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Serum -Glutamyltransferase and Risk of Metabolic Syndrome and Type 2 Diabetes in Middle-Aged Japanese Men

¹ Department of Social and Environmental Medicine F2, Course of Social Medicine, Osaka University Graduate School of Medicine, Osaka, Japan
² Japan Labor and Welfare Association, Tokyo, Japan

Address correspondence and reprint requests to Noriyuki Nakanishi, Department of Social and Environmental Medicine, Course of Social Medicine, Osaka University Graduate School of Medicine F2, 2-2 Yamada-oka, Suita-shi, Osaka 565-0871, Japan. E-mail: noriyuki{at}pbhel.med.osaka-u.ac.jp

	ABSTRACT

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 
OBJECTIVE—To investigate the association between serum -glutamyltransferase (GGT) and risk of metabolic syndrome and type 2 diabetes in Japanese male office workers.

RESEARCH DESIGN AND METHODS—This study included 2,957 metabolic syndrome-free men and 3,260 nondiabetic men aged 35–59 years who did not have medication for hepatitis, alanine aminotransferase (ALT) levels higher than three times the upper limit of the reference range, or a history of cardiovascular disease at study entry. Subjects were reexamined at periodic annual health examinations over a 7-year period. We used a modified National Cholesterol Education Program definition of metabolic syndrome with BMI instead of waist circumference and the revised criteria of the American Diabetes Association for type 2 diabetes.

RESULTS—With adjustment for age, family history of diabetes, BMI, alcohol intake, cigarette smoking, regular physical activity (fasting plasma glucose for the risk of type 2 diabetes), and white blood cell (WBC) count, the risk of metabolic syndrome and type 2 diabetes increased in correlation with the levels of serum GGT, ALT, aspartate aminotransferase (AST), and alkaline phosphatase. Additional adjustment for all of the other liver enzymes attenuated these associations, but serum GGT remained a significant risk factor for the risk of both metabolic syndrome and type 2 diabetes (P for trend <0.001 for both). Top one-fifth versus bottom one-fifth relative risks of metabolic syndrome and type 2 diabetes were 2.23 (95% CI 1.51–3.30) and 2.44 (1.34–4.46), respectively.

CONCLUSIONS—These results indicate that serum GGT may be an important predictor for developing metabolic syndrome and type 2 diabetes in middle-aged Japanese men.

Abbreviations: ALT, alanine aminotransferase • AST, aspartate aminotransferase • CHD, coronary heart disease • GGT, -glutamyltransferase • NCEP, National Cholesterol Education Program • WBC, white blood cell

	INTRODUCTION

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In addition to its diagnostic uses, serum -glutamyltransferase (GGT) has substantial epidemiologic significance (1). Prospective studies (2,3) have shown a significant relationship between serum GGT and the development of specific conditions including coronary heart disease (CHD) and stroke. In addition to alcohol, obesity has been found (4) to have a major effect on serum GGT, and there is increasing evidence (4–8) linking raised serum GGT levels with other metabolic disturbances, such as glycemic disorder, hypertension, hypertriglyceridemia, and low HDL cholesterol. Excess deposition of fat in liver, usually termed nonalcoholic fatty liver disease, is closely associated with elevated serum GGT, obesity, insulin resistance, and hyperinsulinemia (9–11). These interrelations between serum GGT, obesity, other metabolic disturbances, and plasma insulin raise the possibility that elevated GGT levels can help predict the development of metabolic syndrome and type 2 diabetes.

The Adult Treatment Panel III of the National Cholesterol Education Program (NCEP) recently proposed a definition of the metabolic syndrome to aid identification of individuals at risk for both CHD and type 2 diabetes (12). The definition incorporates thresholds for five easily measured variables linked to insulin resistance: waist circumference, triglyceride level, HDL cholesterol level, fasting plasma glucose level, and blood pressure. The NCEP-defined metabolic syndrome classification is triggered when predefined limits of any three of these five criteria are exceeded. BMI, which most observers would accept as a satisfactory substitute for waist circumference in middle-aged men, is as effective as waist circumference for predicting the development of type 2 diabetes and other metabolic disturbances (13,15). Indeed, BMI has been recently adopted instead of waist circumference for analyses of metabolic syndrome (16,17).

Using a modified NCEP definition with BMI instead of waist circumference, we examined the association of serum GGT with metabolic syndrome and type 2 diabetes (as diagnosed with the 1997 revised criteria of the American Diabetes Association [18] for epidemiological studies) in Japanese male office workers and performed a longitudinal study to prospectively examine the association of serum GGT with the development of metabolic syndrome and type 2 diabetes. Possible associations between other liver enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and alkaline phosphatase) and risk of metabolic syndrome and type 2 diabetes were also examined.

	RESEARCH DESIGN AND METHODS

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Our study is an ongoing cohort investigation, designed to clarify risk factors for major diseases, including hypertension, dyslipidemia, and diabetes, among Japanese men who are office workers at one of the biggest building contractors in Japan. A total of 3,681 Japanese males office workers aged 35–59 years participated in cardiovascular risk surveys in May 1994, with a participation rate of 99.6%. The Industrial Safety and Health Law in Japan requires the employer to conduct annual health examinations of all employees. The employee data, which are anonymous, are available for research with the approval of the employer. An institutional review committee approved this study, and all subjects gave their informed consent.

Of 3,681 potential participants, 82 (2.2%) were excluded: 34 (0.9%) were receiving medical treatment for hepatitis, 23 (0.6%) showed ALT levels higher than three times the upper limit of the reference range, and 32 (0.9%) had a past history of either CHD or stroke. Of the 3,599 remaining subjects, 575 (16.0%) were identified as having the metabolic syndrome and 267 (7.4%) as having type 2 diabetes at the initial examination. The metabolic syndrome–free cohort thus comprised 3,024 men and the nondiabetic cohort 3,332 men, and they were reexamined over 7 successive years until May 2001. We also excluded 67 men from the metabolic syndrome–free cohort and 72 men from the nondiabetic cohort who did not participate in consecutive annual health examinations during the follow-up. The final study cohorts for analysis therefore consisted of 2,957 men for development of the metabolic syndrome and 3,260 men for development of type 2 diabetes. They were classified as having the metabolic syndrome or type 2 diabetes when evidence of either of these disorders was found at periodic annual health examinations from May 1995 through May 2001. Sixty-seven participants who started taking medication for diabetes during the observation period were considered to have incidental cases of type 2 diabetes. In view of the age range of the study population, all subjects with type 2 diabetes were diagnosed after 35 years of age.

Study design
Annual health examinations at study entry included medical history, physical examination, a questionnaire on health-related behavior, anthropometric measurements, and biochemical measurements. The participants were asked to fast for at least 8 h and to avoid heavy physical activity for >2 h before the examinations. Medical history and use of prescription drugs were assessed by the examining physicians. A family history of diabetes was defined as having a mother, father, sister, or brother with diagnosed diabetes. As for health-related behavior, data on alcohol intake, smoking habits, and regular physical activity were obtained by interview. The questions about alcohol intake included items about the type of alcoholic beverage, the frequency of alcohol consumption on a weekly basis, and the usual amount consumed daily. Weekly alcohol intake was calculated and then converted to daily alcohol consumption (grams of ethanol per day) by using standard Japanese tables. The questionnaire also asked about smoking habits (never, past, or current smoker); past or current smokers were asked about the number of cigarettes smoked per day and the duration of smoking in years. Participants were asked about the type and frequency on a weekly basis of leisure-time physical activity. Physical exercise was defined as participation in any physical activity, such as jogging, cycling, swimming, or tennis, that was performed long enough to cause sweating. BMI, calculated as weight divided by the square of height in meters, was used as an index of relative weight. After a 5-min rest in a quiet room, systolic and diastolic blood pressures were measured on the right arm by using a standard mercury sphygmomanometer. Blood samples were drawn from an antecubital vein. Serum total cholesterol, HDL cholesterol, and triglyceride levels, fasting plasma glucose level, white blood cell (WBC) count, and enzyme activities for GGT, AST, ALT, and alkaline phosphatase were determined according to standard laboratory procedures (7,19). The five variables used to determine metabolic syndrome status (BMI, blood pressure, triglyceride, HDL cholesterol, and fasting glucose) were also measured at annual health examinations in May from 1995 to 2001. Quality control of the laboratory was internal, and the coefficients of variation within assays for serum triglyceride and HDL cholesterol and plasma glucose were no more than 3% between 1994 and 2001.

The five thresholds used were BMI 25 kg/m², proposed by the Japan Society for the Study of Obesity (20), systolic blood pressure 130 mmHg and/or diastolic blood pressure 85 mmHg, triglyceride level 1.69 mmol/l, HDL cholesterol level <1.03 mmol/l, and fasting plasma glucose level 6.1 mmol/l. Individuals met the criteria for high blood pressure or high fasting plasma glucose level if they were currently using blood pressure medications or hypoglycemic diabetes control. Individuals with a previous physician diagnosis of hypertension or diabetes who did not report medication use were not allocated to the metabolic syndrome group. Individuals were classified as having metabolic syndrome if they fulfilled three or more of the criteria. Type 2 diabetes was defined according to the criteria of the American Diabetes Association (18) and was defined as a fasting plasma glucose concentration of 7.0 mmol/l or treatment with hypoglycemic medications because not every subject was given an oral glucose tolerance test.

Statistical analyses
The ² test and one-way ANOVA were used to analyze the statistical differences among characteristics of the study participants at enrollment in relation to serum GGT levels. Categories of serum GGT comprised the following quintiles: <15, 15–21, 22–31, 32–52, and 53 units/l. For calculation of incidence density, person-years of follow-up were calculated from the date of enrollment to the date of the first incidence of the development of the metabolic syndrome or type 2 diabetes or the date of follow-up where either was diagnosed, whichever came first. Cox’s proportional hazards models were used to calculate adjusted hazard ratios in separate models for metabolic syndrome or type 2 diabetes. For the risk of incident metabolic syndrome, data were adjusted for family history of diabetes, BMI, alcohol consumption, cigarette smoking, physical activity, WBC count, and liver enzymes. For the risk of incident type 2 diabetes, data were also adjusted for fasting plasma glucose. Potentially confounding factors were treated as categorical variables: age, BMI, WBC count, fasting plasma glucose, GGT, AST, ALT, and alkaline phosphatase (graded from 1 to 5 [first through fifth quintiles]); family history of diabetes (no or yes); alcohol consumption (graded as 1 [none] or as quartile 1 [grade 2] to quartile 4 [grade 5] for drinkers); cigarette smoking (graded as 1 [none] or as quartile 1 [grade 2] to quartile 4 [grade 5] for current smokers); and regular physical exercise (graded from 1 to 3 [hardly ever, once a week, or twice or more a week]). The linear trends in risks were evaluated by entering the estimated quantitative median value for each category of exposure.

Data were analyzed with the SPSS statistical package for PC (SPSS, Chicago, IL). All reported P values are two tailed, and those <0.05 were considered statistically significant.

	RESULTS

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The characteristics of the study sample in relation to serum GGT levels are shown in Table 1. Tests for differences in characteristics across the five serum GGT level groups were significant except for family history of diabetes and regular physical activity. Age, BMI, current drinking, current cigarette smoking, systolic and diastolic blood pressures, total cholesterol, triglyceride, fasting plasma glucose, WBC count, AST, ALT, and alkaline phosphatase showed a linear trend in relation to serum GGT. The percentage of those who had the metabolic syndrome and type 2 diabetes also increased in correlation with an increase in serum GGT. HDL cholesterol showed a U-shaped association with serum GGT.

	CONCLUSIONS

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Our results are consistent with those of previous studies (5–8,21) and indicate that elevated serum GGT is associated with an increased risk of the metabolic syndrome and type 2 diabetes. However, the mechanism of how liver enzymes increase the risks of metabolic syndrome and diabetes remains to be elucidated. One explanation for our findings is that the elevation of liver enzymes could be expression of excess deposition of fat in liver, which is regarded as a feature of the insulin resistance syndrome (9–11). This hypothesis is supported by the finding that increased serum GGT levels are strongly associated with an increased risk of developing type 2 diabetes. Another possible pathophysiological mechanism is that elevated liver enzymes may reflect inflammation, which impairs insulin signaling both in the liver and systemically (11,22,23). In this population, mean WBC count increased with an increase in serum GGT. Because WBCs, a major component of the inflammatory process, are activated by cytokines, especially interleukin-6 and interleukin-8 (24), elevated GGT could reflect subclinical inflammation, which would represent the underlying mechanism. In addition, certain mechanisms related to oxidative stress might play a role because cellular GGT has a central role in glutathione homeostasis by initiating the breakdown of extracellular glutathione, a critical antioxidant defense for the cell (1,25). Increases in serum GGT activity may be a response to oxidative stress, making increased transport of glutathione into cells. Supporting a role of serum GGT in the inflammation and oxidative stress, serum GGT level predicted future levels of inflammation and oxidative stress markers, such as fibrinogen, uric acid, C-reactive protein, and F₂-isoprostanes, in a dose-response manner (8).

Our study has several limitations. First, serum GGT during follow-up was not included in the analysis. In this study, serum GGT at study entry was strongly associated with that at the date of diagnosis of metabolic syndrome and type 2 diabetes or at the end of follow-up (Spearman’s rank correlation coefficient 0.751 and 0.750, respectively; P < 0.001 for both). This indicates that those who had the higher serum GGT at study entry tended to continue to do so during follow-up. The observed associations between serum GGT at baseline and the increased risk of metabolic syndrome and type 2 diabetes may thus reflect the effects of serum GGT during a given observation period.

Second, bias in case finding could have occurred. Specifically, men with high serum GGT levels are more likely to visit a doctor for reasons other than metabolic syndrome and diabetes, so the metabolic syndrome and diabetes could have been found by chance. However, because all incidental cases were found during periodic annual screenings in our study, such a bias is unlikely to have occurred.

Finally, we could not include several confounding variables in this study, such as waist circumference and fasting insulin level. The central pattern of distribution, with its higher weighting of waist circumference, is associated with more insulin resistance than the peripheral pattern of distribution (26). Some data (13,15) show that waist circumference predicts diabetes marginally better than BMI. Nevertheless, most physicians routinely assess BMI, whereas the value of waist measurements in clinical practice has not been thoroughly examined and may require modification for different ethnic groups. A number of investigations (13–15) have also shown that BMI can predict the development of type 2 diabetes and other metabolic disturbances as robustly as waist circumference. Moreover, the use of BMI versus waist measurements has been favorably evaluated (16,17) as a determinant of the metabolic syndrome and type 2 diabetes.

Despite these potential limitations, our findings, which were obtained from a cohort of middle-aged Japanese men, support the conclusion that elevated, although still normal, serum GGT is associated with a higher risk of the metabolic syndrome and type 2 diabetes.

	Acknowledgments

 
This study was supported in part by a grant-in-aid from the Smoking Research Foundation, Tokyo, Japan.

	Footnotes

 
A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

Received for publication December 26, 2003. Accepted for publication March 15, 2004.

	References

TOP ABSTRACT INTRODUCTION RESEARCH DESIGN AND METHODS RESULTS CONCLUSIONS References

 

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