Comprehensive clinical and genetic analyses of circulating bile acids and their associations with diabetes and its indices

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

doi:10.2337/db23-0676

Comprehensive clinical and genetic analyses of circulating bile acids and their associations with diabetes and its indices

Diabetes. 2024 May 3:db230676. doi: 10.2337/db23-0676. Online ahead of print.

Authors

Ibrahim Choucair^{1

2}, Deepthi P Mallela^{1

2}, James R Hilser^{3

4}, Jaana A Hartiala³, Ina Nemet^{1

2}, Valentin Gogonea^{1

2

5}, Lin Li^{1

2}, Aldons J Lusis^{6

7}, Michael A Fischbach⁸, W H Wilson Tang^{1

2

9}, Hooman Allayee^{3

4}, Stanley L Hazen^{1

2

9}

Affiliations

¹ Department of Cardiovascular & Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44106, USA.
² Center for Microbiome and Human Health, Cleveland Clinic, Cleveland, OH 44106, USA.
³ Department of Population & Public Health Sciences, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁴ Department of Biochemistry & Molecular Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90033, USA.
⁵ Department of Chemistry, Cleveland State University, Cleveland, OH 44115, USA.
⁶ Department of Medicine/Division of Cardiology, University of California, Los Angeles, CA, USA.
⁷ Department of Microbiology, Medicine and Human Genetics, University of California, Los Angeles, CA, USA.
⁸ Department of Bioengineering and ChEM-H, Stanford University, Stanford, CA, 94305, USA.
⁹ Department of Cardiovascular Medicine, Heart Vascular and Thoracic Institute, Cleveland Clinic, Cleveland, OH 44195, USA.

PMID: 38701355
DOI: 10.2337/db23-0676

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 mellitus (DM) is unclear. Here, we used a recently validated stable-isotope dilution highperformance liquid chromatography with tandem mass spectrometry (LC-MS/MS) method to quantify a panel of BAs in fasting plasma from subjects (n=2,145) and explored structural and genetic determinants of BAs linked to DM, insulin resistance and obesity. Multiple 12α-hydroxylated BAs were associated with DM [adjusted odds ratios (aORs):1.3-1.9 (all P<0.05)] and insulin resistance [aORs:1.3-2.2 (all P<0.05)]. Conversely, multiple 6a-hydroxylated BAs and isolithocholic acid (Iso-LCA) were inversely associated with DM and obesity [aORs:0.3-0.9 (all P<0.05)]. Genome-wide association studies (GWAS) revealed multiple genome-wide significant loci linked with nine of the 14 DM-associated BAs, including a locus for Iso-LCA (rs11866815). Mendelian randomization analyses showed genetically elevated DCA levels were causally associated with higher BMI, and Iso-LCA levels were causally associated with reduced BMI and DM 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 DM.