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Higher direct bilirubin levels during mid-pregnancy are associated with lower risk of gestational diabetes mellitus

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Abstract

Bilirubin concentrations have been recently reported to be negatively associated with type 2 diabetes mellitus. We examined the association between bilirubin concentrations and gestational diabetes mellitus. In a prospective cohort study, 2969 pregnant women were recruited prior to 16 weeks of gestation and were followed up until delivery. The value of bilirubin was tested and oral glucose tolerance test was conducted to screen gestational diabetes mellitus. The relationship between serum bilirubin concentration and gestational weeks was studied by two-piecewise linear regression. A subsample of 1135 participants with serum bilirubin test during 16–18 weeks gestation was conducted to research the association between serum bilirubin levels and risk of gestational diabetes mellitus by logistic regression. Gestational diabetes mellitus developed in 8.5 % of the participants (223 of 2969). Two-piecewise linear regression analyses demonstrated that the levels of bilirubin decreased with gestational week up to the turning point 23 and after that point, levels of bilirubin were increased slightly. In multiple logistic regression analysis, the relative risk of develo** gestational diabetes mellitus was lower in the highest tertile of direct bilirubin than that in the lowest tertile (RR 0.60; 95 % CI, 0.35–0.89). The results suggested that women with higher serum direct bilirubin levels during the second trimester of pregnancy have lower risk for development of gestational diabetes mellitus.

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References

  1. World Health Organization, Diagnostic Criteria and Classification of Hyperglycemia First Detected in Pregnancy (2013), http://apps.who.int/iris/bitstream/10665/85975/1/WHO_NMH_MND_13.2_eng.pdf. Accessed 22 August 2015

  2. J. Leng, P. Shao, C. Zhang, H. Tian, F. Zhang, S. Zhang, L. Dong, L. Li, Z. Yu, J.C. Chan, G. Hu, X. Yang, Prevalence of gestational diabetes mellitus and its risk factors in chinese pregnant women: a prospective population-based study in Tian**, China. PloS One 10(3), 171–186 (2015). doi: 10.6084/m9.figshare.1305840

  3. S. Riskin-Mashiah, G. Younes, A. Damti, R. Auslender, First-trimester fasting hyperglycemia and adverse pregnancy outcomes. Diabetes Care 32(9), 1639–1643 (2009). doi:10.2337/dc09-0688

    Article  PubMed  PubMed Central  Google Scholar 

  4. M. Patrick, H.D. M.E. A. Catalano, The Hyperglycemia and Adverse Pregnancy Outcome Study. Diabetes Care 35, 7 (2012)

    Article  Google Scholar 

  5. R.M. Freathy, M.G. Hayes, M. Urbanek et al., Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, Common Genetic Variants in GCK and TCF7L2 Are Associated With Fasting and Postchallenge Glucose Levels in Pregnancy and With the New Consensus Definition of Gestational Diabetes Mellitus From the International Association of Diabetes and Pregnancy Study Groups. Diabetes 59, 8 (2010). doi:10.2337/db10-0177

    Article  Google Scholar 

  6. S. Hamamoto, H. Kaneto, S. Kamei, M. Shimoda, K. Tawaramoto, Y. Kanda-Kimura, F. Kawasaki, M. Hashiramoto, M. Matsuki, T. Mune, K. Kaku, Low bilirubin levels are an independent risk factor for diabetic retinopathy and nephropathy in Japanese patients with type 2 diabetes. Diabetes Metab. (2015). doi: 10.1016/j.diabet.2015.05.003

  7. A. Abbasi, P.E. Deetman, E. Corpeleijn, R.T. Gansevoort, R.O. Gans, H.L. Hillege, P. van der Harst, R. P. Stolk, G. Navis, B. Z. Alizadeh, S. J. Bakker, Bilirubin as a potential causal factor in type 2 diabetes risk: a mendelian randomization study. Diabetes 64(4), 1459–1469 (2015). doi:10.2337/db14-0228

    Article  CAS  PubMed  Google Scholar 

  8. S. Ryu, Y. Chang, Y. Zhang, H.Y. Woo, M.J. Kwon, H. Park, K. B. Lee, H.J. Son, J. Cho, E. Guallar, Higher serum direct bilirubin levels were associated with a lower risk of incident chronic kidney disease in middle aged Korean men. PloS One 9(2), e75178 (2014). doi:10.1371/journal.pone.0075178

    Article  PubMed  PubMed Central  Google Scholar 

  9. H. Okada, M. Fukui, M. Tanaka, S. Matsumoto, K. Kobayashi, H. Iwase, K. Tomiyasu, K. Nakano, G. Hasegawa, N. Nakamura, Low serum bilirubin concentration is a novel risk factor for the development of albuminuria in patients with type 2 diabetes. Metab. Clin. Exp. 63(3), 409–414 (2014). doi:10.1016/j.metabol.2013.11.011

    Article  CAS  PubMed  Google Scholar 

  10. S.W. Choi, Y.H. Lee, S.S. Kweon, H.R. Song, H. R. Ahn, J. A. Rhee, J.S. Choi, M.H. Shin, Association between total bilirubin and hemoglobin A1c in Korean type 2 diabetic patients. J. Korean Med. Sci. 27(10), 1196–1201 (2012). doi:10.3346/jkms.2012.27.10.1196

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. M. Stojanov, A. Stefanovic, G. Dzingalasevic, J. Ivanisevic, M. Miljkovic, S. Mandic-Radic, M. Prostran, Total bilirubin in young men and women: association with risk markers for cardiovascular diseases. Clin. Biochem. 46(15), 1516–1519 (2013). doi:10.1016/j.clinbiochem.2013.06.020

    Article  CAS  PubMed  Google Scholar 

  12. L. Vitek, The role of bilirubin in diabetes, metabolic syndrome, and cardiovascular diseases. Front. Pharmacol. 3, 55 (2012). doi:10.3389/fphar.2012.00055

    Article  PubMed  PubMed Central  Google Scholar 

  13. Y. Wu, M. Li, M. Xu et al., Low serum total bilirubin concentrations are associated with increased prevalence of metabolic syndrome in Chinese. J. Diabetes 3, 8 (2011)

    Article  Google Scholar 

  14. P.F. McArdle, B.W. Whitcomb, K. Tanner, B.D. Mitchell, A.R. Shuldiner, A. Parsa, Association between bilirubin and cardiovascular disease risk factors: using Mendelian randomization to assess causal inference. BMC Cardiovasc. Disord. 12, 16 (2012). doi:10.1186/1471-2261-12-16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ying-Hwa Chen, L.-Y. Chau, Jaw-Wen Chen, Shing-Jong Lin, Serum Bilirubin and Ferritin Levels Link Heme Oxygenase-1 Gene Promoter Polymorphism and Susceptibility to Coronary Artery Disease in Diabetic Patients. Diabetes Care 31(8), 6 (2008). doi:10.2337/dc07-2126

    Article  Google Scholar 

  16. K. Maiese, New Insights for Oxidative Stress and Diabetes Mellitus. Oxid. Med. Cell. Longev. 2015, 875961 (2015). doi:10.1155/2015/875961

    Article  PubMed  PubMed Central  Google Scholar 

  17. D. Pitocco, M. Tesauro, R. Alessandro, G. Ghirlanda, C. Cardillo, Oxidative stress in diabetes: implications for vascular and other complications. Int. J. Mol. Sci. 14(11), 21525–21550 (2013). doi:10.3390/ijms141121525

    Article  PubMed  PubMed Central  Google Scholar 

  18. G. **n, J. Du, Y.T. Wang, T.T. Liang, Effect of oxidative stress on heme oxygenase-1 expression in patients with gestational diabetes mellitus. Exp. Ther. Med. 7(2), 478–482 (2014). doi:10.3892/etm.2013.1435

    CAS  PubMed  Google Scholar 

  19. C. Zhu, H. Yang, Q. Geng, Q. Ma, Y. Long, C. Zhou, M. Chen, Association of oxidative stress biomarkers with gestational diabetes mellitus in pregnant women: a case-control study. PloS One 10(4), e0126490 (2015). doi:10.1371/journal.pone.0126490

    Article  PubMed  PubMed Central  Google Scholar 

  20. C. Qiu, K. Hevner, D. Abetew, D.A. Enquobahrie, M.A. Williams, Oxidative DNA damage in early pregnancy and risk of gestational diabetes mellitus: a pilot study. Clin. Biochem. 44(10–11), 804–808 (2011). doi:10.1016/j.clinbiochem.2011.04.023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. M. Shang, J. Zhao, L. Yang, L. Lin, Oxidative stress and antioxidant status in women with gestational diabetes mellitus diagnosed by IADPSG criteria. Diabetes Res. Clin. Pract. (2015). doi: 10.1016/j.diabres.2015.05.010

  22. H. Barbara, M.B. Billing, Bilirubin metabolism. Gut. 10, 250–254 (1969)

    Article  Google Scholar 

  23. J.D. Ostrow, J.H. Jandl, R. Schmid, The formation of bilirubin from hemoglobin in VIVO. J. Clin. Invest. 41(8), 1628–1637 (1962)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. M.S. Stoll, E.A. Zenone, J.D. Ostrow, J.E. Zarembo, Preparation and Properties of Bilirubin Photoisomers. Biochem. J. 183, 139–146 (1979)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. R. Cardenas-Vazquez, O. Yokosuka, B.H. Billing, Enzymic oxidation of unconjugated bilirubin by rat liver. Biochem. J. 236, 625–633 (1986)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. V. Gopinathan, N.J. Miller, A.D. Milner, C.A. Rice-Evans, Bilirubin and ascorbate antioxidant activity in neonatal plasma. Fed. Eur. Biochem. Soc. 349, 197–200 (1994)

    Article  CAS  Google Scholar 

  27. P. Novotna, M. Urbanova, Bilirubin, model membranes and serum albumin interaction: the influence of fatty acids. Biochim. Biophys. Acta. 1848(6), 1331–1340 (2015). doi:10.1016/j.bbamem.2015.02.026

    Article  CAS  PubMed  Google Scholar 

  28. R.P. Dullaart, R. de Vries, J.D. Lefrandt, Increased large VLDL and small LDL particles are related to lower bilirubin in Type 2 diabetes mellitus. Clin. Biochem. 47(16–17), 170–175 (2014). doi:10.1016/j.clinbiochem.2014.08.008

    Article  CAS  PubMed  Google Scholar 

  29. R. Kawamoto, D. Ninomiya, Y. Hasegawa, Y. Kasai, T. Kusunoki, N. Ohtsuka, T. Kumagi, M. Abe, Mildly elevated serum bilirubin levels are negatively associated with carotid atherosclerosis among elderly persons. PloS One 9(12), e114281 (2014). doi:10.1371/journal.pone.0114281

    Article  PubMed  PubMed Central  Google Scholar 

  30. E.S. Kim, E.Y. Mo, S.D. Moon, J.H. Han, Inverse association between serum bilirubin levels and arterial stiffness in Korean women with type 2 diabetes. PloS One 9(10), e109251 (2014). doi:10.1371/journal.pone.0109251

    Article  PubMed  PubMed Central  Google Scholar 

  31. P.D. MacLean, E.C. Drake, L. Ross, C. Barclay, Bilirubin as an antioxidant in micelles and lipid bilayers: its contribution to the total antioxidant capacity of human blood plasma. Free Radic. Biol. Med. 43(4), 600–609 (2007). doi:10.1016/j.freeradbiomed.2007.05.020

    Article  CAS  PubMed  Google Scholar 

  32. H. Isogai, N. Hirayama, A possible molecular mechanism of immunomodulatory activity of bilirubin. Int. J. Med. chem. 2013, 467383 (2013). doi:10.1155/2013/467383

    PubMed  PubMed Central  Google Scholar 

  33. Diabetes, I.A. o., Pregnancy Study Groups Consensus, P., B.E. Metzger, S.G. Gabbe, B. Persson, T.A. Buchanan, P.A. Catalano, P. Damm, A.R. Dyer, A. Leiva, M. Hod, J.L. Kitzmiler, L.P. Lowe, H.D. McIntyre, J.J. Oats, Y. Omori, M.I. Schmidt, International association of diabetes and pregnancy study groups recommendations on the diagnosis and classification of hyperglycemia in pregnancy. Diabetes Care 33(3), 676–682 (2010). doi: 10.2337/dc09-1848

  34. C.H. Jung, M.J. Lee, Y.M. Kang, J.Y. Hwang, J.E. Jang, J. Leem, J.Y. Park, H.K. Kim, W.J. Lee, Higher serum bilirubin level as a protective factor for the development of diabetes in healthy Korean men: a 4 year retrospective longitudinal study. Metabolism: clinical and experimental 63(1), 87–93 (2014). doi:10.1016/j.metabol.2013.09.011

    Article  CAS  Google Scholar 

  35. P. Cheriyath, V.S. Gorrepati, I. Peters, V. Nookala, M. E. Murphy, N. Srouji, D. Fischman, High Total Bilirubin as a Protective Factor for Diabetes Mellitus: An Analysis of NHANES Data From 1999–2006. J. Clin. Med. Res. 2(5), 201–206 (2010). doi:10.4021/jocmr425w

    CAS  PubMed  PubMed Central  Google Scholar 

  36. N. Ikeda, T. Inoguchi, N. Sonoda, M. Fujii, R. Takei, E. Hirata, H. Yokomizo, J. Zheng, Y. Maeda, K. Kobayashi, R. Takayanagi, Biliverdin protects against the deterioration of glucose tolerance in db/db mice. Diabetologia 54(8), 2183–2191 (2011). doi:10.1007/s00125-011-2197-2

    Article  CAS  PubMed  Google Scholar 

  37. J. Murray, D.L. Norrie, C. R. Ruthven, Liquor Bilirubin Levels in Normal Pregnancy: a Reassessment of Early Prediction of Haemolytic Disease. Br. Med. J. 4(5732), 387–391 (1970)

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. S.B. Amin, A.A. Lamola, Newborn jaundice technologies: unbound bilirubin and bilirubin binding capacity in neonates. Semin. Perinatol. 35(3), 134–140 (2011). doi:10.1053/j.semperi.2011.02.007

    Article  PubMed  PubMed Central  Google Scholar 

  39. G. Cohen, D.M. Livovsky, J. Kapitulnik, S. Sasson, Bilirubin increases the expression of glucose transporter-1 and the rate of glucose uptake in vascular endothelial cells. Rev. Diabet. Stud. 3(3), 127–133 (2006). doi:10.1900/RDS.2006.3.127

    Article  PubMed  PubMed Central  Google Scholar 

  40. C. Qiu, K. Hevner, D.A. Enquobahrie, M.A. Williams, Maternal serum heme-oxygenase-1 (HO-1) concentrations in early pregnancy and subsequent risk of gestational diabetes mellitus. PloS One 7(11), e48060 (2012). doi:10.1371/journal.pone.0048060

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. B.C. Oveson, T. Iwase, S.F. Hackett, S.Y. Lee, S. Usui, T.W. Sedlak, S.H. Snyder, P.A. Campochiaro, J.U. Sung, Constituents of bile, bilirubin and TUDCA, protect against oxidative stress-induced retinal degeneration. J. Neurochem. 116(1), 144–153 (2011). doi:10.1111/j.1471-4159.2010.07092.x

    Article  CAS  PubMed  Google Scholar 

  42. W.L. Wurster, G.J Pyne-Geithman, I.R Peat, J.F, Clark, Bilirubin oxidation products (BOXes): synthesis, stability and chemical characteristics. Acta. Neuro chir. Suppl. 104, 43–50 (2008)

  43. T. Jansen, A. Daiber, Direct Antioxidant Properties of Bilirubin and Biliverdin. Is there a Role for Biliverdin Reductase? Front. Pharmacol. 3, 30 (2012). doi:10.3389/fphar.2012.00030

    Article  PubMed  PubMed Central  Google Scholar 

  44. T.D. Hull, A. Agarwal, Bilirubin: a potential biomarker and therapeutic target for diabetic nephropathy. Diabetes 63(8), 2613–2616 (2014). doi:10.2337/db14-0691

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

The authors would like to thank the women who took part in the study, the practices who allowed us to access their databases and the staff at the Primary Care Sciences Research Center who helped administer the project.

Funding

Funding was received from National Program on Basic Research Project of China (NO.2013FY114200) for Nianhong Yang.

Author contributions

CL produced the original idea, and CL, NY, LH and XY designed the study. CL and WW analyzed the data, CZ, XZ, RC, JW, XL, HD, YG, QG, XH, GX and MX performed the experiments. All authors wrote up the study.

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Authors and Affiliations

  1. Department of Nutrition and Food Hygiene, Hubei Key Laboratory of Food Nutrition and Safety, MOE Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, 13 Hangkong Road, Wuhan, 430030, Hubei, China

    Chaoqun Liu, Chunrong Zhong, Xuezhen Zhou, Renjuan Chen, Jiangyue Wu, ** Hao & Nianhong Yang

  2. Departments of Epidemiology and Health Statistic, Wuhan, China

    Weiye Wang & Huisi Ding

  3. Hubei Maternal and Child Health Hospital, Wuhan, 430070, Hubei, China

    ** **ong

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  1. Chaoqun Liu
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Correspondence to Nianhong Yang.

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Approval was obtained from Tongji Medical College of Huazhong University of Science and Technology Committee.

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Liu, C., Zhong, C., Zhou, X. et al. Higher direct bilirubin levels during mid-pregnancy are associated with lower risk of gestational diabetes mellitus. Endocrine 55, 165–172 (2017). https://doi.org/10.1007/s12020-016-1103-6

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