Is Islet Amyloid Polypeptide a Significant Factor in Pathogenesis or Pathophysiology of Diabetes?

Islet amyloid polypeptide (IAPP) or amylin, a recently discovered minor secretory peptide of the β-cell related to calcitonin gene–related peptide (CGRP), is a constituent of amyloid deposits in the islets of many non-insulin-dependent (type II) diabetic individuals and some elderly nondiabetic subjects. IAPP is synthesized as a small precursor at a level of ∼1% that of insulin and is processed, amidated, stored in β-granules, and released along with insulin and C-peptide. Analysis of its gene (located on chromosome 12) supports an evolutionary relationship to calcitonin and CGRP, peptides with which it shares some biological actions. Like CGRP, IAPP antagonizes the action of insulin mainly at the level of muscle glycogen synthesis, but the levels required for this effect seem to be considerably higher than reported circulating levels. No evidence for overproduction of IAPP in diabetic subjects has been found thus far, but much more work is necessary to define its normal secretory rates and clearance. Other proposed actions of IAPP include serum calcium–lowering effects and smooth muscle relaxation; the latter effect might promote the uptake of insulin into the circulation within the islets. Deposition of amyloid is species selective due to structural differences within the central part of the molecule and may be initiated intracellularly in type II diabetes by several mechanisms. No differences in the structure of IAPP or its precursor have been found in individuals with maturity-onset diabetes of the young or type II diabetes. The evidence available at this time does not support the view that IAPP plays a significant role in the insulin resistance of type II diabetes or that deposition of amyloid is a primary event in its pathogenesis. However, further studies of the expression and roles of IAPP may provide new insights into islet molecular biology and physiology.