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Butyrate protects pancreatic beta cells from cytokine induced dysfunction

ABSTRACT: 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-1β-induced β cell dysfunction. We showed that long-term exposure of mouse islets to non-cytotoxic concentrations of IL-1β 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-1β. 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE180317 | GEO | 2021/09/27

REPOSITORIES: GEO

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Project description:The NF-κB pathway is a master regulator of inflammatory processes and is implicated in insulin resistance and pancreatic beta cell dysfunction in the metabolic syndrome. While canonical NF-κB signaling is well studied, there is little information on the divergent non-canonical NF-κB pathway in the context of pancreatic islet dysfunction in diabetes. Here, we demonstrate that pharmacological activation of the non-canonical NF-κB inducing kinase (NIK) disrupts glucose homeostasis in zebrafish in vivo. Further, we identify NIK as a critical negative regulator of beta cell function as pharmacological NIK activation results in impaired glucose-stimulated insulin secretion in mouse and human islets. NIK levels are elevated in pancreatic islets isolated from diet-induced obese (DIO) mice, which exhibit increased processing of non-canonical NF-κB components p100 to p52, and accumulation of RelB. Tumor necrosis factor α (TNFα) and receptor activator of NF-κB ligand (RANKL), two ligands associated with diabetes, induce NIK in islets. Mice with constitutive beta cell intrinsic NIK activation present impaired insulin secretion with DIO. NIK activation triggers the non-canonical NF-κB transcriptional network to induce genes identified in human type 2 diabetes genome-wide association studies linked to beta cell failure. These studies reveal that NIK contributes a central mechanism for beta cell failure in diet-induced obesity. We identify a role for Nuclear Factor inducing κB (NIK) in pancreatic beta cell failure. NIK activation disrupts glucose homeostasis in zebrafish in vivo and impairs glucose-stimulated insulin secretion in mouse and human islets in vitro. NIK activation also perturbs beta cell insulin secretion in a diet-induced obesity mouse model. These studies reveal that NIK contributes a central mechanism for beta cell failure in obesity. To uncover the role of NIK in pancreatic beta cells, we performed a gene expression microarray analysis comparing pancreatic islets with constitutive beta cell intrinsicNIK activation from the 16 week old mice (beta cell specific TRAF2 and TRAF2 knockout mice) to their controls (n=3 per group).

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Butyrate protects pancreatic beta cells from cytokine induced dysfunction

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