Thus, a species-specific structural motif in the putative amyloidogenic region of IAPP is associated with both amyloid formation and the development of age-related diabetes mellitus.
The connection between IAPP amyloid formation and diabetes is unknown, but a limited segment of the IAPP molecule, positions 20-29, seems responsible for the aggregation to fibrils.
The role of IAPP and IA in the pathogenesis of human NIDDM and similar forms of diabetes mellitus in cats and macaques may involve several possible mechanisms, including 1) direct physical/chemical damage to beta-cells, resulting in necrosis and loss of functional islet tissue, 2) biologic activities of IAPP that oppose those of insulin or abnormally suppress insulin secretion, and 3) interference by IA deposits of passage of insulin out of beta-cells and/or entrance of glucose and other secretogogues into the islet.
Plasma IAPP concentrations were elevated in the patients with pancreatic cancer as compared with the normal subjects (mean [+/- SD], 22.3 +/- 13.6 vs. 8.0 +/- 5.0 pmol per liter; P < 0.001), normal in the patients with other cancers, and normal or low in the patients with diabetes.
Elevated plasma islet amyloid polypeptide levels have been demonstrated in some diabetic, glucose-intolerant, and obese individuals, as well as in rodent models of diabetes and obesity.
However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice.
S20G mutation of the amylin gene is associated with Type II diabetes in Japanese. Study Group of Comprehensive Analysis of Genetic Factors in Diabetes Mellitus.
Diabetes due to a progressive defect in beta-cell mass in rats transgenic for human islet amyloid polypeptide (HIP Rat): a new model for type 2 diabetes.
We conclude that IAPP-induced beta-cell apoptosis causes defects in insulin secretion and beta-cell mass that lead first to hepatic insulin resistance and IFG and then to extrahepatic insulin resistance, hyperglucagonemia, and diabetes.
Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused beta-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid.
We transplanted a streptozotocin-induced mouse model of diabetes with 100 islets from human IAPP (which encodes islet amyloid polypeptide) transgenic mice that have the propensity to form islet amyloid (n = 8-12) or from non-transgenic mice that do not develop amyloid (n = 6-10) in sets of studies that lasted 1 or 6 weeks.
One hypothesis is that the link between DM and AD is related to the function of insulin-degrading enzyme (IDE), an enzyme that degrades not only insulin and pancreatic amylin but also beta-amyloid (Abeta).
Intriguingly, amylin deposition was also detected in blood vessels and brain parenchyma of patients with late onset AD without clinically apparent diabetes.
Mice hemizygous for transgenic expression of human IAPP did not develop diabetes; however, loss of β cell-specific autophagy in these animals induced diabetes, which was attributable to accumulation of toxic human IAPP oligomers and loss of β cell mass.
This short review provides a brief introduction to amylin biology, the use of an amylin analog to treat diabetes, and consideration of whether amylin could have any role in headache disorders.