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
tamoxifen-switchable 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 stimulus-secretion 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(2+)](i)), and lower
glucose-induced [Ca(2+)](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(2)O(2) concentration increased the islet resting [Ca(2+)](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(2)O(2) concentration than by prolonged culture in high
glucose.