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

The racemic mixture of the antioxidant alpha-lipoic acid (ALA) enhances insulin-stimulated glucose metabolism in insulin-resistant humans and animals. We determined the individual effects of the pure R-(+) and S-(-) enantiomers of ALA on glucose metabolism in skeletal muscle of an animal model of insulin resistance, hyperinsulinemia, and dyslipidemia: the obese Zucker (fa/fa) rat. Obese rats were treated intraperitoneally acutely (100 mg/kg body wt for 1 h) or chronically [10 days with 30 mg/kg of R-(+)-ALA or 50 mg/kg of S-(-)-ALA]. Glucose transport [2-deoxyglucose (2-DG) uptake], glycogen synthesis, and glucose oxidation were determined in the epitrochlearis muscles in the absence or presence of insulin (13.3 nM). Acutely, R-(+)-ALA increased insulin-mediated 2-DG-uptake by 64% (P < 0.05), whereas S-(-)-ALA had no significant effect. Although chronic R-(+)-ALA treatment significantly reduced plasma insulin (17%) and free fatty acids (FFA; 35%) relative to vehicle-treated obese animals, S-(-)-ALA treatment further increased insulin (15%) and had no effect on FFA. Insulin-stimulated 2-DG uptake was increased by 65% by chronic R-(+)-ALA treatment, whereas S-(-)-ALA administration resulted in only a 29% improvement. Chronic R-(+)-ALA treatment elicited a 26% increase in insulin-stimulated glycogen synthesis and a 33% enhancement of insulin-stimulated glucose oxidation. No significant increase in these parameters was observed after S-(-)-ALA treatment. Glucose transporter (GLUT-4) protein was unchanged after chronic R-(+)-ALA treatment but was reduced to 81 +/- 6% of obese control with S-(-)-ALA treatment. Therefore, chronic parenteral treatment with the antioxidant ALA enhances insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant rat skeletal muscle, with the R-(+) enantiomer being much more effective than the S-(-) enantiomer.
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PMID:Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle. 925 95

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

A line of transgenic rats (heterozygotes) carrying a chimeric gene comprising a regulatory portion of murine whey acidic protein and a structural portion of human GH (hGH) genes developed severe obesity with age. To characterize physiological mechanisms that lead to fat accumulation, an array of parameters related to obesity were studied. Blood hGH levels were continuously low, endogenous rat GH secretion was suppressed, and the pulsatility in peripheral GH levels was absent. Plasma glucose, insulin, triglyceride, and FFA levels in the male transgenic rats significantly exceeded those in nontransgenic littermates at 12 and 17 weeks, but not at 7 weeks, of age. All symptoms except hyperlipidemia were restored to normal by treatment with an antidiabetic agent, thiazolidinedione (troglitazone), for 1 week from 17 weeks of age. As phenotypic expression of obesity was already evident before aberration of physiological parameters, it was assumed that animals had a condition in which obesity or hyperlipidemia caused hyperinsulinemia. Gene expression and enzymatic activity of lipoprotein lipase in the adipose tissue in the transgenic rats were not different from those in normal rats. In contrast, the gene expression level of glycerol-3-phosphodehydrogenase was markedly elevated, suggesting that glycerol synthesis was much enhanced in the adipocytes of the transgenic rats. In an i.p. glucose tolerance test, the transgenic rats were not hyperglycemic at 7 weeks of age; however, the animal became hyperglycemic at 15-17 weeks of age. Finally, treatment with recombinant hGH for 1 week to produce pulsatile secretion reduced the size of epididymal and kidney fat pads and restored normal weight gain. These observations suggest that continuously low peripheral GH levels with the lack of pulsatile secretion resulted in obesity and noninsulin-dependent diabetes mellitus.
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PMID:Obesity and insulin resistance in human growth hormone transgenic rats. 964 76

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

Experimental data suggest that elevated FFA levels play a leading role in the impaired GH secretion in obesity and may therefore contribute to the maintenance of overweight. GH has a direct lipolytic effect on adipose tissue; in turn, FFA elevation markedly reduces GH secretion. This suggests the existence of a classical endocrine feedback loop between FFA and GH secretion. However, the FFA mechanism of action is not yet understood. The involvement of somatostatin (SRIH) is controversial, and in vitro experiments suggest a direct effect of FFA on the pituitary. In sheep it is possible to collect hypophysial portal blood and quantify SRIH secretion in hypophysial portal blood under physiological conscious and unstressed conditions. In this study we determined the effects of FFA (Intralipid and heparin) infusion on peripheral GH and portal SRIH levels in intact rams chronically implanted with perihypophysial cannula and in rams actively immunized against SRIH to further determine SRIH-mediated FFA effects on GH axis. Immediately after initiation of Intralipid infusion, we observed a marked increase in the FFA concentration (2160 +/- 200 vs. 295 +/- 28 nmol/ml; P < 0.01) as well as a significant decrease in basal GH secretion (1.8 +/- 0.1 vs. 2.5 +/- 0.3 ng/ml; P < 0.05) and a drastic reduction of the GH response to i.v. GH-releasing hormone injection (4.8 +/- 0.7 ng/ml in FFA group vs. 35.8 +/- 9.7 ng/ml in saline group; P < 0.01). No change in plasma insulin-like growth factor I levels was observed. During the first 2 h of infusion, the GH decrease observed was concomitant with a significant increase in portal SRIH levels (22.1 +/- .2 vs. 13 +/- 1.6 pg/ml; P < 0.01). In rams actively immunized against SRIH, the effect of FFA on basal GH secretion was biphasic. During the first 90 min of infusion, the decrease in GH induced by FFA was significantly blunted in rams actively immunized against SRIH (57 +/- 9% for immunized rams vs. 23.5 +/- 2.5% for control rams). This corresponds to the period of increased SRIH portal levels. After this first 90-min period, no difference was seen between control and immunized rams. Our results show that FFA exert their inhibitory action on the GH axis at both pituitary and hypothalamic levels, the latter mainly during the first 90 min, through increased SRIH secretion.
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PMID:Hypothalamic mediated action of free fatty acid on growth hormone secretion in sheep. 983 17

Prior to the advent of nuclear magnetic resonance (NMR) spectroscopy, human glucose metabolism was studied through tracer and tissue biopsy methodology. NMR spectroscopy now provides a noninvasive means to monitor metabolic flux and intracellular metabolite concentrations continuously. 13C NMR spectroscopy has shown that muscle glycogen synthesis accounts for the majority of insulin-stimulated muscle glucose uptake in normal volunteers and that defects in this process are chiefly responsible for insulin resistance in type 1 and type 2 diabetes mellitus, as well as in other insulin resistant states (obesity, insulin-resistant offspring of type 2 diabetic parents, elevation of plasma FFA concentrations). Furthermore, using 31P NMR spectroscopy to measure intracellular glucose-6-phosphate, it has been shown that defects in insulin-stimulated glucose transport/phosphorylation activity are primarily responsible for the insulin resistance in these states.
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PMID:Applications of NMR spectroscopy to study muscle glycogen metabolism in man. 1007 78

Several types of abnormal lipoprotein particles are observed in patients with insulin resistance: elevated VLDL-triglycerides, remnant lipoprotein, small dense LDL, reduced HDL-cholesterol. These patterns are caused by environmental and genetic factors that alter the lipoprotein metabolism. These lipoprotein abnormalities cause insulin resistance through several factors which decrease LPL and PPAR gamma, on the other hand increase ACS and MTP. It is considered that increased plasma level of FFA will closely associated with these factors and their regulations. Secretion of TNF-alpha from adipocytes increases in obesity and closely relates to the pathogenesis of insulin resistance. But the genetic mechanisms are not still clear. More studies about genetic factors which affect to lipoprotein metabolism will be needed and should be considered about the role on insulin resistance.
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PMID:[Molecular mechanism of insulin resistance in hyperlipidemia]. 1063 92

In lipoatrophic diabetes, a lack of fat is associated with insulin resistance and hyperglycemia. This is in striking contrast to the usual association of diabetes with obesity. To understand the underlying mechanisms, we transplanted adipose tissue into A-ZIP/F-1 mice, which have a severe form of lipoatrophic diabetes. Transplantation of wild-type fat reversed the hyperglycemia, dramatically lowered insulin levels, and improved muscle insulin sensitivity, demonstrating that the diabetes in A-ZIP/F-1 mice is caused by the lack of adipose tissue. All aspects of the A-ZIP/F-1 phenotype including hyperphagia, hepatic steatosis, and somatomegaly were either partially or completely reversed. However, the improvement in triglyceride and FFA levels was modest. Donor fat taken from parametrial and subcutaneous sites was equally effective in reversing the phenotype. The beneficial effects of transplantation were dose dependent and required near-physiological amounts of transplanted fat. Transplantation of genetically modified fat into A-ZIP/F-1 mice is a new and powerful technique for studying adipose physiology and the metabolic and endocrine communication between adipose tissue and the rest of the body.
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PMID:Surgical implantation of adipose tissue reverses diabetes in lipoatrophic mice. 1067 52

Insulin exerts wide variety of biological effects through interaction with its specific receptor, which belongs to a large family of receptor tyrosine kinases. The activated insulin receptor phosphorylates the intracellular substrate IRS protains, which then bind various signalling molecules that contain Src homology 2 domains. The first downstram molecule that was shown to associate with IRS protains is PI3-kinase. PI3-kinase contributes to a wide variety of biological actions. Both Akt(PKB), a serine-threonine kinase with a PH domain, and atypical PKC(PKC zeta, PKC lambda) have been implicated as downstream effectors of PI3-kinase. Insulin resistance contributes to the pathogenesis of NIDDM. Both primary, genetically, and secondary, environmentally factors are important for insulin resistance. The secondary factors include hyperglycemia, hyperlipidemia, obesity, TNF alpha, FFA(free fatty acid).
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PMID:[Insulin signalling system and mechanism of insulin resistance]. 1070 48

Multiple risk factor syndrome (MRFS) is a clustering of cardiovascular risk factors, which describes the epidemiological association of glucose intolerance, central obesity, hypertension, increased triglyceride level and decreased HDL-cholesterol, leading to the atherosclerosis. Insulin resistance is diagnosed clinically by fasting hyperinsulinemia, steady state plasma glucose (SSPG) method, insulin tolerance test and glucose clamp study. Visceral fat accumulation is supposed to play a central role in pathogenesis of MRFS and induces risk factors for cardiovascular disease through the increased TNF-alpha expression in adipose tissue and serum FFA level, which cause insulin resistance state. These risk factors should be prevented at early stage by the intervention in obesity, especially visceral fat accumulation.
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PMID:[Diagnostic criteria of insulin resistance and multiple risk factor syndrome]. 1070 66


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