This 2005 paper describes the mechanism in which elevated GGT triggers oxidative stress within arterial plaque and suggests how GGT and iron metabolism interact in the process leading to fatal cardiac events. In this 2012 research from Turkey set out to determine "The extent to which its value in determining incident cardiometabolic risk (coronary heart disease (CHD), metabolic syndrome (MetS), hypertension and type 2 diabetes) is independent of obesity needs to be further explored in ethnicities." "After appropriate exclusions, a cohort of 1,667 adults of a general population (age 52 ±11 years) was evaluated prospectively at 4 year's follow-up using partly Cox proportional hazard regressions. In this 2011 study from Turkey the investigators enrolled "232 patients (mean age 60.4 years) from our (their) outpatient cardiology clinic, 117 with and 115 without MetS (control group) as defined by the ATP-III criteria. In this study reported in 2011, "This study examined the association between serum GGT concentration and Framingham risk score (FRS) in the Korean population. In this 2011 research from Pakistan the investigators "aimed to elucidate the association between gamma glutamyl transferase (GGT) activity with prevalence of premature coronary artery disease (CAD) in young Pakistani patients undergoing diagnostic coronary angiography." "A total of 218 young adults (age ? 45 years) underwent diagnostic angiography. In this 2012 report out of Turkey the researchers first noted, "The exact mechanisms behind the association between atherosclerosis and gamma-glutamyltransferase (GGT) are unclear. In this 2006 study reported in Turkey, "754 men and 802 women were available for analysis who were followed up briefly yielding only 16% of overall cases of coronary heart disease (CHD).
In a 2006 study of 28,838 Finnish men and women studied up to 11.9 years hazard ratios increased in each of four ascending GGT categories. In this 1999 reported study the researchers preformed "a series of experiments showed that the gamma-glutamate residue of GSH affected interactions of the juxtaposed cysteine thiol with iron, precluding Fe(III) reduction and hence LDL oxidation." "Both processes increased remarkably after addition of purified gamma-GT, which acts by removing the gamma-glutamate residue. Also in 2004, and similar to the previous study, the researchers examined data from  3,128 black and white participants (men and women 17–35 years of age in 1985–1986). In this 2009 study of 1,033 consecutive heart failure patients in Austria, the prevalence of elevated GGT was significantly higher in patients than in sex and age-matched healthy control subjects. Plasma Gamma-Glutamyltransferase, Cysteinyl-Glycine, andOxidized Low-Density LipoproteinA Pathway Associated With Myocardial Infarction Risk? In this prospective study of more than 27,000 subjects reported in Germany in 2010, the researchers found virtually the same results for myocardial infarction as has been demonstrated above in many other studies. This 2010 review was published by researchers from the Berkeley heart Lab and the American Heart Association.
In this 2007 reported by researchers from Tulane University Health Sciences Center, liver enzymes were tracked over time for 12 years in 489 young adults (40% male, 73% white at baseline). In this 2012 reported study of early mortality in Turkey, GGT was measured in 127 consecutive patients with confirmed pulmonary embolism. This 2008 Austrian study included 76,113 men and women and 455,331 serial GGT measurements.
In this 2011 reported study from China "5,404 subjects aged ? 40 years were recruited from two urban communities in Shanghai for cross-sectional analyses. This study adult men and women in Turkey was published in 2010 and was aimed to determine "if the liver function tests (LFT), especially gamma glutamyl transferase (GGT), have a predictive value in diagnosis of metabolic syndrome (MS). This 2008 study covering 6,997 men age 40-59 from 24 British towns followed for up to 24 years reported results consistent with the findings shown above. Reported in 2012, this was a study based on data from the Investigation into Cancer and Nutrition in Potsdam (Germany), Bilthoven and Utrecht (the Netherlands).
In this 2000 research report from Finland, "A prospective cohort study of 14, 874 Finnish men and women aged 25 to 64 years who participated in a cardiovascular risk-factor survey in 1982 or 1987." "Serum GGT concentration was associated with the risk of total and ischemic stroke in both genders. In this section we will demonstrate how moderately elevated to high levels of GGT contribute to the disease process by depleting glutathione levels leading to increased oxidative stress, causing cell damage, lipid peroxidation, DNA mutagenisis and major life-threatening diseases affecting the body's vital organs. The results of serum liver function tests including serum GGT and C-reactive protein (CRP) levels were compared between the two groups. Age- and sex-adjusted cumulative incidence of heart failure by serum GGT median levels (at or greater than and less than the median). Coronary artery calcification (CAC) detected by computerized tomography is an important marker of atherosclerosis and its severity correlates with coronary plaque burden. The investigators noted, "Elevated serum gamma-glutamyl transferase (GGT) has been known to be associated with the cardiovascular disease.
When further fully adjusted for multiple risk factors, the hazard ration in the highest GGT quartile was then 2.34.
GSH-dependent LDL oxidation was similarly promoted by gamma-GT associated with the plasma membrane of human monoblastoid cells, and this process required iron traces that can be found in advanced or late stage atheromas. National Health and Nutrition Examination Survey, these researchers found that GGT was inversely associated with six acknowledged antioxidants, but did not find it associated with vitamin E. The researchers noted, "Our present and previous studies with CARDIA participants consistently suggest that serum GGT might be one of the enzymes related to oxidative stress. The authors concluded, "Prevalence of elevated GGT is high in patients with chronic heart failure.

The HRs (95% CIs) of myocardial infarction per 1-SD increase in log-transformed plasma GGT activity, Cys-Gly, and oxLDL, as derived from Cox proportional hazards regression analysis, with age as the underlying time variable. A pronounce increase in GGT over time was significantly associated with cardiovascular disease mortality in men when compared to men with relatively stable GGT during the period. 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. Data used were from 1,280 participants, aged 35-70 years, with a confirmed diagnosis of diabetes mellitus.
In linear regression analysis, while smoking status was not associated, (male) sex, sex-dependent age, alcohol usage, BMI, fasting triglycerides and C-reactive protein (CRP) were significant independent determinants of circulating GGT. Besides FRS, body mass index, fasting blood glucose, liver enzymes, lipid profile, uric acid and high sensitive C-reactive protein data were used. The aim of this study was to investigate if serum GGT levels are associated with CAC in patients without known coronary heart disease (CHD) who had low-intermediate risk for CHD." "Two hundred and seventy two patients who had low-intermediate risk for coronary artery disease were included in the study.
However, there is a lack of researches on direct examination of relevance between serum GGT and coronary artery calcification (CAC). Collectively, these findings suggested a possible role for gamma-GT in the cellular processes of LDL oxidation and atherogenesis. One reason for this conclusion is that dietary heme iron positively predicted future serum GGT concentration; free iron, which would cause oxidative stress, might mediate this association, although free iron was not measured.
Cumulative 5-year event rates were estimated by univariate sex-stratified Cox proportional hazard regression analysis in 998 patients with CHF according to quintiles of GGT levels at the study entry. Additionally, MetS was associated with sedentary lifestyle in women and with smoking in men.
Women demonstrated similar but less significant results, and only with respect to coronary artery disease.
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.
Four hundred and forty two of these subjects were diagnosed with MS with IDF criteria; while other 466 were sex and age matched healthy control subjects. The relationships remained statistically significant also after adjustment for other risk factors. The prevalences of hypertension and dyslipidemia were significantly higher in patients with MetS.
One pathway by which low SES might influence disease risk is by promoting oxidative stress." "Data from 1,278 participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study were used to examine the association of SES with oxidation correlates and antioxidant nutrients. Accordingly, the aim of this study was to investigate the association between serum GGT levels and the prevalence of CAC in Korean." "The study population consisted of 14,439 male and female adults without coronary artery disease, who were conducted health examination from January 2010 to December 2010.
Histochemical analyses confirmed that this may be the case, showing that gamma-GT activity is expressed by macrophage-derived foam cells within human atheromas, and that these cells colocalize with oxidized LDL." The researchers concluded, "Biochemical and histochemical correlates indicate that gamma-GT can promote LDL oxidation by hydrolyzing GSH into more potent iron reductants.
Additionally, GGT was positively correlated with an 18% per quartile risk of cardiovascular events and a 26% per quartile increased risk of all-cause mortality." And they suggested, "GGT is becoming an important addition to the multimarker approach to cardiovascular risk evaluation.
The aim of this article is to describe changes in chronic disease risk factors (RFs) in Pitkaranta district in Russia during ten year period of time from 1992 to 2002." "Independent random samples, age 25-64, were taken from the population registers. In the same regression model drinking alcohol 2-4 times a month and consumption of five or more alcohol units at one occasion in men, and drinking alcohol 5 times or more a month in women were inversely associated with MetS. As in several of the above studies, the risks were observed to be markedly stronger for younger individuals.
Blood pressure, liver function tests, fasting blood glucose levels and lipid profile of the subjects were recorded." "The mean values of alanine amino transferase (ALT), aspartate aminotransferase (AST) and GGT levels were statistically significantly higher in MS group. In comparing the top 20% quintile to "the rest" only, the knowledge respecting increased mortality risks within the "normal range" had not yet been published. Compared with controls, patients with MetS had significantly higher serum GGT [(median 21, interquartile range (16-33) vs. Analyses relating GGT to FRS ? 20% utilized multiple confounders adjusted logistic regression. Education, occupation, health behaviors, and body mass index (BMI) were assessed during Years 0, 10, and 15 of the study; income and depression were evaluated at Years 10 and 15. Also at that time the evidence indicating GGT''s direct involvement in the oxidative stress process had not been thoroughly investigated.
F(2)-isoprostanes were measured at Year 15, gamma-glutamyltransferase (GGT) at Years 0 and 10, carotenoids at Years 0 and 15, and ascorbic acid at Years 10 and 15." "Cross sectionally, oxidation correlates decreased and antioxidant nutrients increased with increasing SES, estimated in several ways, independent of age, sex, race, and BMI. Serum cholesterol, HDL-cholesterol, triglyceride and GGT values were determined from serum samples.

Moderate frequency of alcohol consumption and binge drinking in men and higher leisure time physical activity in women, were inversely associated with MetS.
Prospectively, lower Year 0 education and occupation predicted greater increases in GGT and greater decreases in carotenoids over 10 to 15 years. The investigators concluded, "Elevated serum GGT levels were independently associated with the prevalence of CAC. The total number of respondents was 2,766." "Systolic and diastolic blood pressure decreased in Pitkaranta from 1992 to 2002. Of special note here is that GGT in the upper half of the population range increased the risk of diabetes by 100% in normal BMI ranges, by 150% in the overweight BMI range and by 268% in the obese BMI ranges (after adjusting for several relevant factors).
The researchers concluded, "Our findings suggest that patients with MetS have higher serum GGT and CRP levels compared with controls. In the multivariate analysis GGT, age, smoking and serum uric acid levels appeared as independent factors predictive of presence of CAC." The researchers concluded, "We demonstrated a significant correlation between serum GGT levels and CAC and CHD risk factors. Serum GGT may be helpful to predict the future risk of CAD (coronary artery disease)." The researchers determined that GGT concentration correlated very well with Framingham risk scores.
Self-reported alcohol use increased, as also mean GGT." The researchers concluded, "The study gives valuable information on developments of RFs in Russia. Some alarming tendencies in lifestyle were seen and chronic disease RF situation has generally worsened. The results also show how big is the challenge to change lifestyles deep in culture--and in the situation where preventive work and policies do not receive strong support. Note that the highlighted text and GGT measures in this population are significantly higher (both in 1992 and 2002-3) than those reported in all other studies on this web site. 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.
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.
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.
Gamma-glutamyltransferase activities of males and persons older than 45 years were significantly higher than each counterpart.
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. The investigators concluded, "These findings suggest that a raised serum GGT level is an independent risk factor for NIDDM. 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.
As shown in Table 1 (see below), the concentrations of FPG and triglycerides markedly increased among the GGT categories.
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.
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. GGT was significantly associated with the 3-year incidence of individual components of the MetS. The investigators studied the incidence of impaired fasting glucose (IFG) and type 2 diabetes over a seven year period.

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