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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We investigated whether variability at the insulin receptor substrate (IRS)-2 locus plays a role in the etiology of early-onset autosomal dominant type 2 diabetes. By means of radiation hybrid mapping, we placed the human IRS-2 gene on 13q at 8.6 cRays from SHGC-37358. Linkage between diabetes and two polymorphic markers located in this region (D13S285 and D13S1295) was then evaluated in 29 families with early-onset autosomal dominant type 2 diabetes. Included were 220 individuals with diabetes, impaired glucose tolerance, or gestational diabetes (mean age at diabetes diagnosis 36 +/- 17 years) and 146 nondiabetic subjects. Overall, strongly negative logarithm of odds (LOD) scores for linkage with diabetes were obtained by multipoint parametric analysis (LOD score -45.4 at D13S285 and -40.9 at D13S1295). No significant evidence of linkage was obtained under the hypothesis of heterogeneity or by nonparametric methods. Fourteen pedigrees for which linkage could not be excluded (LOD score > -2.0) were screened for mutations in the IRS-2 coding region by dideoxy fingerprinting. However, no mutations segregating with diabetes could be detected in these families. These data indicate that IRS-2 is not a major gene for early-onset autosomal dominant type 2 diabetes, although a role of mutations in the promoter region cannot be excluded at this time.
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PMID:Exclusion of insulin receptor substrate 2 (IRS-2) as a major locus for early-onset autosomal dominant type 2 diabetes. 1007 69

Carbon nuclear magnetic resonance (13C NMR) spectroscopy and phosphorus (31p) NMR spectroscopy have been used to help define the contribution of insulin-stimulated muscle glycogen synthesis to whole-body insulin-stimulated glucose metabolism in normal individuals and the extent to which this process is defective in patients with type 2 (non-insulin-dependent) diabetes. Assessments of the response to hyperglycemic-hyperinsulinemic clamping have shown that abnormalities of muscle glycogen synthesis, apparently mediated by a defect in GLUT-4 transport and/or hexokinase activity, play a major role in causing insulin resistance in type 2 diabetes. Studies of the mechanisms by which free fatty acids (FFA) cause insulin resistance in humans indicate that increased FFA levels inhibit glucose transport, which may be a consequence of decreased insulin receptor substrate (IRS-1)-associated phosphatidylinositol 3-kinase activity. 13C NMR spectroscopy studies have documented that liver glycogen concentrations are reduced and the rate of hepatic gluconeogenesis is increased in subjects with type 2 diabetes; thus, the higher rate of glucose production in type 2 diabetes can be attributed entirely to increased rates of hepatic gluconeogenesis. These cellular mechanisms of insulin resistance can be addressed through combination therapy with agents that reverse the principal pathophysiologic defects of type 2 diabetes. The biguanide metformin appears to lower glucose by suppressing hepatic glucose production, whereas the thiazolidinedione troglitazone appears to increase glucose clearance by peripheral tissues. The two agents together have been shown to provide better glucose control than either drug alone, without stimulating insulin secretion.
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PMID:Cellular mechanisms of insulin resistance in humans. 1041 51

Women who develop gestational diabetes mellitus (GDM) have severe insulin resistance and markedly increased risk to develop subsequent type 2 diabetes. We investigated the effects of pregnancy and GDM on glucose transport activity and the expression and phosphorylation of the insulin receptor and insulin receptor substrate (IRS)-1 in human skeletal muscle fiber strips in vitro. Rectus abdominis muscle biopsies were obtained at the time of cesarean section from 11 pregnant women with normal glucose tolerance (pregnant control), 7 pregnant women with GDM, and 11 nonpregnant women undergoing elective surgery (nonpregnant control). Subjects were matched for age and similar degree of obesity. The rate of maximal insulin (10(-7) mol/l)-stimulated 2-deoxyglucose transport was reduced by 32% (P < 0.05) in muscle strips from the pregnant control group and even further in GDM subjects by 54% (P < 0.05 vs. pregnant control). The maximal effect of insulin on tyrosine phosphorylation of the insulin receptor was 37% lower (P < 0.05) in GDM subjects than in pregnant control subjects and was not related to changes in the abundance of the insulin receptor. Compared with nonpregnant control subjects, maximal insulin-stimulated IRS-1 tyrosine phosphorylation was significantly lower by 59 +/- 24% (mean +/- SD) (P < 0.05) and 62 +/- 28% (P < 0.05) in pregnant control and GDM subjects, respectively. This was reflected by a 23% (P < 0.05) and 44% (P < 0.002) reduction in IRS-1 protein levels in muscle from pregnant control and GDM subjects. Both pregnant control and GDM subjects exhibited a 1.5- to 2-fold increase in the levels of IRS-2 (P < 0.01) and p85alpha regulatory subunit of phosphatidylinositol (PI) 3-kinase (P < 0.05), despite reduced glucose transport activity. These data indicate that insulin resistance to glucose transport during pregnancy is uniquely associated with a decrease in IRS-1 tyrosine phosphorylation, primarily due to decreased expression of IRS-1 protein. However, in GDM subjects, a decrease in tyrosine phosphorylation of the insulin receptor beta-subunit is associated with further decreases in glucose transport activity. Thus, impaired insulin receptor autophosphorylation is an important early distinction underlying muscle insulin resistance in young women with GDM, and it may underlie future risk for the development of type 2 diabetes.
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PMID:Impaired glucose transport and insulin receptor tyrosine phosphorylation in skeletal muscle from obese women with gestational diabetes. 1048 Jun 12

Type 2 diabetes is characterized by abnormalities of insulin action in muscle, adipose tissue, and liver and by altered beta-cell function. To analyze the role of the insulin signaling pathway in these processes, we have generated mice with combined heterozygous null mutations in insulin receptor (ir), insulin receptor substrate (irs-1), and/or irs-2. Diabetes developed in 40% of ir/irs-1/irs-2(+/-), 20% of ir/irs-1(+/-), 17% of ir/irs-2(+/-), and 5% of ir(+/-) mice. Although combined heterozygosity for ir/irs-1(+/-) and ir/irs-2(+/-) results in a similar number of diabetic mice, there are significant differences in the underlying metabolic abnormalities. ir/irs-1(+/-) mice develop severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. In contrast, ir/irs-2(+/-) mice develop severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. Triple heterozygotes develop severe insulin resistance in skeletal muscle and liver and marked beta-cell hyperplasia. These data indicate tissue-specific differences in the roles of IRSs to mediate insulin action, with irs-1 playing a prominent role in skeletal muscle and irs-2 in liver. They also provide a practical demonstration of the polygenic and genetically heterogeneous interactions underlying the inheritance of type 2 diabetes.
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PMID:Tissue-specific insulin resistance in mice with mutations in the insulin receptor, IRS-1, and IRS-2. 1064 98

Insulin resistance is observed in several diseases such as non insulin dependent diabetes mellitus (NIDDM) or polycystic ovarian syndrome (PCOS). To understand genetic determinism of this abnormality we have developed a multidisciplinary approach including selection of phenotypes with insulin resistance confirmed in vivo by minimal model of Bergman and characterization of cellular defects in insulin action on circulating erythrocytes and monocytes. Exploration of variability in candidate genes by direct sequencing in some genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gene associated with major defects in insulin binding or kinase activity. In other rare genetic syndromes or patients affected by NIDDM or PCOS defects appear to be located at post-receptor level, where IRS (insulin receptor substrate) genes are the most attractive candidates. Prevalence of some allelic variants suggested a potential role of IRS genes in insulin resistance, although their involvement in the pathogenesis of NIDDM remains controversial. Genotype-phenotype correlations in first degree relatives of an index case caring the Type A syndrome, suggested that association of allelic variants of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synergistic effects, to phenotypic expression of defects in signal transduction. These mechanisms through genetic epistasis, involving several genes in insulin action, fit better with the polygenic nature of current forms of NIDDM and represent a good model in the study of pathogenesis of insulin resistance.
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PMID:[Insulin resistance: from clinical diagnosis to molecular genetics. Implications in diabetes mellitus]. 1098 57

To investigate the role of insulin receptor substrate (IRS)-2 in vivo, we generated IRS-2-deficient mice by gene targeting. Although homozygous IRS-2-deficient mice (IRS-2-/- mice) had a body weight similar to wild-type mice, they progressively developed type 2 diabetes at 10 weeks. IRS-2-/- mice showed insulin resistance and a defect in the insulin-stimulated signaling pathway in liver but not in skeletal muscle. Despite insulin resistance, the amount of beta-cells was reduced to 83% of that in wild-type mice, which was in marked contrast to the 85% increase in the amount of beta-cells in IRS-1-deficient mice (IRS-1-/- mice) to compensate for insulin resistance. Thus, IRS-2 plays a crucial role in the regulation of beta-cell mass. On the other hand, insulin secretion by the same number of cells in response to glucose measured ex vivo was significantly increased in IRS-2-/- mice compared with wild-type mice but was decreased in IRS-1-/- mice. These results suggest that IRS-1 and IRS-2 may play different roles in the regulation of beta-cell mass and the function of individual beta-cells.
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PMID:Disruption of insulin receptor substrate 2 causes type 2 diabetes because of liver insulin resistance and lack of compensatory beta-cell hyperplasia. 1107 55

Our laboratory has demonstrated that insulin rapidly stimulates myosin-bound phosphatase (MBP) activity in vascular smooth muscle cells (VSMCs). In this study, we examined whether diabetes is accompanied by alterations in MBP activation and elucidated the components of the signaling pathway that mediate the effects of diabetes. VSMCs isolated from Goto-Kakizaki (GK) diabetic rats (a model for type 2 diabetes) exhibited marked impairment in MBP activation by insulin that was accompanied by failure of insulin to decrease the phosphorylation of a regulatory myosin-bound subunit (MBS) of MBP and inhibit Rho kinase activity resulting in increased myosin light-chain (MLC)20 phosphorylation and VSMC contraction. In VSMCs isolated from control rats, insulin inactivates Rho kinase and decreases MBS phosphorylation, leading to MBP activation. In addition to this pathway, insulin also appears to activate MBP by stimulating the phosphatidylinositol (PI) 3-kinase/nitric oxide (NO)/cGMP signaling pathway because treatment with the synthetic inhibitors of PI 3-kinase, NO synthase (NOS), and cGMP all blocked insulin's effect on MBP activation, whereas cGMP agonists and sodium nitroprusside (SNP) mimicked insulin's effect on MBP activation. VSMCs from diabetic GK rats exhibit reductions in insulin-mediated induction of inducible NOS protein expression and cGMP generation but normal MBP activation in response to SNP and cGMP agonist. This observation led us to examine the effect of diabetes on the activation status of the upstream insulin-signaling components. Although GK diabetes did not affect insulin-stimulated tyrosine phosphorylation of the insulin receptor or its content, insulin-stimulated insulin receptor substrate (IRS)-1 tyrosine phosphorylation was severely impaired. This was accompanied by marked reductions in IRS-1-associated PI 3-kinase activity. We conclude that insulin stimulates MBP via its regulatory subunit, MBS, by inactivating Rho kinase and stimulating NO/cGMP signaling via PI 3-kinase as part of a complex signaling network that controls MLC20 phosphorylation and VSMC contraction. Defective signaling via Rho kinase and the IRS-1/PI 3-kinase/NOS/cGMP pathway may mediate the inhibitory effects of hyperglycemia and diabetes on MBP activation in this experimental model.
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PMID:Diabetes in the Goto-Kakizaki rat is accompanied by impaired insulin-mediated myosin-bound phosphatase activation and vascular smooth muscle cell relaxation. 1111 23

In recent years, a number of cross-talk systems have been identified which feed into the insulin signalling cascade at the level of insulin receptor substrate (IRS) tyrosine phosphorylation, e.g., receptor and non-receptor tyrosine kinases and G-protein-coupled receptors. At the molecular level, a number of negative modulator and feedback systems somehow interacting with the beta-subunit (catecholamine-, phorbolester-, or tumor necrosis factor-alpha-induced serine/threonine phosphorylation, carboxy-terminal trimming by a thiol-dependent protease, association of inhibitory/regulatory proteins such as RAD, PC1, PED, alpha2-HS-glycoprotein) have been identified as candidate mechanisms for the impairment of insulin receptor function by elevations in the activity and/or amount of the corresponding modification enzymes/inhibitors. Both decreased responsiveness and sensitivity of the insulin receptor beta-subunit for insulin-induced tyrosine autophosphorylation have been demonstrated in several cellular and animal models of metabolic insulin resistance as well as in the adipose tissue and skeletal muscle of diabetic patients and obese Pima Indians compared to non-obese subjects. Therefore, induction of the insulin signalling cascade by bypassing the defective insulin receptor kinase may be useful for the therapy of non-insulin dependent diabetes mellitus. During the past two decades, phosphoinositolglycans (PIGs) of various origin have been demonstrated to exert potent insulin-mimetic metabolic effects upon incubation with cultured or isolated muscle and adipose cells. However, it remained to be elucidated whether these compounds actually manage to trigger insulin signalling and if so at which level of hierarchy within the signalling cascade the site of interference is located. Recent studies using isolated rat adipocytes and chemically synthesized PIG compounds point to IRS1/3 tyrosine phosphorylation by p59Lyn kinase as the site of cross-talk, the negative regulation of which by interaction with caveolin is apparently abrogated by PIG. This putative mechanism is thus compatible with the recently formulated caveolin signalling hypothesis, the supporting data for which are reviewed here. Though we have not obtained experimental evidence for the involvement of PIG in physiological insulin action, the potential cross-talk between insulin and PIG signalling, including the caveolae/detergent-insoluble glycolipid-enriched rafts as the compartments where the corresponding signalling components are concentrated, thus represent novel targets for signal transduction therapy.
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PMID:Signalling via caveolin: involvement in the cross-talk between phosphoinositolglycans and insulin. 1121 27

Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at significantly increased risk of developing type 2 diabetes mellitus (DM). Studies in isolated adipocytes and in cultured skin fibroblasts from PCOS women have demonstrated intrinsic postbinding defects in insulin-mediated glucose metabolism. In fibroblasts, the mitogenic pathway of insulin action is intact, consistent with a selective defect in insulin signaling. While PCOS skeletal muscle is resistant to insulin in vivo, cultured muscle cells have normal insulin sensitivity, consistent with a major role of extrinsic factors in producing insulin resistance in this tissue. Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins may be involved in the pathogenesis of insulin resistance in PCOS. The putative serine kinase is extrinsic to the insulin receptor but its identity is unknown. The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction.
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PMID:Insulin resistance in polycystic ovary syndrome: progress and paradoxes. 1123 18

The pleiotropic actions of insulin are mediated by a single receptor tyrosine kinase. Structure/function relationships of the insulin receptor have been conclusively established, and the early steps of insulin signaling are known in some detail. A generally accepted paradigm is that insulin receptors, acting through insulin receptor substrates, stimulate the lipid kinase activity of phosphatidylinositol 3-kinase. The rapid rise in Tris-phosphorylated inositol (PIP(3)) that ensues triggers a cascade of PIP(3)-dependent serine/threonine kinases. Among the latter, Akt (a product of the akt protooncogene) and atypical protein kinase C isoforms are thought to be involved in insulin regulation of glucose transport and oxidation; glycogen, lipid, and protein synthesis; and modulation of gene expression. The presence of multiple insulin-regulated, PIP(3)-dependent kinases is consistent with the possibility that different pathways are required to regulate different biological actions of insulin. Additional work remains to be performed to understand the distal components of insulin signaling. Moreover, there exists substantial evidence for insulin receptor substrate- and/or phosphatidylinositol 3-kinase-independent pathways of insulin action. The ultimate goal of these investigations is to provide clues to the pathogenesis and treatment of the insulin resistant state that is characteristic of type 2 diabetes.
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PMID:Clinical review 125: The insulin receptor and its cellular targets. 1123 71


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