Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin receptor substrate-1 (IRS-1) plays an important role in insulin-stimulated signaling mechanisms. Therefore, we investigated the frequency and clinical significance of variants in the coding region of this gene in patients with non-insulin-dependent diabetes (NIDDM). Initial screening included a population-based sample of 40 Finnish patients with typical NIDDM. Applying single strand conformation polymorphism analysis the following amino acid substitutions were found among the 40 NIDDM patients: Gly818-Arg, Ser892Gly, and Gly971Arg. The first two variants have not been previously reported. Additional samples of 72 patients with NIDDM and 104 healthy control subjects with completely normal oral glucose tolerance test and a negative family history of diabetes were screened. The most common polymorphism was the Gly971Arg substitution which was found in 11 (9.8%) of 112 NIDDM patients and in 9 (8.7%) of 104 control subjects. The Gly818Arg substitution was found in 2 (1.8%) of NIDDM patients and in 2 (1.9%) of control subjects, and the Ser892Gly substitution was found in 3 (2.7%) NIDDM patients and in 1 (1.0%) control subject. The Gly971Arg substitution was not associated with an impairment in insulin secretion capacity (estimated by insulin responses in an oral glucose tolerance test or by the hyperglycemic clamp) or insulin action (estimated by the euglycemic clamp). Of the three amino acid substitutions observed Ser892Gly is the most interesting one since it abolishes one of the potential serine phosphorylation sites (SPGE) which is located immediately NH2-terminal to the only SH2 binding site of growth factor receptor-bound protein (GRB2), and thus could potentially influence some aspects of signal transduction and metabolic response to insulin.
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PMID:Insulin receptor substrate-1 variants in non-insulin-dependent diabetes. 808 55

Patients with insulin-dependent diabetes who receive pancreas/kidney transplants lose their need for insulin injections, but they become hyperinsulinemic and insulin resistant, and sometimes develop noninsulin-dependent diabetes mellitus. The reason for the insulin resistance is not well understood. Specifically, it is not known whether they become resistant to the action of insulin on lipid metabolism. Euglycemic-hyperinsulinemic clamps were performed in six pancreas/kidney (P/K) recipients, six kidney (K) recipients (to control for immunosuppressive therapy), and eight healthy controls. Measured were leg blood flow (by plethysmography), rates of lipolysis (with [2H5] glycerol), fatty acid oxidation (by indirect calorimetry), fatty acid reesterification (with [2H5]glycerol and [1-13C]palmitate), monocyte membrane insulin binding (with [125I]Tyr-A14 insulin), and insulin receptor mass (by RIA). Fasting plasma insulin concentrations were 2 times higher in P/K and K recipients (108 pmol/L) than in controls (54 pmol/L). Insulin receptor mass in solubilized monocyte membranes from P/K and K recipients was reduced by 61% and 63%, respectively, whereas insulin binding was reduced by 73% and 70%, respectively. P/K and K recipients were resistant to the inhibitory action of insulin on lipolysis (P/K vs. controls, P < 0.01; K vs. controls, P < 0.02) and on fatty acid reesterification (P/K vs. controls, P < 0.02; K vs. controls, P < 0.03). P/K recipients appeared to be more resistant than K recipients, but the differences between the two groups were not statistically significant. We conclude that P/K recipients were hyperinsulinemic, had down-regulated the number of their monocyte insulin receptors, and were resistant to the antilipolytic action of insulin.
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PMID:Insulin receptor down-regulation and impaired antilipolytic action of insulin in diabetic patients after pancreas/kidney transplantation. 812 38

Increased routing of glucose through the hexosamine-biosynthetic pathway has been implicated in the development of glucose-induced insulin resistance of glucose transport in cultured adipocytes. Because both glucosamine and glucose enter this pathway as glucosamine-6-phosphate, we examined the effects of preincubation with glucosamine in isolated rat diaphragms and in fibroblasts overexpressing the human insulin receptor (HIR-cells). In muscles, pre-exposure to glucosamine inhibited subsequent basal and, to a greater extent, insulin-stimulated glucose transport in a time- and dose-dependent manner and abolished the stimulation by insulin of glycogen synthesis. Insulin receptor number, activation of the insulin receptor tyrosine kinase in situ and after solubilization, and the total pool of glucose transporters (GLUT4) were unaffected, and glycogen synthase was activated by glucosamine pretreatment. In HIR-cells, which express GLUT1 and not GLUT4, basal and insulin-stimulated glucose transport were unaffected by glucosamine, but glycogen synthesis was markedly inhibited. Insulin-stimulated activation of protein kinases (MAP and S6) was unaffected, and the fractional velocity and apparent total activity of glycogen synthase was increased in glucosamine-treated HIR-cells. In pulse-labeling studies, addition of glucosamine during the chase prolonged processing of insulin proreceptors to receptors and altered the electrophoretic mobility of proreceptors and processed alpha-subunits, consistent with altered glycosylation. Glucosamine-induced insulin resistance of glucose transport appears to be restricted to GLUT4-expressing cells, i.e., skeletal muscle and adipocytes; it may reflect impaired translocation of GLUT4 to the plasmalemma. The glucosamine-induced imbalance in UDP sugars, i.e., increased UDP-N-acetylhexosamines and decreased UDP-glucose, may alter glycosylation of critical proteins and limit the flux of glucose into glycogen.
Diabetes 1993 Sep
PMID:Pre-exposure to glucosamine induces insulin resistance of glucose transport and glycogen synthesis in isolated rat skeletal muscles. Study of mechanisms in muscle and in rat-1 fibroblasts overexpressing the human insulin receptor. 834 45

Insulin receptor substrate-1 is a major substrate of insulin receptor Tyr kinase. We have now cloned the IRS-1 cDNA from human skeletal muscle, one of the most important target tissues of insulin action, localized and cloned the human IRS-1 gene, and studied the expression of the protein in Chinese hamster ovary cells. Human IRS-1 cDNA encodes a 1242 amino acid sequence that is 88% identical with rat liver IRS-1. The 14 potential Tyr phosphorylation sites include 6 Tyr-Met-X-Met motifs and 3 Tyr-X-X-Met motifs that are completely conserved in human IRS-1. Human IRS-1 has > 50 possible Ser/Thr phosphorylation sites and one potential ATP-binding site close to the NH2-terminal. The human IRS-1 gene contains the entire 5'-untranslated region and protein coding region in a single exon and was localized on chromosome 2 q36-37 by in situ hybridization. By Northern blot analysis, IRS-1 mRNA is rare and consists of two species of 6.9 and 6 kilobase. By using quantitative polymerase chain reaction after reverse transcription of total RNA from human fetal tissues, IRS-1 mRNA could be identified in all tissues. When human IRS-1 cDNA was expressed in Chinese hamster ovary cells, the protein migrated between 170,000-180,000 M(r) in sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was rapidly Tyr phosphorylated upon insulin stimulation. Thus, IRS-1 is widely expressed and highly conserved across species and tissues.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1993 Jul
PMID:Human skeletal muscle insulin receptor substrate-1. Characterization of the cDNA, gene, and chromosomal localization. 851 71

The absence of female sex hormones, as well as testosterone treatment of oophorectomized (OVX) female rats has been demonstrated to result in decreased whole-body insulin-mediated glucose uptake. The cellular mechanism behind this insulin resistance and the role of low levels of female sex hormones as a risk factor for development of peripheral insulin resistance are not yet fully clarified. We assessed the protein expression of GLUT4 and glycogen synthase, as well as insulin-induced translocation of GLUT4 to the plasma membrane, in soleus skeletal muscle from control rats, OVX rats, and OVX rats treated for 8 weeks with testosterone (OVX + T). Whole-body insulin-mediated glucose uptake assessed by the hyperinsulinemic-euglycemic clamp procedure was 25% lower in OVX rats (P < 0.001) and addition of testosterone treatment further decreased insulin-mediated glucose uptake in OVX + T rats by 48% (P < 0.001) compared with controls. GLUT4 protein expression in soleus muscles was unaltered in the OVX and OVX + T rats compared with controls. Insulin induced a 3.7-fold increase (P < 0.05) in the plasma membrane content of GLUT4 in soleus muscle from control rats, whereas plasma membrane content of GLUT4 in soleus muscle from OVX or OVX + T rats was unaltered in response to insulin. Glycogen synthase protein expression in muscle homogenates was decreased by 25% in the OVX group (P < 0.05) and by 37% in the OVX + T group (P < 0.05) when compared with the control group. Insulin receptor and tyrosine kinase activities in the basal and insulin-stimulated states did not differ between the OVX and OVX + T rats. In conclusion, the absence of female sex hormones appears to decrease insulin-mediated whole-body glucose uptake via an impaired insulin-stimulated translocation of GLUT4 to the plasma membrane and by decreased protein expression of glycogen synthase. Testosterone treatment further impairs whole-body insulin-mediated glucose uptake, presumably by additional impairment of glycogen synthase expression.
Diabetes 1996 May
PMID:Mechanisms behind insulin resistance in rat skeletal muscle after oophorectomy and additional testosterone treatment. 862 Oct 12

A 24-year-old woman with ataxia-telangiectasia had traumatic arthritis, elevated serum transaminase values, polyuria, polydipsia, and a serum glucose level of 575 mg/dL. A relatively high daily dose of insulin (2.8 U/kg) was required to achieve near normoglycemia. The fasting insulin concentration was elevated. During an insulin-modified frequently sampled intravenous glucose tolerance test, the first phase of insulin release in response to the administration of glucose was blunted. The insulin sensitivity was similar to that found in individuals with non-insulin-dependent diabetes mellitus. Insulin receptor antibodies were not detected in the serum. We conclude that insulin resistance and islet beta-cell dysfunction are characteristics of diabetes mellitus in ataxia-telangiectasia. Contrary to a previous report, our findings do not support a cause-and-effect relationship between insulin receptor antibodies and insulin resistance in this disorder.
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PMID:Insulin-resistant diabetes mellitus in a black woman with ataxia-telangiectasia. 863 4

Insulin receptor substrates-1 (IRS-1) is the major cytoplasmic substrate of the insulin and IGF-1 receptors. Recent studies have identified multiple sequence variants of IRS-1, especially in patients with non-insulin-dependent diabetes mellitus. In the present study, we have examined insulin-stimulated processes in 32D(IR) cells, a myeloid progenitor cell stably overexpressing the insulin receptor, transfected with wild-type human-IRS-1 or the most common human variant of IRS-1 in which glycine 972 is replaced by arginine. As compared to wild-type IRS-1, insulin stimulation of cells transfected with mutant IRS-1 exhibited a 32% decrease in incorporation of [3H]thymidine into DNA (P = 0.002), a 36% decrease in IRS-1 associated phosphatidylinositol (PI) 3-kinase activity (P = 0.004) and a 25% decrease in binding of the p85 regulatory subunit of PI 3-kinase to IRS-1 (P = 0.002). There was also a tendency for a decrease in Grb2 binding to IRS-1 and insulin-stimulated mitogen-activated protein kinase activity, however, these were not statistically significant. The changes occurred with no change in insulin receptor or IRS-1 tyrosine phosphorylation. These data indicate that the mutation in codon 972 in IRS-1 impairs insulin-stimulated signaling, especially along the PI 3-kinase pathway, and may contribute to insulin resistance in normal and diabetic populations.
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PMID:A common amino acid polymorphism in insulin receptor substrate-1 causes impaired insulin signaling. Evidence from transfection studies. 864 50

Insulin receptor substrate-1 (IRS-1) is involved in insulin signal transduction distal to receptor occupation. Targeted disruption of IRS-1 leads to insulin resistance and hyperglycemia in mice, which suggests that altered IRS-1 expression could contribute to the insulin resistance seen in non-insulin-dependent diabetes mellitus. In vitro studies using phorbol esters have implicated the protein kinase C (PKC) pathway as being involved in the pathogenesis of insulin resistance. Using the MCF-7 breast cancer cell, a role for PKC in regulating IRS-1 expression was examined. In an MCF-7 cell line (MCF-7-PKC-alpha) that exhibits multiple alterations in PKC isoform expression, IRS-1 content was reduced to negligible levels relative to parental MCF-7 cells. This decrease in IRS-1 content was associated with a 30-fold reduction in IRS-1 transcription. In parental MCF-7 cells, PKC inhibitors (GF109203X (bisindolylmaleimide I) and staurosporine) reduced IRS-1 content. Chronic exposure to 12-O-tetradecanoylphorbol-13-acetate (TPA; >8 h) reduced IRS-1 content and down-regulated the novel PKC-delta isoform. Bryostatin 1 inhibited TPA-induced depletion of both IRS-1 and PKC-delta expression in MCF-7 cells. Associated with TPA-induced reduction in IRS-1 content was a reduction in IRS-1 transcription. These data demonstrate that PKC can modulate IRS-1 content and suggest a potential role for PKC-delta in positively regulating IRS-1 expression.
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PMID:Transcriptional regulation of insulin receptor substrate 1 by protein kinase C. 894 87

Insulin receptor substrate-1 (IRS-1), beta 3-adrenergic-receptor (beta 3-AR) and glycogen synthase (GS) genes are candidate genes for non-insulin-dependent diabetes mellitus (NIDDM), insulin resistance, dyslipidaemia and obesity. We studied white Caucasian subjects with NIDDM, 227 being randomly selected, 49 NIDDM within the top two percentiles of insulin resistance; 54 with dyslipidaemia in the top quintile of triglyceride/insulin and the bottom quintile of HDL, and 166 non-diabetic control subjects. We examined the association of the simple tandem repeat DNA polymorphisms (STRPs) near the IRS-1 and GS genes, and the prevalence of mutations at codons of IRS-1 513 and 972, beta 3-AR 64 and GS 464 using restriction fragment length polymorphism (RFLP). The STRP alleles in IRS-1 were significantly different between NIDDM and control subjects (p = 0.015). The IRS-1 972 mutation was significantly different between the four groups with increased prevalence in the insulin resistant and dyslipidaemia subjects (18 and 26% compared with 11% in control subjects; p < 0.0005). Those with or without IRS-1 mutations had similar clinical characteristics and impaired insulin sensitivity. beta 3-AR 64 mutation was not significantly different between the four groups but those with the mutation were more obese, with a test for linear association between number of alleles and degree of obesity in an analysis of variance showing a significant association (p = 0.029). The GS 464 mutation was not detected in any of the diabetic or control subjects and the population association study using GS STRP showed no difference in allelic frequencies between NIDDM patients and control subjects. A mutation in lipoprotein lipase at codon 291, associated in the general population with low HDL cholesterol, was not at increased prevalence in the NIDDM patients with dyslipidaemia. In conclusion, IRS-1 972 had an increased prevalence in subjects with insulin resistance, with or without dyslipidaemia. beta 3-AR 64 was associated with increased obesity but not with insulin resistance or dyslipidaemia. These separate contributions to different features of NIDDM are an example of the polygenic inheritance of this heterogeneous disorder.
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PMID:UKPDS 19: heterogeneity in NIDDM: separate contributions of IRS-1 and beta 3-adrenergic-receptor mutations to insulin resistance and obesity respectively with no evidence for glycogen synthase gene mutations. UK Prospective Diabetes Study. 896 Aug 33

Insulin receptor substrate-1 (IRS-1) occupies a key position in the insulin-signalling pathway. Two mutations of the IRS-1 gene (Gly(972)Arg and Ala(513)Pro) have been described, although their roles in the development of insulin resistance and non-insulin-dependent diabetes mellitus (NIDDM) remain controversial. Insulin resistance has been described in non-diabetic relatives of NIDDM families, suggesting that it may be due to an inherited defect of insulin action. We therefore examined the relationships between the two mutations and insulin sensitivity in 93 non-diabetic first degree relatives from North European families with 2 or more living NIDDM subjects. Anthropometric measurements, an oral glucose tolerance test, and an insulin tolerance test to assess insulin sensitivity (K(ITT)) were performed. Basal insulin sensitivity was assessed by homeostasis model assessment (HOMA). Comparisons were made between the following relative subgroups: with (n = 9) and without (n = 84) the 972 mutation; with (n = 5) and without (n = 88) the 513 mutation; and with either one or both mutations (n = 13) or without either (n = 80). General linear model analysis was used to compare K(ITT) and HOMA between the subgroups with the anthropometric variables known to influence insulin sensitivity as covariates. There were no significant differences between the subgroups for K(ITT) and HOMA. In conclusion, the 513 and 972 mutations, alone and in combination, are not associated with decreased insulin sensitivity in non-diabetic relatives of NIDDM families.
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PMID:Relationship between insulin sensitivity and insulin receptor substrate-1 mutations in non-diabetic relatives of NIDDM families. 916 10


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