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

Author:

Lu Jieli12ORCID,Wang Shuangyuan12,Li Mian12,Gao Zhengnan3,Xu Yu12,Zhao Xinjie4,Hu Chunyan12ORCID,Zhang Yi12,Liu Ruixin12,Hu Ruying5,Shi Lixin6,Zheng Ruizhi12,Du Rui12ORCID,Su Qing7,Wang Jiqiu12,Chen Yuhong12,Yu Xuefeng8ORCID,Yan Li9,Wang Tiange12ORCID,Zhao Zhiyun12,Wang Xiaolin4,Li Qi4,Qin Guijun10ORCID,Wan Qin11,Chen Gang12ORCID,Xu Min12ORCID,Dai Meng12,Zhang Di12,Tang Xulei13,Wang Guixia14ORCID,Shen Feixia15,Luo Zuojie16ORCID,Qin Yingfen16ORCID,Chen Li17ORCID,Huo Yanan18,Li Qiang19,Ye Zhen5,Zhang Yinfei20,Liu Chao21,Wang Youmin22,Wu Shengli23,Yang Tao24ORCID,Deng Huacong25,Li Donghui26,Lai Shenghan27,Mu Yiming28,Chen Lulu29ORCID,Zhao Jiajun30ORCID,Xu Guowang4ORCID,Ning Guang12ORCID,Bi Yufang12ORCID,Wang Weiqing12ORCID

Affiliation:

1. Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

2. Shanghai National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, China

3. Dalian Municipal Central Hospital, Dalian, China

4. Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China

5. Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China

6. Affiliated Hospital of Guiyang Medical College, Guiyang, China

7. Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China

8. Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

9. Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China

10. The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China

11. The Affiliated Hospital of Southwest Medical University, Luzhou, China

12. Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China

13. The First Hospital of Lanzhou University, Lanzhou, China

14. The First Hospital of Jilin University, Changchun, China

15. The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

16. The First Affiliated Hospital of Guangxi Medical University, Nanning, China

17. Qilu Hospital of Shandong University, Jinan, China

18. Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, China

19. The Second Affiliated Hospital of Harbin Medical University, Harbin, China

20. Central Hospital of Shanghai Jiading District, Shanghai, China

21. Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China

22. The First Affiliated Hospital of Anhui Medical University, Hefei, China

23. Karamay Municipal People’s Hospital, Xinjiang, China

24. The First Affiliated Hospital of Nanjing Medical University, Nanjing, China

25. The First Affiliated Hospital of Chongqing Medical University, Chongqing, China

26. Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX

27. Johns Hopkins University School of Medicine, Baltimore, MD

28. Chinese People’s Liberation Army General Hospital, Beijing, China

29. Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

30. Shandong Provincial Hospital affiliated to Shandong University, Jinan, China

Abstract

OBJECTIVE Comprehensive assessment of serum bile acids (BAs) aberrations before diabetes onset remains inconclusive. We examined the association of serum BA profile and coregulation with the risk of developing type 2 diabetes mellitus (T2DM) among normoglycemic Chinese adults. RESEARCH DESIGN AND METHODS We tested 23 serum BA species in subjects with incident diabetes (n = 1,707) and control subjects (n = 1,707) matched by propensity score (including age, sex, BMI, and fasting glucose) from the China Cardiometabolic Disease and Cancer Cohort (4C) Study, which was composed of 54,807 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 an 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 false discovery rate <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 a fully adjusted model additionally adjusted for liver enzymes, HDL cholesterol, diet, 2-h postload glucose, HOMA-insulin resistance, and waist circumference, the risk estimates were similar. Differential correlation network analysis revealed that perturbations in intraclass (i.e., primary and secondary) and interclass (i.e., unconjugated and conjugated) BA coregulation preexisted before diabetes onset. CONCLUSIONS These findings reveal novel changes in BAs exist before incident T2DM and support a potential role of BA metabolism in the pathogenesis of diabetes.

Funder

National Natural Science Foundation of China

Publisher

American Diabetes Association

Subject

Advanced and Specialized Nursing,Endocrinology, Diabetes and Metabolism,Internal Medicine

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