 8-16 (late stage). Fat accumulation and cell activity were measured by Oil Red O staining and 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan assay, respectively. The expression of genes related to insulin sensitivity and adipocyte differentiation was measured by real-time reverse transcriptase-polymerase chain reaction. Fat accumulation and cell activity in 3T3-L1 cells at the early and late stages were reduced at EGCG concentrations > or = 50 microM. However, EGCG doses of 5-10 microM reduced fat accumulation and induced the expression of genes related to insulin sensitivity (including Fabp4, Cd36, Lpl, Pck1, Acox1, Lypla3, and Ucp2) and adipocyte differentiation (Pparg1, Pparg2, Cebps, and Ppargc1a). These increases were only seen at the early, and not late, stages of differentiation. These data indicate that low doses of EGCG, despite reducing triacylglycerol accumulation, induce the expression of genes related to insulin sensitivity in the early stage of differentiation.

  12. Weight Loss Programs May Have Beneficial or Adverse Effects on Fat Mass and Insulin Sensitivity in Overweight and Obese Black Women.

    Science.gov (United States)

    Leon, Benjamin; Miller, Bernard V; Zalos, Gloria; Courville, Amber B; Sumner, Anne E; Powell-Wiley, Tiffany M; Walter, Mary F; Waclawiw, Myron A; Cannon, Richard O

    2014-01-01

    Weight loss interventions have produced little change in insulin sensitivity in black women, but mean data may obscure metabolic benefit to some and adverse effects for others. Accordingly, we analyzed insulin sensitivity relative to fat mass change following a weight loss program. Fifty-four black women (BMI range 25.9 to 54.7 kg/m(2)) completed the 6-month program that included nutrition information and worksite exercise facilities. Fat mass was measured by dual-energy X-ray absorptiometry, and insulin sensitivity index (SI) was calculated from an insulin-modified intravenous glucose tolerance test using the minimal model. Baseline SI (range 0.74 to 7.58 l/mU(-1)•min(-1)) was inversely associated with fat mass (r = -0.516, p fat mass (baseline 40.8 ± 12.4 to 39.4 ± 12.6 kg [mean ± SD], P fat mass. SI for the group was unchanged (baseline 3.3 ± 1.7 to 3.2 ± 1.6, P = 0.67). However, the tertile with greatest fat mass loss (-3.6 kg, range -10.7 to -1.7 kg) improved insulin sensitivity (SI +0.3 ± 1.2), whereas the tertile with net fat mass gain (+0.9 kg, range -0.1 to +3.8 kg) had reduced insulin sensitivity (SI -0.7 ± 1.3) from baseline values (P loss program who lose fat mass may have improved insulin sensitivity, but fat mass gain with diminished sensitivity is common. Additional support for participants who fail to achieve fat mass loss early in an intervention may be required for success.

  13. Regular health checks

    DEFF Research Database (Denmark)

    Grønhøj Larsen, Christian; Jørgensen, Karsten Juhl; Gøtzsche, Peter C

    2012-01-01

    To investigate whether Danish providers of general health checks present a balanced account of possible benefits and harms on their websites and whether the health checks are evidence-based.......To investigate whether Danish providers of general health checks present a balanced account of possible benefits and harms on their websites and whether the health checks are evidence-based....

  14. Automating checks of plan check automation.

    Science.gov (United States)

    Halabi, Tarek; Lu, Hsiao-Ming

    2014-07-08

    While a few physicists have designed new plan check automation solutions for their clinics, fewer, if any, managed to adapt existing solutions. As complex and varied as the systems they check, these programs must gain the full confidence of those who would run them on countless patient plans. The present automation effort, planCheck, therefore focuses on versatility and ease of implementation and verification. To demonstrate this, we apply planCheck to proton gantry, stereotactic proton gantry, stereotactic proton fixed beam (STAR), and IMRT treatments.

  15. 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.

    Science.gov (United States)

    Stefan, Norbert; Vozarova, Barbora; Funahashi, Tohru; Matsuzawa, Yuji; Weyer, Christian; Lindsay, Robert S; Youngren, Jack F; Havel, Peter J; Pratley, Richard E; Bogardus, Clifton; Tataranni, P Antonio

    2002-06-01

    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-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 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 (insulin-stimulated glucose disposal, hyperinsulinemic clamp), and glucose tolerance (75-g oral glucose tolerance test) were measured in 55 Pima Indians (47 men and 8 women, aged 31 +/- 8 years, body fat 29 +/- 8% [mean +/- SD]; 50 with normal glucose tolerance, 3 with impaired glucose tolerance, and 2 with diabetes). Group 1 (19 subjects) underwent skeletal muscle biopsies for the measurement of basal and insulin-stimulated tyrosine phosphorylation of the IR (stimulated by 100 nmol/l insulin). The fold increase after insulin stimulation was calculated as the ratio between maximal and basal phosphorylation. Group 2 (38 subjects) had follow-up measurements of insulin-stimulated glucose disposal. Cross-sectionally, plasma adiponectin concentration was positively associated with insulin-stimulated glucose disposal (r = 0.58, P < 0.0001) and negatively associated with percent body fat (r = -0.62, P < 0.0001) in the whole group. In group 1 plasma adiponectin was negatively associated with the basal (r = -0.65, P = 0.003) and positively associated with the fold increase in IR

  16. 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

    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......, and ParticipantsAn observational clinical study of N=105 subjects with impaired glucose tolerance or type 2 diabetes.Interventions and Main Outcome MeasuresIndividual subject changes in fitness (VO2max), glycemia (HbA1c, fasting glucose, OGTT), insulin sensitivity (Si; hyperinsulinemic-euglycemic clamp), oral...

  17. 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

    /l and a fasting plasma C-peptide concentration above 0.20 nmol/l a few days before insulin withdrawal. Insulin sensitivity was measured as the glucose disappearance rate (k) during an intravenous insulin tolerance test. Two patients were considered insulin-requiring due to high fasting blood glucose levels...... stimulated C-peptide levels and insulin sensitivity (r = 0.41, p less than 0.05). Fasting and stimulated C-peptide concentrations of 0.40 and 0.70 nmol/l, respectively, separated non-insulin-requiring patients from a group consisting of both insulin- and non-insulin-requiring patients. At these C...

  18. Insulin Sensitivity and Islet β Cell Function in Persons with Normal Glucose Tolerance and Different VA/SA Ratio%不同腹内脂肪/皮下脂肪比值的糖耐量正常人群胰岛素敏感性与胰岛β细胞分泌功能的研究

    Institute of Scientific and Technical Information of China (English)

    李萍; 王磊; 刘蓉辉; 宋光耀; 叶蔚

    2011-01-01

    Objective To explore insulin sensitivity and isletβcell function in persons with normal glucose tolerance ( NGT ) and different ratios of visceral adipose tissue area to abdominal subcutaneous adipose tissue area ( VA/SA ). Methods Totally 104 NGT persons, according to the median of VA/SA ratio, were divided as group A ( VA/SA < 0. 4, n = 53 , 20 males and 33 females ) and group B ( VA/SA≥0. 4, n =51, 23 males and 28 females ). All the subjects were given examinations of body mass index ( BMI ), waist circumstance ( WC ), 75 g oral glucose tolerance test ( OGTT ); blood sugar by glucose oxidase method; serum insulin by radioimmunoassay; triglyceride ( TC ), total cholesterol ( TG ), and high density lipoprotein - cholesterol ( HDL - C ) by using Beckman reagents and automatic biochemistry analyzer; VA and SA by using SASIEMENS SOMATOM Sensation 16CT. VA/SA ratio, area under curve of glucose ( AUCglu ), area under curve of insulin ( AUCins ), whole body insulin sensitivity index ( WBISI ) quantitative insulin sensitivity check index ( QUICKI ), and HOMA insulin resistance index ( HOMA - IR ) were calculated for assessment of insulin sensibility; and homeostasis model β - cell function ( HOMA - β ) and insulin secretion index ( △I/ △ G ) for assessment of p - cell function. Results The concentrations of TG, HDL - C, lower density lipoprotein - cholesterol ( LDL - C ), very low density lipoprotein ( VLDL - C ), apolipoprotein A ( ApoA ), and apoli-poprotein B ( ApoB ) were markedly higher in group A than in group B ( P < 0. 01 ); but no statistically significant difference in TG was found between the two groups (P>0. 05). The levels of HOMA - IR, WBISI, QUCKI, AUCglu, and AUCins were significantly higher in group A than in group B ( P <0. 01 ); while the differences in values of HOMA - β and △I/△G between the two groups showed no statistical significance ( P >0. 05 ). The correlations of WBISI, AUCins, and AUCglu with VA/SA ( r = -0. 460, 0

  19. 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.

  20. 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.

  1. RNase L controls terminal adipocyte differentiation, lipids storage and insulin sensitivity via CHOP10 mRNA regulation

    DEFF Research Database (Denmark)

    Fabre, Odile Martine Julie; Salehzada, T; Lambert, K

    2012-01-01

    Adipose tissue structure is altered during obesity, leading to deregulation of whole-body metabolism. Its function depends on its structure, in particular adipocytes number and differentiation stage. To better understand the mechanisms regulating adipogenesis, we have investigated the role...... is associated with CHOP10 mRNA and regulates its stability. CHOP10 expression is conserved in RNase L(-/-)-MEFs, maintaining preadipocyte state while impairing their terminal differentiation. RNase L(-/-)-MEFs have decreased lipids storage capacity, insulin sensitivity and glucose uptake. Expression of ectopic...... RNase L in RNase L(-/-)-MEFs triggers CHOP10 mRNA instability, allowing increased lipids storage, insulin response and glucose uptake. Similarly, downregulation of CHOP10 mRNA with CHOP10 siRNA in RNase L(-/-)-MEFs improves their differentiation in adipocyte. In vivo, aged RNase L(-)/(-) mice present...

  2. Supplementation of Diet With Galacto-oligosaccharides Increases Bifidobacteria, but Not Insulin Sensitivity, in Obese Prediabetic Individuals

    DEFF Research Database (Denmark)

    Canfora, Emanuel E; van der Beek, Christina M; Hermes, Gerben D A

    2017-01-01

    in these processes. We investigated the long-term effects of supplementation with galacto-oligosaccharides (GOS), an acetogenic fiber, on the composition of the human gut microbiota and human metabolism. METHODS: We performed a double-blinded, placebo-controlled, parallel intervention study of 44 overweight or obese......BACKGROUND & AIMS: The gut microbiota affects host lipid and glucose metabolism, satiety, and chronic low-grade inflammation to contribute to obesity and type 2 diabetes. Fermentation end products, in particular the short-chain fatty acid (SCFA) acetate, are believed to be involved....... Before and after this period, we collected data on peripheral and adipose tissue insulin sensitivity, fecal microbiota composition, plasma and fecal SCFA, energy expenditure and substrate oxidation, body composition, and hormonal and inflammatory responses. The primary outcome was the effect of GOS...

  3. 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.

  4. Plasma Taurine, Diabetes Genetic Predisposition, and Changes of Insulin Sensitivity in Response to Weight-Loss Diets.

    Science.gov (United States)

    Zheng, Yan; Ceglarek, Uta; Huang, Tao; Wang, Tiange; Heianza, Yoriko; Ma, Wenjie; Bray, George A; Thiery, Joachim; Sacks, Frank M; Qi, Lu

    2016-10-01

    Taurine metabolism disturbance is closely linked to obesity, insulin resistance, and diabetes. Previous evidence suggested that the preventative effects of taurine on diabetes might be through regulating the expression levels of diabetes-related genes. We estimated whether blood taurine levels modified the overall genetic susceptibility to diabetes on improvement of insulin sensitivity in a randomized dietary trial. We genotyped 31 diabetes-associated variants to calculate a genetic risk score (GRS) and measured plasma taurine levels and glycemic traits among participants from the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial. Seven-hundred eleven overweight or obese participants (age 30-70 y; 60% females) had genetic variants genotyped and blood taurine levels measured. Participants went on 2-year weight-loss diets, which were different in macronutrient composition. Improvements in glycemic traits were measured. We found that baseline taurine levels significantly modified the effects of diabetes GRS on changes in fasting glucose, insulin, and homeostatic model assessment of insulin resistance (HOMA-IR) during the 2-year diet intervention (P-interaction = .04, .01, .002, respectively), regardless of weight loss. High baseline taurine levels were associated with a less reduction in both glucose and HOMA-IR among the participants with the lowest tertile of diabetes GRS (both P = .02), and with a greater reduction in both insulin and HOMA-IR among those with the highest tertile of diabetes GRS (both P = .04). Our data suggest that blood taurine levels might differentially modulate the effects of diabetes-related genes on improvement of insulin sensitivity among overweight/obese patients on weight-loss diets.

  5. 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

  6. The effect of a diiodothyronine mimetic on insulin sensitivity in male cardiometabolic patients: a double-blind randomized controlled trial.

    Directory of Open Access Journals (Sweden)

    Fleur van der Valk

    Full Text Available BACKGROUND AND AIMS: Obesity and its associated cardiometabolic co-morbidities are increasing worldwide. Since thyroid hormone mimetics are capable of uncoupling the beneficial metabolic effects of thyroid hormones from their deleterious effects on heart, bone and muscle, this class of drug is considered as adjacent therapeutics to weight-lowering strategies. This study investigated the safety and efficacy of TRC150094, a thyroid hormone mimetic. MATERIALS AND METHODS: This 4-week, randomized, placebo-controlled, double-blind trial was conducted in India and The Netherlands. Forty subjects were randomized at a 1:1 ratio to receive either TRC150094 dosed at 50 mg or placebo once daily for 4 weeks. Hyperinsulinemic euglycemic clamp and (1H-Magnetic Resonance Spectroscopy (MRS were performed before and after treatment. RESULTS: At baseline, subjects were characterized by markedly impaired hepatic and peripheral insulin sensitivity. TRC150094 dosed 50 mg once daily was safe and well tolerated. Hepatic nor peripheral insulin sensitivity improved after TRC150094 treatment, expressed as the suppression of Endogenous Glucose Production from 59.5 to 62.1%; p = 0.477, and the rate of glucose disappearance from 28.8 to 26.4 µmol kg(-1min(-1, p = 0.185. TRC150094 administration did not result in differences in fasting plasma free fatty acids from 0.51 to 0.51 mmol/L, p = 0.887 or in insulin-mediated suppression of lipolysis from 57 to 54%, p = 0.102. Also, intrahepatic triglyceride content was unaltered. CONCLUSION: Collectively, these data show that, in contrast to the potent metabolic effects in experimental models, TRC150094 at a dose of 50 mg daily does not improve the metabolic homeostasis in subjects at an increased cardiometabolic risk. Further studies are needed to evaluate whether TRC150094 has beneficial effects in patients with more severe metabolic derangement, such as overt diabetes mellitus and hypertriglyceridemia. TRIAL REGISTRATION

  7. 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.

  8. Genome-wide DNA methylation pattern in visceral adipose tissue differentiates insulin-resistant from insulin-sensitive obese subjects.

    Science.gov (United States)

    Crujeiras, A B; Diaz-Lagares, A; Moreno-Navarrete, J M; Sandoval, J; Hervas, D; Gomez, A; Ricart, W; Casanueva, F F; Esteller, M; Fernandez-Real, J M

    2016-12-01

    Elucidating the potential mechanisms involved in the detrimental effect of excess body weight on insulin action is an important priority in counteracting obesity-associated diseases. The present study aimed to disentangle the epigenetic basis of insulin resistance by performing a genome-wide epigenetic analysis in visceral adipose tissue (VAT) from morbidly obese patients depending on the insulin sensitivity evaluated by the clamp technique. The global human methylome screening performed in VAT from 7 insulin-resistant (IR) and 5 insulin-sensitive (IS) morbidly obese patients (discovery cohort) analyzed using the Infinium HumanMethylation450 BeadChip array identified 982 CpG sites able to perfectly separate the IR and IS samples. The identified sites represented 538 unique genes, 10% of which were diabetes-associated genes. The current work identified novel IR-related genes epigenetically regulated in VAT, such as COL9A1, COL11A2, CD44, MUC4, ADAM2, IGF2BP1, GATA4, TET1, ZNF714, ADCY9, TBX5, and HDACM. The gene with the largest methylation fold-change and mapped by 5 differentially methylated CpG sites located in island/shore and promoter region was ZNF714. This gene presented lower methylation levels in IR than in IS patients in association with increased transcription levels, as further reflected in a validation cohort (n = 24; 11 IR and 13 IS). This study reveals, for the first time, a potential epigenetic regulation involved in the dysregulation of VAT that could predispose patients to insulin resistance and future type 2 diabetes in morbid obesity, providing a potential therapeutic target and biomarkers for counteracting this process. Copyright © 2016 Elsevier Inc. All rights reserved.

  9. Symplocos cochinchinensis enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in high energy diet rat model.

    Science.gov (United States)

    Antu, Kalathookunnel Antony; Riya, Mariam Philip; Nair, Anupama; Mishra, Arvind; Srivastava, Arvind K; Raghu, Kozhiparambil Gopalan

    2016-12-04

    This plant has been utilized in Indian system of medicine for treatment of diabetes. This is clearly evident from the composition of Ayurvedic preparation for diabetes 'Nisakathakadi Kashayam' where this is one of the main ingredients of this preparation AIM OF THE STUDY: The study aims in elucidating the molecular mechanisms underlying the insulin sensitizing effects of Symplocos cochinchinensis ethanol extract (SCE) using a high fructose and saturated fat (HFS) fed insulin resistant rat model. Experimental groups consisted of normal diet (ND), ND+SCE 500mg/kg bwd, HFS+vehicle, HFS+metformin 100mg/kg bwd, HFS+SCE 250/500mg/kg bwd. Initially the animals were kept under HFS diet for 8 weeks, and at the end of 8 week period, animals were found to develop insulin resistance and dyslipidemia. Post-administration of SCE, metformin or vehicle were carried out for 3 weeks. Gene and protein expressions relevant to insulin signalling pathway were analysed. HFS significantly altered the normal physiology of animals via proteins and genes relevant to metabolism like stearoyl-CoA desaturase (SCD1), sterol regulatory element binding protein 1 (SREBP-1c), fatty acid synthase (FAS), glucose 6 phosphatase (G6Pase), phosphoenol pyruvate carboxykinase (PEPCK), glucose transporter 2 (GLUT2), protein tyrosine phosphatse 1B (PTP1B), peroxisome proliferator activated receptor alpha (PPAR alpha), sirtuin 1 (SIRT1) and glucokinase. SCE administration attenuates the insulin resistance in HFS rat by the down regulation of SCD1 gene expression that modulates SREBP-1c dependent and independent hepatic lipid accumulation. SCE enhances insulin sensitivity via the down regulation of lipogenesis and insulin resistance in HFS rat model. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  10. Partial Inhibition of Adipose Tissue Lipolysis Improves Glucose Metabolism and Insulin Sensitivity Without Alteration of Fat Mass

    Science.gov (United States)

    Girousse, Amandine; Tavernier, Geneviève; Valle, Carine; Moro, Cedric; Mejhert, Niklas; Dinel, Anne-Laure; Houssier, Marianne; Roussel, Balbine; Besse-Patin, Aurèle; Combes, Marion; Mir, Lucile; Monbrun, Laurent; Bézaire, Véronic; Prunet-Marcassus, Bénédicte; Waget, Aurélie; Vila, Isabelle; Caspar-Bauguil, Sylvie; Louche, Katie; Marques, Marie-Adeline; Mairal, Aline; Renoud, Marie-Laure; Galitzky, Jean; Holm, Cecilia; Mouisel, Etienne; Thalamas, Claire; Viguerie, Nathalie; Sulpice, Thierry; Burcelin, Rémy; Arner, Peter; Langin, Dominique

    2013-01-01

    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. PMID:23431266

  11. 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.

  12. Adiponectin oligomers in human serum during acute and chronic exercise: relation to lipid metabolism and insulin sensitivity.

    Science.gov (United States)

    Bobbert, T; Wegewitz, U; Brechtel, L; Freudenberg, M; Mai, K; Möhlig, M; Diederich, S; Ristow, M; Rochlitz, H; Pfeiffer, A F H; Spranger, J

    2007-01-01

    Beneficial effects of physical exercise include improved insulin sensitivity, which may be affected by a modulated release of adiponectin, which is exclusively synthesized in white adipose tissue and mediates insulin sensitivity. Adiponectin circulates in three different oligomers, which also have a distinct biological function. We therefore aimed to investigate the distribution of adiponectin oligomers in human serum in relation to physical activity. Thirty-eight lean and healthy individuals were investigated. Seven healthy women and 8 healthy men volunteered to investigate the effect of chronic exercise, at 3 different time points with different training intensities. These individuals were all highly trained and were compared to a control group with low physical activity (n = 15). For studying acute exercise effects, 8 healthy men participated in a bicycle test. Adiponectin was determined by ELISA, oligomers were detected by non-denaturating western blot. Total adiponectin and oligomers were unchanged by acute exercise. LDL cholesterol was significantly lower in the chronic exercise group (p = 0.03). Total adiponectin levels and oligomers were not different between these two groups and were unaltered by different training intensities. However, total adiponectin and specifically HMW oligomers correlated with HDL cholesterol (r = 0.459; p = 0.009). We conclude that acute and chronic exercise does not directly affect circulating adiponectin or oligomer distribution in lean and healthy individuals. Whether such regulation is relevant in individuals with a metabolic disorder remains to be determined. However, our data suggest that adiponectin oligomers have distinct physiological functions IN VIVO, and specifically HMW adiponectin is closely correlated with HDL cholesterol.

  13. 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.

  14. 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.

  15. 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.

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

    Science.gov (United States)

    Girousse, Amandine; Tavernier, Geneviève; Valle, Carine; Moro, Cedric; Mejhert, Niklas; Dinel, Anne-Laure; Houssier, Marianne; Roussel, Balbine; Besse-Patin, Aurèle; Combes, Marion; Mir, Lucile; Monbrun, Laurent; Bézaire, Véronic; Prunet-Marcassus, Bénédicte; Waget, Aurélie; Vila, Isabelle; Caspar-Bauguil, Sylvie; Louche, Katie; Marques, Marie-Adeline; Mairal, Aline; Renoud, Marie-Laure; Galitzky, Jean; Holm, Cecilia; Mouisel, Etienne; Thalamas, Claire; Viguerie, Nathalie; Sulpice, Thierry; Burcelin, Rémy; Arner, Peter; Langin, Dominique

    2013-01-01

    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.

  17. 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.

  18. Association of PPARG Pro12Ala polymorphism with insulin sensitivity and body mass index in patients with polycystic ovary syndrome.

    Science.gov (United States)

    Baldani, Dinka Pavicic; Skrgatic, Lana; Cerne, Jasmina Z; Ferk, Polonca; Simunic, Velimir; Gersak, Ksenija

    2014-03-01

    Insulin resistance is one of the key factors in the pathogenesis of polycystic ovary syndrome (PCOS). The peroxisome proliferator-activated receptor gamma (PPARG) plays a role in the regulation of insulin sensitivity. The aim of the present study was to establish a possible association of the PPARG Pro12Ala polymorphism with PCOS and its effect on family and personal history, as well as on the metabolic and endocrine parameters in PCOS patients. A total of 151 PCOS patients and 179 healthy women of reproductive age were enrolled. History, body mass index (BMI), waist-to-hip ratio and the presence of phenotypic hyperandrogenism were recorded. Hormonal, metabolic and biochemical profiles were assessed. A molecular analysis for the genetic polymorphism was performed. One third (29.8%) of the PCOS patients were found to be carriers of at least one variant of the Ala allele (X/Ala), while 70.2% carried two wild-type Pro alleles (Pro/Pro), with an equal distribution observed in the control group. The PCOS patients carrying the X/Ala alleles exhibited lower serum fasting insulin levels, homeostatic model assessment of insulin resistance (HOMA-IR) and BMI compared to Pro/Pro carriers. This finding was significant only in the lean PCOS group. The polymorphic genotype exerted no effect on history, hormonal and clinical hyperandrogenism, lipid status or C-reactive protein, leptin, adiponectin, resistin and ghrelin serum levels in women with PCOS. In conclusion, although the PPARG Pro12Ala polymorphism is not a major determinant of PCOS in the Croatian population, it may exert a positive effect on insulin sensitivity and BMI. As these associations were recorded exclusively in the lean group of patients with PCOS, this polymorphism potentially contributes to a protective role against hyperinsulinemia and obesity.

  19. 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...

  20. 4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling.

    Science.gov (United States)

    Guo, Qinyue; Xu, Lin; Li, Huixia; Sun, Hongzhi; Wu, Shufang; Zhou, Bo

    2017-03-11

    4-phenyl butyric acid (4-PBA) has been considered as a key regulator of insulin resistance in obesity. However the mechanism of 4-PBA involved in insulin resistance remains elusive. We evaluated the effect of 4-PBA on abnormal autophagy and endoplasmic reticulum (ER) stress in obese mice. 4-PBA was administered in obese mice and adipocyte models, and metabolic parameters, autophagy markers, ER stress indicators, Akt/mTOR signaling and insulin signaling molecular were assessed. 4-PBA treatment not only reversed autophagic dysfunction and ER stress, but also improved impaired insulin signaling in tunicamycin-induced adipocytes, and 4-PBA also inhibited activated ER stress and elevated insulin sensitivity in adipocytes with Atg7 siRNA. Additionally, administration of 4-PBA improves glucose tolerance and insulin sensitivity in obese mice via regulating abnormal autophagy and ER stress in adipose tissue. The protective effects of 4-PBA were nullified by suppression of Akt and mTOR in adipocytes, suggesting that 4-PBA inhibits autophagy and restores insulin sensitivity via Akt/mTOR signaling partially. 4-PBA reverses autophagic dysfunction and improves insulin sensitivity in adipose tissue of obese mice via Akt/mTOR signaling partly, which could be regarded as novel opportunities for treatment of insulin resistance. Copyright © 2017 Elsevier Inc. All rights reserved.

  1. Repin1 deficiency improves insulin sensitivity and glucose metabolism in db/db mice by reducing adipose tissue mass and inflammation.

    Science.gov (United States)

    Kunath, Anne; Hesselbarth, Nico; Gericke, Martin; Kern, Matthias; Dommel, Sebastian; Kovacs, Peter; Stumvoll, Michael; Blüher, Matthias; Klöting, Nora

    2016-09-09

    Replication initiator 1 (Repin1) is a zinc finger protein playing a role in insulin sensitivity, body fat mass and lipid metabolism by regulating the expression key genes of glucose and lipid metabolism. Here, we tested the hypothesis that introgression of a Repin1 deletion into db/db mice improves glucose metabolism in vivo. We generated a whole body Repin1 deficient db/db double knockout mouse (Rep1(-/-)x db/db) and systematically characterized the consequences of Repin1 deficiency on insulin sensitivity, glucose and lipid metabolism parameters and fat mass. Hyperinsulinemic-euglycemic clamp studies revealed significantly improved insulin sensitivity in Rep1(-/-)x db/db mice, which are also characterized by lower HbA1c, lower body fat mass and reduced adipose tissue (AT) inflammation area. Our study provides evidence that loss of Repin1 in db/db mice improves insulin sensitivity and reduces chronic hyperglycemia most likely by reducing fat mass and AT inflammation. Copyright © 2016 Elsevier Inc. All rights reserved.

  2. Insulin sensitivity and lipid profile of eutrophic individuals after acute intake of fresh orange juice in comparison to the commercial-pasteurized orange juice

    Science.gov (United States)

    Citrus flavonoids from orange juice (OJ) have shown hypolipidemic, hypotension, and anti-inflammatory properties. However, the extraction and commercial pasteurization of OJ can influence its nutritional composition in comparison to the fresh squeezed OJ. We evaluated the insulin sensitivity, and th...

  3. 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.

  4. 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

  5. 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

  6. Improved insulin sensitivity after exercise training is linked to reduced plasma C14:0 ceramide in obesity and type 2 diabetes.

    Science.gov (United States)

    Kasumov, Takhar; Solomon, Thomas P J; Hwang, Calvin; Huang, Hazel; Haus, Jacob M; Zhang, Renliang; Kirwan, John P

    2015-07-01

    To assess the effect of exercise training on insulin sensitivity and plasma ceramides in obesity and type 2 diabetes (T2D). Twenty-four adults with obesity and normal glucose tolerance (NGT, n = 14) or diabetes (n = 10) were studied before and after a 12-week supervised exercise-training program (5 days/week, 1 h/day, 80-85% of maximum heart rate). Changes in body composition were assessed using hydrostatic weighing and computed tomography. Peripheral tissue insulin sensitivity was assessed by a 40 mU/m(2) /min hyperinsulinemic euglycemic clamp. Plasma ceramides (C14:0, C16:0, C18:0, C18:1, C20:0, C24:0, and C24:1) were quantified using electrospray ionization tandem mass spectrometry after separation with HPLC. Plasma ceramides were similar for the subjects with obesity and NGT and the subjects with diabetes, despite differences in glucose tolerance. Exercise significantly reduced body weight and adiposity and increased peripheral insulin sensitivity in both groups (P exercise training-induced improvements in insulin sensitivity, and plasma C14:0 ceramide may provide a specific target for investigating lipid-related insulin resistance in obesity and T2D. © 2015 The Obesity Society.

  7. 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.

  8. 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...

  9. 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.

  10. 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.

  11. Leptin is associated with cardiopulmonary fitness independent of body-mass index and insulin sensitivity in adolescents with type 1 diabetes: a brief report from the EMERALD study.

    Science.gov (United States)

    Bjornstad, Petter; Cree-Green, Melanie; Baumgartner, Amy; Coe, Gregory; Reyes, Yesenia Garcia; Schafer, Michal; Pyle, Laura; Regensteiner, Judith G; Reusch, Jane E B; Nadeau, Kristen J

    2017-05-01

    Cardiopulmonary fitness is decreased in type 1 diabetes for reasons that are incompletely understood. In this study, leptin was associated with exercise capacity independent of insulin sensitivity (IS) and body mass index (BMI), suggesting that leptin may relate to cardiopulmonary fitness by mechanisms beyond IS and/or obesity. Copyright © 2017 Elsevier Inc. All rights reserved.

  12. 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

  13. 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....

  14. 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....

  15. Fasting serum levels of ferritin are associated with impaired pancreatic beta cell function and decreased insulin sensitivity: a population-based study.

    Science.gov (United States)

    Bonfils, Linéa; Ellervik, Christina; Friedrich, Nele; Linneberg, Allan; Sandholt, Camilla H; Jørgensen, Marit E; Jørgensen, Torben; Hansen, Torben; Pedersen, Oluf; Allin, Kristine H

    2015-03-01

    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. 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 on OGTT examinations. The ORs for type 2 diabetes were 4.2 (95% CI 2.4, 7.2) for the highest vs the lowest quintile of serum ferritin, and 17 (95% CI 8.9, 33) for serum ferritin levels ≥97.5th percentile vs serum ferritin levels were associated with elevated plasma glucose levels at 0, 30 and 120 min (p serum insulin levels at 0 and 120 min (p = 0.02 and p serum ferritin levels are associated with surrogate measures of both impaired beta cell function and decreased insulin sensitivity. Menopause seems to modify the association with insulin sensitivity.

  16. 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

  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. 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 ...

  19. 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...

  20. 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

  1. 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...

  2. Effect of Continuous Positive Airway Pressure Therapy on Glycemic Excursions and Insulin Sensitivity in Patients with Obstructive Sleep Apnea-hypopnea Syndrome and Type 2 Diabetes

    Directory of Open Access Journals (Sweden)

    Li-Xin Guo

    2015-01-01

    Conclusions: CPAP therapy may have a beneficial effect on improving not only blood glucose but also upon insulin sensitivity in T2DM patients with OSAHS. This suggests that CPAP may be an effective treatment for T2DM in addition to intensive diabetes management.

  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. 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

  5. Strawberry and cranberry polyphenols improve insulin sensitivity in insulin-resistant, non-diabetic adults: a parallel, double-blind, controlled and randomised clinical trial.

    Science.gov (United States)

    Paquette, Martine; Medina Larqué, Ana S; Weisnagel, S J; Desjardins, Yves; Marois, Julie; Pilon, Geneviève; Dudonné, Stéphanie; Marette, André; Jacques, Hélène

    2017-02-01

    Plant-derived foods rich in polyphenols are associated with several cardiometabolic health benefits, such as reduced postprandial hyperglycaemia. However, their impact on whole-body insulin sensitivity using the hyperinsulinaemic-euglycaemic clamp technique remains under-studied. We aimed to determine the effects of strawberry and cranberry polyphenols (SCP) on insulin sensitivity, glucose tolerance, insulin secretion, lipid profile, inflammation and oxidative stress markers in free-living insulin-resistant overweight or obese human subjects (n 41) in a parallel, double-blind, controlled and randomised clinical trial. The experimental group consumed an SCP beverage (333 mg SCP) daily for 6 weeks, whereas the Control group received a flavour-matched Control beverage that contained 0 mg SCP. At the beginning and at the end of the experimental period, insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, and glucose tolerance and insulin secretion by a 2-h oral glucose tolerance test (OGTT). Insulin sensitivity increased in the SCP group as compared with the Control group (+0·9 (sem 0·5)×10-3 v. -0·5 (sem 0·5)×10-3 mg/kg per min per pmol, respectively, P=0·03). Compared with the Control group, the SCP group had a lower first-phase insulin secretion response as measured by C-peptide levels during the first 30 min of the OGTT (P=0·002). No differences were detected between the two groups for lipids and markers of inflammation and oxidative stress. A 6-week dietary intervention with 333 mg of polyphenols from strawberries and cranberries improved insulin sensitivity in overweight and obese non-diabetic, insulin-resistant human subjects but was not effective in improving other cardiometabolic risk factors.

  6. Checking Java Programs

    CERN Document Server

    Darwin, Ian

    2007-01-01

    This Short Cut tells you about tools that will improve the quality of your Java code, using checking above and beyond what the standard tools do, including: Using javac options, JUnit and assertions Making your IDE work harder Checking your source code with PMD Checking your compiled code (.class files) with FindBugs Checking your program's run-time behavior with Java PathFinder

  7. MicroRNA-181b Improves Glucose Homeostasis and Insulin Sensitivity by Regulating Endothelial Function in White Adipose Tissue.

    Science.gov (United States)

    Sun, Xinghui; Lin, Jibin; Zhang, Yu; Kang, Sona; Belkin, Nathan; Wara, Akm K; Icli, Basak; Hamburg, Naomi M; Li, Dazhu; Feinberg, Mark W

    2016-03-04

    The pathogenesis of insulin resistance involves dysregulated gene expression and function in multiple cell types, including endothelial cells (ECs). Post-transcriptional mechanisms such as microRNA-mediated regulation of gene expression could affect insulin action by modulating EC function. To determine whether microRNA-181b (miR-181b) affects the pathogenesis of insulin resistance by regulating EC function in white adipose tissue during obesity. MiR-181b expression was reduced in adipose tissue ECs of obese mice, and rescue of miR-181b expression improved glucose homeostasis and insulin sensitivity. Systemic intravenous delivery of miR-181b robustly accumulated in adipose tissue ECs, enhanced insulin-mediated Akt phosphorylation at Ser473, and reduced endothelial dysfunction, an effect that shifted macrophage polarization toward an M2 anti-inflammatory phenotype in epididymal white adipose tissue. These effects were associated with increased endothelial nitric oxide synthase and FoxO1 phosphorylation as well as nitric oxide activity in epididymal white adipose tissue. In contrast, miR-181b did not affect insulin-stimulated Akt phosphorylation in liver and skeletal muscle. Bioinformatics and gene profiling approaches revealed that Pleckstrin homology domain leucine-rich repeat protein phosphatase, a phosphatase that dephosphorylates Akt at Ser473, is a novel target of miR-181b. Knockdown of Pleckstrin homology domain leucine-rich repeat protein phosphatase increased Akt phosphorylation at Ser473 in ECs, and phenocopied miR-181b's effects on glucose homeostasis, insulin sensitivity, and inflammation of epididymal white adipose tissue in vivo. Finally, ECs from diabetic subjects exhibited increased Pleckstrin homology domain leucine-rich repeat protein phosphatase expression. Our data underscore the importance of adipose tissue EC function in controlling the development of insulin resistance. Delivery of miR-181b or Pleckstrin homology domain leucine-rich repeat

  8. Adult-onset obesity reveals prenatal programming of glucose-insulin sensitivity in male sheep nutrient restricted during late gestation.

    Directory of Open Access Journals (Sweden)

    Philip Rhodes

    Full Text Available BACKGROUND: Obesity invokes a range of metabolic disturbances, but the transition from a poor to excessive nutritional environment may exacerbate adult metabolic dysfunction. The current study investigated global maternal nutrient restriction during early or late gestation on glucose tolerance and insulin sensitivity in the adult offspring when lean and obese. METHODS/PRINCIPAL FINDINGS: Pregnant sheep received adequate (1.0M; CE, n = 6 or energy restricted (0.7M diet during early (1-65 days; LEE, n = 6 or late (65-128 days; LEL, n = 7 gestation (term approximately 147 days. Subsequent offspring remained on pasture until 1.5 years when all received glucose and insulin tolerance tests (GTT & ITT and body composition determination by dual energy x-ray absorptiometry (DXA. All animals were then exposed to an obesogenic environment for 6-7 months and all protocols repeated. Prenatal dietary treatment had no effect on birth weight or on metabolic endpoints when animals were 'lean' (1.5 years. Obesity revealed generalised metabolic 'inflexibility' and insulin resistance; characterised by blunted excursions of plasma NEFA and increased insulin(AUC (from 133 to 341 [s.e.d. 26] ng.ml(-1.120 mins during a GTT, respectively. For LEL vs. CE, the peak in plasma insulin when obese was greater (7.8 vs. 4.7 [s.e.d. 1.1] ng.ml(-1 and was exacerbated by offspring sex (i.e. 9.8 vs. 4.4 [s.e.d. 1.16] ng.ml(-1; LEL male vs. CE male, respectively. Acquisition of obesity also significantly influenced the plasma lipid and protein profile to suggest, overall, greater net lipogenesis and reduced protein metabolism. CONCLUSIONS: This study indicates generalised metabolic dysfunction with adult-onset obesity which also exacerbates and 'reveals' programming of glucose-insulin sensitivity in male offspring prenatally exposed to maternal undernutrition during late gestation. Taken together, the data suggest that metabolic function appears little compromised in young

  9. 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

  10. School-based exercise improves fitness, body composition, insulin sensitivity, and markers of inflammation in non-obese children.

    Science.gov (United States)

    Carrel, Aaron L; McVean, Jennifer J; Clark, R Randall; Peterson, Susan E; Eickhoff, Jens C; Allen, David B

    2009-05-01

    Poor cardiovascular fitness (CVF) is a risk factor for obesity, as well as insulin resistance (IR), inflammation, and cardiovascular disease. We have previously shown that a school-based fitness curriculum can improve CVF, as well as IR and body composition in obese children. Whether such a program improves CVF, IR, and other health indicators in non-obese children is unresolved. To determine whether a school-based fitness program improves body composition, CVF, markers of inflammation (e.g. CRP, TNF-alpha, adiponectin), and insulin sensitivity in nonobese children. 35 non-obese middle school children with body mass index below the 95th percentile for age were enrolled in a 'fitness-oriented' gym class. Children underwent fasting evaluation of insulin, glucose, adiponectin, CRP, TNF-alpha, body composition by dual X-ray absorptiometry (DXA), and maximal VO2 treadmill testing at baseline (prior to the school year) and again at end of the school year. Testing for CVF (maximal VO2 treadmill testing), DXA, and fasting evaluation of insulin, glucose, adiponectin, CRP and TNF-alpha. Children demonstrated a decrease in BMI z-score (-0.14 +/- 0.33, p = 0.02), HOMA-IR (-0.15 +/- 0.35, p = 0.016), and TNF-alpha (-2.55 +/- 1.79 pg/ml, p VO2(max) (+1.58 +/- 2.34 ml/kg/min, p < 0.001), adiponectin (+7,553 +/- 11,100 ng/ml, p < 0.001), and muscle mass (+2,282 +/- 1,882.73 g, p < 0.001) after nine months of study. The school-based fitness oriented curriculum resulted in improved body composition and insulin sensitivity, increased CVF, and decreased inflammation in non-obese children. Combined with prior studies, these data demonstrate that school-based fitness curricula can benefit both obese and non-obese children. Partnerships with schools to promote fitness should be part of a public health approach to improving children's health.

  11. Chronic treatment with myo-inositol reduces white adipose tissue accretion and improves insulin sensitivity in female mice.

    Science.gov (United States)

    Croze, Marine L; Vella, Roxane E; Pillon, Nicolas J; Soula, Hédi A; Hadji, Lilas; Guichardant, Michel; Soulage, Christophe O

    2013-02-01

    Type 2 diabetes is a complex disease characterized by a state of insulin resistance in peripheral tissues such as skeletal muscle, adipose tissue or liver. Some inositol isomers have been reported to possess insulin-mimetic activity and to be efficient in lowering blood glucose level. The aim of the present study was to assess in mice the metabolic effects of a chronic treatment with myo-inositol, the most common stereoisomer of inositol. Mice given myo-inositol treatment (0.9 or 1.2 mg g(-1) day(-1), 15 days, orally or intraperitoneally) exhibited an improved glucose tolerance due to a greater insulin sensitivity. Mice treated with myo-inositol exhibited a decreased white adipose tissue accretion (-33%, Padipose tissue deposition was due to a decrease in adipose cell volume (-33%, Pinsulin-stimulated conditions, suggesting a synergistic action of myo-inositol treatment and insulin on proteins of the insulin signalling pathway. Myo-inositol could therefore constitute a viable nutritional strategy for the prevention and/or treatment of insulin resistance and type 2 diabetes. Copyright © 2013 Elsevier Inc. All rights reserved.

  12. Macrophage metalloelastase (MMP12) regulates adipose tissue expansion, insulin sensitivity, and expression of inducible nitric oxide synthase.

    Science.gov (United States)

    Lee, Jung-Ting; Pamir, Nathalie; Liu, Ning-Chun; Kirk, Elizabeth A; Averill, Michelle M; Becker, Lev; Larson, Ilona; Hagman, Derek K; Foster-Schubert, Karen E; van Yserloo, Brian; Bornfeldt, Karin E; LeBoeuf, Renee C; Kratz, Mario; Heinecke, Jay W

    2014-09-01

    Macrophage metalloelastase, a matrix metallopeptidase (MMP12) predominantly expressed by mature tissue macrophages, is implicated in pathological processes. However, physiological functions for MMP12 have not been described. Because mRNA levels for the enzyme increase markedly in adipose tissue of obese mice, we investigated the role of MMP12 in adipose tissue expansion and insulin resistance. In humans, MMP12 expression correlated positively and significantly with insulin resistance, TNF-α expression, and the number of CD14(+)CD206(+) macrophages in adipose tissue. MMP12 was the most abundant matrix metallopeptidase detected by proteomic analysis of conditioned medium of M2 macrophages and dendritic cells. In contrast, it was detected only at low levels in bone marrow derived macrophages and M1 macrophages. When mice received a high-fat diet, adipose tissue mass increased and CD11b(+)F4/80(+)CD11c(-) macrophages accumulated to a greater extent in MMP12-deficient (Mmp12(-/-)) mice than in wild-type mice (Mmp12(+/+)). Despite being markedly more obese, fat-fed Mmp12(-/-) mice were more insulin sensitive than fat-fed Mmp12(+/+) mice. Expression of inducible nitric oxide synthase (Nos2) by Mmp12(-/-) macrophages was significantly impaired both in vivo and in vitro, suggesting that MMP12 might mediate nitric oxide production during inflammation. We propose that MMP12 acts as a double-edged sword by promoting insulin resistance while combatting adipose tissue expansion.

  13. Gsα deficiency in adipose tissue improves glucose metabolism and insulin sensitivity without an effect on body weight.

    Science.gov (United States)

    Li, Yong-Qi; Shrestha, Yogendra B; Chen, Min; Chanturiya, Tatyana; Gavrilova, Oksana; Weinstein, Lee S

    2016-01-12

    Gsα, the G protein that transduces receptor-stimulated cAMP generation, mediates sympathetic nervous system stimulation of brown adipose tissue (BAT) thermogenesis and browning of white adipose tissue (WAT), which are both potential targets for treating obesity, as well as lipolysis. We generated a mouse line with Gsα deficiency in mature BAT and WAT adipocytes (Ad-GsKO). Ad-GsKO mice had impaired BAT function, absent browning of WAT, and reduced lipolysis, and were therefore cold-intolerant. Despite the presence of these abnormalities, Ad-GsKO mice maintained normal energy balance on both standard and high-fat diets, associated with decreases in both lipolysis and lipid synthesis. In addition, Ad-GsKO mice maintained at thermoneutrality on a standard diet also had normal energy balance. Ad-GsKO mice had improved insulin sensitivity and glucose metabolism, possibly secondary to the effects of reduced lipolysis and lower circulating fatty acid binding protein 4 levels. Gsα signaling in adipose tissues may therefore affect whole-body glucose metabolism in the absence of an effect on body weight.

  14. 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......Background: Due to a growing global aquaculture production, fish oil (FO) and fish meal (FM) are partly replaced with vegetable ingredients in aqua feed for Atlantic salmon. These replacements in the feed lead to an altered fatty acid composition in the salmon fillet. We aimed to investigate how...... levels of diacylglycerol (DAG), ceramides and arachidonic acid (AA)-derived oxylipins compared with mice fed WD-FO. In addition, C57BL/6J mice were fed fish oil-enriched diets with different carbohydrate sources, and we observed that sucrose dose-dependently abrogate the antiobesity effect of fish oil...

  15. 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.

  16. Sargassum polycystum reduces hyperglycaemia, dyslipidaemia and oxidative stress via increasing insulin sensitivity in a rat model of type 2 diabetes.

    Science.gov (United States)

    Motshakeri, Mahsa; Ebrahimi, Mahdi; Goh, Yong Meng; Matanjun, Patricia; Mohamed, Suhaila

    2013-05-01

    Sargassum polycystum, a brown seaweed, contains various nutrients and bioactive compounds that have antioxidant and healing properties. The research hypothesises that antioxidants and pigments in dietary S. polycystum extracts can improve insulin sensitivity, blood sugar levels and blood lipid levels in a rat model of type 2 diabetes. The diabetes was induced by a high-sugar, high-fat diet for 16 weeks to enhance insulin resistance, followed by a low-dose intraperitoneal injection of streptozotocin (35 mg kg(-1) body weight). The doses of S. polycystum tested on diabetic rats were 150 and 300 mg kg(-1) body weight for the ethanolic extract or 150 and 300 mg kg(-1) for the water extract. Normal rats, untreated diabetic and metformin-treated diabetic rats (n = 6) were used as control. Both doses of the alcohol extract of S. polycystum and the 300 mg kg(-1) water extract, significantly reduced blood glucose and glycosylated haemoglobin (HbA1C ) levels. Serum total cholesterol, triglyceride levels and plasma atherogenic index were significantly decreased after 22 days treatment in all seaweed groups. Unlike metformin, S. polycystum did not significantly change plasma insulin in the rats, but increased the response to insulin. The consumption of either ethanolic or water extracts of S. polycystum dose dependently reduced dyslipidaemia in type 2 diabetic rats. S. polycystum is a potential insulin sensitiser, for a comestible complementary therapy in the management of type 2 diabetes which can help reduce atherogenic risk. © 2012 Society of Chemical Industry.

  17. The effects of soy isoflavone on insulin sensitivity and adipocytokines in insulin resistant rats administered with high-fat diet.

    Science.gov (United States)

    Zhang, Hong-Min; Chen, Shi-Wei; Zhang, Li-Shi; Feng, Xiao-Fan

    2008-12-01

    The effects of soy isoflavone (SIF) on insulin sensitivity and adipocytokines in high-fat-diet-induced insulin resistant (IR) rats were studied. Male Sprague Dawley rats (n = 80) were randomly assigned into a basal diet fed group and high-fat diet fed group. The high-fat-diet-induced IR rats were assigned into IR model control group and three SIF-treated groups with different dosages. Thirty days later, the fasting blood glucose, insulin and adipocytokines in serum and mRNA expressions of adipocytokines in perirenal white adipose tissue were measured. The Homeostasis Model Assessment of IR was calculated. The administration of 450 mg kg(-1) d(-1) SIF decreased the body weights and depositions of visceral adipose tissue as well as improved insulin resistance in high-fat-diet-induced IR rats. The mechanisms were associated with SIF regulating the expression of adipocytokines, including adiponectin, leptin, resistin and TNF-alpha. SIF supplements may have favourable effects on insulin resistance in high-fat-diet-induced IR rats.

  18. 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.

  19. 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.

  20. 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.

  1. 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

  2. Effect of a 10-week weight loss camp on fatty liver disease and insulin sensitivity in obese Danish children

    DEFF Research Database (Denmark)

    Grønbæk, Henning; Lange, Aksel; Birkebæk, Niels H

    2012-01-01

    BACKGROUND AND OBJECTIVE: Childhood nonalcoholic fatty liver disease (NAFLD) associated with insulin resistance and obesity is a growing problem and increases the risk of cirrhosis, type 2 diabetes mellitus, and cardiovascular complications. We examined the effects of a 10-week "weight loss camp......" residency in obese children on the prevalence and degree of NAFLD and insulin sensitivity with 12-month follow-up. METHODS: At the camp, 117 obese white children (body mass index 28.0 ± 3.6  kg/m, age 12.1 ± 1.3 years) exercised moderately for 1 hour/day and restricted their energy intake to induce weight...... collected from 71 of 117 children at entry, after the 10 weeks at the camp, and 12 months after the camp ended. RESULTS: The children showed an average weight loss of 7.1 ± 2.7  kg during the camp. At baseline, 43% had ultrasonographic liver steatosis, 50% elevated transaminases (>25  IU/L), and reduced...

  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. 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.

  5. 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.

  6. Proinflammatory cytokine production and insulin sensitivity regulated by overexpression of resistin in 3T3-L1 adipocytes

    Directory of Open Access Journals (Sweden)

    Garvey W Timothy

    2006-07-01

    Full Text Available Abstract Resistin is secreted from adipocytes, and high circulating levels have been associated with obesity and insulin resistance. To investigate whether resistin could exert autocrine effects in adipocytes, we expressed resistin gene in 3T3-L1 fibroblasts using a lentiviral vector, and selected several stably-transduced cell lines under blasticidin selection. We observed that 3T3-L1 adipocytes expressing resistin have a decreased gene expression for related transcriptional factors (CCAAT/enhancer binding protein α(C/EBPα , peroxisome proliferator-activated receptor gamma (PPARγ, and adipocyte lipid binding protein (ALBP/aP2 which is one of target genes for the PPARγ during adipocyte differentiation,. Overexpression of resistin increased the levels of three proinflammatory cytokines, tumor necrosis factor alpha (TNFα, interleukin 6 (IL-6 and monocyte chemoattractant protein-1 (MCP-1, which play important roles for insulin resistance, glucose and lipid metabolisms during adipogenesis. Furthermore, overexpressing resistin in adipocytes inhibits glucose transport 4 (GLUT4 activity and its gene expression, reducing insulin's ability for glucose uptake by 30 %. In conclusion, resistin overexpression in stably transduced 3T3-L1 cells resulted in: 1 Attenuation of programmed gene expression responsible for adipogenesis; 2 Increase in expression of proinflammatory cytokines; 3 Decrease in insulin responsiveness of the glucose transport system. These data suggest a new role for resistin as an autocrine/paracrine factor affecting inflammation and insulin sensitivity in adipose tissue.

  7. 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.

  8. Vitamin D supplementation has no effect on insulin sensitivity or secretion in vitamin D-deficient, overweight or obese adults: a randomized placebo-controlled trial.

    Science.gov (United States)

    Mousa, Aya; Naderpoor, Negar; de Courten, Maximilian Pj; Teede, Helena; Kellow, Nicole; Walker, Karen; Scragg, Robert; de Courten, Barbora

    2017-06-01

    Background: Vitamin D supplementation has been proposed as a potential strategy to prevent type 2 diabetes. Existing clinical trials have been limited by short duration, low doses of vitamin D, variability in participants' vitamin D-deficiency status, and the use of surrogate measures of body composition, insulin sensitivity, and insulin secretion.Objective: To address existing knowledge gaps, we conducted a double-blind, randomized, placebo-controlled trial to investigate whether vitamin D supplementation that is provided in a sufficient dose and duration to vitamin D-deficient individuals would improve insulin sensitivity or secretion as measured with the use of gold-standard methods. We hypothesized that vitamin D supplementation would improve insulin sensitivity and secretion compared with placebo.Design: Sixty-five overweight or obese, vitamin D-deficient (25-hydroxyvitamin D [25(OH)D] concentration ≤50 nmol/L) adults were randomly assigned to receive either a bolus oral dose of 100,000 IU cholecalciferol followed by 4000 IU cholecalciferol/d or a matching placebo for 16 wk. Before and after the intervention, participants received gold-standard assessments of body composition (via dual X-ray absorptiometry), insulin sensitivity (via hyperinsulinemic-euglycemic clamps), and insulin secretion [via intravenous-glucose-tolerance tests (IVGTTs)].Results: Fifty-four participants completed the study [35 men and 19 women; mean ± SD age: 31.9 ± 8.5 y; body mass index (in kg/m(2)): 30.9 ± 4.4]. 25(OH)D increased with vitamin D supplementation compared with placebo (57.0 ± 21.3 compared with 1.9 ± 15.1 nmol/L, respectively; P = 0.02). Vitamin D and placebo groups did not differ in change in insulin sensitivity (0.02 ± 2.0 compared with -0.03 ± 2.8 mg · kg(-1) · min(-1), respectively; P = 0.9) or first-phase insulin secretion (-21 ± 212 compared with 24 ± 184 mU/L, respectively; P = 0.9). Results remained nonsignificant after adjustment for age, sex

  9. Evidence for early defects in insulin sensitivity and secretion before the onset of glucose dysregulation in obese youths: a longitudinal study.

    Science.gov (United States)

    Giannini, Cosimo; Weiss, Ram; Cali, Anna; Bonadonna, Riccardo; Santoro, Nicola; Pierpont, Bridget; Shaw, Melissa; Caprio, Sonia

    2012-03-01

    We sought to determine whether obese adolescents with high-"normal" 2-h post-oral glucose tolerance test glucose levels display defects in insulin secretion and sensitivity associated with future development of impaired glucose tolerance (IGT). Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp and insulin secretion by applying mathematical modeling during the hyperglycemic clamp in 60 normal glucose tolerance (NGT) obese adolescents, divided into three groups based on the 2-h glucose values (DI) decreased across NGT categories, while no difference was observed between the highest NGT and IGT subjects. Age and (C)DI were the best predictors of 2-h glucose after two years. Across rising categories of normal 2-h glucose levels, NGT obese adolescents exhibit significant impairment of β-cell function relative to insulin sensitivity associated with the development of IGT.

  10. 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, Pfat dietary 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...

  11. 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 fat 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...

  12. 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....... Insulin resistance was estimated by the homeostasis model assessment (HOMA-IR). RESULTS The mean weight loss was 5.1 kg (range -15.3 to +1.3 kg). BMI decreased from 36.5 to 34.9 kg/m(2) (P=0.003). Saturated FA (SFA) decreased 11% (P=0.0001). Polyunsaturated FA (PUFA)n-6 increased 4% (P =0.003). Long...... 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, Pfat dietary intervention programme increased incorporation of long...

  13. 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...

  14. Trajectories of glycaemia, insulin sensitivity, and insulin secretion before diagnosis of type 2 diabetes: an analysis from the Whitehall II study

    DEFF Research Database (Denmark)

    Tabák, A.G.; Jokela, M.; Akbaraly, T.N.

    2009-01-01

    BACKGROUND: Little is known about the timing of changes in glucose metabolism before occurrence of type 2 diabetes. We aimed to characterise trajectories of fasting and postload glucose, insulin sensitivity, and insulin secretion in individuals who develop type 2 diabetes. METHODS: We analysed data...... from our prospective occupational cohort study (Whitehall II study) of 6538 (71% male and 91% white) British civil servants without diabetes mellitus at baseline. During a median follow-up period of 9.7 years, 505 diabetes cases were diagnosed (49.1% on the basis of oral glucose tolerance test). We...... assessed retrospective trajectories of fasting and 2-h postload glucose, homoeostasis model assessment (HOMA) insulin sensitivity, and HOMA beta-cell function from up to 13 years before diabetes diagnosis (diabetic group) or at the end of follow-up (non-diabetics). FINDINGS: Multilevel models adjusted...

  15. Relat