Butyrate Protects Pancreatic Beta Cells from Cytokine-Induced Dysfunction

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.

Butyrate inhibits IL-1β-induced inflammatory gene expression by suppression of NF-κB activity in pancreatic beta cells

“…We and others have shown that butyrate also directly affects beta cell function both in presence and absence of inflammatory stress ( 47 , 52 , 53 , 54 ). For example, acetate and butyrate prevent oxidative and nitrosative stress ( 53 ) and recently, we found that butyrate protects pancreatic beta cells from IL-1β-induced impairment of insulin secretion and decreased insulin content ( 52 ). Transcriptomic analysis showed that the protective effects are particularly associated with downregulation of inflammatory genes, suggesting an anti-inflammatory role of butyrate in beta cells ( 52 ).…”

“…Beta cells express both FFAR2 and FFAR3 (47) and HDAC inhibitors have proven to be efficient in preventing cytokine-induced beta cell dysfunction both in vitro (48,49) and in vivo (50,51). We and others have shown that butyrate also directly affects beta cell function both in presence and absence of inflammatory stress (47,(52)(53)(54). For example, acetate and butyrate prevent oxidative and nitrosative stress (53) and recently, we found that butyrate protects pancreatic beta cells from IL-1βinduced impairment of insulin secretion and decreased insulin content (52).…”

Role of the Gut Microbiome in Beta Cell and Adipose Tissue Crosstalk: A Review

“…Further studies have confirmed that acetate stimulates insulin secretion ( 88 , 89 ). Butyrate may prevent pro-inflammatory cytokine-beta cell dysfunction and induce insulin secretion ( 90 , 91 ), whereas propionate improved beta cell function and insulin release in humans ( 92 ), although contrary results have also been described ( 93 ). Besides, transmembrane bile acid receptor Takeda G-protein coupled receptor 5 (TGR5) can enhance insulin secretion and improve glucose homeostasis ( 94 , 95 ).…”

Similarities between bacterial GAD and human GAD65: Implications in gut mediated autoimmune type 1 diabetes

“…Butyrate is an important metabolite produced by these symbiotic bacterial populations. Butyrate supports gut integrity and has beta cell-specific anti-inflammatory effects [ 10 – 12 ]. Reducing these microbes and their byproducts may contribute to why children at risk for T1D have higher intestinal permeability and T1D-associated gut dysbiosis.…”