The glucose-lowering effects of α-glucosidase inhibitor require a bile acid signal in mice
Open Access
- 8 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Diabetologia
- Vol. 63 (5), 1002-1016
- https://doi.org/10.1007/s00125-020-05095-7
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).Keywords
This publication has 57 references indexed in Scilit:
- The hyperstimulated β‐cell: prelude to diabetes?Diabetes, Obesity and Metabolism, 2012
- Impaired Generation of 12-Hydroxylated Bile Acids Links Hepatic Insulin Signaling with DyslipidemiaCell Metabolism, 2012
- Banting Lecture 2011Diabetes, 2011
- Rictor/mTORC2 Is Essential for Maintaining a Balance Between β-Cell Proliferation and Cell SizeDiabetes, 2011
- Long-term combination therapy of ezetimibe and acarbose for non-alcoholic fatty liver diseaseJournal of Hepatology, 2009
- HOMA-beta in the UKPDS and ADOPT. Is the natural history of type 2 diabetes characterised by a progressive and inexorable loss of insulin secretory function? Maybe? Maybe not?Diabetes and Vascular Disease Research, 2009
- Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestineJournal of Lipid Research, 2007
- Farnesoid X receptor is essential for normal glucose homeostasisJCI Insight, 2006
- Lifestyle, Diabetes, and Cardiovascular Risk Factors 10 Years after Bariatric SurgeryThe New England Journal of Medicine, 2004
- AcarboseDrugs, 1993