Agouti signaling protein stimulates islet amyloid polypeptide (amylin) secretion in pancreatic beta-cells

Ectopic overexpression of the murine agouti gene results in yellow coat col or, obesity, hyperinsulinemia, and type II diabetes. We have shown the huma n homologue of agouti (agouti signaling protein; ASP) to regulate human adi pocyte metabolism and lipid storage via a Ca2+-dependent mechanism. We have also demonstrated agouti expression in human pancreas, and that ASP stimul ates insulin release via a similar Ca2+-dependent mechanism. Plasma amylin is also elevated in agouti mutant mice. Amylin is cosecreted with insulin f rom beta -cells, and overexpression of human amylin in beta -cells in yello w agouti mutant mice resulted in accelerated pancreatic amyloid deposition, severely impaired beta -cell function, and a diabetic phenotype. We report here that ASP stimulates amylin release in both the HIT-T15 beta -cell lin e and human pancreatic islets in the presence of a wide range of glucose co ncentrations (0-16.7 mmol/L), similar to its effect on insulin release; thi s effect was blocked by 30 mu mol/L nitrendipine, confirming a Ca2+-depende nt mechanism. Accordingly, ASP stimulation of amylin release may serve as a compensatory system to regulate blood glucose in yellow agouti mutants.