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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study was conducted to investigate the possible involvement of protein kinase C (PKC) and serine/threonine phosphorylation of the insulin receptor in insulin resistance and/or obesity. Insulin receptor tyrosine kinase activity was depressed in muscle from obese insulin-resistant patients compared with lean insulin-responsive control subjects. Alkaline phosphatase treatment resulted in a significant 48% increase in in vitro insulin-stimulated receptor tyrosine kinase activity in obese but not lean muscle. To investigate the involvement of PKC in skeletal muscle insulin resistance and/or obesity, membrane-associated PKC activity and the protein content of various PKC isoforms were measured in human skeletal muscle from lean, insulin-responsive, and obese insulin-resistant patients. Membrane-associated PKC activity was not changed; however, PKC-beta protein content, assayed by Western blot analysis, was significantly higher, whereas PKC-theta, -eta, and -mu were significantly lower in muscle from obese patients compared with muscle from lean control subjects. Incubation of muscle strips with insulin significantly increased membrane-associated PKC activity in muscle from obese but not lean subjects. PKC-delta, -beta, and -theta were translocated from the cytosol to the membrane fraction in response to insulin treatment. These results suggest that in skeletal muscle from insulin-resistant obese patients, insulin receptor tyrosine kinase activity was reduced because of hyperphosphorylation on serine/threonine residues. Membrane-associated PKC-beta protein was elevated under basal conditions, and membrane-associated total PKC activity was increased under insulin-stimulated conditions in muscle from obese insulin-resistant patients. Thus, we postulate that the decreased tyrosine kinase activity of the insulin receptor may be caused by serine/threonine phosphorylation by PKC.
Diabetes 2000 Aug
PMID:Involvement of protein kinase C in human skeletal muscle insulin resistance and obesity. 1092 37

Insulin receptor substrate (IRS) proteins play a central role in maintaining basic cellular functions such as growth and metabolism. They act as an interface between multiple growth factor receptors possessing tyrosine kinase activity, such as the insulin receptor, and a complex network of intracellular signalling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified which differ in their subcellular distribution and interaction with SH2 domain proteins. In addition, differential IRS tissue- and developmental-specific expression patterns may contribute to specificity in their signaling potential.
Diabetes Metab Res Rev
PMID:Insulin receptor substrate (IRS) transduction system: distinct and overlapping signaling potential. 1111 2

Insulin receptor substrate (IRS)-1 protein expression is markedly reduced in many insulin-resistant states, although the mechanism for this downregulation is unclear. In this study, we have investigated the early events in the insulin pathway that trigger the degradation of IRS-1. Incubation of the adipocytes with insulin induced a fast electrophoretic mobility shift of IRS-1 and a subsequent degradation of the protein. Wortmannin and rapamycin blocked this mobility shift of IRS-1, maintained the insulin-induced tyrosine phosphorylation of IRS-1, and blocked its degradation. In contrast, a glycogen synthase kinase 3 inhibitor, a mitogen-activated protein kinase/extracellular-regulated kinase inhibitor, and various protein kinase C inhibitors had no effect. Incubation with okadaic acid increased the serine/threonine phosphorylation of IRS-1 and its degradation, mimicking insulin, and its effect was prevented by the proteasome inhibitor lactacystin, as well as by rapamycin. Treatment of the cells with the tyrosine phosphatase inhibitor orthovanadate in the presence of insulin or okadaic acid partially inhibited the degradation of IRS-1. We propose that a rapamycin-dependent pathway participates as a negative regulator of IRS-1, increasing its serine/threonine phosphorylation, which triggers degradation. Thus, regulation of serine/threonine versus tyrosine phosphorylation may modulate IRS-1 degradation, affecting insulin sensitivity.
Diabetes 2001 Jan
PMID:Serine/threonine phosphorylation of IRS-1 triggers its degradation: possible regulation by tyrosine phosphorylation. 1114 90

Insulin elicits diverse biological responses in many tissues and cell types by binding to its specific receptor. The insulin receptor (IR) is a tetramer consisting of two extracellular alpha subunits and two membrane-spanning beta subunits. The binding of insulin to the receptor causes conformational changes that lead to autophosphorylation and activation of the tyrosine kinase intrinsic to the beta subunits. Insulin receptor transphosphorylates several immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules. In order to discover small molecules that activate the human insulin receptor tyrosine kinase (IRTK), a cell-based assay was established and utilized to screen a collection of synthetic chemicals and natural product extracts. This effort led to the identification of a nonpeptidyl, small molecule, insulin-mimetic compound (demethylasterriquinone B-1, DMAQ-B1) that was isolated from a mixture of metabolites produced by a tropical endophytic fungus, Pseudomassaria sp. This compound induced human IRTK activation and increased tyrosine phosphorylation of IR beta subunit. It mediated insulin-like effects, including insulin receptor substrate-1 (IRS-1) phosphorylation and activation of phosphotidylinositide 3-kinase and Akt kinase. DMAQ-B1 also exhibited an insulin-like effect on glucose uptake in adipocytes and skeletal muscle tissue. Furthermore, the compound was relatively selective for IR vs. insulin-like growth factor-I (IGF-I) receptor and other homologous receptor tyrosine kinases. In addition, it activated partially purified native IR or recombinant IR kinase, demonstrating the direct interaction of the small molecule with the IR. Oral administration of DMAQ-B1 resulted in significant glucose lowering in two mouse models of diabetes. Thus, DMAQ-B1 represents the first orally active insulin-mimetic agent. Pharmaceutical intervention aimed at augmenting IR function ultimately may prove beneficial as a novel therapeutic option in patients with diabetes.
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PMID:Discovery of a small molecule insulin receptor activator. 1123 9

Insulin receptor substrate (IRS) molecules are key mediators in insulin signalling and play a central role in maintaining basic cellular functions, such as growth, survival and metabolism. They act as docking proteins for the insulin receptor and a complex network of intracellular signalling molecules containing Src homology 2 (SH2) domains. Four members (IRS-1, IRS-2, IRS-3 and IRS-4) of this family have been identified that differ in tissue distribution, subcellular localisation, developmental expression, binding to the insulin receptor and interaction with SH2 domain-containing proteins. Results from targeted disruption of the IRS genes in mice have provided important clues as to the functional differences among these related molecules and suggest that they play very different roles in vivo. The available data are consistent with the notion that both IRS-1 and IRS-2 are important for insulin action and glucose homeostasis in vivo, whereas IRS-and IRS-4 appear to play a redundant role in the IRS signalling system. Considering their key role in both insulin action and insulin secretion, IRS-1 and IRS-2 molecules have been considered plausible candidate genes involved in the pathogenesis of Type 2 diabetes. Several polymorphisms in the IRS genes have been identified, but only the Gly --> Arg72 substitution of IRS-1, acting with environmental factors, seems to have a pathogenic role in the development of Type 2 diabetes. In contrast, polymorphisms of the other IRS genes do not appear to contribute to Type 2 diabetes.
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PMID:Insulin receptor substrate polymorphisms and type 2 diabetes mellitus. 1125 83

Insulin receptor substrate (IRS) proteins mediate a variety of the metabolic and growth-promoting actions of insulin and IGF-1. After phosphorylation by activated receptors, these intracellular signaling molecules recruit various downstream effector pathways including phosphatidylinositol 3-kinase and Grb2. Ablation of the IRS-2 gene produces a diabetic phenotype; mice lacking IRS-2 display peripheral insulin resistance and beta-cell dysfunction characterized by a 50% reduction in beta-cell mass. In contrast, deletion of IRS-1 retards somatic growth and enhances beta-cell mass. IRS1-/- mice are 50% smaller than controls but have a twofold increase in pancreatic beta-cell mass. Thus, observations from these recently developed animal models implicate the IRS signaling systems in the response of classical insulin target tissues, and they suggest a critical role for these proteins in the regulation of beta-cell function. In humans, type 2 diabetes generally occurs when insulin-secretory reserves fail to compensate for peripheral insulin resistance. Study and identification of the signals downstream of IRS proteins in beta-cells may provide unique insights into the compensatory mechanisms by which these cells respond to insulin resistance. Therefore, the intent of this review is to summarize recent observations regarding the regulation of beta-cell function by members of the IRS protein family.
Diabetes 2001 Feb
PMID:IRS proteins and beta-cell function. 1127 76

Insulin receptor (IR)-deficient pups rapidly become hyperglycemic and hyperinsulinemic and die of diabetic ketoacidosis within a few days. Immunocytochemical analysis of the endocrine pancreas revealed that IR deficiency did not alter islet morphology or the number of beta-, alpha-, delta-, and pancreatic polypeptide (PP) cells. The lack of IR did not result in major changes in the expression of islet hormone genes or of beta-cell-specific marker genes encoding pancreas duodenum homeobox-containing transcription factor-1 (PDX-1), glucokinase (GCK), and GLUT2, as shown by reverse transcriptase-polymerase chain reaction analysis. The serum glucagon levels in IR-deficient and nondiabetic littermates were comparable. Finally, total insulin content in the pancreas of IR-deficient pups was gradually depleted, indicating sustained insulin secretion, not compensated for by increased insulin biosynthesis. These findings are discussed in light of recent results suggesting a role of IR in beta-cell function.
Diabetes 2001 Feb
PMID:Endocrine pancreas in insulin receptor-deficient mouse pups. 1127 77

Because insulin resistance/diabetes may cause inordinate vascular complications in females, we have investigated the effects of insulin and insulin-like growth factor (IGF-1) on vascular reactivity in 12-week-old female Zucker obese (Ob) rats, a rodent model of insulin resistance and its lean (Ln) age-matched counterpart. Endothelium intact aortic rings from Ob animals and their Ln littermates (12 weeks of age) were subjected to contractile concentration responses to phenylephrine (PE) followed by relaxation to isoproterenol (Iso), with and without preincubation for 2 hours with cholera toxin (CTX; 1 microg/mL) or pertussis toxin (PTX; 2 microg/mL) and before and after incubation with either insulin or IGF-1 (100 nmol/L) for 1 hour. Systolic blood pressure was higher (138 +/- 3 v. 109 +/- 4 mm Hg; P <.0001) in the 12-week-old Ob rats. Contractile responses to PE were similar in both groups; however, both insulin and IGF-1 induced a paradoxical increase (P <.001) in contraction in Ob vasculature (929 +/- 92 v. 679 +/- 25 mg, respectively). CTX alone decreased contraction in the Ob (P <.02) and PTX in the Ln (P <.02), but there were no interactions between either IGF-1 or insulin and the toxins. Marked impairment of relaxation to Iso was seen in aortic rings of these female Ob rats (ED(50) = 2.6 micromol/L v. 418 nmol/L, P =.0002), an effect exacerbated by preincubation with either insulin or IGF-1 (P =.0001). Again, no role for G-proteins could be demonstrated. Insulin-dependent glucose uptake was severely impaired (P <.05) in aortic segments of the Ob insulin-resistant rats. Insulin receptor binding, tyrosine kinase activity (TKA), and abundance of several G-protein alpha subunits (inhibitory and stimulatory) in solubilized arterial membrane preparations (assessed by Western blot) were comparable in the 2 groups. These results indicate that resistance to the vascular actions of insulin/IGF-1 in female Ob rats is a postreceptor event that parallels glucose uptake resistance and is independent of G-proteins.
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PMID:Vascular insulin/insulin-like growth factor-1 resistance in female obese Zucker rats. 1131 26

Capsicum frutescens has been used to treat diabetes mellitus by traditional healers in Jamaica. This study was designed to identify any hypoglycaemic principle(s) and to determine the mechanism of action. Purification experiments employing thin layer chromatography (TLC) and high performance liquid chromatography (HPLC) led to the extraction of the active principle, capsaicin. Capsaicin caused a decrease in blood glucose levels of 4.91 +/- 0.52 (n = 6) mmol/dL versus 6.40 +/- 0.13 mmol/dL (n = 6) for the control (p < 0.05) at the 2.5 h time interval when the oral glucose tolerance test (OGTT) was performed on dogs treated with capsaicin and compared with the control. Plasma insulin levels measured at the 2.5 h time interval showed that there was an increase in plasma insulin levels of 5.78 +/- 0.76 microIU/mL (n = 6) for the capsaicin treated dogs versus 3.70 +/- 0.43 microIU/mL (n = 10) for the control (p < 0.05). Insulin receptor studies, using a modification of the method of Gambhir et al. done on monocytes obtained from blood at the 2.5 h time interval showed that there was a decrease in the percentage receptor binding for the capsaicin treated dogs when compared with the control. Insulin affinity results showed that there was a decrease of 2.4 x 10(-4) in monocytes for the capsaicin treated dogs versus 8.77 x 10(-4) for the control (p < 0.05). Also, insulin receptor calculations showed a decrease in number, 2.63 x 10(8) +/- 5.73 x 10(7), compared with 8.77 x 10(8) +/- 1.47 x 10(8) for the control. In conclusion it can be stated that capsaicin is responsible for the hypoglycaemic episodes seen in the dogs and that it also causes an increase in insulin secretion which leads to a reduction of insulin binding on the insulin receptors.
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PMID:The effect of capsaicin on blood glucose, plasma insulin levels and insulin binding in dog models. 1150 29

Insulin receptor substrate (IRS)-2(-/-) mice develop diabetes because of insulin resistance in the liver and failure to undergo beta-cell hyperplasia. Here we show by DNA chip microarray analysis that expression of the sterol regulatory element-binding protein (SREBP)-1 gene, a downstream target of insulin, was paradoxically increased in 16-week-old IRS-2(-/-) mouse liver, where insulin-mediated intracellular signaling events were substantially attenuated. The expression of SREBP-1 downstream genes, such as the spot 14, ATP citrate-lyase, and fatty acid synthase genes, was also increased. Increased liver triglyceride content in IRS-2(-/-) mice assures the physiological importance of SREBP-1 gene induction. IRS-2(-/-) mice showed leptin resistance; low dose leptin administration, enough to reduce food intake and body weight in wild-type mice, failed to do so in IRS-2(-/-) mice. Interestingly, high dose leptin administration reduced SREBP-1 expression in IRS-2(-/-) mouse liver. Thus, IRS-2 gene disruption results in leptin resistance, causing an SREBP-1 gene induction, obesity, fatty liver, and diabetes.
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PMID:Increased expression of the sterol regulatory element-binding protein-1 gene in insulin receptor substrate-2(-/-) mouse liver. 1154 55


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