Aggregation of islet amyloid polypeptide: from physical chemistry to cell biology

Amyloid formation in the pancreas by islet amyloid polypeptide (IAPP) leads to beta-cell death and dysfunction, contributing to islet transplant failure and to type-2 diabetes. IAPP is stored in the beta-cell insulin secretory granules and cosecreted with insulin in response to beta-cell secretagogues. IAPP is believed to play a role in the control of food intake, in controlling gastric emptying and in glucose homeostasis. The polypeptide is natively unfolded in its monomeric state, but is one of the most amyloidogenic sequences known. The mechanisms of IAPP amyloid formation in vivo and in vitro are not understood; the mechanisms of IAPP induced cell death are unclear; and the nature of the toxic species is not completely defined. Recent work is shedding light on these important issues.