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- Title
Oligomerization of Islet Amyloid Polypeptide Precedes the Development of Diabetes.
- Authors
He, Caren L.; Sui, Y.; Zhu, X.; Liu, L. Z.; Gu, X. M.; Zhao, H. L.; Lai, F. M. M.; Tong, P. C. Y.; Chan, J. C. N.
- Abstract
Islet amyloid polypeptide (IAPP) is an amyloidogenic protein associated with pancreatic beta-cell loss in type 2 diabetes. For in vitro studies, human IAPP oligomers can lead to formation of either non-toxic amyloid fibrils or toxic oligomers, the latter causing beta-cell apoptosis. To date, the correlation of oligomerization of IAPP and beta-cell loss in type 2 diabetic mellitus (DM) remains to be elucidated. Pancreas specimens were obtained from autopsies of 6 male human LAPP transgenic mice and 11 human adults (Type 2 DM subjects: n=5, male=2, age=78.6±6.6 years; non-DM control subjects: n--6, male=3, age=80.0±8.2 years). Oligomer depositions were detected by immunostaining with oligomer-specific polyclonal antibody. Fibrillar amyloid was detected by IAPP antibody and thioflavin-T. Mitochondria and oxidative phosphorylation were identified with anti-mitochondria and anti-cytochrome oxidase monoclonal antibodies respectively. All 6 hIAPP transgenic mice developed diabetes with a fasting blood glucose level of 11.9±.5mM by 4 months of age. At 2 months when fasting blood glucose was mildly elevated at 6.5±0.2mM, pancreatic islets showed oligomer deposition without fibrillar amyloid. In human pancreas, normal islets of control group were virtually negative for oligomer deposition. In islets with reduced numbers of β-cells, oligomer deposits were increased. Oligomers were deposited in a scattered manner which was accompanied by discrete fibrillar amyloid plaque. In islets with absence of β-cells, oligomers were intermixed with IAPP fibrillar amyloid. Islet cells with intracellular oligomers showed diminished staining of mitochondria and oxidative phosphorylation. These results suggest that, oligomerization of IAPP is associated with β-cell apoptosis due to mitochondrial depletion and compromised oxidative phosphorylation. In conclusion, the oligomerization of IAPP precedes the development of diabetes and the formation of fibrillar amyloid.
- Subjects
OLIGOMERS; AMYLIN; TYPE 2 diabetes; AMYLOID; PANCREATIC beta cells; APOPTOSIS
- Publication
Diabetes, 2007, Vol 56, pA683
- ISSN
0012-1797
- Publication type
Article