Comprehensive Clinical and Genetic Analyses of Circulating Bile Acids and Their Associations With Diabetes and Its Indices
Document Type
Article
Publication Date
8-2024
Publication Title
Diabetes
Abstract
Bile acids (BAs) are cholesterol-derived compounds that regulate glucose, lipid, and energy metabolism. Despite their significance in glucose homeostasis, the association between specific BA molecular species and their synthetic pathways with diabetes is unclear. Here, we used a recently validated, stable-isotope dilution, high-performance liquid chromatography with tandem mass spectrometry method to quantify a panel of BAs in fasting plasma from 2,145 study participants and explored structural and genetic determinants of BAs linked to diabetes, insulin resistance, and obesity. Multiple 12 alpha-hydroxylated BAs were associated with diabetes (adjusted odds ratio [aOR] range, 1.3-1.9; P < 0.05 for all) and insulin resistance (aOR range, 1.3-2.2; P < 0.05 for all). Conversely, multiple 6 alpha-hydroxylated BAs and isolithocholic acid (iso-LCA) were inversely associated with diabetes and obesity (aOR range, 0.3-0.9; P < 0.05 for all). Genome-wide association studies revealed multiple genome-wide significant loci linked with 9 of the 14 diabetes-associated BAs, including a locus for iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated deoxycholic acid levels were causally associated with higher BMI, and iso-LCA levels were causally associated with reduced BMI and diabetes risk. In conclusion, comprehensive, large-scale, quantitative mass spectrometry and genetics analyses show circulating levels of multiple structurally specific BAs, especially DCA and iso-LCA, are clinically associated with and genetically linked to obesity and diabetes.
Recommended Citation
Ibrahim Choucair, Deepthi P. Mallela, James R. Hilser, Jaana A. Hartiala, Ina Nemet, Valentin Gogonea, Lin Li, Aldons J. Lusis, Michael A. Fischbach, W.H. Wilson Tang, Hooman Allayee, Stanley L. Hazen; Comprehensive Clinical and Genetic Analyses of Circulating Bile Acids and Their Associations With Diabetes and Its Indices. Diabetes 19 July 2024; 73 (8): 1215–1228. https://doi.org/10.2337/db23-0676
DOI
10.2337/db23-0676
Volume
73
Issue
8
Comments
This work was supported by the National Institutes of Health and the Office of Dietary Supplements (grants P01-HL147823, R01-HL167831, R01-HL103866, R01-HL133169, R01-HL148110, and DP1-DK113598) and the Foundation Leducq (grant 17CVD01).