Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action

Eldar-Finkelman, Hagit; Krebs, Edwin G.

doi:10.1073/pnas.94.18.9660

Cited by 288 publications

(205 citation statements)

References 39 publications

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“…This is consistent with previous findings in which insulin resistance in the liver increases the circulating levels of the extracellular domain of the leptin receptor, stabilizing leptin (32). It has been reported that STAT3 could be activated by insulin with some discrepancies as to whether tyrosine 705 or serine 727 or both were activated/phosphorylated (4,5,19). In the present study, the nuclear translocation of STAT3 was observed (Fig.…”

Section: Stat3 Sensitizes Insulin Signalingsupporting

confidence: 82%

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Moh

Zhang

et al. 2008

Diabetes

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OBJECTIVE-Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling.RESEARCH DESIGN AND METHODS-We generated a strain of mice carrying a targeted disruption of Stat3 gene in the liver (L-Stat3 Ϫ/Ϫ mice). Hepatocytes of the L-Stat3 Ϫ/Ϫ mice were isolated to establish cell lines for mechanistic studies. Nuclear translocation and DNA-protein interaction of STAT3 was analyzed with immunofluorescent and chromatin immunoprecipitation methods, respectively. Levels of glucose, insulin, leptin, and glucagon were profiled, and putative downstream molecules of STAT3 were examined in the presence of various stimuli in L-Stat3 Ϫ/Ϫ and control mice. RESULTS-STAT3was found to sensitize the insulin signaling through suppression of GSK-3␤, a negative regulator of insulin signaling pathway. During feeding, both mRNA and protein levels of GSK-3␤ decreased in Stat3 f/ϩ mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. In contrast, the L-Stat3 Ϫ/Ϫ mice lost this control and showed a monophasic increase in the GSK-3␤ level in response to insulin. Administration of GSK-3␤ inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in L-Stat3 Ϫ/Ϫ mice.CONCLUSIONS-These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3␤. Inactivation of STAT3 in the liver contributes significantly to the pathogenesis of insulin resistance.

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Section: Stat3 Sensitizes Insulin Signalingsupporting

confidence: 82%

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Moh

Zhang

et al. 2008

Diabetes

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“…It is, for example, possible that potential feed-back mechanisms, eg. the serine phosphorylation of IRS-1 by GSK-3 [47], operate differently at such high insulin concentrations, or that transendothelial insulin transport is altered [48]. Finally, because at the high insulin concentration used by investigators [22], glucose disposal is maximally stimulated at least in control subjects [46,49], consequences of an altered signalling for glucose disposal are not clear.…”

Section: Discussionmentioning

confidence: 99%

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

et al. 2002

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Aims/hypothesis. Alterations in insulin signalling could contribute to insulin resistance in Type II (non-insulindependent) diabetes mellitus. Some of these alterations could be secondary to the diabetic state, ie. the hyperglycaemia or increased NEFA concentrations. We sought to exclude such secondary factors and to investigate whether Type II diabetes in itself is associated with altered insulin signalling in skeletal muscle. Methods. Hyperinsulinaemic-euglycaemic clamps were performed in 10 obese Type II diabetic patients whose glucose concentrations had been normalised for 8 h by plasma glucose-adapted insulin infusion, 10 BMImatched first-degree relatives of Type II diabetic patients, and 10 BMI-matched non-diabetic subjects. Muscle biopsies were obtained before and at the end of the clamps, and insulin receptor kinase activity, phosphatidylinositol-3′-kinase activity, Akt-Thr 308 -phosphorylation, and glycogen synthase activity determined. Results. At similar steady-state clamp insulin concentrations (~400 pmol/l) similar receptor kinase activities, phosphatidylinositol-3′-kinase activities, AktThr 308 -phosphorylation, and glycogen synthase activities were found in all subject groups although glucose disposal was reduced in the diabetic subjects and relatives. Pre-clamp signalling levels were different between subject groups, most likely due to different preclamp insulin concentrations. Conclusion/interpretation. Our results in subjects at risk for the development of diabetes and Type II diabetic patients with normalized glucose concentrations suggest that Type II diabetes in itself is not associated with reduced signalling intensity at the studied signalling molecules, at least not at the chosen clamp insulin concentration and under the chosen conditions. Alterations responsible for the reduced glucose disposal could be located downstream of the investigated steps or in alternative insulin signalling pathways. A different spatial organisation of the investigated signalling molecules can also not be excluded. [Diabetologia (2002) Type II (non-insulin-dependent) diabetes mellitus is associated with a reduced insulin-stimulated glucose disposal in skeletal muscle and other tissues [1]. Because insulin resistance is also observed in non-diabetic first-degree relatives of diabetic subjects [2,3,4,5], and because it seems to precede the development of frank diabetes [6], an inherited basis of at least a part of the diabetes-associated insulin resistance has been proposed [7]. On the other hand metabolic abnormalities in the diabetic state itself such as hyper-

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“…Eight serine kinases have been highlighted for their activities in phosphorylation of IRS-1 at serine residues. These serine kinases include JNK (12,13,26), IKK (36), Akt (31), mTOR (32), ERK (23,24), PKC (30), glycogen synthase kinase 3 (35), and casein kinase II (54). However, it is not clear how many of these kinases are activated by TNF-␣ at the same time in cells.…”

Section: Inhibition Of Jnk Resulted In Reduction Of Sermentioning

confidence: 99%

“…Glycogen synthase kinase 3 is another serine kinase located downstream of phosphatidylinositol 3-kinase. Glycogen synthase kinase 3 was shown to phosphorylate IRS-1 in vivo and in vitro (35). (g) Activation of IKK.…”

mentioning

confidence: 99%

Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases

Gao

Zuberi

Quon

et al. 2003

Journal of Biological Chemistry

229

145

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Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin action

Cited by 288 publications

References 39 publications

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

STAT3 Sensitizes Insulin Signaling by Negatively Regulating Glycogen Synthase Kinase-3β

Insulin signalling in skeletal muscle of subjects with or without Type II-diabetes and first degree relatives of patients with the disease

Aspirin Inhibits Serine Phosphorylation of Insulin Receptor Substrate 1 in Tumor Necrosis Factor-treated Cells through Targeting Multiple Serine Kinases

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