Effects of c-MYC activation on glucose stimulus-secretion coupling events in mouse pancreatic islets

Alteration of pancreatic [beta]-cell survival and Preproinsulin gene expression by prolonged hyperglycemia may result from increased c-MYC expression. However, it is unclear whether c-MYC effects on [beta]-cell function are compatible with its proposed role in glucotoxicity. We therefore tested the effects of short-term c-MYC activation on key [beta]-cell stimulus-secretion coupling events in islets isolated from mice expressing a tamoxifenswitchable form of c-MYC in [beta]-cells (MycER) and their wild-type littermates. Tamoxifen treatment of wild-type islets did not affect their cell survival, Preproinsulin gene expression, and glucose stimulussecretion coupling. In contrast, tamoxifen-mediated c-MYC activation for 2-3 days triggered cell apoptosis and decreased Preproinsulin gene expression in MycER islets. These effects were accompanied by mitochondrial membrane hyperpolarization at all glucose concentrations, a higher resting intracellular calcium concentration ([[[Ca.sup.2+].sub.i]], and lower glucose-induced [[[Ca.sup.2+]].sub.i] rise and islet insulin content, leading to a strong reduction of glucose-induced insulin secretion. Compared with these effects, 1-wk culture in 30 mmol/l glucose increased the islet sensitivity to glucose stimulation without reducing the maximal glucose effectiveness or the insulin content. In contrast, overnight exposure to a low [H.sub.2][O.sub.2] concentration increased the islet resting [[[Ca.sup.2+]].sub.i] and reduced the amplitude of the maximal glucose response as in tamoxifen-treated MycER islets. In conclusion, c-MYC activation rapidly stimulates apoptosis, reduces Preproinsulin gene expression and insulin content, and triggers functional alterations of [beta]-cells that are better mimicked by overnight exposure to a low [H.sub.2][O.sub.2] concentration than by prolonged culture in high glucose. [beta]-cell mass; apoptosis; cytosolic calcium concentration; insulin secretion; mitochondrial membrane potential