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

CY Westwell-Roper, CA Chehroudi, HC Denroche… - Diabetologia, 2015 - Springer
CY Westwell-Roper, CA Chehroudi, HC Denroche, JA Courtade, JA Ehses, CB Verchere
Diabetologia, 2015Springer
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) …
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 (hIAPP 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 hIAPP 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 hIAPP Tg/0 mice with no effect on insulin sensitivity. The severity and prevalence of islet amyloid was reduced by IL-1Ra in lean hIAPP 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 hIAPP 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.
Springer