Association of Serum Bile Acids Profile and Pathway Dysregulation With the Risk of Developing Diabetes among Normoglycemic Chinese Adults: Findings From the 4C Study

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<b>OBJECTIVE</b> <p>Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We aim to examine the association of serum BA profile and co-regulation with the risk of developing type 2 diabetes (T2DM) among normoglycemic Chinese adults.</p> <p><b>RESEARCH DESIGN AND METHODS</b></p> <p>We tested 23 serum BA species in subjects with incident diabetes (n=1707) and propensity score (including age, sex, BMI and fasting glucose)–matched controls (n=1707) from the China Cardiometabolic Disease and Cancer Cohort(4C) Study, which was composed of 54807 normoglycemic Chinese adults with a median follow-up of 3.03 years. Multivariable-adjusted odds ratios(ORs) for associations of BAs with T2DM were estimated using conditional logistic regression. </p> <p><b>RESULTS</b></p> <p>In multivariable-adjusted logistic regression analysis, per SD increment of unconjugated primary and secondary BAs were inversely associated with incident diabetes, with the OR (95% CI) of 0.89(0.83-0.96) for cholic acid, 0.90(0.84-0.97) for chenodeoxycholic acid and 0.90(0.83-0.96) for deoxycholic acid (P<0.05 and FDR<0.05). On the other hand, conjugated primary BAs (glycocholic acid, taurocholic acid, glycochenodeoxycholic acid, taurochenodeoxycholic acid and sulfated glycochenodeoxycholic acid) and secondary BA (tauroursodeoxycholic acid) were positively related with incident diabetes, with ORs ranging from 1.11 to 1.19(95% CIs ranging between 1.05 and 1.28).<a> In fully adjusted model additionally adjusted for liver enzyme, HDL, 2 hour-postload glucose</a>, HOMA-IR and waist circumference, the risk estimates are similar. Differential correlation network analysis revealed that perturbations in intra-class (i.e. primary and secondary) and interclass (i.e. unconjugated and conjugated) BAs co-regulation preexisted before diabetes onset.<b></b></p> <p><b>CONCLUSIONS</b></p> These findings reveal novel changes in BA exist prior to incident type 2 diabetes and support a potential role of BA metabolism in the pathogenesis of diabetes.