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Islet
amyloid polypeptide: mechanisms of amyloidogenesis in the pancreatic
islets and potential roles in diabetes mellitus
K H Johnson, T D O'Brien, C Betsholtz, P Westermark Abstract
broadcast on www.provet.co.uk
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Abstract
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 beta cells and is cosecreted with insulin in response to
glucose and other secretagogues. Prepro-IAPP is synthesized in beta 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 beta 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
beta 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.
Reference
LABORATORY INVESTIGATION , 66(5):522-535 1992
Updated January 2016
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