1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...
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19<br />
D. Islet-cell amyloid<br />
The relevance of amyloid deposition in the deterioration of beta-cell function has<br />
been the subject of debate for many years. As indicated in the Introduction, deposits<br />
composed mainly of islet amyloid polypeptide (IAPP), also known as amylin, have been<br />
reported in up to 90% of DM2 individuals, compared with 10%-13% of non-diabetic<br />
counterparts (4). IAPP is a 37 amino-acid, beta-cell peptide which is co-stored and co-<br />
released with insulin in response to beta-cell secretagogues. The normally soluble peptide is<br />
found in the circulation at 5-15 pmol/l concentration in man and like C-peptide (but not<br />
insulin) it is excreted by the kidney; the relationship of circulating insulin-like molecules to<br />
IAPP would therefore be more accurately with C-peptide than insulin (73).<br />
Several bodies of evidence support a potential role of IAPP in the pathophysiology<br />
of beta-cell loss in DM2. In effect, spontaneous DM2 occuring in humans, monkeys and<br />
cats, all share close homology in IAPP sequence which spontaneously form amyloid fibrils<br />
in an aqueous environment. Nevertheless, proline substitutions in the region IAPP 24-29<br />
that does not form fibrils in an aqueous solution, as found in rats and mice, do not<br />
spontaneously develop DM2 but instead require selective genetic manipulation to develop<br />
diabetes (ref. cit in 73). Transgenic mice expressing human IAPP (hIAPP) in beta-cells<br />
when obese, spontaneously develop diabetes characterized by islet amyloid and decreased<br />
beta-cell mass (74). Prospective studies in these mice support the hypothesis that the<br />
mechanism of the decreased beta-cell mass is increased apoptosis (75). It has been<br />
suggested that fibril size of IAPP may determine the capacity of amyloid to cause cell death<br />
and that intermediate-sized oligomeric material is chiefly responsible for beta-cell toxicity.<br />
Exposure of mouse islets to intermediate-sized aggregates of hIAPP caused disruption and<br />
vesiculation of cell membranes after 24 hours, and both necrotic and apoptotic cells were<br />
evident after 48 hours. These particles were more cytotoxic to mouse islet cells than<br />
matured particles containing large aggregates (76). The findings from the Mayo Clinic that<br />
only a minority (about 10%) of the cases with IFG had islet amyloid (evaluated in slides<br />
stained by Congo Red and examined under polarized light for birefringence) present while<br />
already having a deficit in presumptive beta-cell mass of approximately 40%, is consistent