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.