Resveratrol treatment restores peripheral insulin action in diabetic IRS2-deficient mice in a Sirt1-independent manner

Abstract

[Background and aims]: Mice with complete deletion of insulin receptor substrate (IRS) 2 develop hyperglycaemia, impaired hepatic insulin signalling and elevated gluconeogenesis. The elevated expression and activity of PTP1B in the liver of hyperglycaemic IRS2-/- mice block insulin receptor (IR)/IRS1-mediated insulin signalling by increasing the association of IR with this phosphatase. Accordingly, PTP1B inhibition by genetic (double mutant IRS2-/-PTP1B-/-) and pharmacological (resveratrol treatment) strategies promotes insulin sensitivity in the liver of IRS2-/- mice through the restoration of IRS1-mediated Akt/Foxo1 phosphorylation and the inhibition of gluconeogenic enzymes. Moreover, resveratrol, a plant-derived polyphenolic compound, has been receiving increasing attention as a potent activator of the histone deacetylase Sirt1 with anti-oxidant and anti-neoplasic properties. In fact, recent studies have demonstrated that both resveratrol treatment and moderate increase of Sirt1 levels improved insulin sensitivity. On that basis, the purpose in this study was to investigate if resveratrol action on IRS2-/- mice is mediated by Sirt1 activation. For this goal, we have generated IRS2-/- mice with moderate over-expression of Sirt1. [Materials and methods]: We characterized whole body glucose homeostasis, insulin sensitivity and insulin signalling in liver and muscle of hyperglycaemic IRS2-/- deficient mice, IRS2-/- mice treated with resveratrol (IRS2-/-Resv) and IRS2-/- mice that moderate over-express Sirt1 (IRS2-/-Sirt1). mRNA levels, protein expression and enzymatic activity of PTP1B in liver and muscle have been analyzed. [Results]: Resveratrol treatment improved systemic insulin sensitivity in hyperglycemic IRS2-/- mice but did not change glucose tolerance due to the inability to revert beta cell failure. On the other hand, moderate over-expression of Sirt1 in IRS2-/- mice did not recover neither peripheral insulin resistance nor glucose intolerance. In both liver and muscle of hyperglycaemic IRS2-/- mice levels of PTP1B were increased. Resveratrol treatment of IRS2-/- mice significantly decreased PTP1B mRNA and inhibited its activity in both tissues, thereby restoring IRS1-mediated PI3kinase/Akt signalling. Conversely, moderate over-expression of Sirt1 could not normalized PTP1B levels and, consequently, insulin signalling in liver and muscle remained impaired. [Conclusion]: In conclusion, our results have established that elevated PTP1B expression in liver and muscle of hyperglycaemic IRS2-/- mice impaired insulin signalling. Accordingly, PTP1B inhibition by resveratrol promotes insulin sensitivity in IRS2-/- mice through the restoration of IRS1-mediated signalling in peripheral tissues. Moreover, we have demonstrated that the effects of resveratrol on insulin action in IRS2-/- mice are not mediated through Sirt1 activation.