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Open Access 01-05-2020 | Insulins | Article

The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice

Authors: Yixuan Qiu, Linyan Shen, Lihong Fu, Jie Yang, Canqi Cui, Tingting Li, Xuelin Li, Chenyang Fu, Xianfu Gao, Weiqing Wang, Guang Ning, Yanyun Gu

Published in: Diabetologia | Issue 5/2020

Abstract

Aims/hypothesis

Bile-acid (BA) signalling is crucial in metabolism homeostasis and has recently been found to mediate the therapeutic effects of glucose-lowering treatments, including α-glucosidase inhibitor (AGI). However, the underlying mechanisms are yet to be clarified. We hypothesised that BA signalling may be required for the glucose-lowering effects and metabolic benefits of AGI.

Methods

Leptin receptor (Lepr)-knockout (KO) db/db mice and high-fat high-sucrose (HFHS)-fed Fxr (also known as Nr1h4)-KO mice were treated with AGI. Metabolic phenotypes and BA signalling in different compartments, including the liver, gut and endocrine pancreas, were evaluated. BA pool profiles were analysed by mass spectrometry. The islet transcription profile was assayed by RNA sequencing. The gut microbiome were assayed by 16S ribosomal RNA gene sequencing.

Results

AGI lowered microbial BA levels in BA pools of different compartments in the body, and increased gut BA reabsorption in both db/db and HFHS-fed mouse models via altering the gut microbiome. The AGI-induced changes in BA signalling (including increased activation of farnesoid X receptor [FXR] in the liver and inhibition of FXR in the ileum) echoed the alterations in BA pool size and composition in different organs. In Fxr-KO mice, the glucose- and lipid-lowering effects of AGI were partially abrogated, possibly due to the Fxr-dependent effects of AGI on decelerating beta cell replication, alleviating insulin hypersecretion and improving hepatic lipid and glucose metabolism.

Conclusions/interpretation

By regulating microbial BA metabolism, AGI elicited diverse changes in BA pool composition in different host compartments to orchestrate BA signalling in the whole body. The AGI-induced changes in BA signalling may be partly required for its glucose-lowering effects. Our study, hence, sheds light on the promising potential of regulating microbial BA and host FXR signalling for the treatment of type 2 diabetes.

Data availability

Sequencing data are available from the BioProject Database (accession no. PRJNA600345; www.ncbi.nlm.nih.gov/bioproject/600345).

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Title: The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice
Authors: Yixuan Qiu
Linyan Shen
Lihong Fu
Jie Yang
Canqi Cui
Tingting Li
Xuelin Li
Chenyang Fu
Xianfu Gao
Weiqing Wang
Guang Ning
Yanyun Gu
Publication date: 01-05-2020
Publisher: Springer Berlin Heidelberg
Keywords: Insulins
Insulins
Published in: Diabetologia / Issue 5/2020
Print ISSN: 0012-186X
Electronic ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-020-05095-7

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