Role of nuclear receptors in the modulation of insulin secretion in lipid-induced insulin resistance

2008 ◽  
Vol 36 (5) ◽  
pp. 891-900 ◽  
Author(s):  
Mary C. Sugden ◽  
Mark J. Holness
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Nuclear Receptors ◽  
Feedback Loop ◽  
Farnesoid X Receptor ◽  
Lipid Lowering ◽  
Whole Body ◽  
Glucose Disposal ◽  
Healthy Individuals

In healthy individuals, a hyperbolic relationship exists between whole-body insulin-sensitivity and insulin secretion. Thus, for any difference in insulin-sensitivity, a reciprocal proportionate change occurs in insulin secretion. Such a feedback loop is evident in healthy individuals ingesting diets high in saturated fat and in late pregnancy where, despite lipid-induced insulin resistance, glucose tolerance is maintained through augmented GSIS (glucose-stimulated insulin secretion). NRs (nuclear receptors) are members of a superfamily of ligand-regulated and orphan transcription factors. On activation by a cognate ligand, many ligand-activated NRs recruit the RXR (retinoid X receptor) for heterodimer formation. Such NRs include the PPARs (peroxisome-proliferator-activated receptors), which are involved in lipid sensing and liporegulation. PPARs exert important lipid-lowering effects in vivo, thereby opposing the development of lipid-induced insulin resistance by relieving the inhibition of insulin-stimulated glucose disposal by muscle and lowering the necessity for augmented GSIS to counter lipid-induced insulin resistance. Long-chain fatty acids are proposed as natural PPAR ligands and some specific endogenous pathways of lipid metabolism are believed to generate PPAR agonists. Other NRs, e.g. the LXR (liver X receptor), which senses expansion of the metabolically active pool of cholesterol, and the FXR (farnesoid X receptor; NR1H4), which, like the LXR, is involved in sterol metabolism, also modulate systemic lipid levels and insulin-sensitivity. In this review, we discuss how these NRs impact insulin secretion via effects on the insulin-sensitivity–insulin secretion feedback loop and, in some cases, via direct effects on the islet itself. In addition, we discuss interactions between these nutrient/metabolite-responsive NRs and NRs that are central to the action of metabolically important hormones, including (i) the glucocorticoid receptor, critical for maintaining glucose homoeostasis in stress, inflammation and during fasting, and (ii) the thyroid hormone receptors, vital for maintenance of oxidative functions. We present data indicating that the RXR occupies a key role in directly modulating islet function and that its heterodimerization with at least two of its partners modulates GSIS.

scholarly journals Small intestinal metabolism is central to whole-body insulin resistance

Gut ◽  
2020 ◽  
pp. gutjnl-2020-322073
Author(s):  
Giulia Angelini ◽  
Serenella Salinari ◽  
Lidia Castagneto-Gissey ◽  
Alessandro Bertuzzi ◽  
James Casella-Mariolo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Insulin Signalling ◽  
Whole Body ◽  
Glucose Disposal ◽  
Jejunal Loop ◽  
Oral Glucose ◽  
Metabolic Signature ◽  
Jejunal Bypass

ObjectiveTo assess the role of jejunum in insulin resistance in humans and in experimental animals.DesignTwenty-four subjects undergoing biliopancreatic diversion (BPD) or Roux-en-Y gastric bypass (RYGB) were enrolled. Insulin sensitivity was measured at baseline and at 1 week after surgery using oral glucose minimal model.We excluded the jejunum from intestinal continuity in pigs and created a jejunal loop with its vascular and nerve supply intact accessible from two cutaneous stomas, and reconnected the bowel with an end-to-end anastomosis. Glucose stable isotopes were given in the stomach or in the jejunal loop.In vitro studies using primary porcine and human hepatocytes or myoblasts tested the effects of plasma on gluconeogenesis or glucose uptake and insulin signalling.ResultsWhole-body insulin sensitivity (SI∙104: 0.54±0.12 before vs 0.82±0.11 after BPD, p=0.024 and 0.41±0.09 before vs 0.65±0.09/pM/min after RYGB, p=not significant) and Glucose Disposition Index increased only after BPD. In pigs, insulin sensitivity was significantly lower when glucose was administered in the jejunal loop than in the stomach (glucose rate of disappearance (Rd) area under the curve (AUC)/insulin AUC∙10: 1.82±0.31 vs 2.96±0.33 mmol/pM/min, p=0.0017).Metabolomics showed a similar pattern before surgery and during jejunal-loop stimulation, pointing to a higher expression of gluconeogenetic substrates, a metabolic signature of impaired insulin sensitivity.A greater hepatocyte phosphoenolpyruvate-carboxykinase and glucose-6-phosphatase gene expression was elicited with plasma from porcine jejunal loop or before surgery compared with plasma from jejunectomy in pigs or jejunal bypass in humans.Stimulation of myoblasts with plasma from porcine jejunal loop or before surgery reduced glucose uptake, Ser473-Akt phosphorylation and GLUT4 expression compared with plasma obtained during gastric glucose administration after jejunectomy in pigs or after jejunal bypass in humans.ConclusionProximal gut plays a crucial role in controlling insulin sensitivity through a distinctive metabolic signature involving hepatic gluconeogenesis and muscle insulin resistance. Bypassing the jejunum is beneficial in terms of insulin-mediated glucose disposal in obesity.Trial registration numberNCT03111953.

Increased intrahepatic triglyceride is associated with peripheral insulin resistance: in vivo MR imaging and spectroscopy studies

2007 ◽  
Vol 293 (6) ◽  
pp. E1663-E1669 ◽  
Author(s):  
Jong-Hee Hwang ◽  
Daniel T. Stein ◽  
Nir Barzilai ◽  
Min-Hui Cui ◽  
Julia Tonelli ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Magnetic Resonance ◽  
Subcutaneous Fat ◽  
Liver Fat ◽  
Whole Body ◽  
Glucose Disposal ◽  
Resonance Spectroscopy ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Triglyceride Accumulation

Recent studies have indicated that the mass/content of intramyocellular lipid (IMCL), intrahepatic triglyceride (IHTG), visceral fat (VF), and even deep abdominal subcutaneous fat (SF) may all be correlated with insulin resistance. Since simultaneous measurements of these parameters have not been reported, the relative strength of their associations with insulin action is not known. Therefore, the goals of this study were 1) to simultaneously measure IMCL, IHTG, VF, and abdominal SF in the same nondiabetic individuals using noninvasive 1H-magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MRI) and 2) to examine how these fat stores are correlated with systemic insulin sensitivity as measured by whole body glucose disposal (Rd) during euglycemic-hyperinsulinemic clamp studies. Positive correlations were observed among IMCL, IHTG, and VF. There were significant inverse correlations between whole body Rd and both IMCL and VF. Notably, there was a particularly tight inverse correlation between IHTG and whole body Rd ( r = −0.86, P < 0.001), consistent with an association between liver fat and peripheral insulin sensitivity. This novel finding suggests that hepatic triglyceride accumulation has important systemic consequences that may adversely affect insulin sensitivity in other tissues.

Preoperative oral carbohydrate treatment attenuates immediate postoperative insulin resistance

2001 ◽  
Vol 280 (4) ◽  
pp. E576-E583 ◽  
Author(s):  
Mattias Soop ◽  
Jonas Nygren ◽  
Peter Myrenfors ◽  
Anders Thorell ◽  
Olle Ljungqvist
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Treatment Group ◽  
Whole Body ◽  
Glucose Disposal ◽  
Peripheral Tissues ◽  
Major Mechanism ◽  
Replacement Surgery ◽  
Oxidation Rates ◽  
Postoperative Changes

Postoperative insulin resistance is a well-characterized metabolic state that has been shown to correlate with the length of postoperative stay in hospital. Preoperative intravenous or oral carbohydrate treatment has been shown to attenuate the development of postoperative insulin resistance measured 1 day after surgery. To study the effects of preoperative oral carbohydrate treatment on postoperative changes in insulin resistance and substrate utilization, in the absence of postoperative confounding factors, 15 patients were double-blindly treated with either a carbohydrate-rich beverage (12.5%) ( n = 8) or placebo ( n = 7) before undergoing total hip replacement surgery. Insulin sensitivity, endogenous glucose release, and substrate oxidation rates were measured before and immediately after surgery. Whole body insulin sensitivity decreased by 18% in the treatment group vs. 43% in the placebo group ( P < 0.05, Student's t-test for unpaired data). In both groups, the major mechanism of insulin resistance was an inhibition of insulin-induced nonoxidative glucose disposal after surgery. The better preservation of insulin sensitivity in the treatment group was attributable to a less reduced glucose disposal in peripheral tissues and increased glucose oxidation rates.

scholarly journals Whole body overexpression of PGC-1α has opposite effects on hepatic and muscle insulin sensitivity

2009 ◽  
Vol 296 (4) ◽  
pp. E945-E954 ◽  
Author(s):  
Huiyun Liang ◽  
Bogdan Balas ◽  
Puntip Tantiwong ◽  
John Dube ◽  
Bret H. Goodpaster ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Troponin I ◽  
Physiological Stress ◽  
Fiber Type ◽  
Glucose Production ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Glucose Disposal ◽  
Peripheral Tissues

Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1α expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1α is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1α and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1α was moderately (∼2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1α overexpression resulted in increased expression of hepatocyte nuclear factor-4α and the gluconeogenic enzymes phospho enolpyruvate carboxykinase and glucose-6-phosphatase. PGC-1α overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1α overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1α overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IκB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1α overexpression in liver and muscle suggests that PGC-1α is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.

scholarly journals Effect of gender on lipid-induced insulin resistance in obese subjects

2008 ◽  
Vol 158 (1) ◽  
pp. 61-68 ◽  
Author(s):  
Bodil Vistisen ◽  
Lars I Hellgren ◽  
Torill Vadset ◽  
Celena Scheede-Bergdahl ◽  
Jørn Wulff Helge ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Body Mass ◽  
Plasma Concentrations ◽  
Whole Body ◽  
Glucose Disposal ◽  
Muscle Lipid ◽  
Obese Subjects ◽  
Skeletal Muscle Insulin Sensitivity

ObjectiveIn obese subjects, chronically elevated plasma concentrations of non-esterified fatty acids (NEFAs) exert a marked risk to contract insulin resistance and subsequently type 2 diabetes. When NEFA is acutely increased due to i.v. infusion of lipid, glucose disposal during a hyperinsulinemic–euglycemic clamp is reduced. This effect has been explained by a NEFA-induced decrease in skeletal muscle insulin sensitivity caused by accumulation of the lipid intermediates such as ceramide and diacylglycerol in the myocytes. However, neither the lipid-induced reduction of glucose disposal nor the intramyocellular lipid deposition has been compared directly in obese females and males.DesignWe studied eight obese females and eight obese males (body mass index (BMI): 32.6±1.4 and 32.8±0.8 respectively, non significant (NS)) matched for cardiorespiratory fitness relative to lean body mass (43.7±1.6 and 47.6±1.3 ml/kg min respectively, NS).MethodsEach subject underwent two hyperinsulinemic–euglycemic clamps with infusion of lipid or saline respectively. Furthermore, the subjects exercised during the last half an hour of each clamp.ResultsThe lipid-induced reduction in glucose disposal during the clamp was similar in females and males (46±10 and 60±4% respectively, NS). However, whole-body insulin sensitivity as well as non-oxidative glucose disposal was higher in obese females compared with obese males both during lipid and saline infusion (P<0.001 andP=0.01 respectively). Muscle ceramide, triacylglycerol (TAG), diacylglycerol (DAG), and glycogen content were similar between sexes and remained unchanged during the clamp and when exercise was superimposed.ConclusionsThe lipid-induced inhibition of glucose disposal is similar in obese females and males. However, obese females are more insulin sensitive compared with obese males (both during saline and lipid infusion), which is not due to differences in the concentration of the muscle lipid intermediates such as ceramide and DAG.

Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation

2002 ◽  
Vol 283 (3) ◽  
pp. E556-E564 ◽  
Author(s):  
Gianluca Perseghin ◽  
Paola Scifo ◽  
Massimo Danna ◽  
Alberto Battezzati ◽  
Stefano Benedini ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Lipid Oxidation ◽  
Body Fat ◽  
Resting Energy Expenditure ◽  
Plasma Free Fatty Acid ◽  
Whole Body ◽  
Glucose Disposal ◽  
Family History Of Diabetes ◽  
History Of

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% ( n = 7) or >30% ( n = 7) and 14 young, nonobese men with body fat <25% ( n = 7) or >25% ( n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized1H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal ( P = 0.80), IMCL content in both soleus ( P = 0.22) and tibialis anterior ( P = 0.75) muscles, and plasma free fatty acid levels ( P = 0.075) compared with leaner subjects in association with increased lipid oxidation ( P < 0.05), resting energy expenditure ( P = 0.046), resting oxygen consumption ( P = 0.049), and plasma leptin levels ( P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.

Abdominal obesity in BTBR male mice is associated with peripheral but not hepatic insulin resistance

2007 ◽  
Vol 292 (3) ◽  
pp. E936-E945 ◽  
Author(s):  
Jessica B. Flowers ◽  
Angie T. Oler ◽  
Samuel T. Nadler ◽  
YounJeong Choi ◽  
Kathryn L. Schueler ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Genetic Difference ◽  
Inbred Mouse ◽  
Hepatic Insulin Resistance ◽  
Whole Body ◽  
Glucose Disposal ◽  
Mouse Strains ◽  
Chow Diet

Insulin resistance is a common feature of obesity. BTBR mice have more fat mass than most other inbred mouse strains. On a chow diet, BTBR mice have elevated insulin levels relative to the C57BL/6J (B6) strain. Male F1 progeny of a B6 × BTBR cross are insulin resistant. Previously, we reported insulin resistance in isolated muscle and in isolated adipocytes in this strain. Whereas the muscle insulin resistance was observed only in male F1 mice, adipocyte insulin resistance was also present in male BTBR mice. We examined in vivo mechanisms of insulin resistance with the hyperinsulinemic euglycemic clamp technique. At 10 wk of age, BTBR and F1 mice had a >30% reduction in whole body glucose disposal primarily due to insulin resistance in heart, soleus muscle, and adipose tissue. The increased adipose tissue mass and decreased muscle mass in BTBR and F1 mice were negatively and positively correlated with whole body glucose disposal, respectively. Genes involved in focal adhesion, actin cytoskeleton, and inflammation were more highly expressed in BTBR and F1 than in B6 adipose tissue. The BTBR and F1 mice have higher levels of testosterone, which may be related to the pathological changes in adipose tissue that lead to systemic insulin resistance. Despite profound peripheral insulin resistance, BTBR and F1 mice retained hepatic insulin sensitivity. These studies reveal a genetic difference in body composition that correlates with large differences in peripheral insulin sensitivity.

scholarly journals Perioperative Infusion of Glucagon-Like Peptide-1 Prevents Insulin Resistance After Surgical Trauma in Female Pigs

Endocrinology ◽  
2019 ◽  
Vol 160 (12) ◽  
pp. 2892-2902
Author(s):  
Martin Hagve ◽  
Petter F Gjessing ◽  
Mikal J Hole ◽  
Kirsten M Jansen ◽  
Ole Martin Fuskevåg ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Whole Body ◽  
Glucose Disposal ◽  
Control Group ◽  
Surgical Trauma ◽  
Glucose Release ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

Abstract Insulin resistance is an independent negative predictor of outcome after elective surgery and increases mortality among surgical patients in intensive care. The incretin hormone glucagon-like peptide-1 (GLP-1) potentiates glucose-induced insulin release from the pancreas but may also increase insulin sensitivity in skeletal muscle and directly suppress hepatic glucose release. Here, we investigated whether a perioperative infusion of GLP-1 could counteract the development of insulin resistance after surgery. Pigs were randomly assigned to three groups; surgery/control, surgery/GLP-1, and sham/GLP-1. Both surgery groups underwent major abdominal surgery. Whole-body glucose disposal (WGD) and endogenous glucose release (EGR) were assessed preoperatively and postoperatively using D-[6,6-2H2]-glucose infusion in combination with hyperinsulinemic euglycemic step-clamping. In the surgery/control group, peripheral insulin sensitivity (i.e., WGD) was reduced by 44% relative to preoperative conditions, whereas the corresponding decline was only 9% for surgery/GLP-1 (P < 0.05). Hepatic insulin sensitivity (i.e., EGR) remained unchanged in the surgery/control group but was enhanced after GLP-1 infusion in both surgery and sham animals (40% and 104%, respectively, both P < 0.05). Intraoperative plasma glucose increased in surgery/control (∼20%) but remained unchanged in both groups receiving GLP-1 (P < 0.05). GLP-1 diminished an increase in postoperative glucagon levels but did not affect skeletal muscle glycogen or insulin signaling proteins after surgery. We show that GLP-1 improves intraoperative glycemic control, diminishes peripheral insulin resistance after surgery, and suppresses EGR. This study supports the use of GLP-1 to prevent development of postoperative insulin resistance.

Whole body insulin resistance in rat offspring of mothers consuming alcohol during pregnancy or lactation: comparing prenatal and postnatal exposure

2004 ◽  
Vol 96 (1) ◽  
pp. 167-172 ◽  
Author(s):  
Li Chen ◽  
B. L. Grégoire Nyomba
Keyword(s):  
Insulin Resistance ◽  
Birth Weight ◽  
Glucose Tolerance ◽  
The Body ◽  
Whole Body ◽  
Glucose Disposal ◽  
Tolerance Index ◽  
Sensitivity Index ◽  
Intravenous Glucose ◽  
Rat Offspring

This study examined the effects of maternal ethanol (EtOH) consumption during pregnancy or lactation on glucose homeostasis in the adult rat offspring. Glucose disposal was determined by minimal model during an intravenous glucose tolerance test in rats that had a small or normal birth weight after EtOH exposure in utero and in rats whose mothers were given EtOH during lactation only. All three EtOH groups had decreased glucose tolerance index and insulin sensitivity index, but their glucose effectiveness was not different from that of controls. In addition, EtOH rat offspring that were small at birth had elevated plasma, liver, and muscle triglyceride levels. The data show that EtOH exposure during pregnancy programs the body to insulin resistance later in life, regardless of birth weight, but that this effect also results in dyslipidemia in growth-restricted rats. In addition, insulin resistance is also evident after EtOH exposure during lactation.

Effects of treadmill exercise to exhaustion on the insulin response to hyperglycemia in untrained men

1991 ◽  
Vol 70 (1) ◽  
pp. 246-250 ◽  
Author(s):  
J. P. Kirwan ◽  
R. E. Bourey ◽  
W. M. Kohrt ◽  
M. A. Staten ◽  
J. O. Holloszy
Keyword(s):  
Insulin Secretion ◽  
Early Phase ◽  
Pancreatic Beta Cell ◽  
Late Phase ◽  
Insulin Response ◽  
Creatine Kinase Activity ◽  
Whole Body ◽  
Glucose Disposal ◽  
C Peptide ◽  
Hyperglycemic Clamp

The effects of a single bout of exercise to exhaustion on pancreatic insulin secretion were determined in seven untrained men by use of a 3-h hyperglycemic clamp with plasma glucose maintained at 180 mg/100 ml. Clamps were performed either 12 h after an intermittent treadmill run at approximately 77% maximum O2 consumption or without prior exercise. Arterialized blood samples for glucose, insulin, and C-peptide determination were obtained from a heated hand vein. The peak insulin response during the early phase (0–10 min) of the postexercise clamp was higher (81 +/- 8 vs. 59 +/- 9 microU/ml; P less than 0.05) than in the nonexercise clamp. Incremental areas under the insulin (376 +/- 33 vs. 245 +/- 51 microU.ml-1.min) and C-peptide (17 +/- 2 vs. 12 +/- 1 ng.ml-1.min) curves were also greater (P less than 0.05) during the early phase of the postexercise clamp. No differences were observed in either insulin concentrations or whole body glucose disposal during the late phase (15–180 min). Area under the C-peptide curve was greater during the late phase of the postexercise clamp (650 +/- 53 vs. 536 +/- 76 ng.ml-1.min, P less than 0.05). The exercise bout induced muscle soreness and caused an elevation in plasma creatine kinase activity (142 +/- 32 vs. 305 +/- 31 IU/l; P less than 0.05) before the postexercise clamp. We conclude that in untrained men a bout of running to exhaustion increased pancreatic beta-cell insulin secretion during the early phase of the hyperglycemic clamp. Increased insulin secretion during the late phase of the clamp appeared to be compensated by increased insulin clearance.

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