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The association of plasma levels of liver enzymes and risk of gestational diabetes mellitus: a systematic review and dose–response meta-analysis of observational studies

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Abstract

Aims

Relationship between liver enzymes such as gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), aspartate transaminase (AST) and alkaline phosphatase and risk of gestational diabetes mellitus (GDM) is a controversial issue. The aim of this systematic review and dose–response meta-analysis was to investigate the association between liver enzymes and risk of GDM in observational studies.

Methods

A comprehensive systematic literature search was conducted in MEDLINE/PubMed, SCOPUS and Web of Science databases up to September 2019. Combined odds ratios (ORs) with 95% confidence intervals (CIs) were evaluated by DerSimonian and Laird random-effects models. Dose–response analyses of these relationships were also carried out.

Results

Eight studies with 25,451 participants containing 2549 cases were included in this study. Pooled results showed a significant association between GGT levels and risk of GDM (OR 2.10, 95% CI 1.14–3.86, I2 84%). In addition, random-effects model indicated a dramatic and direct significant association between GGT and risk of GDM in nonlinear (p < 0.001) and linear (p < 0.001) dose–response analysis. Associations between ALT and AST with risk of GDM were found to be non-significant (OR 1.32, 95% CI 0.91–1.90, I2 65% and OR 0.76, 95% CI 0.52–1.10, I2 16%, respectively).

Conclusion

This systematic review and dose–response meta-analysis highlights GGT as a significant and robust predictor of the incidence of GDM in pregnant women.

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References

  1. Goldman M, Kitzmiller JL, Abrams B, Cowan RM, Laros RK Jr (1991) Obstetric complications with GDM. Effects of maternal weight. Diabetes 40(Suppl 2):79–82

    Article  PubMed  Google Scholar 

  2. Petitt DJ, Bennett PH, Knowler WC, Baird HR, Aleck KA (1985) Gestational diabetes mellitus and impaired glucose tolerance during pregnancy. Long-term effects on obesity and glucose tolerance in the offspring. Diabetes 34(Suppl 2):119–122

    Article  PubMed  Google Scholar 

  3. Kawasaki M, Arata N, Miyazaki C, Mori R, Kikuchi T, Ogawa Y et al (2018) Obesity and abnormal glucose tolerance in offspring of diabetic mothers: a systematic review and meta-analysis. PLoS ONE 13(1):e0190676

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Li Y, Wang W, Zhang D (2019) Maternal diabetes mellitus and risk of neonatal respiratory distress syndrome: a meta-analysis. Acta Diabetol 56(7):729–740

    Article  PubMed  Google Scholar 

  5. Adane AA, Mishra GD, Tooth LR (2016) Diabetes in pregnancy and childhood cognitive development: a systematic review. Pediatrics 137(5):e20154234

    Article  PubMed  Google Scholar 

  6. Tamayo T, Tamayo M, Rathmann W, Potthoff P (2016) Prevalence of gestational diabetes and risk of complications before and after initiation of a general systematic two-step screening strategy in Germany (2012–2014). Diabetes Res Clin Pract 115:1–8

    Article  CAS  PubMed  Google Scholar 

  7. A American Diabetes (2004) Gestational diabetes mellitus. Diabetes Care 27(Suppl 1):S88–S90

    Google Scholar 

  8. Ovesen PG, Fuglsang J, Andersen MB, Wolff C, Petersen OB, David McIntyre H (2018) Temporal trends in gestational diabetes prevalence, treatment, and outcomes at Aarhus University Hospital, Skejby, between 2004 and 2016. J Diabetes Res 2018:5937059

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  9. Ferrara A (2007) Increasing prevalence of gestational diabetes mellitus: a public health perspective. Diabetes Care 30(Suppl 2):S141–S146

    Article  PubMed  Google Scholar 

  10. Cho NH, Shaw JE, Karuranga S, Huang Y, da RochaFernandes JD, Ohlrogge AW et al (2018) IDF diabetes atlas: global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Res Clin Pract 138:271–281

    Article  CAS  PubMed  Google Scholar 

  11. Crowther CA, Hiller JE, Moss JR, McPhee AJ, Jeffries WS, Robinson JS et al (2005) Effect of treatment of gestational diabetes mellitus on pregnancy outcomes. N Engl J Med 352(24):2477–2486

    Article  CAS  PubMed  Google Scholar 

  12. Agbozo F, Abubakari A, Narh C, Jahn A (2018) Accuracy of glycosuria, random blood glucose and risk factors as selective screening tools for gestational diabetes mellitus in comparison with universal diagnosing. BMJ Open Diabetes Res Care 6(1):e000493

    Article  PubMed  PubMed Central  Google Scholar 

  13. Goldenberg RL, McClure EM, Harrison MS, Miodovnik M (2016) Diabetes during pregnancy in low- and middle-income countries. Am J Perinatol 33(13):1227–1235

    Article  PubMed  Google Scholar 

  14. Utz B, De Brouwere V (2016) "Why screen if we cannot follow-up and manage?" Challenges for gestational diabetes screening and management in low and lower-middle income countries: results of a cross-sectional survey. BMC Pregnancy Childbirth 16(1):341

    Article  PubMed  PubMed Central  Google Scholar 

  15. Younossi ZM, Golabi P, de Avila L, Paik JM, Srishord M, Fukui N et al (2019) The global epidemiology of NAFLD and NASH in patients with type 2 diabetes: a systematic review and meta-analysis. J Hepatol 71:793–801

    Article  PubMed  Google Scholar 

  16. Sanyal D, Mukherjee P, Raychaudhuri M, Ghosh S, Mukherjee S, Chowdhury S (2015) Profile of liver enzymes in non-alcoholic fatty liver disease in patients with impaired glucose tolerance and newly detected untreated type 2 diabetes. Indian J Endocrinol Metab 19(5):597–601

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Fraser A, Harris R, Sattar N, Ebrahim S, Davey Smith G, Lawlor DA (2009) Alanine aminotransferase, gamma-glutamyltransferase, and incident diabetes: the British Women's Heart and Health Study and meta-analysis. Diabetes Care 32(4):741–750

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rahmani J, Miri A, Namjoo I, Zamaninour N, Maljaei MB, Zhou K et al (2019) Elevated liver enzymes and cardiovascular mortality: a systematic review and dose–response meta-analysis of more than one million participants. Eur J Gastroenterol Hepatol 31(5):555–562

    Article  CAS  PubMed  Google Scholar 

  19. Ruhl CE, Everhart JE (2009) Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology 136(2):477–485 (e11)

    Article  CAS  PubMed  Google Scholar 

  20. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al (2000) Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 283(15):2008–2012

    Article  CAS  Google Scholar 

  21. Stang A (2010) Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 25(9):603–605

    Article  Google Scholar 

  22. Jackson D, White IR, Thompson SG (2010) Extending DerSimonian and Laird's methodology to perform multivariate random effects meta-analyses. Stat Med 29(12):1282–1297

    Article  PubMed  Google Scholar 

  23. Harre FE Jr, Lee KL, Pollock BG (1988) Regression models in clinical studies: determining relationships between predictors and response. JNCI J Natl Cancer Inst 80(15):1198–1202

    Article  Google Scholar 

  24. Xiong T, Zhong C, Sun G, Zhou X, Chen R, Li Q et al (2019) Early maternal circulating alkaline phosphatase with subsequent gestational diabetes mellitus and glucose regulation: a prospective cohort study in China. Endocrine 65(2):295–303

    Article  CAS  PubMed  Google Scholar 

  25. Zhu Y, Hedderson MM, Quesenberry CP, Feng J, Ferrara A (2018) Liver enzymes in early to mid-pregnancy, insulin resistance, and gestational diabetes risk: a longitudinal analysis. Front Endocrinol (Lausanne) 9:581

    Article  Google Scholar 

  26. Kong M, Liu C, Guo Y, Gao Q, Zhong C, Zhou X et al (2018) Higher level of GGT during mid-pregnancy is associated with increased risk of gestational diabetes mellitus. Clin Endocrinol (Oxf) 88(5):700–705

    Article  CAS  Google Scholar 

  27. Yarrington CD, Cantonwine DE, Seely EW, McElrath TF, Zera CA (2016) The association of alanine aminotransferase in early pregnancy with gestational diabetes. Metab Syndr Relat Disord 14(5):254–258

    Article  CAS  PubMed  Google Scholar 

  28. Leng J, Zhang C, Wang P, Li N, Li W, Liu H et al (2016) Plasma levels of alanine aminotransferase in the first trimester identify high risk chinese women for gestational diabetes. Sci Rep 6:27291

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Sridhar SB, Xu F, Darbinian J, Quesenberry CP, Ferrara A, Hedderson MM (2014) Pregravid liver enzyme levels and risk of gestational diabetes mellitus during a subsequent pregnancy. Diabetes Care 37(7):1878–1884

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Tan PC, Aziz AZ, Ismail IS, Omar SZ (2012) Gamma-glutamyltransferase, alanine transaminase and aspartate transaminase levels and the diagnosis of gestational diabetes mellitus. Clin Biochem 45(15):1192–1196

    Article  CAS  PubMed  Google Scholar 

  31. Tan PC, Mubarak S, Omar SZ (2008) Gamma-glutamyltransferase level in pregnancy is an independent risk factor for gestational diabetes mellitus. J Obstet Gynaecol Res 34(4):512–517

    Article  CAS  PubMed  Google Scholar 

  32. Kim C, Newton KM, Knopp RH (2002) Gestational diabetes and the incidence of type 2 diabetes: a systematic review. Diabetes Care 25(10):1862–1868

    Article  PubMed  Google Scholar 

  33. Scavini M, Secchi A (2019) Diabetes in pregnancy. Acta Diabetol 56(7):719–721

    Article  PubMed  Google Scholar 

  34. Pintaudi B, Fresa R, Dalfrà M, Dodesini AR, Vitacolonna E, Tumminia A et al (2018) The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study. Acta Diabetol 55(12):1261–1273

    Article  CAS  PubMed  Google Scholar 

  35. Shokry E, Marchioro L, Uhl O, Bermúdez MG, García-Santos JA, Segura MT et al (2019) Impact of maternal BMI and gestational diabetes mellitus on maternal and cord blood metabolome: results from the PREOBE cohort study. Acta Diabetol 56(4):421–430

    Article  PubMed  Google Scholar 

  36. Doi Y, Kubo M, Yonemoto K, Ninomiya T, Iwase M, Tanizaki Y et al (2007) Liver enzymes as a predictor for incident diabetes in a Japanese population: the Hisayama study. Obesity 15(7):1841–1850

    Article  CAS  PubMed  Google Scholar 

  37. Lee D-H, Ha M-H, Kim J-H, Christiani D, Gross MD, Steffes M et al (2003) Gamma-glutamyltransferase and diabetes—a 4 year follow-up study. Diabetologia 46(3):359–364

    Article  CAS  PubMed  Google Scholar 

  38. Nakanishi N, Suzuki K, Tatara K (2004) Serum γ-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care 27(6):1427–1432

    Article  CAS  PubMed  Google Scholar 

  39. Lee DH, Silventoinen K, Jacobs DR Jr, Jousilahti P, Tuomileto J (2004) γ-Glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. J Clin Endocrinol Metab 89(11):5410–5414

    Article  CAS  PubMed  Google Scholar 

  40. Fei G, Pan JM, Hou XH, Fang QC, Lu HJ, Tang JL et al (2012) Liver enzymes concentrations are closely related to prediabetes: findings of the Shanghai Diabetes Study II (SHDS II). Biomed Environ Sci 25(1):30–37

    Google Scholar 

  41. Inoue K, Matsumoto M, Miyoshi Y, Kobayashi Y (2008) Elevated liver enzymes in women with a family history of diabetes. Diabetes Res Clin Pract 79(3):e4–e7

    Article  CAS  PubMed  Google Scholar 

  42. Clark JM, Diehl AM (2003) Defining nonalcoholic fatty liver disease: implications for epidemiologic studies. Gastroenterology 124(1):248–250

    Article  PubMed  Google Scholar 

  43. Kugelman A, Choy HA, Liu R, Shi MM, Gozal E, Forman HJ (1994) gamma-Glutamyl transpeptidase is increased by oxidative stress in rat alveolar L2 epithelial cells. Am J Respir Cell Mol Biol 11(5):586–592

    Article  CAS  PubMed  Google Scholar 

  44. Lieberman MW, Barrios R, Carter BZ, Habib GM, Lebovitz R, Rajagopalan S et al (1995) gamma-Glutamyl transpeptidase: What does the organization and expression of a multipromoter gene tell us about its functions? Am J Pathol 147(5):1175

    CAS  PubMed  PubMed Central  Google Scholar 

  45. Oberley LW (1988) Free radicals and diabetes. Free Radic Biol Med 5(2):113–124

    Article  CAS  PubMed  Google Scholar 

  46. Ceriello A, Motz E (2004) Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol 24(5):816–823

    Article  CAS  PubMed  Google Scholar 

  47. Zhang H, Forman HJ, Choi J (2005) γ-Glutamyl transpeptidase in glutathione biosynthesis. Methods Enzymol 401:468–483

    Article  CAS  PubMed  Google Scholar 

  48. McLennan SV, Heffernan S, Wright L, Rae C, Fisher E, Yue DK et al (1991) Changes in hepatic glutathione metabolism in diabetes. Diabetes 40(3):344–348

    Article  CAS  PubMed  Google Scholar 

  49. Lee D-H, Steffes MW, Jacobs D (2008) Can persistent organic pollutants explain the association between serum γ-glutamyltransferase and type 2 diabetes? Diabetologia 51(3):402–407

    Article  CAS  PubMed  Google Scholar 

  50. Vozarova B, Stefan N, Lindsay RS, Saremi A, Pratley RE, Bogardus C et al (2002) High alanine aminotransferase is associated with decreased hepatic insulin sensitivity and predicts the development of type 2 diabetes. Diabetes 51(6):1889–1895

    Article  CAS  PubMed  Google Scholar 

  51. Lee D-H, Jacobs DR Jr (2005) Association between serum gamma-glutamyltransferase and C-reactive protein. Atherosclerosis 178(2):327–330

    Article  CAS  PubMed  Google Scholar 

  52. Nathwani RA, Pais S, Reynolds TB, Kaplowitz N (2005) Serum alanine aminotransferase in skeletal muscle diseases. Hepatology 41(2):380–382

    Article  CAS  PubMed  Google Scholar 

  53. Tan PC, Aziz AZ, Ismail IS, Omar SZ (2012) Gamma-glutamyltransferase, alanine transaminase and aspartate transaminase levels and the diagnosis of gestational diabetes mellitus. Clin Biochem 45(15):1192–1196

    Article  CAS  PubMed  Google Scholar 

  54. Tiikkainen M, Bergholm R, Vehkavaara S, Rissanen A, Häkkinen A-M, Tamminen M et al (2003) Effects of identical weight loss on body composition and features of insulin resistance in obese women with high and low liver fat content. Diabetes 52(3):701–707

    Article  CAS  PubMed  Google Scholar 

  55. Nannipieri M, Gonzales C, Baldi S, Posadas R, Williams K, Haffner SM et al (2005) Liver enzymes, the metabolic syndrome, and incident diabetes: the Mexico City diabetes study. Diabetes Care 28(7):1757–1762

    Article  CAS  PubMed  Google Scholar 

  56. Schindhelm RK, Dekker JM, Nijpels G, Heine RJ, Diamant M (2005) No independent association of alanine aminotransferase with risk of future type 2 diabetes in the Hoorn study. Diabetes Care 28(11):2812

    Article  PubMed  Google Scholar 

  57. Kunutsor SK, Apekey TA, Walley J (2013) Liver aminotransferases and risk of incident type 2 diabetes: a systematic review and meta-analysis. Am J Epidemiol 178(2):159–171

    Article  PubMed  Google Scholar 

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Affiliated Hospital of Inner Mongolia University for Nationalities, Tongliao, 028000, Neimenggu, China

    Wei Zhao, Li Zhang & Guoliang Zhang

  2. Department of Clinical Nutrition and Dietetics, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Hamed Kord Varkaneh & Ammar Salehisahlabadi

  3. Department of Community Nutrition, Student Research Committee, Faculty of Nutrition and Food Technology, National Nutrition and Food Technology Research Institute, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Jamal Rahmani

  4. Centre for Sport, Exercise and Life Sciences, Coventry University, Coventry, CV1 5FB, UK

    Cain Clark

  5. School of Medicine, University College Cork, Cork, Ireland

    Paul M. Ryan

  6. Arab Diploma in Family Medicine, AICPD, Cairo, Egypt

    Hebatullah M. Abdulazeem

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  1. Wei Zhao
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  2. Li Zhang
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Zhao, W., Zhang, L., Zhang, G. et al. The association of plasma levels of liver enzymes and risk of gestational diabetes mellitus: a systematic review and dose–response meta-analysis of observational studies. Acta Diabetol 57, 635–644 (2020). https://doi.org/10.1007/s00592-019-01458-8

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