Endocrinol Metab.  2022 Apr;37(2):272-280. 10.3803/EnM.2022.1416.

Cumulative Exposure to High γ-Glutamyl Transferase Level and Risk of Diabetes: A Nationwide Population-Based Study

• Park JY
• Han K
• Kim HS
• Cho JH
• Yoon KH
• Kim MK
• Lee SH

• KMID: 2529219
• DOI: http://doi.org/10.3803/EnM.2022.1416

Abstract

Background
Elevated γ-glutamyl transferase (γ-GTP) level is associated with metabolic syndrome, impaired glucose tolerance, and insulin resistance, which are risk factors for type 2 diabetes. We aimed to investigate the association of cumulative exposure to high γ-GTP level with risk of diabetes.
Methods
Using nationally representative data from the Korean National Health Insurance system, 346,206 people who were free of diabetes and who underwent 5 consecutive health examinations from 2005 to 2009 were followed to the end of 2018. High γ-GTP level was defined as those in the highest quartile, and the number of exposures to high γ-GTP level ranged from 0 to 5. Hazard ratio (HR) and 95% confidence interval (CI) for diabetes were analyzed using the multivariable Cox proportional-hazards model.
Results
The mean follow-up duration was 9.2±1.0 years, during which 15,183 (4.4%) patients developed diabetes. There was a linear increase in the incidence rate and the risk of diabetes with cumulative exposure to high γ-GTP level. After adjusting for possible confounders, the HR of diabetes in subjects with five consecutive high γ-GTP levels were 2.60 (95% CI, 2.47 to 2.73) in men and 3.05 (95% CI, 2.73 to 3.41) in women compared with those who never had a high γ-GTP level. Similar results were observed in various subgroup and sensitivity analyses.
Conclusion
There was a linear relationship between cumulative exposure to high γ-GTP level and risk of diabetes. Monitoring and lowering γ-GTP level should be considered for prevention of diabetes in the general population.

Keyword

Diabetes mellitus; Gamma-glutamyltransferase; Risk

Reference

1. Saeedi P, Petersohn I, Salpea P, Malanda B, Karuranga S, Unwin N, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019; 157:107843.

2. Jung CH, Son JW, Kang S, Kim WJ, Kim HS, Kim HS, et al. Diabetes fact sheets in Korea, 2020: an appraisal of current status. Diabetes Metab J. 2021; 45:1–10.

3. Lee BW, Lee YH, Park CY, Rhee EJ, Lee WY, Kim NH, et al. Non-alcoholic fatty liver disease in patients with type 2 diabetes mellitus: a position statement of the fatty liver research group of the Korean Diabetes Association. Diabetes Metab J. 2020; 44:382–401.

4. Koenig G, Seneff S. Gamma-glutamyltransferase: a predictive biomarker of cellular antioxidant inadequacy and disease risk. Dis Markers. 2015; 2015:818570.

5. Ndrepepa G, Colleran R, Kastrati A. Gamma-glutamyl transferase and the risk of atherosclerosis and coronary heart disease. Clin Chim Acta. 2018; 476:130–8.

6. Onat A, Can G, Ornek E, Cicek G, Ayhan E, Dogan Y. Serum γ-glutamyltransferase: independent predictor of risk of diabetes, hypertension, metabolic syndrome, and coronary disease. Obesity (Silver Spring). 2012; 20:842–8.

7. Andre P, Balkau B, Born C, Charles MA, Eschwege E; D.E.S.I.R. study group. study group. Three-year increase of gamma-glutamyltransferase level and development of type 2 diabetes in middle-aged men and women: the D.E.S.I.R. cohort. Diabetologia. 2006; 49:2599–603.

8. Lee DH, Ha MH, Kim JH, Christiani DC, Gross MD, Steffes M, et al. Gamma-glutamyltransferase and diabetes: a 4-year follow-up study. Diabetologia. 2003; 46:359–64.

9. Wannamethee SG, Shaper AG, Lennon L, Whincup PH. Hepatic enzymes, the metabolic syndrome, and the risk of type 2 diabetes in older men. Diabetes Care. 2005; 28:2913–8.

10. Ko SH, Baeg MK, Han KD, Ko SH, Ahn YB. Increased liver markers are associated with higher risk of type 2 diabetes. World J Gastroenterol. 2015; 21:7478–87.

11. Wang H, Li L, Zhang S. Non-linear relationship between gamma-glutamyl transferase and type 2 diabetes mellitus risk: secondary analysis of a prospective cohort study. J Int Med Res. 2020; 48:300060520937911.

12. Ahn HR, Shin MH, Nam HS, Park KS, Lee YH, Jeong SK, et al. The association between liver enzymes and risk of type 2 diabetes: the Namwon study. Diabetol Metab Syndr. 2014; 6:14.

13. De Silva N, Borges MC, Hingorani AD, Engmann J, Shah T, Zhang X, et al. Liver function and risk of type 2 diabetes: bidirectional Mendelian randomization study. Diabetes. 2019; 68:1681–91.

14. Kim HK, Song SO, Noh J, Jeong IK, Lee BW. Data configuration and publication trends for the Korean National Health Insurance and Health Insurance Review & Assessment Database. Diabetes Metab J. 2020; 44:671–8.

15. Huh Y, Nam GE. Overcoming increasing morbid obesity in Korea. J Obes Metab Syndr. 2021; 30:77–80.

16. Ko SH, Han K, Lee YH, Noh J, Park CY, Kim DJ, et al. Past and current status of adult type 2 diabetes mellitus management in Korea: a National Health Insurance Service database analysis. Diabetes Metab J. 2018; 42:93–100.

17. Kaneko K, Yatsuya H, Li Y, Uemura M, Chiang C, Hirakawa Y, et al. Association of gamma-glutamyl transferase and alanine aminotransferase with type 2 diabetes mellitus incidence in middle-aged Japanese men: 12-year follow up. J Diabetes Investig. 2019; 10:837–45.

18. Mantovani A, Byrne CD, Bonora E, Targher G. Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: a meta-analysis. Diabetes Care. 2018; 41:372–82.

19. Mohamed J, Nazratun Nafizah AH, Zariyantey AH, Budin SB. Mechanisms of diabetes-induced liver damage: the role of oxidative stress and inflammation. Sultan Qaboos Univ Med J. 2016; 16:e132–41.

20. Lee DH, Blomhoff R, Jacobs DR Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res. 2004; 38:535–9.

21. Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med. 2011; 51:993–9.

22. Meisinger C, Lowel H, Heier M, Schneider A, Thorand B; KORA Study Group. Serum gamma-glutamyltransferase and risk of type 2 diabetes mellitus in men and women from the general population. J Intern Med. 2005; 258:527–35.

23. Lee JH, Lee HS, Lee YJ. Serum γ-glutamyltransferase as an independent predictor for incident type 2 diabetes in middleaged and older adults: findings from the KoGES over 12 years of follow-up. Nutr Metab Cardiovasc Dis. 2020; 30:1484–91.

24. Wang Y, Wu T, Zang X, Liu X, Xu W, Lai P, et al. Relationship between serum gamma-glutamyl transferase level and impaired fasting glucose among Chinese community-dwelling adults: a follow-up observation of 6 years. Metab Syndr Relat Disord. 2021; 19:100–6.

25. Fujita M, Ueno K, Hata A. Association of gamma-glutamyltransferase with incidence of type 2 diabetes in Japan. Exp Biol Med (Maywood). 2010; 235:335–41.

26. Zhao W, Tong J, Liu J, Liu J, Li J, Cao Y. The dose-response relationship between gamma-glutamyl transferase and risk of diabetes mellitus using publicly available data: a longitudinal study in Japan. Int J Endocrinol. 2020; 2020:5356498.