| First Author | Westwell-Roper CY | Year | 2015 |
| Journal | Diabetologia | Volume | 58 |
| Issue | 3 | Pages | 575-85 |
| PubMed ID | 25491100 | Mgi Jnum | J:219633 |
| Mgi Id | MGI:5629438 | Doi | 10.1007/s00125-014-3447-x |
| Citation | Westwell-Roper CY, et al. (2015) IL-1 mediates amyloid-associated islet dysfunction and inflammation in human islet amyloid polypeptide transgenic mice. Diabetologia 58(3):575-85 |
| abstractText | 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-1beta 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. |
