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Abstract
Background
This study was conducted to establish reference intervals (RIs) for serum gamma-glutamyltransferase (GGT), and to evaluate the association between serum GGT levels within RIs and the prevalence of metabolic syndrome (MetS) and type 2 diabetes mellitus (DM) in men and women.
Methods
A total of 363 healthy adults (137 men and 226 women) were enrolled for establishing the RIs of serum GGT. A cross-sectional study was conducted with 919 individuals (519 men and 400 women) to evaluate the associations between gender-specific serum GGT RI quartiles and prevalence of MetS and DM.
Results
The RIs for serum GGT levels (central 95th percentile ranges) were 9.0–70.6 IU/L and 4.0–31.3 IU/L in men and women, respectively. In men, the odds ratios (ORs) and 95% confidence intervals (CIs) for the prevalence of MetS in 4 serum GGT quartiles (lowest to highest) were 1.0 (reference), 3.6 (0.7–18.0), 8.8 (2.0–39.1), and 17.4 (4.0–75.3), respectively, while the ORs (95% CIs) for the prevalence of DM were 1.0 (reference), 1.0 (0.3–3.0), 1.7 (0.6–4.6), and 2.6 (1.0–6.6), respectively. In women, the corresponding ORs (95% CIs) were 1.0 (reference), 3.3 (0.6–16.6), 5.8 (1.2–27.3), and 18.8 (4.3–82.2) for MetS, respectively, and 1.0 (reference), 1.6 (0.3–9.7), 1.6 (0.3–9.9), and 8.0 (1.7–36.7) for DM, respectively. These significant relationships persisted after adjusting for age, alcohol intake, body mass index, and smoking.
References
1. Nakanishi N, Suzuki K, Tatara K. Serum gamma-glutamyltransferase and risk of metabolic syndrome and type 2 diabetes in middle-aged Japanese men. Diabetes Care. 2004; 27:1427–32.
2. Rantala AO, Lilja M, Kauma H, Savolainen MJ, Reunanen A, Kesäniemi YA. Gamma-glutamyl transpeptidase and the metabolic syndrome. J Intern Med. 2000; 248:230–8.
3. Teschke R, Brand A, Strohmeyer G. Induction of hepatic microsomal gamma-glutamyltransferase activity following chronic alcohol consumption. Biochem Biophys Res Commun. 1977; 75:718–24.
4. 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.
5. Perry IJ, Wannamethee SG, Shaper AG. Prospective study of serum gamma-glutamyltransferase and risk of NIDDM. Diabetes Care. 1998; 21:732–7.
6. Miura K, Nakagawa H, Nakamura H, Tabata M, Nagase H, Yoshida M, et al. Serum gamma-glutamyl transferase level in predicting hypertension among male drinkers. J Hum Hypertens. 1994; 8:445–9.
7. Jousilahti P, Rastenyte D, Tuomilehto J. Serum gamma-glutamyl transferase, self-reported alcohol drinking, and the risk of stroke. Stroke. 2000; 31:1851–5.
8. Brenner H, Rothenbacher D, Arndt V, Schuberth S, Fraisse E, Fliedner TM. Distribution, determinants, and prognostic value of gamma-glutamyltransferase for all-cause mortality in a cohort of construction workers from southern Germany. Prev Med. 1997; 26:305–10.
9. Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Oshima T, Chayama K. Endothelial function and oxidative stress in renovascular hypertension. N Engl J Med. 2002; 346:1954–62.
10. Witztum JL and Berliner JA. Oxidized phospholipids and isoprostanes in atherosclerosis. Curr Opin Lipidol. 1998; 9:441–8.
11. Chisolm GM and Steinberg D. The oxidative modification hypothesis of atherogenesis: an overview. Free Radic Biol Med. 2000; 28:1815–26.
12. Walter MF, Jacob RF, Jeffers B, Ghadanfar MM, Preston GM, Buch J, et al. Serum levels of thiobarbituric acid reactive substances predict cardiovascular events in patients with stable coronary artery disease: a longitudinal analysis of the PREVENT study. J Am Coll Cardiol. 2004; 44:1996–2002.
13. Taysi S, Polat F, Gul M, Sari RA, Bakan E. Lipid peroxidation, some extracellular antioxidants, and antioxidant enzymes in serum of patients with rheumatoid arthritis. Rheumatol Int. 2002; 21:200–4.
14. Niwa Y, Miyake S, Sakane T, Shingu M, Yokoyama M. Auto-oxidative damage in Behcet's disease–endothelial cell damage following the elevated oxygen radicals generated by stimulated neutrophils. Clin Exp Immunol. 1982; 49:247–55.
15. Zhang J, Perry G, Smith MA, Robertson D, Olson SJ, Graham DG, et al. Parkinson's disease is associated with oxidative damage to cytoplasmic DNA and RNA in substantia nigra neurons. Am J Pathol. 1999; 154:1423–9.
16. Carlisle ML, King MR, Karp DR. Gamma-glutamyl transpeptidase activity alters the T cell response to oxidative stress and Fas-induced apoptosis. Int Immunol. 2003; 15:17–27.
17. Lee DH, Blomhoff R, Jacobs DR Jr. Is serum gamma glutamyltransferase a marker of oxidative stress? Free Radic Res. 2004; 38:535–9.
18. Lee DH, Jacobs DR Jr, Gross M, Kiefe CI, Roseman J, Lewis CE, et al. Gamma-glutamyltransferase is a predictor of incident diabetes and hypertension: the Coronary Artery Risk Development in Young Adults (CARDIA) Study. Clin Chem. 2003; 49:1358–66.
19. Lee DH, Silventoinen K, Jacobs DR Jr, Jousilahti P, Tuomileto J. Gamma-Glutamyltransferase, obesity, and the risk of type 2 diabetes: observational cohort study among 20,158 middle-aged men and women. J Clin Endocrinol Metab. 2004; 89:5410–4.
20. Lim JS, Lee DH, Park JY, Jin SH, Jacobs DR Jr. A strong interaction between serum gamma-glutamyltransferase and obesity on the risk of prevalent type 2 diabetes: results from the Third National Health and Nutrition Examination Survey. Clin Chem. 2007; 53:1092–8.
21. Lee DH and Jacobs DR Jr. Association between serum concentrations of persistent organic pollutants and gamma glutamyltransferase: results from the National Health and Examination Survey 1999–2002. Clin Chem. 2006; 52:1825–7.
22. Lee DH, Lee IK, Song K, Steffes M, Toscano W, Baker BA, et al. A strong dose-response relation between serum concentrations of persistent organic pollutants and diabetes: results from the National Health and Examination Survey 1999–2002. Diabetes Care. 2006; 29:1638–44.
23. Suh I. Cardiovascular mortality in Korea: a country experiencing epidemiologic transition. Acta Cardiol. 2001; 56:75–81.
24. Clinical and Laboratory Standards Institute. Defining, Establishing, and Verifying Reference Intervals in the Clinical Laboratory; Approved Guideline. Third Edition. Clinical and Laboratory Standards Institute;2008.
25. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA. 2001; 285:2486–97.
26. World Health Organization. The Asia-Pacific perspective: Redefining obesity and its treatment. In: IOTF;. 2000.
27. Kim SH. Normal serum r-glutamyl transpeptidase activity of normal Koreans. J Korean Surg Soc. 1977; 1977:33–41.
28. Lee DH, Ha MH, Kam S, Chun B, Lee J, Song K, et al. A strong secular trend in serum gamma-glutamyltransferase from 1996 to 2003 among South Korean men. Am J Epidemiol. 2006; 163:57–65.
29. Ross JS, Stagliano NE, Donovan MJ, Breitbart RE, Ginsburg GS. Atherosclerosis and cancer: common molecular pathways of disease development and progression. Ann N Y Acad Sci. 2001; 947:271–92. ; discussion 92–3.
30. Droge W. Free radicals in the physiological control of cell function. Physiol Rev. 2002; 82:47–95.
31. Kim DJ, Noh JH, Cho NH, Lee BW, Choi YH, Jung JH, et al. Serum gamma-glutamyltransferase within its normal concentration range is related to the presence of diabetes and cardiovascular risk factors. Diabet Med. 2005; 22:1134–40.
32. Kang YH, Min HK, Son SM, Kim IJ, Kim YK. The association of serum gamma glutamyltransferase with components of the metabolic syndrome in the Korean adults. Diabetes Res Clin Pract. 2007; 77:306–13.
33. Lee MY, Weon CS, Ko CH, Lee BJ, Lee Y, Kim MJ, et al. Relations between serum gamma-glutamyltransferase and prevalence of diabetes mellitus. The Korean Journal of Medicine. 2004; 67:498–506.
34. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Bugianesi E, Lenzi M, et al. Nonalcoholic fatty liver disease: a feature of the metabolic syndrome. Diabetes. 2001; 50:1844–50.
35. Yokoyama H, Hirose H, Moriya S, Saito I. Significant correlation between insulin resistance and serum gamma-glutamyl transpeptidase (gamma-GTP) activity in non-drinkers. Alcohol Clin Exp Res. 2002; 26:91S–4S.
36. Ortega E, Koska J, Salbe AD, Tataranni PA, Bunt JC. Serum gamma-glutamyl transpeptidase is a determinant of insulin resistance independently of adiposity in Pima Indian children. J Clin Endocrinol Metab. 2006; 91:1419–22.
37. Ceriello A and Motz E. Is oxidative stress the pathogenic mechanism underlying insulin resistance, diabetes, and cardiovascular disease? The common soil hypothesis revisited. Arterioscler Thromb Vasc Biol. 2004; 24:816–23.
38. Lee DH, Steffes MW, Jacobs DR Jr. Can persistent organic pollutants explain the association between serum gamma-glutamyltransferase and type 2 diabetes? Diabetologia. 2008; 51:402–7.
39. Lee DH and Jacobs DR Jr. Is serum gamma-glutamyltransferase a marker of exposure to various environmental pollutants? Free Radic Res. 2009; 43:533–7.
Table 1.
Clinical and biochemical characteristics of the subjects selected for establishing the reference intervals for serum GGT levels
| Characteristics | Men∗ | Women∗ | P value by t-test |
|---|---|---|---|
| Number of subjects | 137 | 226 | |
| Age (yr) | 43.5±9.5 | 43.3±10.8 | 0.823 |
| Systolic BP (mmHg) 1 | 120.0±8.0 | 110.6±10.8 | <0.001 |
| Diastolic BP (mmHg) | 76.0±7.7 | 70.8±8.8 | <0.001 |
| Height (cm) 1 | 170.3±5.7 | 158.9±5.5 | <0.001 |
| Weight (kg) | 70.1±10.1 | 57.1±6.9 | <0.001 |
| BMI (kg/m2) | 24.1±3.0 | 22.6±2.6 | <0.001 |
| Total cholesterol (mg/dL) 1 | 183.4±31.5 | 181.9±31.4 | 0.659 |
| HDL-cholesterol (mg/dL) | 46.9±10.7 | 54.1±12.5 | <0.001 |
| LDL-cholesterol (mg/dL) 1 | 123.0±30.9 | 114.8±31.2 | 0.015 |
| Triglyceride (mg/dL) 1 | 120.8±67.4 | 88.7±47.0 | <0.001 |
| Fasting glucose (mg/dL) | 87.5±9.4 | 84.6±8.4 | 0.002 |
| GGT (IU/L) | 28.3±16.0 | 13.2±6.0 | <0.001 |
| AST (IU/L) | 22.8±6.1 | 19.0±4.9 | <0.001 |
| ALT (IU/L) | 24.0±11.7 | 14.6±6.2 | <0.001 |
| Uric acid (mg/dL) | 6.0±1.0 | 4.2±0.8 | <0.001 |
| GGT (central 95th percentile, IU/L) | 9.0–70.6 | 4.0–31.3 |
Table 2.
Clinical and biochemical characteristics of all subjects with serum GGT levels within the reference intervals
| Characteristics | Men∗ | Women∗ | P value by t-test |
|---|---|---|---|
| Number of subjects | 519 | 400 | |
| Age (yr) | 47±10.7 | 47.1±12.2 | 0.940 |
| Systolic BP (mmHg) | 124.5±13.9 | 116.3±15.5 | <0.001 |
| Diastolic BP (mmHg) | 77.8±9.6 | 73.1±10.3 | <0.001 |
| Height (cm) | 170.3±5.7 | 158.2±5.8 | <0.001 |
| Weight (kg) | 70.6±9.7 | 57.5±7.9 | <0.001 |
| BMI (kg/m2) | 24.3±2.8 | 23.0±3.0 | <0.001 |
| Total cholesterol (mg/dL) | 183.6±32.5 | 181.2±32.6 | 0.258 |
| HDL-cholesterol (mg/dL) | 45.0±10.6 | 52.4±12.2 | <0.001 |
| LDL-cholesterol (mg/dL) | 122.5±32.0 | 114.9±32.3 | <0.001 |
| Triglyceride (mg/dL) | 137.2±79.9 | 97.1±64.4 | <0.001 |
| Fasting glucose (mg/dL) | 92.7±19.7 | 88.8±20.7 | 0.004 |
| GGT (IU/L) | 30.5±15.1 | 13.6±6.0 | <0.001 |
| AST (IU/L) | 23.6±8.6 | 20.2±6.0 | <0.001 |
| ALT (IU/L) | 24.4±13.5 | 15.9±7.8 | <0.001 |
| Uric acid (mg/dL) | 6.0±1.1 | 4.3±0.9 | <0.001 |
| Metabolic syndrome (%) | 9.2 | 10.5 | 0.527 |
| Type 2 DM (%) | 7.5 | 5. | 0.114 |
Table 3.
Clinical and biochemical characteristics of male and female subgroups according to the quartiles of sex-specific serum GGT reference intervals
| Quartiles (Q) of serum GGT | ||||||||||
|---|---|---|---|---|---|---|---|---|---|---|
| Men (N=519) | P value by ANOVA | Women (N=400) | P value by ANOVA | |||||||
| Q1∗ (<19 IU/L) | Q2∗ (20–26 IU/L) | Q3∗ (27–41 IU/L) | Q4∗ (42–70 IU/L) | Q1∗ (<9 IU/L) | Q2∗ (10–12 IU/L) | Q3∗ (13–17 IU/L) | Q4∗ (18–31 IU/L) | |||
| Number of subjects | 140 | 122 | 133 | 124 | 107 | 102 | 100 | 91 | ||
| Age (yr) | 47.4±13.4 | 46.9±10.7 | 46.9±9.4 | 46.7±8.6 | 0.956 | 44.9±12.2 | 46.2±11.6 | 47.1±12.0 | 50.6±12.5 | 0.007 |
| BMI (kg/m2) | 23.0±2.5 | 24.0±2.5 | 24.7±2.7 | 25.8±2.9 | <0.001 | 21.9±2.5 | 22.8±2.7 | 23.3±2.9 | 24.1±3.4 | <0.001 |
| Current smoker (%) | 13.6 | 17.2 | 18.1 | 23.4 | 0.041 | 0.0 | 1.0 | 1.0 | 3.3 | 0.209 |
| Drinker (>1 time/month) (%) | 59.3 | 61.5 | 72.9 | 71.0 | 0.043 | 21.5 | 23.5 | 23.0 | 24.2 | 0.974 |
| Hypertension (%) | 17.1 | 28.7 | 28.6 | 28.2 | 0.073 | 10.3 | 10.8 | 20.0 | 28.6 | 0.001 |
| Metabolic syndrome (%) | 1.4 | 4.9 | 11.3 | 20.2 | <0.001 | 1.9 | 5.9 | 10.0 | 26.4 | <0.001 |
| Type 2 DM (%) | 5.0 | 4.9 | 8.3 | 12.1 | 0.098 | 1.9 | 2.9 | 3.0 | 13.2 | 0.001 |
| Total cholesterol (mg/dL) 1 | 172.7±31.9 | 178.8±30.8 | 189.1±31.0 | 194.9±31.8 | <0.001 | 176.5±33.4 | 176.0±29.2 | 182.0±30.3 | 191.7±35.5 | 0.002 |
| HDL-cholesterol (mg/dL) | 45.9±10.7 | 46.3±11.0 | 44.4±10.3 | 43.4±10.3 | 0.105 | 55.3±14.5 | 52.7±10.0 | 53.2±12.2 | 47.8±10.2 | <0.001 |
| LDL-cholesterol (mg/dL) 1 | 113.2±30.1 | 118.1±30.0 | 128.0±33.6 | 131.3±31.2 | <0.001 | 109.9±31.7 | 109.0±28.1 | 115.5±29.5 | 126.6±37.4 | <0.001 |
| Triglyceride (mg/dL) 1 | 106.1±50.3 | 124.2±65.9 | 144.5±88.6 | 177.5±91.6 | <0.001 | 76.1±28.2 | 91.2±41.7 | 96.5±51.9 | 128.9±104.5 | <0.001 |
| Fasting glucose (mg/dL) | 89.0±13.8 | 90.8±17.7 | 93.6±22.2 | 97.9±23.7 | 0.002 | 83.7±7.8 | 85.9±11.6 | 89.0±26.3 | 97.9±28.3 | <0.001 |
| GGT (IU/L) | 14.7±3.3 | 22.9±1.9 | 32.9±4.4 | 53.0±8.1 | <0.001 | 7.4±1.6 | 10.9±0.8 | 14.9±1.4 | 22.6±4.2 | <0.001 |
| AST (IU/L) | 20.6±4.7 | 23.2±11.4 | 23.4±5.9 | 27.5±9.6 | <0.001 | 18.8±4.9 | 18.9±4.3 | 20.3±4.8 | 23.3±8.4 | <0.001 |
| ALT (IU/L) | 17.6±5.8 | 21.4±9.7 | 25.3±10.5 | 33.8±19.3 | <0.001 | 13.1±4.8 | 13.9±4.9 | 16.3±5.8 | 21.0±11.9 | <0.001 |
| Uric acid (mg/dL) | 5.58±1.18 | 5.94±0.96 | 6.08±1.07 | 6.24±1.12 | <0.001 | 4.1±0.8 | 4.2±0.9 | 4.4±1.0 | 4.4±0.9 | 0.010 |
Table 4.
Odds ratios and 95% confidence intervals for the prevalence of metabolic syndrome according to quartiles of sex-specific serum GGT RIs in men and women
| Quartiles (Q) of serum GGT | P trend | ||||
|---|---|---|---|---|---|
| Q1 | Q2 | Q3 | Q4 | ||
| Men | (<19 IU/L) | (20–26 IU/L) | (27–41 IU/L) | (42–70 IU/L) | |
| Number of subjects (N=519) | 140 | 122 | 133 | 124 | |
| GGT (IU/L) (mean±SD) | 14.7±3.3 | 22.9±1.9 | 32.9±4.4 | 53.0±8.1 | |
| Odds ratio (95% CI) | |||||
| Model 1∗ | 1 | 3.6 (0.7–18.0) | 8.8 (2.0–39.1) | 17.4 (4.0–75.3) | <0.001 |
| Model 2∗ | 1 | 3.9 (0.8–20.1) | 10 (2.2–45.6) | 20.6 (4.7–90.9) | <0.001 |
| Model 3∗ | 1 | 3.3 (0.6–17.4) | 7.6 (1.6–35.3) | 12.6 (2.8–57.3) | <0.001 |
| Women | (<9 IU/L) | (10–12 IU/L) | (13–17 IU/L) | (18–31 IU/L) | |
| Number of subjects (N=400) | 107 | 102 | 100 | 91 | |
| GGT (IU/L) (mean±SD) | 7.41±1.6 | 10.9±0.8 | 14.9±1.3 | 22.6±4.2 | |
| Odds ratio (95% CI) | |||||
| Model 1∗ | 1 | 3.3 (0.6–16.6) | 5.8 (1.2–27.3) | 18.8 (4.3–82.2) | <0.001 |
| Model 2∗ | 1 | 3.2 (0.6–16.3) | 5.5 (1.2–26.0) | 15.8 (3.6–69.8) | <0.001 |
| Model 3∗ | 1 | 2.2 (0.4–11.4) | 3.1 (0.6–15.2) | 8.5 (1.9–39.1) | 0.001 |
Table 5.
Odds ratios and 95% confidence intervals for the prevalence of diabetes mellitus according to quartiles of sex-specific serum GGT reference intervals in men and women
| Quartiles (Q) of serum GGT | P trend | ||||
|---|---|---|---|---|---|
| Q1 | Q2 | Q3 | Q4 | ||
| Men | (<19 IU/L) | (20–26 IU/L) | (27–41 IU/L) | (42–70 IU/L) | |
| Number of subjects (N=519) | 140 | 122 | 133 | 124 | |
| GGT (IU/L) (mean±SD) | 14.7±3.3 | 22.9±1.9 | 32.9±4.4 | 53.0±8.1 | |
| Odds ratio (95% CI) | |||||
| Model 1∗ | 1 | 1.0 (0.3–3.0) | 1.7 (0.6–4.6) | 2.6 (1.0–6.6) | 0.099 |
| Model 2∗ | 1 | 1.2 (0.4–3.6) | 2.2 (0.8–6.0) | 3.5 (1.3–9.3) | 0.033 |
| Model 3∗ | 1 | 1.2 (0.4–3.6) | 2.2 (0.8–6.0) | 3.5 (1.3–9.3) | 0.033 |
| Women | (<9 IU/L) | (10–12 IU/L) | (13–17 IU/L) | (18–31 IU/L) | |
| Number of subjects (N=400) | 107 | 102 | 100 | 91 | |
| GGT (IU/L) (mean±SD) | 7.41±1.6 | 10.9±0.8 | 14.9±1.3 | 22.6±4.2 | |
| Odds ratio (95% CI) | |||||
| Model 1∗ | 1 | 1.6 (0.3–9.7) | 1.6 (0.3–9.9) | 8.0 (1.7–36.7) | 0.001 |
| Model 2∗ | 1 | 1.6 (0.2–10.0) | 1.4 (0.2–9.3) | 6.1 (1.3–29.8) | 0.012 |
| Model 3∗ | 1 | 1.6 (0.2–10.0) | 1.4 (0.2–9.3) | 6.1 (1.3–29.8) | 0.012 |
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