| First Author | Templin AT | Year | 2020 |
| Journal | Diabetologia | Volume | 63 |
| Issue | 11 | Pages | 2385-2395 |
| PubMed ID | 32728889 | Mgi Jnum | J:298717 |
| Mgi Id | MGI:6477250 | Doi | 10.1007/s00125-020-05232-2 |
| Citation | Templin AT, et al. (2020) Low concentration IL-1beta promotes islet amyloid formation by increasing hIAPP release from humanised mouse islets in vitro. Diabetologia 63(11):2385-2395 |
| abstractText | AIMS/HYPOTHESIS: Aggregation of the beta cell secretory product human islet amyloid polypeptide (hIAPP) results in islet amyloid deposition, a pathological feature of type 2 diabetes. Amyloid formation is associated with increased levels of islet IL-1beta as well as beta cell dysfunction and death, but the mechanisms that promote amyloid deposition in situ remain unclear. We hypothesised that physiologically relevant concentrations of IL-1beta stimulate beta cell islet amyloid polypeptide (IAPP) release and promote amyloid formation. METHODS: We used a humanised mouse model of endogenous beta cell hIAPP expression to examine whether low (pg/ml) concentrations of IL-1beta promote islet amyloid formation in vitro. Amyloid-forming islets were cultured for 48 h in the presence or absence of IL-1beta with or without an IL-1beta neutralising antibody. Islet morphology was assessed by immunohistochemistry and islet mRNA expression, hormone content and release were also quantified. Cell-free thioflavin T assays were used to monitor hIAPP aggregation kinetics in the presence and absence of IL-1beta. RESULTS: Treatment with a low concentration of IL-1beta (4 pg/ml) for 48 h increased islet amyloid prevalence (93.52 +/- 3.89% vs 43.83 +/- 9.67% amyloid-containing islets) and amyloid severity (4.45 +/- 0.82% vs 2.16 +/- 0.50% amyloid area/islet area) in hIAPP-expressing mouse islets in vitro. This effect of IL-1beta was reduced when hIAPP-expressing islets were co-treated with an IL-1beta neutralising antibody. Cell-free hIAPP aggregation assays showed no effect of IL-1beta on hIAPP aggregation in vitro. Low concentration IL-1beta did not increase markers of the unfolded protein response (Atf4, Ddit3) or alter proIAPP processing enzyme gene expression (Pcsk1, Pcsk2, Cpe) in hIAPP-expressing islets. However, release of IAPP and insulin were increased over 48 h in IL-1beta-treated vs control islets (IAPP 0.409 +/- 0.082 vs 0.165 +/- 0.051 pmol/5 islets; insulin 87.5 +/- 8.81 vs 48.3 +/- 17.3 pmol/5 islets), and this effect was blocked by co-treatment with IL-1beta neutralising antibody. CONCLUSIONS/INTERPRETATION: Under amyloidogenic conditions, physiologically relevant levels of IL-1beta promote islet amyloid formation by increasing beta cell release of IAPP. Neutralisation of this effect of IL-1beta may decrease the deleterious effects of islet amyloid formation on beta cell function and survival. |
