Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin resistance, defined as the inability of insulin to exert a normal biological action at the level of its target tissues, is one of the principal pathogenetic defects of type 2 diabetes. Metformin, the most widely-prescribed insulin-sensitizing agent in current clinical use, improves blood glucose control mainly by improving insulin-mediated suppression of hepatic glucose production, and by enhancing insulin-stimulated glucose disposal in skeletal muscle. Experimental studies show that metformin-mediated improvements in insulin sensitivity may be associated with several mechanisms, including increased insulin receptor tyrosine kinase activity, enhanced glycogen synthesis, and an increase in the recruitment and activity of GLUT4 glucose transporters. In adipose tissue, metformin promotes the re-esterification of free fatty acids and inhibits lipolysis, which may indirectly improve insulin sensitivity through reduced lipotoxicity. The improved glycaemia with metformin is not associated with increased circulating levels of insulin, and the risk of hypoglycaemia with metformin is minimal. The therapeutic profile of metformin supports its use for the control of blood glucose, in diabetic patients and for the prevention of diabetes in subjects with impaired glucose tolerance. Moreover, the improvement by metformin of cardiovascular risk factors associated with the dysmetabolic syndrome may account for the significant improvements in macrovascular outcomes observed in the UK Prospective Diabetes Study.
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PMID:Reducing insulin resistance with metformin: the evidence today. 1450 98

Impaired insulin secretion and insulin resistance are thought to be two major causes of type 2 diabetes mellitus. There are two kinds of diabetic model mice: one is a K(ATP) channel knockout (Kir6.2KO) mouse which is defective in glucose-induced insulin secretion, and the other is a transgenic mouse expressing the tyrosine kinase-deficient (dominant-negative form of) human insulin receptor (hIR(KM)TG), and which has insulin resistance in muscle and fat. However, all of these mice have no evidence of overt diabetes. To determine if the double mutant Kir6.2KO/hIR(KM)TG mice would have diabetes, we generated mutant mice by crossbreeding, which would show both impaired glucose-induced insulin secretion and insulin resistance in muscle and fat. We report here that: 1) blood glucose levels of randomly fed and 6 h fasted double mutant (Kir6.2KO/hIR(KM)TG) mice were comparable with those of wild type mice; 2) in intraperitoneal glucose tolerance test (ipGTT), Kir6.2KO/hIR(KM)TG mice had an impaired glucose tolerance; and 3) during ipGTT, insulin secretion was not induced in either Kir6.2KO/hIR(KM)TG or Kir6.2KO mice, while the hIR(KM)TG mice showed a more prolonged insulin secretion than did wild type mice; 4) hyperinsulinemic euglycemic clamp test revealed that Kir6.2KO, Kir6.2KO/hIR(KM)TG and hIR(KM)TG mice, showed decreased whole-body glucose disposal compared with wild type mice; 5) Kir6.2KO, but not Kir6.2KO/hIR(KM)TG mice had some obesity and hyperleptinemia compared with wild type mice. Thus, the defects in glucose-induced insulin secretion (Kir6.2KO) and an insulin resistance in muscle and fat (hIR(KM)TG) were not sufficient to lead to overt diabetes.
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PMID:K(ATP) channel knockout mice crossbred with transgenic mice expressing a dominant-negative form of human insulin receptor have glucose intolerance but not diabetes. 1511 62

Inhibition of protein tyrosine phosphatase 1B (PTP1B) has been proposed as a novel therapy to treat type 2 diabetes and obesity. In order to identify novel PTP1B inhibitors, we have developed a robust screen in Saccharomyces cerevisiae where growth is dependent on PTP1B catalytic activity. This was based on the observation that overexpression of v-Src, a tyrosine kinase, in yeast leads to lethality through mitotic dysfunction and this lethality can be reversed by co-expression of PTP1B. The expression levels of v-Src and PTP1B were optimized to obtain a balance between robust growth and sensitivity to inhibitors. Screening was carried out in 96-well plates and growth of the liquid culture measured by absorbance at 600 nm. Initial characterization was performed using vanadate as well as some novel PTP1B inhibitors. Vanadate specifically inhibited PTP1B-dependent growth in a dose dependent manner with an EC50 of 0.92 +/- 0.07 mM. This simple yeast growth interference assay has the potential for use as a high throughput screen for PTP1B inhibitors in sample collections or crude mixtures.
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PMID:Using yeast to screen for inhibitors of protein tyrosine phosphatase 1B. 1545 Sep 46

Impaired insulin receptor (IR) signaling leads to insulin resistance and type 2 diabetes mellitus. Several inhibitors of the IR tyrosine kinase activity have recently been described and associated with human insulin resistance. Among these negative regulators, protein tyrosine phosphatases (PTPs) are likely to play a pivotal role in IR signaling. Transgenic studies revealed that PTP1B and TCPTP are primary candidates but IR of these animals can be finally dephosphorylated, suggesting that other PTPs are also involved in the dephosphorylation of IR. In this study, we showed that receptor-type PTPepsilon (PTP epsilonM) dephosphorylated IR in rat primary hepatocytes and tyrosines 972, 1158, 1162 and 1163 were primary targets of PTP epsilonM. Wild type as well as substrate-trapping DA forms of PTPepsilonM suppressed phosphorylation of IR downstream enzymes such as Akt, extracellular regulated kinase (ERK) and glycogen synthase kinase 3 (GSK3). It was also demonstrated that PTPepsilonM suppressed insulin-induced glycogen synthesis and inhibited insulin-induced suppression of phosphoenol pyruvate carboxykinase (PEPCK) expression in primary hepatocytes. Furthermore, adenovirally introduced PTPepsilonM also exhibited inhibitory activity against suppression of PEPCK expression in mouse liver. These results suggest that PTPepsilonM is a negative regulator of IR signaling and involved in insulin-induced glucose metabolism mainly through direct dephosphorylation and inactivation of IR in hepatocytes and liver.
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PMID:Receptor-type protein tyrosine phosphatase epsilon (PTPepsilonM) is a negative regulator of insulin signaling in primary hepatocytes and liver. 1573 37

alpha2-Heremans-Schmid glycoprotein (AHSG) is an abundant plasma protein synthesized predominantly in the liver. The AHSG gene, consisting of seven exons and spanning 8.2 kb of genomic DNA, is located at chromosome 3q27, a susceptibility locus for type 2 diabetes and the metabolic syndrome. AHSG is a natural inhibitor of the insulin receptor tyrosine kinase, and AHSG-null mice exhibit significantly enhanced insulin sensitivity. These observations suggested that the AHSG gene is a strong positional and biological candidate for type 2 diabetes susceptibility. Direct sequencing of the AHSG promoter region and exons identified nine common single nucleotide polymorphisms (SNPs) with a minor allele frequency > or =5%. We carried out a detailed genetic association study of the contribution of these common AHSG SNPs to genetic susceptibility of type 2 diabetes in French Caucasians. The major allele of a synonymous coding SNP in exon 7 (rs1071592) presented significant evidence of association with type 2 diabetes (P = 0.008, odds ratio 1.27 [95% CI 1.06-1.52]). Two other SNPs (rs2248690 and rs4918) in strong linkage disequilibrium with rs1071592 showed evidence approaching significance. A haplotype carrying the minor allele of SNP rs1071592 was protective against type 2 diabetes (P = 0.014). However, our analyses indicated that rs1071592 is not associated with the evidence for linkage of type 2 diabetes to 3q27.
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PMID:A synonymous coding polymorphism in the alpha2-Heremans-schmid glycoprotein gene is associated with type 2 diabetes in French Caucasians. 1604 17

Reduced insulin-mediated glucose transport in skeletal muscle is a hallmark of the pathophysiology of T2DM (Type II diabetes mellitus). Impaired intracellular insulin signalling is implicated as a key underlying mechanism. Attention has focused on early signalling events such as defective tyrosine phosphorylation of IRS1 (insulin receptor substrate-1), a major target for the insulin receptor tyrosine kinase. This is required for normal induction of signalling pathways key to many of the metabolic actions of insulin. Conversely, increased serine/threonine phosphorylation of IRS1 following prolonged insulin exposure (or in obesity) reduces signalling capacity, partly by stimulating IRS1 degradation. We now show that IRS1 levels in human muscle are actually increased 3-fold following 1 h of hyperinsulinaemic euglycaemia. Similarly, transient induction of IRS1 (3-fold) in the liver or muscle of rodents occurs following feeding or insulin injection respectively. The induction by insulin is also observed in cell culture systems, although to a lesser degree, and is not due to reduced proteasomal targeting, increased protein synthesis or gene transcription. Elucidation of the mechanism by which insulin promotes IRS1 stability will permit characterization of the importance of this novel signalling event in insulin regulation of liver and muscle function. Impairment of this process would reduce IRS1 signalling capacity, thereby contributing to the development of hyperinsulinaemia/insulin resistance prior to the appearance of T2DM.
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PMID:A novel regulation of IRS1 (insulin receptor substrate-1) expression following short term insulin administration. 1612 72

Melatonin, which is synthesized in the pineal gland and other tissues, has a variety of physiological, immunological, and biochemical functions. It is a direct scavenger of free radicals and has indirect antioxidant effects due to its stimulation of the expression and activity of antioxidative enzymes such as glutathione peroxidase, superoxide dismutase and catalase, and NO synthase, in mammalian cells. Melatonin also reduces serum lipid levels in mammalian species, and helps to prevent oxidative stress in diabetic subjects. Long-term melatonin administration to diabetic rats reduced their hyperlipidemia and hyperinsulinemia, and restored their altered ratios of polyunsaturated fatty acid in serum and tissues. It was recently reported that melatonin enhanced insulin-receptor kinase and IRS-1 phosphorylation, suggesting the potential existence of signaling pathway cross-talk between melatonin and insulin. Because TNF-alpha has been shown to impair insulin action by suppressing insulin receptor-tyrosine kinase activity and its IRS-1 tyrosine phosphorylation in peripheral tissues such as skeletal muscle cells, it was speculated that melatonin might counteract TNF-alpha-associated insulin resistance in type 2 diabetes. This review will focus on the physiological and metabolic effects of melatonin and highlight its potential use for the treatment of cholesterol/lipid and carbohydrate disorders.
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PMID:Metabolic effects of melatonin on oxidative stress and diabetes mellitus. 1621 26

Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays a key role in insulin signaling. Recent studies have identified several polymorphisms in the human IRS-1 gene (Irs-1) that are increased in prevalence among type 2 diabetic patients. To determine whether variation in the Irs-1 contributes to genetic susceptibility to type 2 diabetes in Turkish people, PCR-RFLP and DNA sequencing method were utilized to analyze the coding region of Irs-1 in 70 subject and 116 control patients. Three missense mutations were detected (Gly972Arg, Ala512Pro, Ser892Gly). There was no significant association found with any of these variants and diabetes. The Gly972Arg mutation, however, was relatively more common in with 10/70 diabetic patients and 15/116 non-diabetic controls being heterozygous and 1/70 being and 0/116 non-diabetic controls being homozygous for this variant. As a conclusion, Ala512Pro, Ser892Gly mutations were rare and Met613Val, Ser1043Tyr and Cys1095Tyr mutations were not found in the populations studied. Gly972Arg is more common than other known mutations in our population but may not be a major determinant in genetic susceptibility to type 2 diabetes.
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PMID:Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Turkish with type 2 diabetes mellitus. 1628 38

The male obese Wistar Diabetic Fatty (WDF) rat is a genetic model of obesity and non-insulin dependent diabetes (NIDDM). The obese Zucker rat shares the same gene for obesity on a different genetic background but is not diabetic. This study evaluated the degree of insulin resistance in both obese strains by examining the binding and post binding effects of muscle insulin receptors in obese rats exhibiting hyperinsulinemia and/or hyperglycemia. Insulin receptor binding and affinity and tyrosine kinase activity were measured in skeletal muscle from male WDF fa/fa (obese) and Fa/? (lean) and Zucker fa/fa (obese) and Fa/Fa (homozygous lean) rats. Rats were fed a high sucrose (68% of total Kcal) or Purina stock diet for 14 weeks. At 27 weeks of age, adipose depots were removed for adipose cellularity analysis and the biceps femoris muscle was removed for measurement of insulin binding and insulin-stimulated receptor kinase activity. Plasma glucose (13.9 vs. 8.4 mM) and insulin levels (14,754 vs. 7440 pmol/L) were significantly higher in WDF obese than in Zucker obese rats. Insulin receptor number and affinity and TK activity were unaffected by diet. Insulin receptor number was significantly reduced in obese WDF rats ( 2.778 +/- 0.617 pmol/mg protein), compared to obese Zucker rats (4.441 +/- 0.913 pmol/mg potein). Both obese strains exhibited down regulation of the insulin receptor compared to their lean controls. Maximal tyrosine kinase (TK) activity was significantly reduced in obese WDF rats (505 +/- 82 fmol/min/mg protein) compared to obese Zucker rats (1907 +/- 610 fmol/min/mg protein). Only obese WDF rats displayed a decrease in TK activity per receptor. These observations establish the obese WDF rat as an excellent model for exploring mechanisms of extreme insulin resistance, particularly post-receptor tyrosine kinase-associated defects, in non-insulin dependent diabetes.
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PMID:The male obese Wistar diabetic fatty rat is a new model of extreme insulin resistance. 1635 98

The decrease in insulin sensitivity to target tissues or insulin resistance leads to type 2 diabetes mellitus, an insidious disease threatening global health. Numerous evidences made free fatty acids (FFAs) responsible for insulin resistance and type 2 diabetes. We demonstrate here that the damage of insulin acitivity by a free fatty acid, palmitate could be prevented by a lupinoside. An incubation of 3T3 L1 adipocytes with a FFA i.e. palmitate inhibited insulin stimulated uptake of (3)H-2 deoxyglucose (2 DOG) significantly. Addition of a lupinoside purified from Pueraria tuberosa, lupinoside PA(4) (LPA(4)) strongly prevented this inhibition. We then examined insulin signaling pathway where palmitate significantly inhibited insulin stimulated phosphorylation of Insulin receptor tyrosine kinase, IRS 1and PI3 kinase, PDK1 and Akt/PKB. LPA(4) rescued this inhibition of signaling molecule by palmitate. Insulin mediated translocation of Glut4, the glucose transporter in insulin target cells, was effectively blocked by palmitate while, LPA(4) waived this block. Administration of LPA(4) to nutritionally induced diabetic rats significantly reduced the increase in plasma glucose. All these indicate LPA(4) to be a potentially therapeutic agent for insulin resistance and type 2 diabetes.
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PMID:A Lupinoside prevented fatty acid induced inhibition of insulin sensitivity in 3T3 L1 adipocytes. 1714 45


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