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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is an adipocyte hormone involved in the regulation of energy homeostasis. Generally accepted biological effects of leptin are inhibition of food intake and stimulation of metabolic rate in ob/ob mice that are defective in the leptin gene. In contrast to these centrally mediated effects of leptin, we are reporting here on leptin effects on isolated rat adipocytes. Leptin impairs several metabolic actions of insulin, i.e. stimulation of glucose transport, glycogen synthase, lipogenesis, inhibition of isoproterenol-induced lipolysis, and protein kinase A activation, as well as stimulation of protein synthesis. Insulin effects were reduced by leptin (2 nM) with a half-life of about 8 h. At low leptin concentrations (<1 nM), the insulin sensitivity was reduced leading to a shift to the right in the dose-response curve. At higher concentrations the responsiveness was diminished, resulting in nearly complete inhibition of insulin effects at >30 nM leptin. The IC50 value of leptin was 3.1 +/- 1 nM after 15 h of preincubation of adipocytes in primary culture. The natural splice variant des-Gln49-leptin exhibited a significantly lower potency. Adipocytes regained full insulin sensitivity within a few hours after leptin removal. The stimulation of glucose transport by vanadate was not affected by leptin. These data show specific and potent impairment of insulin action by leptin in the physiological concentration range of both leptin and insulin, which may be related to the pathophysiology of insulin resistance in both non-insulin-dependent diabetes mellitus and obesity.
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PMID:Leptin impairs metabolic actions of insulin in isolated rat adipocytes. 909 5

Segregation analysis of body-mass index (BMI) supported recessive inheritance of obesity, in pedigrees ascertained through siblings with non-insulin dependent diabetes mellitus (NIDDM). BMI was estimated as 39 kg/m2 for those subjects homozygous at the inferred locus. Two-locus segregation analysis provided weak support for a second recessive locus, with BMI estimated as 32 kg/m2 for homozygotes. NIDDM prevalence was increased among those subjects presumed to be homozygous at either locus. Using both parametric and nonparametric methods, we found no evidence of linkage of obesity to any of nine candidate genes/regions, including the Prader-Willi chromosomal region (PWS), the human homologue of the mouse agouti gene (ASP), and the genes for leptin (OB), the leptin receptor (OBR/DB), the beta3-adrenergic receptor (ADRB3), lipoprotein lipase (LPL), hepatic lipase (LIPC), glycogen synthase (GYS), and tumor necrosis factor alpha (TNFA).
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PMID:Recessive inheritance of obesity in familial non-insulin-dependent diabetes mellitus, and lack of linkage to nine candidate genes. 932 33

Intra-abdominal and subcutaneous adipose tissue display important metabolic differences that underlie the association of visceral, but not subcutaneous, fat with obesity-related cardiovascular and metabolic problems. Because the molecular mechanisms contributing to these differences are not yet defined, we compared by reverse transcription-polymerase chain reaction the expression of 15 mRNAs that encode proteins of known importance in adipocyte function in paired omental and subcutaneous abdominal biopsies. No difference in mRNA expression between omental and subcutaneous adipose tissue was observed for hormone sensitive lipase, lipoprotein lipase, 6-phosphofructo-1-kinase, insulin receptor substrate 1, p85alpha regulatory subunit of phosphatidylinositol-3-kinase, and Rad. Total amount of insulin receptor expression was significantly higher in omental adipose tissue. Most of this increase was accounted for by expression of the differentially spliced insulin receptor lacking exon 11, which is considered to transmit the insulin signal less efficiently than the insulin receptor with exon 11. Perhaps consistent with a less efficient insulin signaling, a twofold reduction in GLUT4, glycogen synthase, and leptin mRNA expression was observed in omental adipose tissue. Finally peroxisome proliferator activated receptor-gamma (PPAR-gamma) mRNA levels were significantly lower in visceral adipose tissue in subjects with a BMI <30 kg/m2, but not in obese subjects, indicating that relative PPAR-gamma expression is increased in omental fat in obesity. This suggests that altered expression of PPAR-gamma might play a role in adipose tissue distribution and expansion.
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PMID:Depot-specific differences in adipose tissue gene expression in lean and obese subjects. 942 81

Evidence, gained from human studies, is reviewed showing that elevation of plasma FFA levels produce peripheral and probably also hepatic insulin resistance in obese healthy and diabetic subjects. First, plasma FFA levels are elevated in most obese subjects. Second, physiological elevations of plasma FFA inhibit acutely as well as chronically insulin stimulated glucose uptake in a dose dependent fashion. Responsible for this inhibition is a FFA induced defect in insulin stimulated glucose transport and/or phosphorylation which develops after 3-4 hours of raising plasma FFA and a second defect, consisting of inhibition of glycogen synthase, the rate limiting enzyme of glycogen synthesis, which develops after 4-6 hours. FFA induced inhibition of fatty acid oxidation (Randle effect) does not affect insulin stimulated glucose uptake or glycogen synthesis and thus does not cause insulin resistance. Elevated plasma FFA levels also modestly increase insulin suppressed endogenous glucose production (EGP) although this effect has not been found by all investigators. The reasons why it has been difficult to demonstrate unequivocal effects of FFA on EGP include 1) the fact that FFA promote insulin secretion which counteracts its effect on EGP (FFA increase, while insulin decreases EGP); 2) the recognition that FFA induced increase in gluconeogenesis may be compensated by intrahepatic downregulation of EGP (i.e., by a decrease in glycogenolysis). The FFA induced insulin resistance is physiologically important during starvation by preserving carbohydrate for oxidation in the central nervous system and during pregnancy, where the well recognized accelerated starvation pattern provides carbohydrate for the growing fetus. In obesity, however, there is no need to spare carbohydrate and the FFA induced insulin resistance may result in type 2 diabetes and other cardiovascular risk factors.
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PMID:Free fatty acids (FFA), a link between obesity and insulin resistance. 945 Sep 85

1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of beta3-adrenoceptors (beta3-AR) in adipose tissue. 2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-epsilon and PKC-theta) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro- and macrovascular complications of diabetes. 3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), beta3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-beta LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance. 4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.
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PMID:Mechanisms of insulin resistance and new pharmacological approaches to metabolism and diabetic complications. 949 93

A decreased ratio of fat to carbohydrate oxidation rate (an elevated respiratory quotient) predicts the development of obesity. Skeletal muscle accounts for a major fraction of total body lipid oxidation and is the principle site for reduced glucose storage in insulin-resistant subjects. The potentially important role that muscle has in promoting obesity or insulin resistance may be based on metabolic control intrinsic to skeletal muscle. Cultured skeletal muscle provides a system to examine the importance of inherent metabolic traits in muscle biopsies from obese and insulin-resistant subjects. Glycogen synthase fractional activity (GSFA) was measured in cultured myoblasts from 21 Pima Indians characterized in vivo using indirect calorimetry and a euglycemic hyperinsulinemic clamp. Basal GSFA in cultured muscle cells is inversely correlated with postabsorptive respiratory quotient of the muscle donors (r = -0.66, P = 0.001) and with in vivo high dose insulin-stimulated glucose storage rates (r = 0.47, P = 0.04). These results indicate that the postabsorptive respiratory quotients and insulin-mediated glucose storage rates in vivo share a common regulatory mechanism with GSFA in cultured myoblasts. Abnormal regulation of glycogen synthase phosphorylation state may be an intrinsic defect in skeletal muscle associated with obesity and insulin resistance.
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PMID:Postabsorptive respiratory quotient and insulin-stimulated glucose storage rate in nondiabetic pima indians are related To glycogen synthase fractional activity in cultured myoblasts. 959 81

Insulin resistance, as is found in skeletal muscle of individuals with obesity and NIDDM, appears to involve a reduced capacity of the hormone to stimulate glucose uptake and/or phosphorylation. The glucose phosphorylation step, as catalyzed by hexokinase II, has been described as rate limiting for glucose disposal in muscle, but overexpression of this enzyme under control of a muscle-specific promoter in transgenic mice has had limited metabolic impact. In the current study, we investigated in a cultured muscle model whether expression of glucokinase, which in contrast to hexokinase II is not inhibited by glucose-6-phosphate (G-6-P), would have a pronounced metabolic impact. We used a recombinant adenovirus containing the cDNA-encoding rat liver glucokinase (AdCMV-GKL) to increase the glucose phosphorylating activity in cultured human muscle cells by fourfold. G-6-P levels increased in AdCMV-GKL-treated cells in a glucose concentration-dependent manner over the range of 1-30 mmol/l, whereas the much smaller increases in G-6-P in control cells were maximal at glucose concentrations <5 mmol/l. Further, cells expressing glucokinase accumulated 17 times more 2-deoxyglucose-6-phosphate than control cells. In AdCMV-GKL-treated cells, the time-dependent rise in G-6-P correlated with an increase in the activity ratio of glycogen synthase. AdCMV-GKL-treated cells also exhibited a 2.5- to 3-fold increase in glycogen content and a four- to fivefold increase in glycolytic flux, proportional to the increase in glucose phosphorylating capacity. All of these observations were made in the absence of insulin. Thus we concluded that expression of glucokinase in cultured human muscle cells results in proportional increases in insulin-independent glucose disposal, and that muscle glucose storage and utilization becomes controlled in a glucose concentration-dependent manner in AdCMV-GKL-treated cells. These results encourage testing whether delivery of glucokinase to muscle in vivo has an impact on glycemic control, which could be a method for circumventing the failure of insulin to stimulate glucose uptake and/or phosphorylation in muscle normally in insulin-resistant subjects.
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PMID:Expression of glucokinase in cultured human muscle cells confers insulin-independent and glucose concentration-dependent increases in glucose disposal and storage. 972 26

In obesity several mechanisms contribute to produce insulin resistance. Elevation of plasma FFA increases the concentration of cytoplasmic long-chain-CoA (LC-CoA) and mitochondrial acetyl-CoA. The latter inhibits pyruvate dehydrogenase (PDH) and, therefore, glucose oxidation. LC-CoA exerts an array of effects, some mediated by peroxisome proliferator-activated receptors, including modulation of gene expression of enzymes of glycolipid metabolism, thus inhibiting glucose utilization and potentiating FFA oxidation. Enhanced availability of glucose plus insulin forces glucose utilization (activation of PDH and glycogen synthase) and leads to increased production of malonyl-CoA (via citrate), which inhibits carnitine palmitoyl transferase 1 and therefore FFA beta-oxidation. In obesity there is often enhanced availability of both FFA and glucose plus insulin. The latter, by increasing malonyl-CoA, may limit FFA beta-oxidation. This, however, leads to further increases in LC-CoA, which worsens insulin resistance. All these mechanisms occur through both short-term and long-term effects. Therefore, when insulin sensitivity is measured with the hyperinsulinemic clamp, which artificially suppresses FFA levels, the FFA short-term effects are lost. More physiological methods are those utilizing OGTT data, allowing calculation of an Insulin Sensitivity Index for glycemia, or ISI(gly), through the formula: 2/((INSp x GLYp)+1), where INSp and GLYp are the measured insulin and glycemic areas expressed by taking mean normal value as 1. The corresponding Insulin Resistance Index, or IRI(gly), can be obtained through the formula: 2/((1/(INSp x GLYp))+1). Substitution of glycemic (GLYp) with FFA (FFAp) values allows the calculation of indices of insulin sensitivity and resistance for FFA, i.e., ISI(ffa) and IRI(ffa).
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PMID:Insulin resistance in obesity: metabolic mechanisms and measurement methods. 978 4

Insulin-mediated non-oxidative glucose metabolism is more or less identical to glycogen synthesis in skeletal muscle and that is why this pathway is specifically discussed in this paper. All three major steps in non-oxidative glucose processing--glucose transport, phosphorylation and glycogen synthesis--are found to be reduced in response to insulin in insulin-resistant type 2 diabetic subjects compared with controls. The insulin-signalling cascade from the insulin receptor to PI-3-K was also found to be abnormal, resulting in a severely reduced phosphorylation degree of the IRS-1 (IRS-2?)-PI-3-K complex, which can explain both reduced glucose transport and glycogen synthesis. The most pronounced finding in our studies is reduced glycogen synthase activation by insulin which is found in prediabetic subjects with normal glucose tolerance as well as in type 2 diabetics, but more severely. This defect was not reversible after treatment (normalization of blood glucose) and is therefore a candidate for the primary defect which is likely to be of genetic origin, but also could be caused by genetic imprinting, intrauterine malnutrition and social inheritance (obesity). Most of the abnormalities in non-oxidative glucose metabolism may be of secondary origin due to hyperglycemia itself or obesity. Both events may stimulate production of glucosamine, malonyl CoA and intramuscular triglyceride accumulation. These metabolites can theoretically induce most of the defects in glucose processing and furthermore impair insulin signalling. Whether the primary defect in activation of glycogen synthase is due to an abnormality in the enzyme complex itself or in the insulin signalling cascade still has to be investigated.
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PMID:Mechanisms of insulin resistance in non-oxidative glucose metabolism: the role of glycogen synthase. 1021 38

In skeletal muscle of normal subjects, the concentration of glucose 6-phosphate (G6P) at which the activity of glycogen synthase (GS) is half maximal (Ka) is decreased by in vivo insulin, and the fractional activity is increased without a change in GS maximal activity (Vmax). We have shown that moderate chronic calorie restriction, previously shown in rodents to be effective in slowing aging, resulted in the prevention of obesity and type 2 diabetes in primates (rhesus monkeys, Macaca mulatta). However, unexpectedly, in a subgroup of calorie-restricted monkeys, insulin during a euglycemic hyperinsulinemic clamp caused an unanticipated decrease in skeletal muscle GS fractional activity. These same monkeys had the lowest whole-body glucose disposal rate (M), the greatest increase in skeletal muscle G6P content and the greatest increase in skeletal muscle glycogen phosphorylase activity during the euglycemic hyperinsulinemic clamp compared to the remaining calorie-restricted monkeys with normal insulin action. To determine whether this highly unusual insulin-mediated decrease in GS fractional activity was due to increased phosphorylation (increased Ka), we measured the activity of skeletal muscle GS at 9 different G6P concentrations before and during the euglycemic hyperinsulinemic clamp in 6 calorie-restricted monkeys. G6P Ka increased (n = 4) and Vmax decreased (n = 5) during the clamp. Basal G6P Ka was inversely related to basal GSfv (r = -0.94, p < 0.002). G6P Ka and skeletal muscle G6P content were positively related under insulin-stimulated conditions (r = 0.93, p < 0.005). The change in G6P Ka (insulin-stimulated minus basal) was inversely related to M (r = -0.94, p < 0.002) and positively related to the change in skeletal muscle G6P content (r = 0.93, p < 0.005). We conclude that moderate calorie restriction results in a reversal of normal insulin action at the skeletal muscle with inactivation of glycogen synthase which is likely to be due to an increase in phosphorylation of GS together with a decrease in Vmax of GS during a euglycemic hyperinsulinemic clamp in most of the calorie-restricted monkeys. These alterations are likely to be involved in the anti-diabetogenic effects of calorie restriction.
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PMID:Insulin unexpectedly increases the glucose 6-phosphate Ka of skeletal muscle glycogen synthase in calorie-restricted monkeys. 1021 41


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