Amyloidogenicity of naturally occurring full-length animal IAPP variants.

The aggregation of the 37-amino acid polypeptide human islet amyloid polypeptide (hIAPP), as either insoluble amyloid or as small oligomers, appears to play a direct role in the death of human pancreatic ß-islet cells in type 2 diabetes. hIAPP is considered to be one of the most amyloidogenic proteins known. The quick aggregation of hIAPP leads to the formation of toxic species, such as oligomers and fibers, that damage mammalian cells (both human and rat pancreatic cells). Whether this toxicity is necessary for the progression of type 2 diabetes or merely a side effect of the disease remains unclear. If hIAPP aggregation into toxic amyloid is on-path for developing type 2 diabetes in humans, islet amyloid polypeptide (IAPP) aggregation would likely need to play a similar role within other organisms known to develop the disease. In this work, we compared the aggregation potential and cellular toxicity of full-length IAPP from several diabetic and nondiabetic organisms whose aggregation propensities had not yet been determined for full-length IAPP.

Nonhuman IAPP Variants Inhibit Human IAPP Aggregation.

AIM: To identify naturally occurring variants of IAPP capable of inhibiting the aggregation of human IAPP and protecting living cells from the toxic effects of human IAPP. BACKGROUND: The loss of insulin-producing ß-cells and the overall progression of type 2 diabetes appears to be linked to the formation of toxic human IAPP (hIAPP, Islet Amyloid Polypeptide, amylin) amyloid in the pancreas. Inhibiting the initial aggregation of hIAPP has the potential to slow, if not stop entirely, the loss of ß-cells and halt the progression of the disease. OBJECTIVE: To identify and characterize naturally occurring variants of IAPP capable of inhibiting human IAPP aggregation. METHODS: Synthetic human IAPP was incubated with synthetic IAPP variants identified from natural sources under conditions known to promote amyloid-based aggregation. To identify IAPP variants capable of inhibiting human IAPP aggregation, Thioflavin T-binding fluorescence, atomic force microscopy, and cell-rescue assays were performed. RESULTS: While most IAPP variants showed little to no ability to inhibit human IAPP aggregation, several variants showed some ability to inhibit aggregation, with two variants showing substantial inhibitory potential. CONCLUSION: Several naturally occurring IAPP variants capable of inhibiting human IAPP aggregation were identified and characterized.