Increased expression of the transcription factor c-MYC may contribute to high glucose induction of b-cell apoptosis and dysfunction. In this study, we compared the effects of c-MYC activation and high glucose concentrations on glucose stimulus-secretion coupling events in mouse islets.

pIns-c-MycER^TAM+/- (Myc⁺) mice express, in b-cells, a c-Myc/oestrogen-receptor fusion protein activated by 4-OH-tamoxifen (TAM). Islets from Myc⁺ mice and their wild-type littermates (WT) were cultured for 1 week in RPMI medium containing 10-30 mmol/l glucose with or without TAM for the last 2-3 days. After culture, islet caspase activation and glucose-induced changes in cytosolic Ca²⁺ concentration ([Ca²⁺]_c) and insulin secretion were measured. Results are means for at least 7 islets from 3 experiments.

In TAM-treated or -untreated WT islets, stepwise increases in glucose concentration induced identical concentration-dependent rises in [Ca²⁺]_c and insulin secretion. In comparison, Myc+ islets displayed a 1.6-fold higher caspase activity (P < 0.05), a 60% lower insulin/DNA content ratio, and a reduced glucose-induced rise in [Ca²⁺]_c and insulin secretion (P < 0.01). TAM treatment of Myc⁺ islets further increased caspase activity ~3.5 fold (P < 0.001), reduced their insulin/DNA content ratio by ~64% (P = 0.001), increased resting [Ca²⁺]_c by ~45 nmol/l (P < 0.0001), and reduced the maximal glucose-induced rise in [Ca²⁺]_c and insulin secretion. In contrast, 1 week culture in 30 mmol/l glucose increased the glucose sensitivity without affecting the maximal glucose effectiveness for changes in [Ca²⁺]_c and insulin secretion.

c-MYC activation triggers b-cell apoptosis and functional alterations different from those induced by high glucose concentrations.