INCREASED INSULIN-SECRETION AND GLUCOSE-TOLERANCE IN MICE LACKING ISLET AMYLOID POLYPEPTIDE (AMYLIN)

Islet amyloid polypeptide (IAPP or amylin) is costored and cosecreted with insulin and may regulate insulin secretion and blood glucose hand ling. However, the role and importance of endogenous IAPP in the regul ation of insulin release and glucose homeostasis have been controversi al. Here we report on the generation and phenotypic analysis of IAPP-d eficient mice. These mice have normal, or near to normal, basal levels of circulating insulin and glucose. However, following glucose admini stration, IAPP-deficient males presented increased insulin responses p aralleled with a more rapid blood glucose elimination compared to wild -type controls. Blood glucose elimination was also found to be enhance d in IAPP-deficient females, but the insulin response in this gender d id not differ from controls. In a transgenic rescue experiment, using an insulin-promoter human-IAPP fusion gene, insulin responses and bloo d glucose elimination were reversed in LAPP-deficient males, whereas t he female phenotype appeared unaffected. Our results provide the first firm evidence of a physiological role for endogenous IAPP and indicat e that IAPP, apparently in a gender-dependent manner, limits the degre e of glucose-induced insulin secretion and the rate of blood glucose e limination. (C) 1998 Academic Press.