Abstract
Pancreatic beta cell dysfunction caused by metabolic and inflammatory stress contributes to the development of type 2 diabetes (T2D). Butyrate, produced by the gut microbiota, has shown beneficial effects on glucose metabolism in animals and humans 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 cytokine-induced beta cell dysfunction in vitro. Mouse islets, rat INS-1E, and human EndoC-βH1 beta cells were exposed long-term to non-cytotoxic concentrations of cytokines and/or butyrate to resemble the slow onset of inflammation in T2D. Beta cell function was assessed by glucose-stimulated insulin secretion (GSIS), gene expression by qPCR and RNA-sequencing, and proliferation by incorporation of EdU into newly synthesized DNA. Butyrate protected beta cells from cytokine-induced impairment of GSIS and insulin content in the three beta cell models. Beta cell proliferation was reduced by both cytokines and butyrate. Expressions of the beta cell specific genes Ins, MafA, and Ucn3 reduced by the cytokine IL-1β were not affected by butyrate. In contrast, butyrate upregulated the expression of secretion/transport-related genes and downregulated inflammatory genes induced by IL-1β in mouse islets. In summary, butyrate prevents pro-inflammatory cytokine-induced beta cell dysfunction.
Highlights
Impaired insulin secretion from pancreatic beta cells is characteristic for type 2 diabetes (T2D), and is the main cause of glucose intolerance
The dysfunction is characterized by reduced glucosestimulated insulin secretion (GSIS) capacity and insulin content, and is associated with decreased expression of several beta cell genes known to be important for proper beta cell function [5,6,7]
We have recently shown that the long-term exposure of beta cells to low noncytotoxic concentrations of pro-inflammatory cytokines such as IL-1β induces a state of dedifferentiation similar to what is observed in T2D [12]
Summary
Impaired insulin secretion from pancreatic beta cells is characteristic for type 2 diabetes (T2D), and is the main cause of glucose intolerance. In the pathogenesis of T2D, it is hypothesized that during progression to diabetes, beta cells become dysfunctional and undergo changes into a less mature phenotype as a result of metabolic and inflammatory stress [1,2,3]. This decline in beta cell function is already present in individuals with impaired glucose tolerance and further progresses to severe dysfunction in T2D, without changes in beta cell volume [4]. This indicates that an increased number of islet cells have undergone dedifferentiation into a non-functional islet cell phenotype [8]
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