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  • Review Article
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Bile acids in glucose metabolism and insulin signalling — mechanisms and research needs

Abstract

Of all the novel glucoregulatory molecules discovered in the past 20 years, bile acids (BAs) are notable for the fact that they were hiding in plain sight. BAs were well known for their requirement in dietary lipid absorption and biliary cholesterol secretion, due to their micelle-forming properties. However, it was not until 1999 that BAs were discovered to be endogenous ligands for the nuclear receptor FXR. Since that time, BAs have been shown to act through multiple receptors (PXR, VDR, TGR5 and S1PR2), as well as to have receptor-independent mechanisms (membrane dynamics, allosteric modulation of N-acyl phosphatidylethanolamine phospholipase D). We now also have an appreciation of the range of physiological, pathophysiological and therapeutic conditions in which endogenous BAs are altered, raising the possibility that BAs contribute to the effects of these conditions on glycaemia. In this Review, we highlight the mechanisms by which BAs regulate glucose homeostasis and the settings in which endogenous BAs are altered, and provide suggestions for future research.

Key points

  • Pathways in multiple tissues have been reported to link bile acids (BAs) with glycaemia.

  • Physiological and disease settings, and several medications, influence BA levels and composition.

  • When interpreting studies with genetic and pharmacological modulations of BA receptors, one should take into consideration that these modulations affect BA concentration, distribution and composition.

  • Rodent models with humanized BA composition will increase the relevance of basic research findings to human health.

  • Human cells and organoid models should be used to address the interspecies differences in BA receptor structure.

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Fig. 1: Bile acid synthesis, modification and physicochemical properties.
Fig. 2: Bile acid composition.
Fig. 3: Effects of bile acids on metabolic processes throughout the body.
Fig. 4: Physiological and pathological conditions and therapies that influence bile acids.

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Acknowledgements

The authors thank S. Higuchi and E. Bertaggia for helpful discussions. This work was supported by National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) grants DK115825 and DK007328, American Diabetes Association grant 18-IBS-275, and the Russell Berrie Foundation.

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Ahmad, T.R., Haeusler, R.A. Bile acids in glucose metabolism and insulin signalling — mechanisms and research needs. Nat Rev Endocrinol 15, 701–712 (2019). https://doi.org/10.1038/s41574-019-0266-7

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