J Korean Med Sci.  2025 Feb;40(6):e13. 10.3346/jkms.2025.40.e13.

A Longitudinal Increase in Serum Gamma-Glutamyl Transferase Levels, but Not in Alanine Aminotransferase Levels, Improves the Prediction of Risk of Impaired Fasting Glucose in Male

• Im J
• Jung S
• Yang Y
• Kim KN

• KMID: 2565146
• DOI: http://doi.org/10.3346/jkms.2025.40.e13

Abstract

Background
Impaired fasting glucose (IFG), being a pre-diabetic condition, can increase the risk of overt diabetes; thus early detection and prediction of IFG are important to reduce the incidence of overt diabetes. Some predictive factors, including serum alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT), have been reported in several studies, but none of the studies have investigated the effect of longitudinal changes in individual serum ALT and GGT levels on the risk of IFG.
Methods
We aimed to investigate the association between changes in the serum ALT and GGT levels and the risk of IFG using a checkup database between 1999 and 2014.
Results
A total of 3,598 males and 3,275 females were enrolled in the study. We performed a follow-up test of serum ALT or GGT in each individual, and classified the cases in which the serum ALT or GGT level was increased or decreased during the follow-up test compared to the baseline. According to the multivariate Cox proportional hazards model, the hazard ratio was 1.76 (95% confidence interval, 1.45–2.12; P < 0.001) in male subjects with an increased serum GGT level compared to male subjects with a decrease in the serum GGT level at followup compared to the baseline. However, the relationship between the serum ALT level and incidence of new-onset IFG was not statistically significant in both sexes; and in females, the relationship between the serum GGT level and incidence of new-onset IFG was also not statistically significant.
Conclusion
We revealed that a longitudinal increase in serum GGT levels was related to an increased risk of IFG in males. Therefore, monitoring the changes in serum GGT levels is important for predicting new-onset IFG, and it can be used as an early indicator of onset of overt diabetes in males.

Keyword

Impaired Fasting Glucose; Gamma-Glutamyl Transferase; Alanine; Aminotransferase

Reference

1. Nichols GA, Hillier TA, Brown JB. Progression from newly acquired impaired fasting glusose to type 2 diabetes. Diabetes Care. 2007; 30(2):228–233. PMID: 17259486.

2. Nichols GA, Hillier TA, Brown JB. Normal fasting plasma glucose and risk of type 2 diabetes diagnosis. Am J Med. 2008; 121(6):519–524. PMID: 18501234.

3. Fang M, Wang D, Coresh J, Selvin E. Undiagnosed diabetes in US adults: prevalence and trends. Diabetes Care. 2022; 45(9):1994–2002. PMID: 35817030.

4. Kim BY, Won JC, Lee JH, Kim HS, Park JH, Ha KH, et al. Diabetes fact sheets in Korea, 2018: an appraisal of current status. Diabetes Metab J. 2019; 43(4):487–494. PMID: 31339012.

5. 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(1):14. PMID: 24502834.

6. Bonnet F, Ducluzeau PH, Gastaldelli A, Laville M, Anderwald CH, Konrad T, et al. Liver enzymes are associated with hepatic insulin resistance, insulin secretion, and glucagon concentration in healthy men and women. Diabetes. 2011; 60(6):1660–1667. PMID: 21521874.

7. Cho HC. The association between serum GGT concentration and diabetic peripheral polyneuropathy in type 2 diabetic patients. Korean Diabetes J. 2010; 34(2):111–118. PMID: 20548843.

8. Doi Y, Kubo M, Yonemoto K, Ninomiya T, Iwase M, Tanizaki Y, et al. Liver enzymes as a predictor for incident diabetes in a Japanese population: the Hisayama study. Obesity (Silver Spring). 2007; 15(7):1841–1850. PMID: 17636103.

9. Ford ES, Schulze MB, Bergmann MM, Thamer C, Joost HG, Boeing H. Liver enzymes and incident diabetes: findings from the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam study. Diabetes Care. 2008; 31(6):1138–1143. PMID: 18346992.

10. Kawamoto R, Tabara Y, Kohara K, Miki T, Ohtsuka N, Kusunoki T, et al. Serum gamma-glutamyl transferase within its normal concentration range is related to the presence of impaired fasting glucose and diabetes among Japanese community-dwelling persons. Endocr Res. 2011; 36(2):64–73. PMID: 21539445.

11. Lee YS, Cho Y, Burgess S, Davey Smith G, Relton CL, Shin SY, et al. Serum gamma-glutamyl transferase and risk of type 2 diabetes in the general Korean population: a Mendelian randomization study. Hum Mol Genet. 2016; 25(17):3877–3886. PMID: 27466193.

12. Nano J, Muka T, Ligthart S, Hofman A, Darwish Murad S, Janssen HL, et al. Gamma-glutamyltransferase levels, prediabetes and type 2 diabetes: a Mendelian randomization study. Int J Epidemiol. 2017; 46(5):1400–1409. PMID: 28338987.

13. Hogg N, Singh RJ, Konorev E, Joseph J, Kalyanaraman B. S-Nitrosoglutathione as a substrate for gamma-glutamyl transpeptidase. Biochem J. 1997; 323(2):477–481. PMID: 9163341.

14. Wickham S, West MB, Cook PF, Hanigan MH. Gamma-glutamyl compounds: substrate specificity of gamma-glutamyl transpeptidase enzymes. Anal Biochem. 2011; 414(2):208–214. PMID: 21447318.

15. Yan Y, Li S, Liu Y, Bazzano L, He J, Mi J, et al. Temporal relationship between inflammation and insulin resistance and their joint effect on hyperglycemia: the Bogalusa Heart Study. Cardiovasc Diabetol. 2019; 18(1):109. PMID: 31443647.

16. Jeong JH, Jung S, Kim KN. Considering serum alanine aminotransferase and gamma-glutamyltransferase levels together strengthen the prediction of impaired fasting glucose risk: a cross-sectional and longitudinal study. Sci Rep. 2021; 11(1):3333. PMID: 33564044.

17. Greenfield TK. Ways of measuring drinking patterns and the difference they make: experience with graduated frequencies. J Subst Abuse. 2000; 12(1-2):33–49. PMID: 11288473.

18. Bellentani S, Saccoccio G, Costa G, Tiribelli C, Manenti F, Sodde M, et al. Drinking habits as cofactors of risk for alcohol induced liver damage. The Dionysos Study Group. Gut. 1997; 41(6):845–850. PMID: 9462221.

19. Yu JH, Kim JS, Lee MR, Yoon SY, Cho SY, Yoo SH, et al. Risks of borderline liver enzyme abnormalities to the incidence of impaired fasting glucose and diabetes mellitus: a 7 year follow up study of workers. Ann Occup Environ Med. 2016; 28(1):18. PMID: 27057316.

20. Nakanishi N, Nishina K, Li W, Sato M, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and development of impaired fasting glucose or type 2 diabetes in middle-aged Japanese men. J Intern Med. 2003; 254(3):287–295. PMID: 12930239.

21. Rösen P, Nawroth PP, King G, Möller W, Tritschler HJ, Packer L. The role of oxidative stress in the onset and progression of diabetes and its complications: a summary of a Congress Series sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes Metab Res Rev. 2001; 17(3):189–212. PMID: 11424232.

22. Matsuoka T, Kajimoto Y, Watada H, Kaneto H, Kishimoto M, Umayahara Y, et al. Glycation-dependent, reactive oxygen species-mediated suppression of the insulin gene promoter activity in HIT cells. J Clin Invest. 1997; 99(1):144–150. PMID: 9011569.

23. Lee DH, Blomhoff R, Jacobs DR Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res. 2004; 38(6):535–539. PMID: 15346644.

24. Krotkiewski M, Björntorp P, Sjöström L, Smith U. Impact of obesity on metabolism in men and women. Importance of regional adipose tissue distribution. J Clin Invest. 1983; 72(3):1150–1162. PMID: 6350364.

25. Pouliot MC, Després JP, Nadeau A, Moorjani S, Prud’Homme D, Lupien PJ, et al. Visceral obesity in men. Associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992; 41(7):826–834. PMID: 1612197.