Insulin, acting in an autocrine manner, promotes β-cell survival and growth and its own biosynthesis and secretion. Prolonged exposure of β-cells to high levels of saturated fatty acids (SFAs) impairs insulin signaling, reducing the ability of insulin to promote its release. The p66Shc protein is an inducer of cellular oxidative stress and apoptosis, and its mRNA levels are increased in pancreatic islets from overweight/obese subjects. Here we evaluated the role of p66Shc in pancreatic β-cell insulin resistance (IR) occurring in obesity and lipotoxic conditions. Insulin effects on its own content and C-peptide secretion were studied in pancreatic islets from overweight/obese (BMI ≥25 kg/m2) compared to lean (BMI <25 kg/m2) human donors, and in INS-1E cells, murine pancreatic islets and human pancreatic islets exposed to palmitate. To evaluate the role of p66Shc in lipotoxicity-induced β-cell IR, p66Shc levels were silenced or overexpressed. Pancreatic islets from overweight/obese subjects showed a reduced ability of insulin to increase its own biosynthesis and C-peptide secretion. Similarly, prolonged exposure to palmitate augmented p66Shc levels and induced IR in INS-1E cells, human islets and murine islets. When p66Shc protein levels were reduced, insulin-induced C-peptide secretion was enhanced, and the palmitate-induced reductions of C-peptide levels and insulin content were both reversed. By contrast, p66Shc overexpression resulted in inhibition of insulin-induced C-peptide secretion and increase of insulin content, both in absence and presence of palmitate. These effects of p66Shc were found to require p70S6K (Thr389) and IRS-1 (Ser307) phosphorylation, which inhibited insulin-stimulated Akt phosphorylation.
In conclusion, the protein p66Shc exerts an inhibitory effect on β-cell insulin signaling and can mediate the ability of SFAs and excess body fat to cause β-cell IR, which results in both reduced survival and impaired secretory function.
L. Dipaola: None. A. Natalicchio: Other Relationship; Self; Novo Nordisk Inc., Sanofi-Aventis. G. Biondi: None. N. Marrano: None. M. Bugliani: None. A. Cignarelli: Consultant; Self; Eli Lilly and Company. Speaker's Bureau; Self; Merck Sharp & Dohme Corp., Novo Nordisk A/S. S. Perrini: None. P. Marchetti: None. L. Laviola: Advisory Panel; Self; Abbott, Boehringer Ingelheim Pharmaceuticals, Inc., Lilly Diabetes, Novo Nordisk Inc. Board Member; Self; AstraZeneca, Roche Diabetes Care, Sanofi-Aventis. Speaker's Bureau; Self; Medtronic, Mundipharma, Takeda Pharmaceutical Company Limited. F. Giorgino: Advisory Panel; Self; Aegerion Pharmaceuticals, AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, MedImmune, Merck Sharp & Dohme Corp., Novo Nordisk A/S, Roche Diabetes Care, Sanofi. Consultant; Self; Roche Diabetes Care, Sanofi. Research Support; Self; Eli Lilly and Company, LifeScan, Inc., Takeda Pharmaceutical Company Limited. Other Relationship; Self; AstraZeneca, Eli Lilly and Company, Sanofi.