Glucagon-like peptide-1 stimulates insulin secretion by a Ca 2+-independent mechanism in Zucker diabetic fatty rat islets of Langerhans

Abstract

This study investigates the mechanisms responsible for glucagon-like peptide-1 (GLP-1)-induced insulin secretion in Zucker diabetic fatty (ZDF) rats and their lean control (ZLC) littermates. Glucose, and 100 nmol/L GLP-1 (7-37 hydroxide) in the presence of stimulatory glucose concentrations, induced insulin secretion in islets from ZLC animals. In contrast, ZDF islets hypersecreted insulin at low glucose (5 mmol/L) and were poorly responsive to 15 mmol/L glucose stimulation, but increased insulin secretion following exposure to GLP-1. The insulin secretory response to 100 nmol/L GLP-1 was reduced by 88% in ZLC islets exposed to exendin 9-39. The intracellular Ca 2+ concentration ([Ca 2+] i) increased in fura-2-loaded ZLC islets following stimulation with 12 mmol/L glucose alone or GLP-1 in the presence of 12 mmol/L glucose. The increases in [Ca 2+] i and insulin secretion in ZLC islets induced by GLP-1 were attenuated by 1 μmol/L nitrendipine. In contrast, neither glucose nor GLP-1 substantially increased [Ca 2+] i in ZDF islets. Furthermore, insulin secretory responses to GLP-1 were not significantly inhibited in ZDF islets by nitrendipine. However, the insulin secretory response to GLP-1 in both ZLC and ZDF islets was ablated by cholera toxin. Our findings indicate that in ZLC islets, GLP-1 induces insulin secretion by a mechanism that depends on Ca 2+ influx through voltage-dependent Ca 2+ channels, whereas in ZDF islets, the action of GLP-1 is mediated by Ca 2+-independent signaling pathways.