Pathophysiology/Complications

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

  1. Jieli Lu1,2⇑,
  2. Shuangyuan Wang1,2,
  3. Mian Li1,2,
  4. Zhengnan Gao3,
  5. Yu Xu1,2,
  6. Xinjie Zhao4,
  7. Chunyan Hu1,2,
  8. Yi Zhang1,2,
  9. Ruixin Liu1,2,
  10. Ruying Hu5,
  11. Lixin Shi6,
  12. Ruizhi Zheng1,2,
  13. Rui Du1,2,
  14. Qing Su7,
  15. Jiqiu Wang1,2,
  16. Yuhong Chen1,2,
  17. Xuefeng Yu8,
  18. Li Yan9,
  19. Tiange Wang1,2,
  20. Zhiyun Zhao1,2,
  21. Xiaolin Wang4,
  22. Qi Li4,
  23. Guijun Qin10,
  24. Qin Wan11,
  25. Gang Chen12,
  26. Min Xu1,2,
  27. Meng Dai1,2,
  28. Di Zhang1,2,
  29. Xulei Tang13,
  30. Guixia Wang14,
  31. Feixia Shen15,
  32. Zuojie Luo16,
  33. Yingfen Qin16,
  34. Li Chen17,
  35. Yanan Huo18,
  36. Qiang Li19,
  37. Zhen Ye5,
  38. Yinfei Zhang20,
  39. Chao Liu21,
  40. Youmin Wang22,
  41. Shengli Wu23,
  42. Tao Yang24,
  43. Huacong Deng25,
  44. Donghui Li26,
  45. Shenghan Lai27,
  46. Yiming Mu28,
  47. Lulu Chen29,
  48. Jiajun Zhao30,
  49. Guowang Xu4,
  50. Guang Ning1,2,
  51. Yufang Bi1,2 and
  52. Weiqing Wang1,2⇑, for the 4C Study Group*
  1. 1Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
  2. 2Shanghai 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. 3Dalian Municipal Central Hospital, Dalian, China
  4. 4Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, China
  5. 5Zhejiang Provincial Center for Disease Control and Prevention, Hangzhou, China
  6. 6Affiliated Hospital of Guiyang Medical College, Guiyang, China
  7. 7Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China
  8. 8Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  9. 9Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
  10. 10The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
  11. 11The Affiliated Hospital of Southwest Medical University, Luzhou, China
  12. 12Fujian Provincial Hospital, Fujian Medical University, Fuzhou, China
  13. 13The First Hospital of Lanzhou University, Lanzhou, China
  14. 14The First Hospital of Jilin University, Changchun, China
  15. 15The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China
  16. 16The First Affiliated Hospital of Guangxi Medical University, Nanning, China
  17. 17Qilu Hospital of Shandong University, Jinan, China
  18. 18Jiangxi Provincial People’s Hospital Affiliated to Nanchang University, Nanchang, China
  19. 19The Second Affiliated Hospital of Harbin Medical University, Harbin, China
  20. 20Central Hospital of Shanghai Jiading District, Shanghai, China
  21. 21Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing, China
  22. 22The First Affiliated Hospital of Anhui Medical University, Hefei, China
  23. 23Karamay Municipal People’s Hospital, Xinjiang, China
  24. 24The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  25. 25The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  26. 26Department of Gastrointestinal Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX
  27. 27Johns Hopkins University School of Medicine, Baltimore, MD
  28. 28Chinese People’s Liberation Army General Hospital, Beijing, China
  29. 29Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
  30. 30Shandong Provincial Hospital affiliated to Shandong University, Jinan, China
  1. Corresponding authors: Jieli Lu, jielilu{at}hotmail.com, and Weiqing Wang, wqingw61{at}163.com

  1. J.L., S.W., M.L., Z.G., and Y.X. contributed equally to this work.

Diabetes Care 2021 Feb; 44(2): 499-510. https://doi.org/10.2337/dc20-0884

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.

Footnotes

  • Received April 19, 2020.
  • Accepted October 29, 2020.
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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
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, Guang Ning, Yufang Bi, Weiqing Wang
Diabetes Care Feb 2021, 44 (2) 499-510; DOI: 10.2337/dc20-0884
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