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

1. Insulin resistance is an early and major feature in the development of non-insulin-dependent diabetes mellitus (NIDDM), but it is also associated with hyperlipidaemia, hypertension, obesity and cardiovascular disease, the so-called 'insulin-resistance syndrome' (Syndrome X). 2. There is a strong genetic determination of NIDDM and insulin resistance, but the environmental factors of calorie excess, reduced activity and obesity also make a major contribution. 3. Central (abdominal) obesity is much more strongly associated with insulin resistance than is overall obesity. From twin studies, there appears to be specific genetic determinants of central abdominal fat, independent of overall obesity. 4. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Isocaloric alteration of macronutrients substantially affects insulin sensitivity in rats but not, at least in the short-term, in humans. 5. Exercise training improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat. 6. Metformin has been the only available drug that has been used clinically to significantly improve insulin sensitivity, but the new 'glitazones' (thiazolidinediones) have a more specific effect via altered lipid metabolism.
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PMID:Pathogenesis of the insulin resistance syndrome (syndrome X). 931 89

GLUT4, the insulin-responsive glucose transporter, plays an important role in postprandial glucose disposal. Altered GLUT4 activity is suggested to be one of the factors responsible for decreased glucose uptake in muscle and adipose tissue in obesity and diabetes. To assess the effect of GLUT4 expression on whole-body glucose homeostasis, we disrupted the murine GLUT4 gene by homologous recombination. Male mice heterozygous for the mutation (GLUT4 +/-) exhibited a decrease in GLUT4 expression in adipose tissue and skeletal muscle. This decrease in GLUT4 expression did not result in obesity but led to increased serum glucose and insulin, reduced muscle glucose uptake, hypertension, and diabetic histopathologies in the heart and liver similar to those of humans with non-insulin-dependent diabetes mellitus (NIDDM). The male GLUT4 +/- mice represent a good model for studying the development of NIDDM without the complications associated with obesity.
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PMID:GLUT4 heterozygous knockout mice develop muscle insulin resistance and diabetes. 933 13

Rats fed a high-fat diet develop skeletal muscle insulin resistance. There is disagreement regarding whether a decrease in the GLUT4 isoform of the glucose transporter is responsible. We found that feeding rats a high-fat diet that reduced the responsiveness of glucose transport to insulin in skeletal muscles by approximately 25-45% in 4 weeks, had no significant effect on muscle GLUT4 content. There is also controversy regarding whether the contraction/anoxia activated pathway of glucose transport stimulation is affected by fat feeding. We found that stimulation of muscle glucose transport by either swimming, in situ contractions, or anoxia was depressed to a similar extent as insulin responsiveness in high-fat-fed rats. It has been suggested that the muscle insulin resistance caused by a high-fat diet is due to increased fat oxidation and glucose-fatty acid cycle activity. However, we found that insulin-stimulated glucose transport was reduced by approximately 40% when muscles of fat-fed rats were incubated under anoxic conditions under which fatty acid oxidation should not occur. Rats maintained on the high-fat diet up to 32 weeks developed the characteristics of the abdominal obesity syndrome, including insulin resistance, hyperinsulinemia, hyperglycemia, elevated LDL cholesterol and VLDL triglycerides, and marked visceral obesity. We conclude that 1) in rats fed a high-fat diet the muscle insulin resistance is not due to a decrease in total GLUT4 content or to increased fat oxidation, 2) fat feeding also results in resistance of muscle glucose transport to stimulation via the contraction/anoxia pathway, and 3) rats fed a high-fat diet may be a useful model of the abdominal obesity syndrome.
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PMID:Insulin resistance of muscle glucose transport in rats fed a high-fat diet: a reevaluation. 935 23

GLUT4, the insulin responsive-glucose transporter, mediates the rate limiting step of glucose metabolism in skeletal muscle and adipose tissue. GLUT4 expression is up-regulated by exercise training and thyroid hormone treatment and is down-regulated by fasting, streptozotocin-induced diabetes, obesity, high-fat diet, and denervation. Since overexpression of GLUT4 in insulin resistant db/db mice and high-fat diet-fed mice has been observed to dramatically improve glycemic control, increasing GLUT4 expression may be an effective strategy with which to alleviate insulin resistance. This review discusses recent findings on the regulation of the GLUT4 gene and on progress in the identification of regulatory elements in the promoter of the gene.
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PMID:Regulatory elements in the insulin-responsive glucose transporter (GLUT4) gene. 940 24

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

Genetically obese Zucker rats exhibit mild hyperglycaemia and hyperinsulinaemia suggesting the existence of peripheral insulin resistance. We have examined the effects of YM268, an analogue of thiazolidinedione, on the content and translocation of a glucose transporter (GLUT4) in epididymal adipose tissue in 11-week-old obese and lean Zucker rats. The administration of YM268 at a dose of 10 mg/kg for 2 weeks ameliorated hyperglycaemia, hyperinsulinaemia, and impaired glucose tolerance after glucose load in obese rats. The GLUT4 content per fat pad in obese rats was reduced to 36% of that in lean littermates. Obese rats treated with YM268 increased GLUT4 concentrations in their fat pads from a basal value of 36% up to 191% of the level in lean rats. Furthermore, in adipocytes prepared from obese rats, an increase in the ratio of GLUT4 in plasma membrane to the total amount of GLUT4 (PM-GLUT4 ratio) induced by the submaximal concentration of insulin (0.3 nmol/l) was significantly attenuated compared with that in lean rats. But the maximum effect of insulin (3 nmol/l) was not attenuated. Meanwhile, YM268 had no significant effect on the attenuated PM-GLUT4 ratio in response to insulin in obese rats. These data suggested that one of the mechanisms by which YM268 improved insulin resistance in obese Zucker rats was to normalize the decreased GLUT4 content in the adipose tissue.
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PMID:Insulin sensitizer YM268 ameliorates insulin resistance by normalizing the decreased content of GLUT4 in adipose tissue of obese Zucker rats. 943 23

We investigated the effect of long-term administration of highly purified eicosapentaenoic acid ethyl ester (EPA-E), an n-3 polyunsaturated fatty acid derived from fish oil, in comparison to the effects of lard, olive oil, safflower oil, or distilled water as the control on the development of insulin resistance in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a model of spontaneous non-insulin-dependent diabetes mellitus (NIDDM) with obesity. After 17 or 18 weeks of treatment, the glucose infusion rate (GIR) in the euglycemic insulin-glucose clamp test only showed a significant increase in EPA-E-treated rats compared with control rats given distilled water alone as the vehicle. The GIR in EPA-E-treated animals was approximately three times greater than in the controls. This is the first report to display the influence of various fatty acids on the development of insulin resistance in OLETF rats. We demonstrated that EPA-E prevents the onset of insulin resistance, whereas olive oil and safflower oil have no effect and lard exacerbates insulin resistance. Fatty acid analysis of phospholipids in skeletal muscle showed a significant increase of the C18:2, C20:5, and C22:5 components in EPA-E-treated rats and, conversely, a significant decrease in C20:4. In addition, EPA-E-treated rats showed a significant increase in GLUT4 mRNA in skeletal muscle when compared with control rats. Our results indicate that the beneficial effect of EPA-E on insulin resistance in OLETF rats is likely to be dependent on modification of the phospholipid components of the skeletal muscle membrane. These findings suggest that dietary fatty acids may play a key role in the development of insulin resistance in patients with NIDDM.
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PMID:Influence of highly purified eicosapentaenoic acid ethyl ester on insulin resistance in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous non-insulin-dependent diabetes mellitus. 943 43

The direct role of hormones on leptin synthesis has not yet been studied in cultured adipose cells or tissue from lean and obese subjects. Moreover, this hormonal regulation has never been addressed in human visceral fat, although this site plays a determinant role in obesity-linked disorders. In this study, we investigated the hormonal control of ob expression and leptin production in cultured visceral adipose tissue from lean and obese subjects. We more particularly focused on the interactions between glucocorticoids and insulin. We also briefly tackled the role of cAMP, which is still unknown in man. Visceral (and subcutaneous) adipose tissues from eight obese (body mass index, 41 +/- 2 kg/m2) and nine nonobese (24 +/- 1 kg/m2) subjects were sampled during elective abdominal surgery, and explants were cultured for up to 48 h in MEM. The addition of dexamethasone to the medium increased ob gene expression and leptin secretion in a time-dependent manner. Forty-eight hours after dexamethasone (50 nmol/L) addition, the cumulative integrated ob messenger ribonucleic acid (mRNA) and leptin responses were, respectively, approximately 5- and 4-fold higher in obese than in lean subjects. These responses closely correlated with the body mass index. The stimulatory effect of the glucocorticoid was also concentration dependent (EC50 = approximately 10 nmol/L). Although the maximal response was higher in obese than in lean subjects, the EC50 values were roughly similar in both groups. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion. Singularly, insulin even inhibited the dexamethasone-induced rise in ob mRNA and leptin release. This inhibition was observed in both lean and obese subjects, whereas the expected stimulation of insulin on glucose metabolism and the accumulation of mRNA species for the insulin-sensitive transporter GLUT4 and glyceraldehyde-3-phosphate dehydrogenase occurred in lean patients only. This inhibitory effect was already detectable at 10 nmol/L insulin and was also observed in subcutaneous fat. Although a lowering of intracellular cAMP concentrations is involved in some of the effects of insulin on adipose tissue, this cannot account for the present finding, because the addition of cAMP to the medium also decreased ob mRNA and leptin secretion (regardless of whether dexamethasone was present). In conclusion, glucocorticoids, at physiological concentrations, stimulated leptin secretion by enhancing the pretranslational machinery in human visceral fat. This effect was more pronounced in obese subjects due to a greater responsiveness of the ob gene and could contribute to the metabolic abnormalities associated with central obesity by para/endocrine actions of hyperleptinemia on adipocytes and liver. Unlike dexamethasone, insulin had no direct stimulatory effect on ob gene expression and leptin secretion, and even prevented the positive response to dexamethasone by a cAMP-independent mechanism that remained functional despite insulin resistance.
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PMID:Multihormonal control of ob gene expression and leptin secretion from cultured human visceral adipose tissue: increased responsiveness to glucocorticoids in obesity. 950 46

The resistance to insulin (insulin resistance, IR) is a common feature and a possible link between such frequent disorders as non-insulin dependent diabetes mellitus (NIDDM), hypertension and obesity. Pharmacological amelioration of IR and understanding its pathophysiology are therefore essential for successful management of these disorders. In this review, we will discuss the mechanisms of action of thiazolidinediones (TDs), a new family of insulin-sensitizing agents. Experimental studies of various models of IR and an increasing number of clinical studies have shown that TDs normalize a wide range of metabolic abnormalities associated with IR. By improving insulin sensitivity in skeletal muscles, the adipose tissue and hepatocytes, TDs reduce fasting hyperglycaemia and insulinaemia. Furthermore, TDs markedly influence lipid metabolism--they decrease plasma triglyceride, free fatty acid and LDL-cholesterol levels, and increase plasma HDL-cholesterol concentrations. Although TDs do not stimulate insulin secretion, they improve the secretory response of beta cells to insulin secretagogues. TDs act at various levels of glucose and lipid metabolism--ameliorate some defects in the signalling cascade distal to the insulin receptor and improve glucose uptake in insulin-resistant tissues via increased expression of glucose transporters GLUT1 and GLUT4. TDs also activate glycolysis in hepatocytes, oppose intracellular actions of cyclic AMP, and increase intracellular magnesium levels. TDs bind to peroxisome proliferator activating receptors gamma (PPAR gamma), members of the steroid/thyroid hormone nuclear receptor superfamily of transcription factors involved in adipocyte differentiation and glucose and lipid homeostasis. Activation of PPAR gamma results in the expression of adipocyte-specific genes and differentiation of various cell types in mature adipocytes capable of active glucose uptake and energy storage in the form of lipids. Furthermore, TDs inhibit the pathophysiological effects exerted by tumour-necrosis factor (TNF alpha), a cytokine involved in the pathogenesis of IR. These effects are most likely also mediated by stimulation of PPAR gamma. In mature adipocytes, PPAR gamma stimulation inhibits stearoyl-CoA desaturase 1 (SCD1) enzyme activity resulting in a change of cell membrane fatty acid composition. Apart from their metabolic actions, TDs modulate cardiovascular function and morphology independently of the insulin-sensitizing effects. TDs decrease blood pressure in various models of hypertension as well as in hypertensive insulin-resistant patients, and inhibit proliferation, hypertrophy and migration of vascular smooth muscle cells (VSMC) induced by growth factors. These processes are considered to be crucial in the development of vascular remodelling, atherosclerosis and diabetic organ complications. TDs induce vasodilation by blockade of Ca2+ mobilisation from intracellular stores and by inhibition of extracellular calcium uptake via L-channels. Furthermore, TDs interfere with pressor systems (catecholamines, renin-angiotensin system) and enhance endothelium-dependent vasodilation. A key role of TDs effects in vascular remodelling is played by inhibition of the mitogen-activated protein (MAP) kinase pathway. This signalling pathway is important for VSMC growth and migration in response to stimulation with tyrosine-kinase dependent growth factors. In addition to the vasoprotective mechanisms mentioned above, troglitazone, the latest representative of this pharmacological group, possesses antioxidant actions comparable to vitamin E. In summary, TDs have the unique ability to attack mechanisms responsible for metabolic alterations as well as for vascular abnormalities characteristic for IR. Therefore, TDs represent a powerful research tool in attempts to find a common denominator underlying the pathophysiology of the metabolic syndrome X. A recently reported link between MAP kinase signalling pathway and PPAR gamma
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PMID:Thiazolidinediones--tools for the research of metabolic syndrome X. 980 67

1. Skeletal muscle is a major glucose-utilizing tissue in the absorptive state and alterations in muscle insulin-stimulated glucose uptake lead to derangements in whole body glucose disposal. 2. Furthermore, muscle GLUT4 overexpression in transgenic animals ameliorates insulin resistance associated with obesity or diabetes, which suggests that increasing GLUT4 in muscle by pharmacological intervention may be an effective therapy in insulin-resistant states. 3. This highlights the importance of understanding the pathways that upregulate GLUT4 glucose transporter expression in muscle. 4. We review studies describing the regulation of GLUT4 and the information currently available on the mechanisms that control GLUT4 expression in muscle.
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PMID:Searching for ways to upregulate GLUT4 glucose transporter expression in muscle. 980 66


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