the incidence of diabetes mellitus is increasing among the asian populations as well as in the western countries . people with diabetes are at elevated risk for a number of serious health problems , including cardiovascular disease , premature death , blindness , kidney failure , amputations , and cognitive decline . diabetes is often asymptomatic in its early stages and can remain undetected for several years . therefore , early diagnosis of the condition is important as careful diabetes management can reduce long - term complications . according to recent studies , serum gamma - glutamyltransferase ( ggt ) and serum uric acid ( ua ) are emerging potential markers of diabetes development . serum ggt is an enzyme that has a pivotal role in the maintenance of intracellular antioxidant defenses , and some studies have suggested that oxidative stress could be involved in the development of diabetes . also , mounting evidence indicates that ggt relates to incidence of prediabetes and diabetes in adults , and is an appealing biochemical risk indicator for diabetes prediction . in addition , serum ua , a by - product of oxidation of purines that is filtered by glomeruli in the kidney and reabsorbed by the proximal tubule , may promote insulin resistance by inhibiting endothelial cell function . indeed , some studies found that higher serum ua is associated with higher future risk of diabetes , independent of other known risk factors . however , there are few reports on the association of serum ggt and ua levels with diabetes prediction in the general population , and little is known about the combined effect of these biomarkers on the development of diabetes . the aim of this study was to investigate the combined association of increased ua and ggt levels in development of diabetes . individuals numbering at 37,582 received heath screening at the health promotion center , ajou university hospital , suwon , korea from january 1999 to december 2001 ( analysis for the first period ) , and 149,620 individuals received health screening from january 2006 to december 2014 ( analysis for the second period ) . if an individual received health screening more than once in the first period , the first screening results were used . if an individual received health screening more than once in second period , the last screening results were used . of these , 6015 individuals received health screening in both periods ( baseline and follow - up screening ) . for the present study , individuals with diabetes at baseline screening were excluded ( n  =  400 ) . furthermore , we excluded 945 individuals who met one of the following conditions at baseline and at follow - up screening : 472 who had missing data for any components of the fasting blood glucose , serum ggt or serum ua values ; 313 with a medical history of chronic liver disease ( including chronic hepatitis b or c ) , liver cirrhosis , or were taking drugs influencing the liver function ( hepatotonics and herbal medication ) ; 72 that were taking diuretics ; 127 were on hormone replacement therapy or were taking corticosteroids , oral contraceptives , fibrate , phenytoin , or phenobarbital ; 30 with diagnosis of a malignancy ; 83 with a diagnosis of cardiovascular disease ( coronary , cerebrovascular , and peripheral artery disease and heart failure ) ; 525 with excess alcohol consumption(>20  g / day in female or > 30  g / day in male , which have been shown to cause liver damage in previous studies ) to avoid the presence of alcoholic liver disease in our study sample ; 41 were excluded because of ggt levels 3 times the upper level of the reference value ( 195  u / l)we excluded these individuals to reduce confounding as a result of subjects with ggt elevation caused by viral or toxic agents ; 191 with estimated glomerular filtration rate ( egfr ) 60  ml / min to exclude chronic kidney disease . finally , the participant sample included 4670 individuals ( 1983 women and 2687 men ) . before collection of blood samples , after overnight fasting , a venous blood sample was obtained by trained technicians to measure fasting blood glucose , ggt , ua , liver enzymes , total cholesterol , triglycerides ( tg ) , high - density lipoprotein cholesterol ( hdl - c ) , and low - density lipoprotein cholesterol ( ldl - c ) . serum ggt was assayed by the standard method recommended by the international federation for clinical chemistry using l - f - glutamyl-3-carboxy-4-nitroanilide as substrate with a toshiba 200fr autoanalyzer ( toshiba medical systems , tokyo , japan ) . fasting blood glucose , liver enzymes , lipid levels , and ua were also assayed by the toshiba 200fr automatic analyzer . blood pressure ( bp ) was measured using a standard mercury manometer with the participant in a sitting position for 5  minutes before measurement and expressed by rounding off , and it was measured on 3 occasions and averaged for a final value . hypertension was defined as having a systolic bp 140  mmhg or a diastolic bp 90  mmhg or being on antihypertensive medications . development of diabetes was defined as having a fasting blood glucose 126  mg / dl , or using oral hypoglycemic agents or insulin at the follow - up examination . hyperlipidemia was defined as ldl 160  mg / dl or tg 200  mg / dl , or by the use of antihyperlipidemic medications . body mass index ( bmi ) was calculated as weight ( kilograms ) divided by height squared ( square meter ) . we also used a questionnaire with self - reporting for a history of hypertension , diabetes mellitus , hyperlipidemia , smoking status , and alcohol consumption . alcohol consumption in individuals was calculated and then converted to weekly alcohol consumption levels ( grams of ethanol per week ) using the graduated frequency method . individuals with reporting periods of amenorrhea > 12 months were classified as being postmenopausal . medical history and use of medications were based on information obtained by interviewers trained in collecting data . initially , we used a simple descriptive analysis for general characteristics . the study individuals were grouped into 4 quartiles according to the levels of their serum ggt and ua . analyses relating the levels of serum ggt and ua to development of diabetes utilized the cox regression analysis . the cox regression analysis was also used to assess the combined effect of serum ggt and ua on development of diabetes . covariates such as the baseline examination values of age , bmi , ldl - c , log - transformed alcohol consumption , smoking status , hypertension , and hyperlipidemia were included in the cox regression analysis . all statistical analyses were performed using the spss v20.0 software ( spss , chicago , il ) with p  <  .05 considered statistically significant . the institutional review board of ajou university hospital ( suwon , republic of korea ) approved the study ( approval no . individuals numbering at 37,582 received heath screening at the health promotion center , ajou university hospital , suwon , korea from january 1999 to december 2001 ( analysis for the first period ) , and 149,620 individuals received health screening from january 2006 to december 2014 ( analysis for the second period ) . if an individual received health screening more than once in the first period , the first screening results were used . if an individual received health screening more than once in second period , the last screening results were used . of these , 6015 individuals received health screening in both periods ( baseline and follow - up screening ) . for the present study , individuals with diabetes at baseline screening were excluded ( n  =  400 ) . furthermore , we excluded 945 individuals who met one of the following conditions at baseline and at follow - up screening : 472 who had missing data for any components of the fasting blood glucose , serum ggt or serum ua values ; 313 with a medical history of chronic liver disease ( including chronic hepatitis b or c ) , liver cirrhosis , or were taking drugs influencing the liver function ( hepatotonics and herbal medication ) ; 72 that were taking diuretics ; 127 were on hormone replacement therapy or were taking corticosteroids , oral contraceptives , fibrate , phenytoin , or phenobarbital ; 30 with diagnosis of a malignancy ; 83 with a diagnosis of cardiovascular disease ( coronary , cerebrovascular , and peripheral artery disease and heart failure ) ; 525 with excess alcohol consumption(>20  g / day in female or > 30  g / day in male , which have been shown to cause liver damage in previous studies ) to avoid the presence of alcoholic liver disease in our study sample ; 41 were excluded because of ggt levels 3 times the upper level of the reference value ( 195  u / l)we excluded these individuals to reduce confounding as a result of subjects with ggt elevation caused by viral or toxic agents ; 191 with estimated glomerular filtration rate ( egfr ) 60  ml / min to exclude chronic kidney disease . finally , the participant sample included 4670 individuals ( 1983 women and 2687 men ) . after overnight fasting , a venous blood sample was obtained by trained technicians to measure fasting blood glucose , ggt , ua , liver enzymes , total cholesterol , triglycerides ( tg ) , high - density lipoprotein cholesterol ( hdl - c ) , and low - density lipoprotein cholesterol ( ldl - c ) . serum ggt was assayed by the standard method recommended by the international federation for clinical chemistry using l - f - glutamyl-3-carboxy-4-nitroanilide as substrate with a toshiba 200fr autoanalyzer ( toshiba medical systems , tokyo , japan ) . fasting blood glucose , liver enzymes , lipid levels , and ua were also assayed by the toshiba 200fr automatic analyzer . blood pressure ( bp ) was measured using a standard mercury manometer with the participant in a sitting position for 5  minutes before measurement and expressed by rounding off , and it was measured on 3 occasions and averaged for a final value . hypertension was defined as having a systolic bp 140  mmhg or a diastolic bp 90  mmhg or being on antihypertensive medications . development of diabetes was defined as having a fasting blood glucose 126  mg / dl , or using oral hypoglycemic agents or insulin at the follow - up examination . hyperlipidemia was defined as ldl 160  mg / dl or tg 200  mg / dl , or by the use of antihyperlipidemic medications . body mass index ( bmi ) was calculated as weight ( kilograms ) divided by height squared ( square meter ) . we also used a questionnaire with self - reporting for a history of hypertension , diabetes mellitus , hyperlipidemia , smoking status , and alcohol consumption . alcohol consumption in individuals was calculated and then converted to weekly alcohol consumption levels ( grams of ethanol per week ) using the graduated frequency method . individuals with reporting periods of amenorrhea > 12 months were classified as being postmenopausal . medical history and use of medications were based on information obtained by interviewers trained in collecting data . the study individuals were grouped into 4 quartiles according to the levels of their serum ggt and ua . analyses relating the levels of serum ggt and ua to development of diabetes utilized the cox regression analysis . the cox regression analysis was also used to assess the combined effect of serum ggt and ua on development of diabetes . covariates such as the baseline examination values of age , bmi , ldl - c , log - transformed alcohol consumption , smoking status , hypertension , and hyperlipidemia were included in the cox regression analysis . all statistical analyses were performed using the spss v20.0 software ( spss , chicago , il ) with p  <  .05 considered statistically significant . the institutional review board of ajou university hospital ( suwon , republic of korea ) approved the study ( approval no . among the 4670 individuals who comprised our study , 1983 ( 42.5% ) were women and 2687 ( 57.5% ) were men ( table 1 ) . of these , 1479 ( 31.7% ) were current smokers , and 293 ( 6.3% ) were hypertensive , and 140 ( 5.4% ) had hyperlipidemia . compared to women , men had higher diabetes risk factors such as hypertension , hyperlipidemia , alcohol consumption , and current smoking ( p  <  .001 ) . baseline characteristics of the study subjects . in women , after adjustments for conventional diabetes risk factors such as age , bmi , ldl - c , log - transformed alcohol consumption , smoking status , hypertension , and hyperlipidemia , we discovered that the development rate for diabetes increased significantly in higher quartiles of ggt and ua . from the lowest to the highest quartiles , respectively , the hazard ratios ( 95% confidence interval [ ci ] ; p value ) for diabetes across the ggt quartiles were 1.00 , 2.05 ( 0.689.24 ; .284 ) , 3.13 ( 0.8711.22 ; .080 ) , and 3.88 ( 1.1213.43 ; .032 ) ; for the ua quartiles , they were 1.00 , 3.24 ( 0.8412.48 ; .087 ) , 5.97 ( 1.7420.51 ; .005 ) , and 7.58 ( 2.1726.42 ; .002 ) . in men , after adjustments for diabetes risk factors , we found that the development rate of diabetes increased significantly in relation to the higher quartiles of ggt . the hazard ratios ( 95% ci ; p value ) for diabetes across the quartiles of ggt were 1.00 , 2.42 ( 1.105.31 ; .028 ) , 3.40 ( 1.597.27 ; .002 ) , and 5.08 ( 2.3910.80 ; < .001 ) , from the lowest to the highest quartiles , respectively . however , the development of diabetes was not significantly different among the quartiles of ua in men ( table 2 ) . these sex - dependent relationships between ua and development of diabetes were confirmed by the significant interaction ( sex    ua ) term ( p  =  .021 , data not shown ) . hazard ratios of the diabetes mellitus by serum ggt and ua . the women were divided into 2 groups according to their menopausal status to explore the potential hormonal effects in sex - dependent relationships between ua and the development of diabetes . in postmenopausal women , the development of diabetes increased in relation to the higher quartiles of ua . for this population , the hazard ratios ( 95% ci ; p value ) for diabetes across the quartiles of ua were 1.00 , 3.28 ( 0.6616.38 ; .147 ) , 6.96 ( 1.6030.34 ; .010 ) , and 7.26 ( 1.6432.15 ; .009 ) , from the lowest to highest quartiles , respectively . but in premenopausal women , the development of diabetes was not significantly different among the quartiles of ua ( table 3 ) . women were also divided into 9 groups according to the ggt and ua levels ( 1st and 2nd quartile , 3rd quartile , and 4th quartile ) ( fig . adjusted hazard ratios ( 95% ci ; p value ) of diabetes rate in the 4th quartile of ggt and ua was 5.29 ( 1.8715.18 ; .002 ) , as compared with the reference group ( 1st and 2nd quartile of ggt and ua ) . this finding was supported by the fact that the interaction ( ggt    ua ) term for ggt and ua was statistically significant ( p  =  .003 ) . adjusted hazard ratios ( 95% confidence interval ; p value ) of the development of diabetes mellitus according to the combined categories of ua and ggt levels ( 1st and 2nd quartile , 3rd quartile , and 4th quartile ) in women . interaction terms for ua and ggt combinations were statistically significant ( p  =  .003 ) in women . the model was adjusted for age , bmi , ldl - c , log - transformed alcohol consumption , smoking status , hypertension , and hyperlipidemia . bmi  =  body mass index , ggt  =  gamma - glutamyltransferase , ldl - c  =  low - density lipoprotein cholesterol , ua  =  uric acid . in our longitudinal study , we found that the development of diabetes significantly increased according to serum ggt quartiles for both sexes , after adjusting for established diabetes risk factors ( age , bmi , ldl - c , log - transformed alcohol consumption , smoking status , and hypertension , and hyperlipidemia ) , although the development of diabetes was not associated with the quartiles of ua in men . in women , the highest quartile of serum ggt and ua showed higher hazard ratios for development of diabetes . furthermore , we showed that the hazard ratios for development of diabetes were significantly increased in relation to the combination of serum ggt and ua . recent prospective studies for association of elevated serum ggt level with the development of diabetes and mortality have reported similar results . the bogalusa heart study reported that elevations in levels of ggt were related to incidence of prediabetes and diabetes in apparently healthy adults . after adjustment for baseline confounding factors , serum ggt was an independent predictor of development of diabetes during the 15 years of follow - up in a dose - response relationship in the general population . in addition , some longitudinal studies for association between serum ua and diabetes have shown similar results . the atherosclerosis risk in communities study reported a graded increase in diabetes risk across baseline ua level . a canadian study , with a prospective cohort of 5124 individuals , found that for every 1-mg / dl increase in serum ua level , the risk of diabetes increased by 15% to 20% . although the biological mechanisms are not completely understood , mounting evidence suggests that ggt and ua may be involved in the development of diabetes . concerning ggt levels , serum ggt may predict diabetes incidence as a marker for oxidative stress related to glutathione levels , with glutathione performing critical antioxidant defense for the cell . increased ggt activity can be a response to oxidative stress , indicative of marked transportation of glutathione into cells . in this regard , increased serum ggt may identify those individuals with persistently higher oxidative and other cellular stress levels . pancreatic -cells are particularly vulnerable to oxidative stress as they have relatively low levels of reactive oxygen intermediate scavenging enzymes such as superoxide dismutase , catalase , and glutathione peroxidase . indeed , oxidative stress is known to impair insulin secretion by pancreatic -cells . with regards to ua levels , ua may promote insulin resistance by leading to endothelial dysfunction and nitric oxide inhibition . these mechanisms may be responsible for the association of ggt and ua levels with the onset of diabetes . the present study also evaluated whether there was a synergistic effect between serum ggt and ua on the development of diabetes . in women , we found that the adjusted hazard ratios for development of diabetes in the 4th quartile of serum ggt and ua were significantly higher compared with the reference group . this finding may be supported by the observation that both ggt and ua were associated with oxidative stress and inflammation . the development of diabetes was not associated with the quartiles of serum ua level after adjusting for established diabetes risk factors in men . chinese studies found that serum ua levels were associated with insulin resistance and plasma glucose levels , more strongly in women than in men . in male participants , the correlation between serum ua levels and cumulative incidence of impaired fasting glucose shows a u - shape curve . however , other studies showed that serum ua and ggt were associated with development of diabetes in both sexes . although the reason for this sex difference is still a matter of debate , sex hormones may play a role . thus , in postmenopausal women , for example , increased serum ua levels may result from menopause - related changes in metabolism ( 29 ) , and may be associated with an increased risk in development of diabetes . in our study , the development of diabetes increased in relation to the higher quartiles of ua in postmenopausal women , but not in premenopausal women . first , to the best of our knowledge , this was the first longitudinal study to examine the combined effects of serum ua and ggt on onset of diabetes in a general population . second , the study was relatively large - scale in size , including both sexes . first , from self - reported questionnaires , we only accessed parts of an individual 's medical history , and it is possible that the smoking status and use of drugs or supplements were underreported . second , our data did not guarantee that it represented the whole population because it was not derived from a random selection . in conclusion , this study demonstrated that the combined effect of serum ggt and ua is associated with a diabetes risk in korean women and that the use of the measurements of a combination of ggt and ua appears to have an additional benefit in the prediction of the future development of diabetes . to prevent cardiovascular events , this enhanced relationship between both increased ua and ggt levels and an increased incidence of diabetes should be noted , even in subjects without diabetes mellitus at baseline .
abstractgamma - glutamyltransferase ( ggt ) and uric acid ( ua ) are novel diabetes risk factors . 
 however , little is known about the combined effects of ggt and ua on the development of diabetes . here , we assessed the combined effects of ggt and ua on the development of diabetes in a korean population.we evaluated 1983 women and 2687 men without diabetes . from the baseline health screening to the follow - up examination , the development of diabetes , based on changes in ggt and ua quartile levels , was analyzed . furthermore , the quartile of ggt and quartile of ua were analyzed together to determine any synergistic effect from the 4th quartile of ggt and ua on the development of diabetes.in women , the development of diabetes gradually increased with an increase in the circulating levels of ggt and ua . for the highest quartile of ggt and ua , 
 hazard ratios of diabetes compared with the lowest quartile were 3.88 ( 95% confidence interval [ ci ] : 1.1213.43 , p  =  .032 ) and 7.58 ( 95% ci : 2.1726.42 , p  =  .002 ) after adjusting for confounders , respectively . 
 hazard ratios of diabetes after combining both 4th quartiles of ggt and ua were 5.29 ( 95% ci : 1.8715.18 , p  =  .002 ) , as compared with the first and second quartiles . in men , 
 however , the development of diabetes was not significantly different among the quartiles of ua.ggt and ua levels can synergize in predicting the development of diabetes in korean women .