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The p66Shc protein mediates insulin resistance and secretory dysfunction in pancreatic beta-cells under lipotoxic conditions

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posted on 12.07.2022, 17:15 authored by Giuseppina Biondi, Nicola Marrano, Lucia Dipaola, Anna Borrelli, Martina Rella, Rossella D’Oria, Valentina A. Genchi, Cristina Caccioppoli, Immacolata Porreca, Angelo Cignarelli, Sebastio Perrini, Piero Marchetti, Leonardo Vincenti, Luigi Laviola, Francesco Giorgino, Annalisa Natalicchio

 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. 

Funding

This work was supported by AGER 2 Project (grant n° 2016-0174, COMPETITIVE e Claims of Olive oil to iMProvE The market ValuE of the product), Ministero dell’Università e della Ricerca of Italy (Progetti di Rilevante Interesse Nazionale, 2015), the European Union (European Social Fund, PON R&I 2014–2020, AIM 1810057), and the “Fondazione per la Ricerca Biomedica Saverio e Isabella Cianciola”.

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