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Oliveira J.M.,Institute dInvestigations Biomediques August Pi i Sunyer | Oliveira J.M.,Research Center Biomedica En Red Of Diabetes | Oliveira J.M.,Free University of Colombia | Rebuffat S.A.,Institute dInvestigations Biomediques August Pi i Sunyer | And 6 more authors.
Canadian Journal of Physiology and Pharmacology | Year: 2014

Insulin receptor substrate 2 (IRS2) is a widely expressed protein that regulates crucial biological processes including glucose metabolism, protein synthesis, and cell survival. IRS2 is part of the insulin-insulin-like growth factor (IGF) signaling pathway and mediates the activation of the phosphotidylinositol 3-kinase (PI3K)-Akt and the Ras-mitogen-activated protein kinase (MAPK) cascades in insulin target tissues and in the pancreas. The best evidence of this is that systemic elimination of the Irs2 in mice (Irs2-/-) recapitulates the pathogenesis of type 2 diabetes (T2D), in that diabetes arises as a consequence of combined insulin resistance and beta-cell failure. Indeed, work using this knockout mouse has confirmed the importance of IRS2 in the control of glucose homeostasis and especially in the survival and function of pancreatic beta-cells. These studies have shown that IRS2 is critically required for beta-cell compensation in conditions of increased insulin demand. Importantly, islets isolated from T2D patients exhibit reduced IRS2 expression, which supports the likely contribution of altered IRS2-dependent signaling to beta-cell failure in human T2D. For all these reasons, the Irs2-/- mouse has been and will be essential for elucidating the inter-relationship between beta-cell function and insulin resistance, as well as to delineate therapeutic strategies to protect beta-cells during T2D progression.


Oliveira J.M.,Institute dInvestigations Biomediques August Pi i Sunyer | Oliveira J.M.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asoc | Rebuffat S.A.,Institute dInvestigations Biomediques August Pi i Sunyer | Rebuffat S.A.,Research Center Biomedica En Red Of Diabetes fermedades Metabolicas Asoc | And 15 more authors.
American Journal of Physiology - Endocrinology and Metabolism | Year: 2014

Pancreatic β-cells play a central role in type 2 diabetes (T2D) development, which is characterized by the progressive decline of the functional β-cell mass that is associated mainly with increased β-cell apoptosis. Thus, understanding how to enhance survival of β-cells is key for the management of T2D. The insulin receptor substrate-2 (IRS-2) protein is pivotal in mediating the insulin/IGF signaling pathway in β-cells. In fact, IRS-2 is critically required for β-cell compensation in conditions of increased insulin demand and for β-cell survival. Tungstate is a powerful antidiabetic agent that has been shown to promote β-cell recovery in toxininduced diabetic rodent models. In this study, we investigated whether tungstate could prevent the onset of diabetes in a scenario of dysregulated insulin/IGF signaling and massive β-cell death. To this end, we treated mice deficient in IRS2 (Irs2-/-), which exhibit severe β-cell loss, with tungstate for 3 wk. Tungstate normalized glucose tolerance in Irs2-/- mice in correlation with increased β-cell mass, increased β-cell replication, and a striking threefold reduction in β-cell apoptosis. Islets from treated Irs2-/- exhibited increased phosphorylated Erk1/2. Interestingly, tungstate repressed apoptosis-related genes in Irs2-/- islets in vitro, and ERK1/2 blockade abolished some of these effects. Gene expression profiling showed evidence of a broad impact of tungstate on cell death pathways in islets from Irs2-/- mice, consistent with reduced apoptotic rates. Our results support the finding that β-cell death can be arrested in the absence of IRS2 and that therapies aimed at reversing β-cell mass decline are potential strategies to prevent the progression to T2D. © 2014 the American Physiological Society.

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