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, highperformance 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 12ahydroxylated 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 6a-hydroxylated BAs and isolithocholic acid (isoLCA) 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 isoLCA 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,.
| Original language | English |
|---|---|
| Pages (from-to) | 1215-1228 |
| Number of pages | 14 |
| Journal | Diabetes |
| Volume | 73 |
| Issue number | 8 |
| DOIs |
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| State | Published - Aug 2024 |
Bibliographical note
Publisher Copyright:© 2024 by the American Diabetes Association.
Funding
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). Acknowledgments. The authors thank Taylor Weeks, Cleveland Clinic, for assistance with the preparation of the manuscript, its figures, and its submission. Funding. 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). Duality of Interest. S.L.H. reports being named as co-inventor on pending and issued patents held by the Cleveland Clinic relating to cardiovascular diagnostics and therapeutics; being a paid consultant for and having received research funds from Zehna Therapeutics; and being eligible to receive royalty payments for inventions or discoveries related to cardiovascular diagnostics or therapeutics from Cleveland HeartLab, Quest Diagnostics, and Procter & Gamble. M.A.F. is a cofounder and director of Federation Bio and Viralogic; a cofounder of Revolution Medicines; and reports consultancy work for NGM Bio; ownership interest in Kelonia and NGM Bio; patents or royalties involving Federation Bio; advisory or leadership roles with Federation Bio and Kelonia; is on the board of NGM Biopharmaceuticals; and is an innovation partner at The Column Group. W.H.W.T. reports being a consultant for Sequana Medical A.G., Owkin Inc., Re-lypsa Inc., and PreCardiac Inc.; having received honorarium from Springer Nature for authorship or editorship and American Board of Internal Medicine for exam writing committee participation, all of which are unrelated to the subject and contents of this article. No other potential conflicts of interest relevant to this article were reported. Author Contributions. I.C. and D.P.M. contributed equally to data collection, formal analysis, and writing and editing of the manuscript. J.R.H., J.A.H., and I.N. contributed to data acquisition and formal analysis, and review and editing of the manuscript. L.L. contributed to initial statistical analyses. V.G., A.J.L., M.A.F., and W.H.W.T. contributed to formal analysis; writing, review, and editing of the manuscript; and funding acquisition. H.A. and S.L.H. contributed equally to study conceptualization; analysis; writing, reviewing, and editing the manuscript; project supervision and administration; and funding acquisition. H.A. and S.L.H. are the guarantors of this work and, as such, had full access to all the data in the study and take full responsibility for the integrity of data and the accuracy of the data analysis.
| Funders | Funder number |
|---|---|
| National Institutes of Health (NIH) | |
| Office of Dietary Supplements | R01-HL133169, R01-HL103866, P01-HL147823, R01-HL148110, DP1-DK113598, R01-HL167831 |
| Fondation Leducq | 17CVD01 |
ASJC Scopus subject areas
- Internal Medicine
- Endocrinology, Diabetes and Metabolism
