Glucose regulation of islet amyloid polypeptide gene expression in rat pancreatic islets

Intracellular pathways by which glucose regulates islet amyloid polypeptide (IAPP) gene expression in pancreatic islets were studied. IAPP mRNA levels were threefold higher in islets cultured with 16.7 mM glucose compared with control (5.5 mM glucose). Mannose and amino acids but not 2-deoxyglucose or 6-deoxyglucose mimicked the effect of glucose. Mannoheptulose (a glycolysis inhibitor) and verapamil and diazoxide (which affect calcium signaling pathway) abolished the difference in islet IAPP mRNA content between high and low glucose. At low glucose, IAPP mRNA levels were increased 1.9-fold in islets treated with forskolin or dibutyryl adenosine 3',5'-cyclic monophosphate (DBcAMP) but not with 12-O-tetradecanoylphorbol 13-acetate. Insulin mRNA levels were 1.6-fold higher in islets cultured at high glucose than controls; glucose metabolism was required, whereas no effects of cAMP or diazoxide were observed. IAPP and insulin were cosecreted into the media. We conclude that glucose regulation of IAPP mRNA abundance requires intracellular metabolism of the hexose and that calcium may serve as a mediator of this effect; cAMP but not protein kinase C possibly participates in this regulation.