The p66Shc protein mediates insulin resistance and secretory dysfunction in pancreatic beta-cells under lipotoxic conditions
We evaluated the role of the p66Shc redox adaptor protein in pancreatic beta-cell 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 p66Shc 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, p66Shc 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, p66Shc overexpression impaired insulin-induced augmentation of insulin content and C-peptide secretion both in the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by p53-induced increase in p66Shc protein levels and JNK-induced p66Shc phosphorylation at Ser36 and appear to involve the phosphorylation of the ribosomal protein S6 kinase at Thr389 and of insulin receptor substrate-1 at Ser307, resulting in the inhibition of insulin-stimulated protein kinase b phosphorylation at Ser473. Thus, the p66Shc protein mediates the impaired beta-cell function and insulin resistance induced by saturated fatty acids and excess body fat.