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.

中文翻译：

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p66Shc 蛋白在脂毒性条件下介导胰腺 β 细胞的胰岛素抵抗和分泌功能障碍

我们评估了 p66Shc 氧化还原衔接蛋白在胰腺 β 细胞胰岛素抵抗中的作用，这种抵抗在脂毒性条件和体脂过多的情况下发展。体外长期暴露于棕榈酸酯或超重/肥胖的存在会增加 p66Shc 表达水平，并导致外源性胰岛素增加细胞胰岛素含量和 INS-1E 细胞以及人和鼠胰岛分泌的 C 肽水平的能力受损。在 INS-1E 细胞中，p66Shc 敲低导致胰岛素诱导的胰岛素含量增加和 C 肽分泌增加，并阻止棕榈酸酯削弱胰岛素这些作用的能力。相反，p66Shc 过表达会在棕榈酸酯不存在和存在的情况下损害胰岛素诱导的胰岛素含量增加和 C 肽分泌。在脂毒性条件下，p66Shc 的作用由 p53 诱导的 p66Shc 蛋白水平增加和 JNK 诱导的 Ser36 磷酸化 p66Shc 介导，并且似乎涉及核糖体蛋白 S6 激酶在 Thr389 和胰岛素受体底物 1 在 Ser307 的磷酸化，导致抑制胰岛素刺激的蛋白激酶 b 在 Ser473 位点的磷酸化。因此，p66Shc 蛋白介导由饱和脂肪酸和过量体脂诱导的受损 β 细胞功能和胰岛素抵抗。