EXPRESSION OF HUMAN ISLET AMYLOID POLYPEPTIDE AMYLIN IMPAIRS INSULIN-SECRETION IN MOUSE PANCREATIC BETA-CELLS

Non-insulin-dependent diabetes mellitus (NIDDM) is associated histopat hologically with islet amyloid deposits of which a major component is islet amyloid polypeptide (IAPP)/amylin. We examined whether endogenou s IAPP controls insulin secretion via a local effect within pancreatic islets and whether overexpression of this peptide contributes to panc reatic beta-cell dysfunction in this disease. Transgenic mice expressi ng human IAPP in pancreatic beta cells were used in this study. Human IAPP expression did not influence the mouse proinsulin mRNA level and insulin content. Glucose-induced insulin secretion was decreased in th e isolated pancreatic islets of transgenic mice. MIN6, a glucose-respo nsive pancreatic beta-cell line, was transfected with human IAPP cDNA by a lipofectin method. Human IAPP expression was confirmed by RNA blo t and immunohistochemical analysis. In two transfectants expressing th e largest amount of human IAPP, insulin secretion was increased in res ponse to glucose stimulation; however, the magnitude of the insulin re sponse in cells transfected with human IAPP was smaller than in contro l clones. Insulin content was not influenced by the expression. We con clude that endogenous IAPP inhibits insulin secretion. via an autocrin e effect within pancreatic islets, and that the impaired insulin secre tion in this disease may be partly caused by overexpression of IAPP, C opyright (C) 1997 by W,B, Sanders Company.