We evaluated the role of the p66~Shc redox adaptor protein in pancreatic beta-celI insulin resistance that develops under lipotoxic conditions and with excess body fat. Prolonged exposure to palmitate in vitro or the presence of overweight/obesity augmented p66~Shc expression levels and caused an impaired ability of exogenous insulin to increase cellular insulin content and secreted C-peptide levels in INS-1E cells and human and murine islets. In INS-1E cells, p66~Shc knockdown resulted in enhanced insulin-induced augmentation of insulin content and C-peptide secretion and prevented the ability of palmitate to impair these effects of insulin. Conversely, p66~Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66~Shc are mediated by a p53-induced increase in p66~Shc protein levels and JNK-induced p66~Shc phosphorylation at Ser~36 and appear to involve the phosphorylation of the ribo-somal protein S6 kinase at Thr~389 and of insulin receptor substrate 1 at Ser~307, resulting in the inhibition of insulin-stimulated protein kinase B phosphorylation at Ser473. Thus, the p66~Shc protein mediates the impaired beta-cell function and insulin resistance induced by saturated fatty acids and excess body fat.
展开▼
