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ORIGINAL ARTICLE

Agouti Signaling Protein Stimulates Islet Amyloid Polypeptide (Amylin) Secretion in Pancreatic ß-Cells

Department of Nutrition, University of Tennessee, Knoxville,Tennessee37996

Ectopic overexpression of the murine agouti gene results in yellow coat color, obesity, hyperinsulinemia, and type II diabetes. We have shown the human homologue of agouti (agouti signaling protein; ASP) to regulate human adipocyte metabolism and lipid storage via a Ca²⁺-dependent mechanism. We have also demonstrated agouti expression in human pancreas, and that ASP stimulates insulin release via a similar Ca²⁺-dependent mechanism. Plasma amylin is also elevated in agouti mutant mice. Amylin is cosecreted with insulin from ß-cells, and overexpression of human amylin in ß-cells in yellow agouti mutant mice resulted in accelerated pancreatic amyloid deposition, severely impaired ß-cell function, and a diabetic phenotype. We report here that ASP stimulates amylin release in both the HIT-T15 ß-cell line and human pancreatic islets in the presence of a wide range of glucose concentrations (0–16.7 mmol/L), similar to its effect on insulin release; this effect was blocked by 30 µmol/L nitrendipine, confirming a Ca²⁺-dependent mechanism. Accordingly, ASP stimulation of amylin release may serve as a compensatory system to regulate blood glucose in yellow agouti mutants.

Key Words: agouti • agouti signaling protein • amylin • calcium • diabetes • pancreatic islet