Our main findings with regard to the three cardiometabolic phenotype classes (i.e., MHL, MHO, and MUHO) are as follows. The frequency of females decreased as a dose-dependent variable of GGT tertile, which means that the lowest frequency was observed in the third GGT tertile. In MHL, MHO, and MUHO groups, significant changes in the mean WC, TG, cholesterol, FBS, DBP, SBP, and low HDL can be seen by increasing the GGT levels. The odds of MHO and MUHO increased according to the GGT tertile. The highest odds occurred in the third GGT tertile. This significant correlation was more pronounced after adjusting for confounding factors.
Our results confirm the findings of an earlier study, showing a positive correlation between serum GGT and MetS after adjusting for demographics, BMI, alcohol consumption, and smoking [16–21]. Xue et al. noted that risk of MetS increased 4.37 folds in the highest GGT quartiles after adjusting for confounding factors [18]. In another cross-sectional study, Lee et al. adjusted for age and drinking status, and obtained comparable results with an odds ratio of 2.97 in the highest GGT quartile [19]. Although the results of these studies show that GGT increases the risk of MetS, other studies show an increase in the risk of MetS even with a normal range of GGT [22, 23].
In most cases, the findings related to the association between MetS and GGT levels were adjusted for BMI. Recent studies show a subset of overweight and obese individuals who have been documented to have normal metabolic profiles [24]. According to some reports, “metabolically-normal” individuals with elevated body size may have a similar risk of chronic disease to normal-weight individuals and individuals without metabolic abnormalities [25]. In contrast, approximately 24% of normal-weight U.S. adults (BMI < 25.0 kg/m2) are considered metabolically abnormal [26], which places them at a high risk for chronic diseases, and as compared to the MHNW individuals, those are generally associated with elevated BMI. Understanding the effect of body size in individuals, which puts them at a higher risk for the metabolic syndrome, can have implications for public health and clinical practice. To the best of the authors’ knowledge, there is no published studies on the association between cardiometabolic phenotype and GGT levels, except for one study with a small sample size (n = 140), which investigated the correlation between the GGT levels and MHO and at-risk obese individuals in young non-diabetic obese women [27]. While some metabolically-healthy normal-weight and obese participants have an increased risk of unhealthy phenotype, others may have considerably stable and desirable metabolic profiles, which is a matter of concern [28].
Accordingly, it is important to determine reliable biomarkers to distinguish healthy subjects at risk for transition to an unhealthy metabolic condition. GGT is an accessible marker in basic blood tests which can easily be measured and interpreted. Therefore, in this study, we examine the association between the cardiometabolic phenotype and the GGT levels. In this regard, our findings indicated the highest prevalence of MHO and MUHL in the third GGT tertile (highest level); however, a number of MHL individuals are also in the third GGT tertile. This indicates that these metabolically-healthy subjects may be at risk of a transition to a metabolically-unhealthy condition.
These findings are similar to those of Mankowska-Cyl et al., who noted that the elevated GGT was more prevalent in at-risk obese women than MHO women [27].
Furthermore, by evaluating the metabolic syndrome components ( WC, DBP, SBP, TG, FBS, and low HDL), we observed a dose-response manner, which was increasing per GGT tertile. These findings indicate that higher GGT levels may represent metabolic modifications, and they can function as a clinical guide for different cardiometabolic phenotype classes. ROC was described to assess the distinguishing function of GGT among different cardiometabolic phenotype classes, which demonstrates a cutoff value of 18.5 UL/l for GGT, and it may indicate the transition of an MHO individual to the MUHO class.
The detailed mechanism of this relationship was not completely clarified. However, some possible descriptions can be suggested, e.g., serum GGT levels have been stated as one of the oxidative stress markers [29, 30]. Elevated serum GGT activity leads to the shift of extra glutathione into cells and glutathione metabolism, which causes oxidative stress [18]. It has been documented that oxidative stress plays a predominant role in the pathogenesis of the metabolic syndrome [19, 20].
Furthermore, gamma-glutamyltransferase plays a pro-inflammatory role in mediating the interconversion of leukotrine-C4 (LT-C4) into leukotriene -D4, where LT-C4 is a glutathione-containing inflammatory mediator [31]. Thus, by studying the predefined and novel cardiovascular risk factors, a correlation can be found between serum GGT and the increased risk of MetS in MUHL and MHO individuals.
The main limitation of this study was that the causal inferences between serum GGT and cardio metabolic phenotype could not be investigated because of the cross-sectional nature of its background. The low number of MUHL participants was another limitation of this study. The major strength of the present study was that it was the first work to study the association between GGT and cardiometabolic phenotype in healthcare workers. The advantage of serum GGT is in the availability of this marker in routine clinical practice and its standardized measurement methods. It can be helpful to distinguish the transition from MHO to MUHO, which may lead to an early and more accurate identification of MHO subjects who are at a risk of transition to MUHL, while it can also facilitate better preventive strategies. Using the data of a cohort study with a large sample size is another strength of this study.