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

Insulin resistance of skeletal muscle in humans, animals, and cells is often strongly correlated with increased lipid availability. The elevation of certain intracellular lipid species can lead to the activation of signal transduction pathways that inhibit normal insulin action. Thus, increased diacylglycerol levels in muscle are associated with the activation of one or more isoforms of the protein kinase C family, which is known to attenuate insulin signaling, especially at the level of IRS-1. In addition, de novo synthesis of ceramide can inhibit more distal sites by the activation of protein phosphatase 2A and hence promote the dephosphorylation and inactivation of protein kinase B. Such mechanisms may account at least in part for the reduced insulin sensitivity occurring in obesity and type 2 diabetes where lipid oversupply is a major factor.
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PMID:Protein kinase C and lipid-induced insulin resistance in skeletal muscle. 1207 44

Increased release and action of proinflammatory cytokines are thought to be responsible for the occurrence of insulin resistance in inflammatory and metabolic diseases including obesity-linked diabetes. Recent work has identified several signal transduction pathways activated by cytokines which can impede on insulin receptor signaling in skeletal muscle, liver, and adipose cells. A majority of these complex and interrelated pathways appear to converge at the level of insulin receptor substrate-1 by promoting its serine phosphorylation in order to mediate heterologous inhibition of insulin receptor substrate-1 signaling which, in turn, counterregulates the insulin response. Other possible mechanisms of insulin resistance in cytokine-treated cells include nitration of insulin receptor substrate-1 tyrosine residues by nitric oxide-derived reactive nitrogen species as well as direct interference with insulin signaling molecules further downstream such as protein kinase B/Akt. A detailed knowledge of the complex network of intracellular signaling pathways triggered by cytokines may be instrumental in the development of new approaches to prevent insulin resistance in acute and chronic inflammatory settings.
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PMID:Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. 1210 72

Insulin resistance of skeletal muscle glucose transport is a key defect in the development of impaired glucose tolerance and Type 2 diabetes. It is well established that both an acute bout of exercise and chronic endurance exercise training can have beneficial effects on insulin action in insulin-resistant states. This review summarizes the present state of knowledge regarding these effects in the obese Zucker rat, a widely used rodent model of obesity-associated insulin resistance, and in insulin-resistant humans with impaired glucose tolerance or Type 2 diabetes. A single bout of prolonged aerobic exercise (30-60 min at approximately 60-70% of maximal oxygen consumption) can significantly lower plasma glucose levels, owing to normal contraction-induced stimulation of GLUT-4 glucose transporter translocation and glucose transport activity in insulin-resistant skeletal muscle. However, little is currently known about the effects of acute exercise on muscle insulin signaling in the postexercise state in insulin-resistant individuals. A well-established adaptive response to exercise training in conditions of insulin resistance is improved glucose tolerance and enhanced skeletal muscle insulin sensitivity of glucose transport. This training-induced enhancement of insulin action is associated with upregulation of specific components of the glucose transport system in insulin-resistant muscle and includes increased protein expression of GLUT-4 and insulin receptor substrate-1. It is clear that further investigations are needed to further elucidate the specific molecular mechanisms underlying the beneficial effects of acute exercise and exercise training on the glucose transport system in insulin-resistant mammalian skeletal muscle.
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PMID:Invited review: Effects of acute exercise and exercise training on insulin resistance. 1213 93

Insulin receptor substrate 1 (IRS-1) gene polymorphisms have been identified in type 2 diabetic patients; however, it is unclear how such polymorphisms contribute to the development of diabetes. Here we introduced obesity in heterozygous IRS-1 knockout (IRS-1(+/-)) mice by gold-thioglucose (GTG) injection and studied the impact of reduced IRS-1 expression on obesity-linked insulin resistance. GTG injection resulted in approximately 30% weight gain in IRS-1(+/-) and wild type (WT) mice, compared with saline-injected controls. There was no difference in insulin sensitivity between lean IRS-1(+/-) and lean WT. Elevated fasting insulin levels but no change in fasting glucose were noted in obese IRS-1(+/-) and WT compared with the respective lean controls. Importantly, fasting insulin in obese IRS-1(+/-) was 1.5-fold higher (P<0.05) than in obese WT, and an insulin tolerance test showed a profound insulin resistance in obese IRS-1(+/-) compared with obese WT. The islets of obese IRS-1(+/-) were 1.4-fold larger than those of obese WT. The expression of insulin receptor and IRS-1 and IRS-2 was decreased in obese IRS-1(+/-), which could in part explain the profound insulin resistance in these mice. Our results suggest that IRS-1 is the suspected gene for type 2 diabetes and its polymorphisms could worsen insulin resistance in the presence of other additional factors, such as obesity.
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PMID:Heterozygous knockout of the IRS-1 gene in mice enhances obesity-linked insulin resistance: a possible model for the development of type 2 diabetes. 1217 70

Rhesus monkeys frequently develop obesity and insulin resistance followed by type 2 diabetes when allowed free access to chow. This insulin resistance is partly due to defective glucose transport into skeletal muscle. In this study, we examined signaling factors required for insulin-stimulated glucose transport in muscle biopsies taken during euglycemic-hyperinsulinemic clamps in nondiabetic, obese prediabetic, and diabetic monkeys. Insulin increased activities of insulin receptor substrate (IRS)-1-dependent phosphatidylinositol (PI) 3-kinase and its downstream effectors, atypical protein kinase Cs (aPKCs) (zeta/lambda/iota) and protein kinase B (PKB) in muscles of nondiabetic monkeys. Insulin-induced increases in glucose disposal and aPKC activity diminished progressively in prediabetic and diabetic monkeys. Decreases in aPKC activation appeared to be at least partly due to diminished activation of IRS-1-dependent PI 3-kinase, but direct activation of aPKCs by the PI 3-kinase lipid product PI-3,4,5-(PO(4))(3) was also diminished. In conjunction with aPKCs, PKB activation was diminished in prediabetic muscle but, differently from aPKCs, seemed to partially improve in diabetic muscle. Interestingly, calorie restriction and avoidance of obesity largely prevented development of defects in glucose disposal and aPKC activation. Our findings suggest that defective activation of aPKCs contributes importantly to obesity-dependent development of skeletal muscle insulin resistance in prediabetic and type 2 diabetic monkeys.
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PMID:Skeletal muscle insulin resistance in obesity-associated type 2 diabetes in monkeys is linked to a defect in insulin activation of protein kinase C-zeta/lambda/iota. 1235 30

Ciliary neurotrophic factor (CNTF) is primarily known for its roles as a lesion factor released by the ruptured glial cells that prevent neuronal degeneration. However, CNTF has also been shown to cause weight loss in a variety of rodent models of obesity/type II diabetes, whereas a modified form also causes weight loss in humans. CNTF administration can correct or improve hyperinsulinemia, hyperphagia, and hyperlipidemia associated with these models of obesity. In order to investigate the effects of CNTF on fat cells, we examined the expression of CNTF receptor complex proteins (LIFR, gp130, and CNTFRalpha) during adipocyte differentiation and the effects of CNTF on STAT, Akt, and MAPK activation. We also examined the ability of CNTF to regulate the expression of adipocyte transcription factors and other adipogenic proteins. Our studies clearly demonstrate that the expression of two of the three CNTF receptor complex components, CNTFRalpha and LIFR, decreases during adipocyte differentiation. In contrast, gp130 expression is relatively unaffected by differentiation. In addition, preadipocytes are more sensitive to CNTF treatment than adipocytes, as judged by both STAT 3 and Akt activation. Despite decreased levels of CNTFRalpha expression in fully differentiated 3T3-L1 adipocytes, CNTF treatment of these cells resulted in a time-dependent activation of STAT 3. Chronic treatment of adipocytes resulted in a substantial decrease in fatty-acid synthase and a notable decline in SREBP-1 levels but had no effect on the expression of peroxisome proliferator-activated receptor gamma, acrp30, adipocyte-expressed STAT proteins, or C/EBPalpha. However, CNTF resulted in a significant increase in IRS-1 expression. CNTFRalpha receptor expression was substantially induced in the fat pads of four rodent models of obesity/type II diabetes as compared with lean littermates. Moreover, we demonstrated that CNTF can activate STAT 3 in adipose tissue and skeletal muscle in vivo. In summary, CNTF affects adipocyte gene expression, and the specific receptor for this cytokine is induced in rodent models of obesity/type II diabetes.
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PMID:The regulation and activation of ciliary neurotrophic factor signaling proteins in adipocytes. 1242 52

Diet-induced obesity is known to cause peripheral insulin resistance in rodents. We have recently found that feeding cod protein to high-fat-fed rats prevents the development of insulin resistance in skeletal muscle. In the present study, we have further explored the cellular mechanisms behind this beneficial effect of cod protein on skeletal muscle insulin sensitivity. Rats were fed a standard chow diet or a high-fat diet in which the protein source was either casein, soy, or cod proteins for 4 weeks. Whole-body and muscle glucose disposal were reduced by approximately 50% in rats fed high-fat diets with casein or soy proteins, but these impairments were not observed in animals fed cod protein. Insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrate (IRS) proteins were similar in muscle of chow- and high-fat-fed rats regardless of the dietary protein source. However, IRS-1-associated phosphatidylinositol (PI) 3-kinase activity was severely impaired (-60%) in muscle of high-fat-fed rats consuming casein or soy protein. In marked contrast, feeding rats with cod protein completely prevented the deleterious effect of fat feeding on insulin-stimulated PI 3-kinase activity. The activation of the downstream kinase Akt/PKB by insulin, assessed by in vitro kinase assay and phosphorylation of GSK-3beta, were also impaired in muscle of high-fat-fed rats consuming casein or soy protein, but these defects were also fully prevented by dietary cod protein. However, no effect of cod protein was observed on atypical protein kinase C activity. Normalization of PI 3-kinase/Akt activation by insulin in rats fed high-fat diets with cod protein was associated with improved translocation of GLUT4 to the T-tubules but not to the plasma membrane. Taken together, these results show that dietary cod protein is a natural insulin-sensitizing agent that appears to prevent obesity-linked muscle insulin resistance by normalizing insulin activation of the PI 3-kinase/Akt pathway and by selectively improving GLUT4 translocation to the T-tubules.
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PMID:Dietary cod protein restores insulin-induced activation of phosphatidylinositol 3-kinase/Akt and GLUT4 translocation to the T-tubules in skeletal muscle of high-fat-fed obese rats. 1250 90

Interleukin-6 (IL-6) is one of several pro-inflammatory cytokines implicated in insulin resistance during infection, cachexia, and obesity. We recently demonstrated that IL-6 inhibits insulin signaling in hepatocytes (Senn, J. J., Klover, P. J., Nowak, I. A., and Mooney, R. A. (2002) Diabetes 51, 3391-3399). Members of the suppressors of cytokine signaling (SOCS) family associate with the insulin receptor (IR), and their ectopic expression inhibits IR signaling. Since several SOCS proteins are induced by IL-6, a working hypothesis is that IL-6-dependent insulin resistance is mediated, at least in part, by induction of SOCS protein(s) in insulin target cells. To examine the involvement of SOCS protein(s) in IL-6-dependent inhibition of insulin receptor signaling, HepG2 cells were treated with IL-6 (20 ng/ml) for periods from 1 min to 8 h. IL-6 induced SOCS-3 transcript at 30 min with a maximum effect at 1 h. SOCS-3 protein levels were also markedly elevated at 1 h. Transcript and protein levels returned to near basal levels by 2 h. SOCS-3 induction by IL-6 paralleled IL-6-dependent inhibition of IR signal transduction. Ectopically expressed SOCS-3 associated with the IR and suppressed insulin-dependent receptor autophosphorylation, insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, association of IRS-1 with the p85 subunit of phosphatidylinositol 3-kinase, and activation of Akt. SOCS-3 was also a direct inhibitor of insulin receptor autophosphorylation in vitro. In mice exposed to IL-6 for 60-90 min, hepatic SOCS-3 expression was increased. This was associated with inhibition of hepatic insulin-dependent receptor autophosphorylation and IRS-1 tyrosine phosphorylation. These data suggest that induction of SOCS-3 in liver may be an important mechanism of IL-6-mediated insulin resistance.
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PMID:Suppressor of cytokine signaling-3 (SOCS-3), a potential mediator of interleukin-6-dependent insulin resistance in hepatocytes. 1256 Mar 30

Elevated levels of resistin have been proposed to cause insulin resistance and therefore may serve as a link between obesity and type 2 diabetes. However, its role in skeletal muscle metabolism is unknown. In this study, we examined the effect of resistin on insulin-stimulated glucose uptake and the upstream insulin-signaling components in L6 rat skeletal muscle cells that were either incubated with recombinant resistin or stably transfected with a vector containing the myc-tagged mouse resistin gene. Transfected clones expressed intracellular resistin, which was released in the medium. Incubation with recombinant resistin resulted in a dose-dependent inhibition of insulin-stimulated 2-deoxyglucose (2-DG) uptake. The inhibitory effect of resistin on insulin-stimulated 2-DG uptake was not the result of impaired GLUT4 translocation to the plasma membrane. Furthermore, resistin did not alter the insulin receptor (IR) content and its phosphorylation, nor did it affect insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation, its association with the p85 subunit of phosphatidylinositol (PI) 3-kinase, or IRS-1-associated PI 3-kinase enzymatic activity. Insulin-stimulated phosphorylation of Akt/protein kinase B-alpha, one of the downstream targets of PI 3-kinase and p38 MAPK phosphorylation, was also not affected by resistin. Expression of resistin also inhibited insulin-stimulated 2-DG uptake when compared with cells expressing the empty vector (L6Neo) without affecting GLUT4 translocation, GLUT1 content, and IRS-1/PI 3-kinase signaling. We conclude that resistin does not alter IR signaling but does affect insulin-stimulated glucose uptake, presumably by decreasing the intrinsic activity of cell surface glucose transporters.
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PMID:Resistin inhibits glucose uptake in L6 cells independently of changes in insulin signaling and GLUT4 translocation. 1261 60

Hypertension, insulin resistance, and obesity are common age-related metabolic disorders that are often associated with increased oxidative stress and the resultant vascular damage. Underlying mechanisms have been suggested, and age-related overproduction of oxidative stress is one possible candidate. Since we recently found a vasoactive peptide, adrenomedullin, to be an endogenous antioxidant that potently inhibits oxidative stress-induced vascular damage, in the current study we evaluated oxidative stress-induced changes in aged mice. Insulin sensitivities in young and aged adrenomedullin-deficient mice were measured by means of the hyperinsulinemic-euglycemic clamp method; insulin resistance was apparent in aged adrenomedullin-deficient mice with increased urinary excretion of 8-iso-prostaglandin F2alpha, a marker of oxidative stress, but not in young adrenomedullin-deficient mice. Concomitantly, only aged adrenomedullin-deficient mice not only showed increased production of muscular reactive oxygen species, as demonstrated by the electron spin resonance method, but also had significantly decreased insulin-stimulated glucose uptake into the soleus muscle associated with impairment of insulin signals such as insulin receptor substrate-1,2 and phosphatidylinositol-3 kinase activities. In turn, these abnormalities could be nearly reversed by either treatment with 4-hydroxy-2,2,6,6-tetramethyl-piperidine-N-oxyl, a membrane-permeable superoxide dismutase mimetic, or adrenomedullin supplementation. Evidence presented in this report suggests that age-related accumulation of oxidative stress is involved in blood pressure regulation and insulin resistance in aged adrenomedullin-deficient mice, and adrenomedullin is thus an endogenous substance counteracting oxidative stress-induced insulin resistance associated with aging.
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PMID:Deficiency of adrenomedullin induces insulin resistance by increasing oxidative stress. 1266 90


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