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- Title
The p66Shc Protein Mediates Insulin Resistance and Secretory Dysfunction in Pancreatic β-Cells Under Lipotoxic Conditions.
- Authors
Biondi, Giuseppina; Marrano, Nicola; Dipaola, Lucia; Borrelli, Anna; Rella, Martina; D'Oria, Rossella; Genchi, Valentina A.; Caccioppoli, Cristina; Porreca, Immacolata; Cignarelli, Angelo; Perrini, Sebastio; Marchetti, Piero; Vincenti, Leonardo; Laviola, Luigi; Giorgino, Francesco; Natalicchio, Annalisa
- Abstract
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.
- Subjects
ANIMAL experimentation; APOPTOSIS; ISLANDS of Langerhans; CELLULAR signal transduction; INSULIN; INSULIN resistance; FATTY acids; C-peptide; MICE
- Publication
Diabetes, 2022, Vol 71, Issue 8, p1763
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db21-1066