Newly Identified Pancreatic Protein Islet Amyloid Polypeptide: What Is Its Relationship to Diabetes?

Islet amyloid polypeptide (IAPP) or amylin is a newly identified 37–amino acid COOH-terminal–amidated polypeptide that is the major protein constituent of amyloid deposits in insulinomas and amyloid deposits in pancreatic islets of non-insulin-dependent (type II) diabetic humans and adult diabetic cats. IAPP is stored with insulin in β-cell secretory vesicles and is cosecreted with insulin in response to glucose and several secretagogues. IAPP has been demonstrated in normal pancreatic islets of many species, but IAPP-derived amyloid develops commonly in the islets of only a few species (e.g., humans and cats), especially in association with age-related diabetes. IAPP from the human and cat inherently contains a short amyloidogenic sequence that is not present in species that do not form islet amyloid. Studies in animals indicate that an aberration in the synthesis or processing of IAPP, leading to a local increase in concentration of IAPP in the islet, is also required to facilitate the conversion of IAPP to amyloid. The formation of islet amyloid may contribute to the development of type II diabetes by causing disruption of islet cells and by replacement of islets. It has also been proposed that an abnormality of IAPP homeostasis underlies the pathogenesis of type II diabetes. A significant causal relationship between IAPP and type II diabetes is based on reports that IAPP inhibits glucose-stimulated insulin release by β-cells and that IAPP inhibits insulin-stimulated rates of glycogen synthesis and glucose uptake by skeletal muscle cells. These findings clearly have potentially great relevance to type II diabetes in that impaired insulin secretion and peripheral resistance to insulin are the clinical hallmarks of this form of diabetes. However, studies generally have not supported a role for IAPP as a physiologically relevant modulator of insulin secretion, and it is yet to be demonstrated whether IAPP in physiological concentrations can induce the peripheral insulin resistance that is characteristic of type II diabetes. The potential role of this newly identified pancreatic polypeptide in the genesis of type II diabetes thus needs further investigation and confirmation in model systems utilizing physiological concentrations of IAPP. The significance of the strikingly greater responsiveness of IAPP secretion relative to insulin in severely hyperglycemic states also is not clear. However, this observation may provide an important clue to the normal function of IAPP and points to an important area of future exploration.