Butyrate protects pancreatic beta cells from cytokine induced dysfunction

Beta cell dysfunction, caused by metabolic and inflammatory stress, contributes to the development of type 2 diabetes. Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism and may directly affect beta cell function, but the mechanisms are poorly described. The aim of this study was to investigate the effect of butyrate on IL-1ß-induced ß cell dysfunction. We showed that long-term exposure of mouse islets to non-cytotoxic concentrations of IL-1ß impaired insulin secretion and content and reduced proliferation. This dysfunction was prevented when the islets were exposed to butyrate and butyrate alone also boosted insulin secretion. In contrast, butyrate further downregulated the proliferation. To get a better indication of mechanisms of actions we investigated the global mRNA expression profiles using RNA sequencing. Our results indicated that the protective effects of butyrate are associated with upregulation of secretion/transport-related genes and downregulation of inflammatory genes induced by IL-1ß. In addition, several cell cycle related genes were strongly inhibited by butyrate. In conclusion, butyrate plays an essential role in supporting beta cell function under inflammatory conditions, suggesting a potential for therapeutic use in treatment and prevention of T2D. Overall design: RNA sequencing was performed on RNA extracted from mouse islets exposed to IL-1ß (50 pg/ml), butyrate (0.2 mM), the combination or left unexposed for 10 days. The islets were isolated from 12-week-old C57BL/6JRj male mice (Janivier). In total, four independent experiments were performed.