1 BETA-CELL FAILURE IN DIABETES AND PRESERVATION BY ...

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