The object of this 2005 study was to "to examine gender-specific associations between gamma-glutamyltransferase (GGT) and incident type 2 diabetes mellitus in a representative population-based sample in Germany." The study recruited 1,851 men and 1,836 women during its baseline years of 1984 -1985.
Risk Analysis Table - The table below was derived from data in above Table 2  from the full text.
In another 2005 study of liver enzymes in a population 1,441 men in Mexico City, "Raised GGT alone was associated with all the features of the metabolic syndrome. The aim of this 2011 study conducted in Iran "was to assess the association between serum GGT concentrations and glucose intolerance, in the first-degree relatives (FDR) of type 2 diabetic patients. In this 1997 study, "GGT levels were assessed among 8,043 construction workers ages 25-64 who underwent occupational health examinations in six centers in Southern Germany from 1986 to 1988. Can persistent organic pollutants explain the association between serum ?-glutamyltransferase and type 2 diabetes? In this 2007 review article the authors hypothesize that "associations of GGT within its normal range with type 2 diabetes may reflect detrimental effects of xenobiotics found in the environment, such as persistent organic pollutants (POPs).
In this March, 2012 laboratory study of "human hepatoblastoma C3A (liver) cells treated with various combinations of of oleate, octanoate, lactate (L), pyruvate (P) and ammonia (N) acutely or for 72h, before measurements of triglyceride concentration, cell respiration, ROS (reactive oxygen species) production, mitochondrial membrane potential, ketogenesis and gluconeogenesis, TCA cycle metabolite analysis and electron microscopy. The authors noted "Recent population-based epidemiologic studies have convincingly shown that serum-glutamyltransferase (GGT) activity is associated with many cardiovascular disease risk factors and predicts new-onset type 2 diabetes, hypertension, stroke, and myocardial infarction." "We read with interest the recent article by Lim et al. In this 2010 study, " the relation of GGT or alcohol drinking with DM (diabetes mellitus) incidence considering the body mass index (BMI) in healthy Japanese workers" was investigated. In 2009 this group of Korean investigators "hypothesized that serum concentrations of GGT and ALT are associated with the development of MetS.
In this 2008 study from China, "A total of 5,404 subjects aged ? 40 years were recruited from two urban communities in Shanghai for cross-sectional analyses. This 2003 study investigated "the association between serum GGT and risk for development of diabetes" in Japanese men. In this 2008 reported study the investigators "sought to examine the association between plasma concentrations of liver enzymes gamma-glutamyltransferase (GGT) and alanine transaminase (ALT) and incident diabetes, prospectively." "We conducted a case-cohort analysis of data from participants mainly aged 35-65 years in the European Prospective Investigation into Cancer and Nutrition-Potsdam Study. In a study 2007 in japan of 1,804 non-diabetic subjects 40 to 79 years of age who were followed prospectively for a mean of 9.0 years, 135 subjects developed diabetes. The investigators in this 2008 reported study "analyzed the National Health and Nutrition Examination Survey, 1999 to 2004, a nationally representative sample of the noninstitutionalized US population. The objective of this 2012 published study undertaken in Malaysia was "To evaluate gamma-glutamyltransferase (GGT), alanine transaminases (ALT) and aspartate transaminases (AST) levels and prevalent gestational diabetes mellitus (GDM)." "Random plasma glucose, GGT, ALT and AST and the 50-g glucose challenge test were done on antenatal women followed by diagnostic 3-point 75-g oral glucose tolerance test within two weeks. Can serum gamma-glutamyltransferase levels be useful at diagnosing gestational diabetes mellitus?
The association between BMI and the incidence of DM (diabetes mellitus) was enhanced by increased GGT levels in women. HRs were calculated and adjusted for age, family history of diabetes, smoking habits, baseline glucose type, alcohol consumption and ALT.

A subgroup of 681 participants without MetS at baseline was included in the longitudinal analyses." "Both GGT and ALT were strongly and positively associated with MetS risks in simple and multivariate analyses. The investigators studied the incidence of impaired fasting glucose (IFG) and type 2 diabetes over a seven year period. The analytic sample included 787 participants with incident diabetes and 2,224 participants without diabetes." "Concentrations of GGT and ALT were significantly associated with incident diabetes after extensive adjustment.
In these quintiles the concentrations of the enzymes are not only regarded as being absolutely normal, but are actually even in the lower range of the "normal" values." In their conclusion the researchers state the following, "Moreover, our findings suggest that even minute changes, still within the so called "normal range" could point towards a potential dysmetabolic state. Higher serum GGT levels were positively associated with diabetes mellitus, independent of, alcohol consumption, body mass index, hypertension and other confounders. According to glucose tolerance test, 153 were normal and 217 and 181 were diabetic and prediabetic respectively.
Adjusted odds ratios (ORs) and 95% CIs of newly recognized diabetes (205 cases) by category of BMI and quartiles (Q) of serum GGT. Supporting this hypothesis, cross-sectional investigation of background exposure to POPs in the National Health and Nutrition Examination Survey showed relationships similar to those observed for GGT, including a powerful association with prevalent diabetes and no association between obesity and diabetes for very low POP concentrations.
Gamma-glutamyltransferase activities of males and persons older than 45 years were significantly higher than each counterpart.
Cases of NIDDM were ascertained by repeated postal questionnaires to the men and by regular systematic review of primary care records." During the follow-up 194 men developed diabetes.
Further adjustment for HOMA-IR and ALT did not change the association of GGT and MetS materially, whereas adjustment for HOMA-IR and GGT substantially attenuated the ALT-MetS association." Mean GGT values for each quartile were 14, 20, 28, and 50. These observations could therefore lead to avoiding the usage of cut-off values for normalcy for these two biomarkers. The researchers concluded, with respect to other liver enzymes, "only raised GGT is an independent predictor of deterioration of glucose tolerance to IGT or diabetes. Similar to the conclusion described above, the researchers concluded, "BMI was not associated with prevalent type 2 diabetes when GGT was low normal, suggesting that obesity itself may not be a sufficient risk factor for type 2 diabetes.
Gamma-glutamyltransferase levels increased significantly with the number of cigarettes smoked per day and the frequency of alcohol consumption except for the persons who did not take alcohol.
As shown in Table 1 (see below), the concentrations of FPG and triglycerides markedly increased among the GGT categories. In addition, they should encourage the use of both GGT and ALT as continuous biomarkers that could be used for early signaling of dysmetabolism. When the sample is divided into quartiles of the GGT levels, increase in GGT is positively correlated with increased MS prevalence. This association persisted in separate analysis among men and women." The authors concluded, "In nonparametric models, the positive association between serum GGT and diabetes appeared to be present across the full range of GGT, without any threshold effect. This relation was reduced but not eliminated by control for body mass index, diabetes, hypertension, alcohol consumption, and other covariates in multivariable analysis.

After 72h, despite the similarities in triglyceride accumulation, LPON treatment, but not oleate, dramatically affected mitochondrial function as evidenced by decreased respiration, increased mitochondrial membrane potential and ROS formation with concomitant enhanced ketogenesis.
Additionally, gamma-glutamyltransferase significantly correlated with urinary 8-hydroxydeoxyguanine, and with more blood factors including serum tocopherols, carotenoids, antioxidative enzymes, lipid peroxide, and free fatty acids than urinary 8-hydroxydeoxyguanine did. GGT was significantly associated with the 3-year incidence of individual components of the MetS.
Finally, our results support the notion that in the era of early detection, prevention and treatment of metabolic disorders, one cannot be confident that relatively low concentrations of liver enzymes exclude the presence of dysmetabolic changes.
In ROC analysis GGT is as strongly associated with the IDF diagnostic components as is each individual IDF component, except elevated systolic blood pressure. First and 2nd quartiles of serum GGT were combined because of small numbers of cases of newly recognized diabetes. The addition of the antioxidant N-acetyl-L-cysteine prevented mitochondrial dysfunction and reversed metabolic changes seen with LPON, strongly suggesting ROS involvement in mediating mitochondrial impairment. The researchers concluded, "GGT, a predictor of type 2 diabetes, was associated with a risk of incident MetS. In covariance analysis, there was significant relationship between elevated GGT levels and MS presence after adjustment for age, sex and MS diagnostic criteria; but not AST and ALT levels.
The researchers concluded, "Our data indicate that ROS formation, rather than cellular steatosis per se, impairs mitochondrial function. Such individuals might benefit from a more intensive therapeutic approach to decrease their global cardiovascular risk, regardless of potential unmeasured effects of lifestyle or obesity. The investigators concluded, "These findings suggest that a raised serum GGT level is an independent risk factor for NIDDM. Conceivably, the significant association of serum GGT concentrations with FPG and triglycerides, observed in our investigation, may be biologically explained by some underlying mechanisms such as hepatic steatosis, insulin resistance, and increased oxidative stress.
As noted in other more recent studies on this page, the relationship of GGT to diabetes still exists when appropriate adjustments are made for fat. The more recent studies suggest this relationship is most likely mediated by oxidative stress. The next article on this page (#18) is a letter to the editor written b by two of the same authors of the editorial (article #2) on our IRON-Diabetes page.

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