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

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 A vy /A at the agouti locus, respectively) with or without beta cell human IAPP expression (h IAPP Tg/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 h IAPP Tg/0 mice, together with amyloid deposition and fasting hyperglycaemia. IL-1Ra improved glucose tolerance and reduced plasma proinsulin:insulin in both lean and obese h IAPP Tg/0 mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean h IAPP Tg/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 h IAPP Tg/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.