Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance.

Saad, Mário José Abdalla; Araki, Eiichi; Miralpeix, Montserrat; Rothenberg, Paul; White, Morris F.; Kahn, C. Ronald

doi:10.1172/jci116060

Cited by 296 publications

(213 citation statements)

References 47 publications

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“…Taken together, these findings suggest that high cortisol levels may have a role in the alterations seen in the early steps of insulin action in these rats. Hyperinsulinaemia per se can also induce similar alterations in early steps of insulin action, as demonstrated in previous studies of animal models of insulin resistance and in cell culture [35,49,50]. However, as the insulin levels observed in pregnant rats are only slightly higher than in virgin animals, this increase may not be responsible for all of the observed effects.…”

Section: Discussionsupporting

confidence: 64%

“…However, the stoichiometry of IRS-1 phosphorylation was also reduced in the liver and muscle of pregnant rats, demonstrating a reduction in IRS-1 phosphorylation greater than when taking into account the decrease in IRS-1 protein. In this context, changes in the insulin receptor kinase in the same direction may have at least a permissive role, since the IRS-1 protein levels are not the only determinant of IRS-1 phosphorylation levels [35,36]. Whether these regulatory defects induced by chronic hyperinsulinaemia reflect alterations in receptor and IRS-1 serine phosphorylation or some other regulatory event is unknown.…”

Section: Discussionmentioning

confidence: 99%

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Defects in insulin signal transduction in liver and muscle of pregnant rats

et al. 1997

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Insulin resistance during pregnancy has been reported both in women and in experimental animals [1][2][3][4][5][6][7], but the mechanism of this resistance remains unclear. In vivo studies have shown that pregnant rats become progressively resistant to insulin after day 16 of gestation [5]. In these animals, the insulin resistance of skeletal muscle has been clearly demonstrated in vitro, while the insulin resistance in vivo in peripheral tissues and liver has been substantiated in studies using the euglycaemic-hyperinsulinaemic clamp technique [6,7].Insulin initiates its metabolic and growth-promoting effects by binding to the a subunit of its tetrameric receptor, thereby activating the kinase in the b subunit [8]. This interaction catalyses the intramolecular autophosphorylation of specific tyrosine residues of the b subunit which further enhances the tyrosine kinase activity of the receptor toward other protein substrates [8]. In most cells, this primary event leads to the subsequent tyrosyl phosphorylation of a cytoplasmic protein with an apparent molecular weight of 160-185 kDa, called insulin receptor substrate 1 (IRS-1) [9][10][11]. Considerable evidence indicates that insulin receptor tyrosine Diabetologia (1997) 40: 179-186 Defects in insulin signal transduction in liver and muscle of pregnant rats Summary Pregnancy is known to induce insulin resistance, but the exact molecular mechanism involved is unknown. In the present study, we have examined the levels and phosphorylation state of the insulin receptor and of insulin receptor substrate 1(IRS-1), as well as the association between IRS-1 and phosphatidylinositol 3-kinase (PI 3-kinase) in the liver and muscle of pregnant rats (day 20 of gestation) by immunoprecipitation and immunoblotting with anti-insulin receptor, anti-IRS-1, anti-PI 3-kinase and antiphosphotyrosine antibodies. There were no changes in the insulin receptor concentration in the liver and muscle of pregnant rats. However, insulin stimulation of receptor autophosphorylation, as determined by immunoblotting with antiphosphotyrosine antibody, was reduced by 30 ± 6 % (p < 0.02) in muscle and 36 ± 5 % (p < 0.01) in liver at day 20 of gestation. IRS-1 protein levels decreased by 45 ± 6 % (p < 0.002) in liver and by 56 ± 9 % (p < 0.002) in muscle of pregnant rats. In samples previously immunoprecipitated with anti-IRS-1 antibody and blotted with antiphosphotyrosine antibody, the insulin-stimulated IRS-1 phosphorylation levels in the muscle and liver of pregnant rats decreased by 70 ± 9 % (p < 0.01) and 75 ± 8 % (p < 0.01), respectively. The insulin-stimulated IRS-1 association with PI 3-kinase decreased by 81 ± 6 % in muscle (p < 0.01) and 79 ± 11 % (p < 0.01) in the liver during pregnancy. These data suggest that changes in the early steps of insulin signal transduction may have a role in the insulin resistance observed in pregnancy. [Diabetologia (1997) 40: 179-186]

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Section: Discussionsupporting

confidence: 64%

Section: Discussionmentioning

confidence: 99%

Defects in insulin signal transduction in liver and muscle of pregnant rats

et al. 1997

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“…In previous studies in rat tissues, IRS-1 tyrosine phosphorylation correlated to a greater extent to insulin receptor phosphorylation levels, than to IRS-1 pro-tein expression, suggesting that modest reductions in IRS-1 protein amount would not be sufficient to affect insulin signal transduction [57]. In light of these previous data we can suggest that the increase in serine phosphorylation level of IR and IRS-1 could be the main determinant of reductions in tyrosine phosphorylation of these proteins.…”

Section: Discussionmentioning

confidence: 82%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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“…The defect is exacerbated by additive defect in insulin receptor kinase that is also present in tissues of patients with overt diabetes (14,29,30). More recently, defects in the insulin receptor-mediated signal transduction pathway, including IRS-1 phosphorylation and PI 3-kinase activation, have been found in tissues from Type 2 diabetic patients or rodent models (16,31,32). Thus, augmenting insulin signaling by targeting insulin receptor activation may represent a potential approach to alleviate insulin resistance and improve glucose homeostasis in Type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

Activation of Insulin Signal Transduction Pathway and Anti-diabetic Activity of Small Molecule Insulin Receptor Activators

Qureshi¹,

Ding²,

Li³

et al. 2000

Journal of Biological Chemistry

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We recently described the identification of a non-peptidyl fungal metabolite (L-783,281, compound 1), which induced activation of human insulin receptor (IR) tyrosine kinase and mediated insulin-like effects in cells, as well as decreased blood glucose levels in murine models of Type 2 diabetes (Zhang, B., Salituro, G., Szalkowski, D., Li, Z., Zhang, Y., Royo, I., Vilella, D., Diez, M. T., Pelaez, F., Ruby, C., Kendall, R. L., Mao, X., Griffin, P., Calaycay, J., Zierath, J. R., Heck, J. V., Smith, R. G. & Moller, D. E. (1999) Science 284, 974 -977). Here we report the characterization of an active analog (compound 2) with enhanced IR kinase activation potency and selectivity over related receptors (insulin-like growth factor I receptor, epidermal growth factor receptor, and platelet-derived growth factor receptor). The IR activators stimulated tyrosine kinase activity of partially purified native IR and recombinant IR tyrosine kinase domain. Administration of the IR activators to mice was associated with increased IR tyrosine kinase activity in liver. In vivo oral treatment with compound 2 resulted in significant glucose lowering in several rodent models of diabetes. In db/db mice, oral administration of compound 2 elicited significant correction of hyperglycemia. In a streptozotocin-induced diabetic mouse model, compound 2 potentiated the glucose-lowering effect of insulin. In normal rats, compound 2 improved oral glucose tolerance with significant reduction in insulin release following glucose challenge. A structurally related inactive analog (compound 3) was not effective on insulin receptor activation or glucose lowering in db/db mice. Thus, small molecule IR activators exert insulin mimetic and sensitizing effects in cells and in animal models of diabetes. These results have implications for the future development of new therapies for diabetes mellitus.Insulin elicits a diverse array of biological responses by binding to its specific receptor (1). The insulin receptor (IR) 1 is a heterotetrameric protein consisting of two extracellular ␣ subunits and two transmembrane ␤ subunits. The binding of the ligand to the ␣ subunit of IR not only concentrates insulin at its site of action, but also induces conformational changes in the receptor, which in turn stimulates the tyrosine kinase activity intrinsic to the ␤ subunit of the IR. Extensive studies have indicated that the ability of the receptor to autophosphorylate and phosphorylate intracellular substrates is essential for its mediation of the complex cellular responses of insulin (2-5).Insulin receptors trans-phosphorylate several immediate substrates (on Tyr residues), including insulin receptor substrate (IRS) proteins 1-4, Shc, and Gab 1, each of which provide specific docking sites for other signaling proteins containing Src homology 2 domains (6). These events lead to the activation of downstream signaling molecules, including phosphatidylinositol 3-kinase (PI 3-kinase). Numerous studies have adduced that PI 3-kinase is required for the metabolic effec...

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Regulation of insulin receptor substrate-1 in liver and muscle of animal models of insulin resistance.

Cited by 296 publications

References 47 publications

Defects in insulin signal transduction in liver and muscle of pregnant rats

Defects in insulin signal transduction in liver and muscle of pregnant rats

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Activation of Insulin Signal Transduction Pathway and Anti-diabetic Activity of Small Molecule Insulin Receptor Activators

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