Role of Islet Glucokinase, Glucose Metabolism, and Insulin Pathway in the Enhancing Effect of Islet Neogenesis-Associated Protein on Glucose-Induced Insulin Secretion

OBJECTIVE: To demonstrate the role of islet glucokinase, glucose metabolism, and intracellular insulin mediators in the enhancing effect of islet neogenesis-associated protein pentadecapeptide (INGAP-PP) on glucose-induced insulin secretion. METHODS: Islets from normal rats were cultured for 4 days in the absence or presence of 10 μg/mL INGAP-PP, with/without Wortmannin or LY294002. Islets were incubated with different glucose concentrations to measure insulin secretion and content, hexokinase and glucokinase activity, glucose oxidation and utilization, glucokinase, insulin receptor, insulin receptor substrate (IRS)-1/2, and PI3K concentration and phosphorylation. RESULTS: The INGAP-PP significantly increased insulin release at high but not at low glucose concentration, glucokinase activity, glucose metabolism, glucokinase, insulin receptor, IRS-2 and PI3K protein concentration, insulin receptor and IRS-1/2 tyrosine phosphorylation, and the association of p85 with IRS-1. Wortmannin and LY294002 blocked INGAP-PP effect on insulin secretion and glucokinase protein levels in a dose-dependent manner. CONCLUSIONS: The enhancing effect of INGAP-PP on glucose-induced insulin release could be partly ascribed to its effect on glucokinase activity and glucose metabolism and is mainly mediated by the PI3K/AKT pathway. These results, together with the low hypoglycemia risk associated with the use of INGAP-PP, offer a new alternative for diabetes prevention and treatment.