[en] 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-1β 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-1β 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-1β promote islet amyloid formation in vitro. Amyloid-forming islets were cultured for 48 h in the presence or absence of IL-1β with or without an IL-1β 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-1β. RESULTS: Treatment with a low concentration of IL-1β (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-1β was reduced when hIAPP-expressing islets were co-treated with an IL-1β neutralising antibody. Cell-free hIAPP aggregation assays showed no effect of IL-1β on hIAPP aggregation in vitro. Low concentration IL-1β 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-1β-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-1β neutralising antibody. CONCLUSIONS/INTERPRETATION: Under amyloidogenic conditions, physiologically relevant levels of IL-1β promote islet amyloid formation by increasing beta cell release of IAPP. Neutralisation of this effect of IL-1β may decrease the deleterious effects of islet amyloid formation on beta cell function and survival.
Disciplines :
Endocrinology, metabolism & nutrition
Author, co-author :
Templin, Andrew T.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Mellati, Mahnaz
Meier, Daniel T.
Esser, Nathalie ; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Hogan, Meghan F.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Castillo, Joseph J.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Akter, Rehana; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Raleigh, Daniel P.
Zraika, Sakeneh; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Hull, Rebecca L.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Kahn, Steven E.; University of Washington - UW > Department of Medicine > Division of Metabolism, Endocrinology and Nutrition
Language :
English
Title :
Low concentration IL-1β promotes islet amyloid formation by increasing hIAPP release from humanised mouse islets in vitro.
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