Agouti signaling protein stimulates islet amyloid polypeptide (amylin) secretion in pancreatic beta-cells.
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 Ca(2+)-dependent mechanism. We have also demonstrated agouti expression in human pancreas, and that ASP stimulates insulin release via a similar Ca(2+)-dependent mechanism. Plasma amylin is also elevated in agouti mutant mice. Amylin is cosecreted with insulin from beta-cells, and overexpression of human amylin in beta-cells in yellow 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 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 mumol/L nitrendipine, confirming a Ca(2+)-dependent mechanism. Accordingly, ASP stimulation of amylin release may serve as a compensatory system to regulate blood glucose in yellow agouti mutants.
Xue
B
B
Department of Nutrition, University of Tennessee, 1215 West Cumberland Avenue, Room 229, Knoxville TN 37996-1900, USA.
Zemel
M B
MB
D054366:Agouti Signaling Protein; D000682:Amyloid / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology
D054366:Agouti Signaling Protein; D000682:Amyloid; D036341:Intercellular Signaling Peptides and Proteins; D058228:Islet Amyloid Polypeptide; D011506:Proteins; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D002118:Calcium