IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice

Abstract

Aims/hypothesis: 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 induces islet macrophage proIL-1β synthesis. We evaluated the effect of IL-1 receptor antagonist (IL-1Ra) on islet inflammation and dysfunction in a mouse model of type 2 diabetes with amyloid formation. Methods: Lean and obese male mice (A/a or Avy/A at the agouti locus, respectively) with or without beta cell human IAPP expression (hIAPPTg/0) were treated with PBS or IL-1Ra (50 mg kg−1 day−1) from 16 weeks of age. Intraperitoneal glucose and insulin tolerance tests were performed after 8 weeks. Pancreases were harvested for histology and gene expression analysis. Results: Aggregation of human IAPP was associated with marked upregulation of proinflammatory gene expression in islets of obese hIAPPTg/0 mice, together with amyloid deposition and fasting hyperglycaemia. IL-1Ra improved glucose tolerance and reduced plasma proinsulin:insulin in both lean and obese hIAPPTg/0 mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean hIAPPTg/0 mice, suggesting a feed-forward mechanism by which islet inflammation promotes islet amyloid at the early stages of disease. IL-1Ra limited Il1a, Il1b, Tnf and Ccl2 expression in islets from obese hIAPPTg/0 mice, suggesting an altered islet inflammatory milieu. Conclusions/interpretation: These data provide the first in vivo evidence—using a transgenic mouse model with amyloid deposits resembling those found in human islets—that IAPP-induced beta cell dysfunction in type 2 diabetes may be mediated by IL-1. Anti-IL-1 therapies may limit islet inflammation and dysfunction associated with amyloid formation.