Bile acids (BAs) and BA receptors emerge as new modulators of glucose homeostasis 1. FXR (farnesoid × receptor) is a nuclear receptor that controls BA and lipid metabolism 23. Several studies have highlighted an unexpected role of FXR in metabolic homeostasis 45. While FXR-deficient mice exhibit insulin resistance 67, treatment of ob/ob and db/db diabetic mice with a synthetic FXR agonist improves blood glucose levels as well as insulin sensitivity 68. However, the picture is more complex since FXR deficiency improves glucose homeostasis and attenuates body weight gain in an obese genetic background 9.

The addition of cholic acid (CA) to the diet increases energy expenditure and prevents the development of high fat-induced obesity and insulin resistance in mice 10. This metabolic effect of CA is mediated by the binding to the G-protein-coupled receptor TGR5 1112, leading to the induction of the cAMP-dependent thyroid hormone activation enzyme DIO2 (type 2 iodothyronine deiodinase) in brown adipose tissue 10. Human TGR5 is activated by several BAs, with lithocholic acid (LCA) and deoxycholic acid (DCA) being the most potent natural agonists 12. In addition, the activation of TGR5 by a semi-synthetic specific agonist induces GLP-1 secretion and improves glucose tolerance in mice 13.

The aim of the present study was to ascertain whether plasma BA concentrations are linked to insulin sensitivity, assessed both by the homeostasis model assessment (HOMA-IR) and the gold-standard hyperinsulinemic-euglycemic clamp method, in a variety of subjects including healthy volunteers, obese and type 2 diabetic (T2D) patients.

Besides their role as detergent molecules, BAs appear to modulate a broad spectrum of metabolic pathways including lipid and glucose homeostasis 1. These findings are mainly based on animal studies and the clinical impact of BAs on metabolic homeostasis remains to be determined in human. Here, we show that plasma CDCA, CA and DCA concentrations were negatively associated with insulin sensitivity in a variety of subjects, including healthy volunteers, obese and T2D patients. In contrast, plasma levels of these BAs were not correlated with glycaemic status. Importantly, HOMA-IR remained positively related to those plasma BAs levels in multivariable analysis. When assessing insulin sensitivity by the clamp procedure, we further observed an inverse relationship between plasma CDCA and CA concentrations and insulin sensitivity (i.e. GIR).

Our data sustain the hypothesis for a role of plasma BAs and FXR in insulin resistance. FXR-deficient mice, which exhibit high plasma BA concentrations 23, display impaired peripheral insulin sensitivity 67. Conversely, treatment with synthetic specific FXR agonists improved insulin sensitivity in rodents 68, and in patients with non-alcoholic fatty liver disease 16. Previous studies have suggested a link between BA pool size and glucose metabolism in humans. In a study performed in 6 Pima Indians with T2D, the BA pool was found to be increased during untreated hyperglycaemia and conversely decreased upon insulin therapy 17. In contrast, the BA pool size remained unaltered upon insulin treatment in another study involving 14 patients with T2D 18. Very recently, a well-designed study has retrieved an increase in the DCA absolute pool size, without change in total pool size in patients with T2D 19. Accordingly, plasma DCA levels were significantly increased in T2D patients in comparison with controls in the present study. In lipid-lowering trials, BA sequestrants, which disrupt the enterohepatic circulation of BAs, have been shown to lower plasma glucose and HbA1c 20. However, the changes in BA metabolism following colesevelam treatment were not related to changes in glucose metabolism in patients with T2D 19. In contrast, a metabolomic study in healthy and pre-diabetic individuals found a correlation between plasma BAs levels and insulin sensitivity 21. Thus, additional studies using FXR or TGR5 agonists are needed to unravel the effect of BAs on insulin sensitivity in human.

In mice, plasma BAs increase energy expenditure via a TGR5-mediated signalling cascade in brown adipose tissue 10. This pathway has been suggested to operate in human skeletal myocytes 10, but its clinical relevance has been challenged recently 22. Here, we found a slight positive correlation between CDCA and CA plasma levels and energy expenditure. In contrast, plasma levels of DCA, one of the best ligand of TGR5 12, did not associate with BMR. Moreover, circulating BAs failed to correlate with energy expenditure in multivariable regression analysis. One limitation of our study is that all the components of the plasma BA profile were not analyzed. Thus, we can not exclude that some low abundant plasma BA species (for instance, LCA) might affect insulin sensitivity or energy expenditure.

In summary, we found that plasma CDCA and CA, and in a lesser extent DCA, were related to insulin resistance in a wide range of subjects. These data sustain the hypothesis for a role of BAs in glucose homeostasis.

BA: bile acid; BMI: body mass index; BMR: basal metabolic rate; CA: cholic acid; CDCA: chenodeoxycholic acid; DCA: deoxycholic acid; DIO-2: type 2 iodothyronine deiodinase; FXR: farnesoid × receptor; GIR: glucose infusion rate; GLP-1: glucagon-like peptide 1; HOMA: homeostasis model assessment; LCA: lithocholic acid; T2D: type 2 diabetes.

The authors declare that they have no competing interests.

BC conceived of the study, participated in its design and coordination and drafted the manuscript. MC performed the dosage of BAs. YZ, ED performed the clamps. BGD performed the statistical analysis. EP, ML and MK contributed to the analysis of the data and critical revision of the manuscript. All authors read and approved the final manuscript.