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

Autor:	Biondi G; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Marrano N; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Dipaola L; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Borrelli A; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Rella M; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., D'Oria R; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Genchi VA; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Caccioppoli C; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Porreca I; Genetic Research Centre 'Gaetano Salvatore' BioGeM, Ariano Irpino, Italy., Cignarelli A; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Perrini S; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Marchetti P; Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy., Vincenti L; Division of General Surgery, University Hospital Polyclinic, Bari, Italy., Laviola L; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Giorgino F; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy., Natalicchio A; Department of Emergency and Organ Transplantation, University of Bari, Bari, Italy.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2022 Aug 01; Vol. 71 (8), pp. 1763-1771.
DOI:	10.2337/db21-1066
Abstrakt:	We evaluated the role of the p66Shc redox adaptor protein in pancreatic β-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 in both the absence and presence of palmitate. Under lipotoxic condition, the effects of p66Shc are mediated by a 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 β-cell function and insulin resistance induced by saturated fatty acids and excess body fat. (© 2022 by the American Diabetes Association.)
Databáze:	MEDLINE
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