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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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posted on 21.12.2020, 07:16 by Jieli Lu, Shuangyuan Wang, Mian Li, Zhengnan Gao, Yu Xu, Xinjie Zhao, Chunyan Hu, Yi Zhang, Ruixin Liu, Ruying Hu, Lixin Shi, Ruizhi Zheng, Rui Du, Qing Su, Jiqiu Wang, Yuhong Chen, Xuefeng Yu, Li Yan, Tiange Wang, Zhiyun Zhao, Xiaolin Wang, Qi Li, Guijun Qin, Qin Wan, Gang Chen, Min Xu, Meng Dai, Di Zhang, Xulei Tang, Guixia Wang, Feixia Shen, Zuojie Luo, Yingfen Qin, Li Chen, Yanan Huo, Qiang Li, Zhen Ye, Yinfei Zhang, Chao Liu, Youmin Wang, Shengli Wu, Tao Yang, Huacong Deng, Donghui Li, Shenghan Lai, Yiming Mu, Lulu Chen, Jiajun Zhao, Guowang Xu, Yufang Bi, Guang Ning, Weiqing Wang, the 4C Study Group
OBJECTIVE

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.

RESEARCH DESIGN AND METHODS

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.

RESULTS

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). In fully adjusted model additionally adjusted for liver enzyme, HDL, 2 hour-postload glucose, 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.

CONCLUSIONS

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.

Funding

This work was supported by the Ministry of Science and Technology of China under Award Number 2016YFC1305600, 2016YFC1305202, 2016YFC1304904, , 2017ZX09304007 and 2018YFC1311800, the National Natural Science Foundation of China under Award Number 81930021, 81970728, 81970691, 81670795 and 81621061, Shanghai Outstanding Academic Leaders Plan (18XD1402500, 20XD1422800), and Shanghai Medical and Health Development Foundation.

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