Sodium butyrate potentiates insulin secretion from rat islets at the expense of compromised expression of \u03b2 cell identity genes

Shushu Wang,Qianqian Liu,Libin Zhou,Miaomiao Yuan,Feiye Zhou,Zhaoqian Xu,Kecheng Zhu,Chunxiang Sheng,Yun Liu,Linlin Zhang,Jieli Lu,Xiao Wang

doi:10.1038/s41419-022-04517-1

Shushu Wang, Qianqian Liu + Show 10 more

Open Access

https://doi.org/10.1038/s41419-022-04517-1

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Abstract

Short-chain fatty acids (SCFAs) produced by the gut microbiota have been well demonstrated to improve metabolic homeostasis. However, the role of SCFAs in islet function remains controversial. In the present study, none of the sodium acetate, sodium propionate, and sodium butyrate (SB) displayed acute impacts on insulin secretion from rat islets, whereas long-term incubation of the three SCFAs significantly potentiated pancreatic β cell function. RNA sequencing (RNA-seq) revealed an unusual transcriptome change in SB-treated rat islets, with the downregulation of insulin secretion pathway and β cell identity genes, including Pdx1, MafA, NeuroD1, Gck, and Slc2a2. But these β cell identity genes were not governed by the pan-HDAC inhibitor trichostatin A. Overlapping analysis of H3K27Ac ChIP-seq and RNA-seq showed that the inhibitory effect of SB on the expression of multiple β cell identity genes was independent of H3K27Ac. SB treatment increased basal oxygen consumption rate (OCR), but attenuated glucose-stimulated OCR in rat islets, without altering the expressions of genes involved in glycolysis and tricarboxylic acid cycle. SB reduced the expression of Kcnj11 (encoding KATP channel) and elevated basal intracellular calcium concentration. On the other hand, SB elicited insulin gene expression in rat islets through increasing H3K18bu occupation in its promoter, without stimulating CREB phosphorylation. These findings indicate that SB potentiates islet function as a lipid molecule at the expense of compromised expression of islet β cell identity genes.

Highlights

The pancreatic β cell plays a vital role in the maintenance of glucose homeostasis by secreting an appropriate amount of insulin [1]
SCFAs potentiates β cell function while downregulating insulin secretion pathway To determine the impact of SCFAs on islet β cell function, isolated rat islets were treated with sodium acetate (SA), sodium propionate (SP), and sodium butyrate (SB)
When the incubation time was prolonged to 24 h, SCFAs significantly increased insulin secretion from rat islets at 3.3, 8.3, and 16.7 mM glucose (Fig. 1A), without changing insulin content (Fig. S1B)

Summary

Introduction

The pancreatic β cell plays a vital role in the maintenance of glucose homeostasis by secreting an appropriate amount of insulin [1]. Pancreatic β cell dysfunction is one of the main contributors to the initiation and progression of type 2 diabetes [2]. To respond with an appropriate insulin release to fluctuating glucose levels, it is indispensable for β cells to develop a maturation machinery that defines their functional identity. Intensive studies in animal models have led to the identification of multiple molecular markers which maintain the function and identity of β cells, including Slc2a2, Gck, Pdx, MafA, Nkx, Nkx, and NeuroD1 [3–7]. The down-regulation of these important functional genes and transcription factors indicates the loss of mature β cell identity. Protein acetylation is involved in the maintenance of β cell function and identity. H3K27ac has been considered a key marker of cell identity [8]. The loss of β cell identity under stressful environments such as glucotoxicity is usually accompanied by β cell dedifferentiation towards progenitor-like cells or transdifferentiation to other islet cell types [3, 9]

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