Distinct actions of oligomers and fibrils of islet amyloid polypeptide on Toll-like receptor 2 and NLRP3 inflammasome activation (INM7P.423)

Abstract

Aggregation of islet amyloid polypeptide (IAPP) to form amyloid contributes to beta cell dysfunction in type 2 diabetes. Human but not non-amyloidogenic rodent IAPP activates TLR2 and NLRP3 to induce IL-1β secretion by islet macrophages. It is unclear which form of IAPP aggregate induces IL-1β and whether this pathway is relevant to disease pathogenesis. We therefore evaluated the contributions of soluble and fibrillar IAPP to IL-1β secretion by bone marrow-derived macrophages (BMDMs) and assessed the effects of IL-1 receptor antagonist (IL-1Ra) on glucose homeostasis in transgenic mice with beta cell expression of human IAPP. BMDMs treated with soluble but not fibrillar IAPP provided a TLR2-dependent priming stimulus for ATP-induced IL-1β secretion, suggesting that pre-fibrillar species interact with TLR2. Fibrillar but not soluble IAPP aggregates were required for IL-1β secretion in LPS-primed BMDMs and are therefore likely the principal stimulus for NLRP3. Moreover, IL-1Ra (50 mg/kg/d for 8 weeks) improved glucose tolerance in obese human IAPP transgenic mice (AUC=1360±110 vs. 880±70; p<0.05) with no effect in wild-type littermates. These data provide the first in vivo evidence that IAPP-induced islet dysfunction in type 2 diabetes is mediated by IL-1, and suggest that both soluble and fibrillar IAPP aggregates participate in this process. Islet inflammation and amyloid formation are therefore important therapeutic targets to improve beta cell function in type 2 diabetes.