The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic β-Cells Under Lipotoxic Conditions

We evaluated the role of the p66(Shc) 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 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 ribosomal 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 Ser(473). Thus, the p66(Shc) protein mediates the impaired beta-cell function and insulin resistance induced by saturated fatty acids and excess body fat.

Automated summary

In this study, the role of p66(Shc) redox adaptor protein in pancreatic beta-cell insulin resistance under lipotoxic conditions and excess body fat was evaluated. The findings suggest that p66(Shc) protein mediates impaired beta-cell function and insulin resistance induced by saturated fatty acids and excess body fat.