Islet amyloid polypeptide: Mechanisms of amyloidogenesis in the pancreatic islets and potential roles in diabetes mellitus

Amyloid deposits characteristically associated with pancreatic islets of those species (e.g., humans, cats, and monkeys) that develop age-associated forms of diabetes have been shown to represent a concentrated and polymerized form of a previously unknown islet-derived protein identified either as IAPP or amylin. IAPP, a highly conserved and carboxy-terminally amidated 37 amino acid polypeptide with approximately 45% amino acid sequence identity to CGRP, is produced by islet β cells and is cosecreted with insulin in response to glucose and other secretagogues. Prepro-IAPP is synthesized in β cells as an 89 to 93 amino acid molecule, and mature IAPP appears to be formed by enzymatic processing similar to that involved in the formation of insulin. Glucose-stimulated IAPP secretion generally parallels that of insulin and, on a molar basis, IAPP represents about 1% of the amount of insulin secreted. A significant dissociation of IAPP and insulin secretion (associated with relatively greater upregulation of IAPP secretion) is observed in response to marked hyperglycemia, suggesting that IAPP and insulin expression are differentially regulated. The amyloidogenicity of IAPP in only a very limited number of species is importantly related to the amino acid residues inherently found in the 20-29 region of IAPP from those species. The 25-28 region of human and cat IAPP is identical in structure and appears to be the most important amyloidogenic sequence common to the human and cat. In vitro fibrillogenesis studies have shown that amino acid substitutions in this region especially affect the amyloidogenicity of IAPP. Studies in dogs and cats suggest that aberrations in β cell synthesis (or processing) of IAPP may lead to an increased concentration of IAPP in the local milieu, thus providing a second prerequisite for the self aggregation of IAPP to form islet amyloid. IAPP has been implicated to have physiological roles in glucose regulation, hemodynamics, calcium homeostasis, and as an anorectic agent. The major current interest in IAPP concerns its potential relationships to glucose metabolism and the development of type 2 diabetes. Evidence has been provided which indicates that IAPP can inhibit glucose- stimulated insulin secretion by β cells, and that IAPP can also potentially contribute to the pathogenesis of type 2 diabetes by increasing hepatic glucose output and by inducing peripheral insulin resistance. The significance of these various implicated actions of IAPP with respect to the pathogenesis of type 2 diabetes has been questioned primarily on the basis that the concentrations of IAPP used to produce these affects have generally been more than 1000-fold higher than concentrations found normally in the circulation. The high concentration of IAPP used to demonstrate the reported effects on β cells, liver, and muscle are within the same range of IAPP concentrations needed to displace CGRP from its receptors. It is possible, therefore, that the reported effects of IAPP on these cells is mediated by binding of IAPP to CGRP receptors. Resolution of these key questions concerning IAPP concentration and effect relationships, together with the identification of specific IAPP receptors, are of vital importance to understanding the real significance of IAPP in type 2 diabetes. Increased production and secretion of IAPP have been implicated as important factors in both the development of islet amyloidogenesis and the development of type 2 diabetes. The possible linkage of aberrations in IAPP production and secretion to amyloidogenesis appears to be supported by studies in cats and dogs. It is also interesting that overproduction and hypersecretion of IAPP by β cells has been demonstrated to occur in isolated islets from rats with spontaneous or experimentally induced obesity and hyperinsulinemia (116). These observations in rats are potentially important in that obesity and hyperinsulinemia are commonly observed in humans with type 2 diabetes. Further documentation is needed to confirm the existence of spontaneous in vivo aberrations of IAPP production in humans and cats. Also, it needs to be determined whether potential aberrations in IAPP secretion are only secondary to prolonged hyperglycemia or obesity or whether primary genetic factors may be implicated. Studies to date have not supported a genetic linkage between IAPP and type 2 diabetes. However, further studies of the 5'-upstream regulating region of the IAPP gene are needed to clarify the role of IAPP gene regulation in this most common form of diabetes in humans.