Islet amyloid polypeptide in the islets of Langerhans: friend or foe?

Islet amyloid polypeptide (IAPP), or amylin, was originally discovered as t he constituent peptide in amyloid occurring in human insulinomas and in pan creatic islets in human subjects with Type II (non-insulin-dependent) diabe tes mellitus. Its normal expression in beta cells and its co-secretion with insulin in response to nutrient stimuli, suggest a metabolic function for the peptide. Specifically, IAPP has most frequently been shown to inhibit i nsulin secretion, implying that IAPP has a role in the regulation of islet hormone homeostasis. The physiological significance of IAPP in islets has b een difficult to assess; very high IAPP concentrations are required to alte r insulin secretion. Moreover, until recently, IAPP receptors have not been characterised at the molecular level, thus leaving the actual target cells for IAPP unidentified. Furthermore, in experimental diabetes in rodents, t he ratio of IAPP expression to that of insulin invariably is increased. In view of the pleiotropic effects attributed to IAPP, such regulation could b e both adverse and beneficial in diabetes. Metabolic characterisation of mi ce carrying a null mutation in the IAPP gene or which overexpress IAPP in b eta cells have recently confirmed that IAPP is a physiological inhibitor of insulin secretion. Based on experiments in which IAPP-deficient mice devel op a more severe form of alloxan-induced diabetes, we argue that the action of IAPP in the islets normally is beneficial for beta-cell function and su rvival; thus, the established up regulation of IAPP expression compared wit h that of insulin in experimental rodent diabetes could serve to protect is lets under metabolically challenging circumstances.