AMP-activated protein kinase agonist dose dependently improves function and reduces apoptsis in gluctoxic β-cels without changing triglyceride levels

Abstract

Prolonged hyperglycaemia leads to impaired glucose-stimulated insulin secretion (GSIS) and apoptosis in insulin-producing β-cells. The detrimental effects have been connected with glucose-induced lipid accumulation in the β-cell. AMP-activated protein kinase (AMPK) agonist, 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR), promotes utilization of nutrient stores for energy production. It was tested how impaired GSIS and elevated apoptosis observed in insulinoma (INS)-1E cells after prolonged culture at 27 mM glucose were affected by the inclusion of 0.3 or 1 mM AICAR during culture. Glucose-induced impairment of insulin release was reverted by the inclusion of 0.3 but not 1 mM AICAR, which did not affect insulin content. The glucose-induced rise in triglyceride (TG) content observed in the cells cultured at 27 mM glucose was not altered by the inclusion of either 0.3 or 1 mM AICAR. Inclusion of 1 but not 0.3 mM AICAR during culture induced phosphorylation of AMPK and its downstream target acyl-CoA carboxylase. Phosphorylation was paralleled by reduced number of apoptotic cells and lowered expression of pro-apoptotic C/EBP homologous protein (CHOP). In conclusion, AICAR dose dependently improves β-cell function and reduces apoptosis in β-cells exposed to prolonged hyperglycaemia without changing TG levels. © 2008 Society for Endocrinology.