Prolonged culture in low glucose induces apoptosis of rat pancreatic β-cells through induction of c-myc

Abstract

Prolonged culture in low-glucose concentrations (⩽5 mM) induces apoptosis in pancreatic β-cells by a poorly defined mechanism. We now show that, in both purified rat β-cells and isolated rat islets, culture in the presence of 3 or 5 mM (G3–G5) instead of 10 mM glucose (G10) induces a large increase in c-myc expression before onset of a caspase-dependent apoptosis. These effects were prevented by addition of leucine and glutamine to G3 and G5, and were mimicked by addition of the mitochondrial poison azide to G10. In contrast, inhibition of Ca 2+ influx and insulin secretion with diazoxide under control conditions did not stimulate islet c-myc expression nor β-cell apoptosis. In rat β-cells, adenovirus-mediated c-myc overexpression increased their rate of apoptosis, whereas antisense-c-myc expression reduced low-glucose-induced apoptosis by ∼50%. In the insulin producing MIN6 cell line, apoptosis induction by either low glucose or an activator of AMP-activated protein kinase (AMPK) was associated with c-myc mRNA and protein upregulation. In conclusion, stimulation of β-cell apoptosis by prolonged culture at low glucose partly results from early and sustained induction of β-cell c-myc expression. These effects may be due to sustained restriction in nutrient-derived metabolic signals.