Metabolic syndrome (MetS) is a group of chronic metabolic disorders characterized by excess waist circumference, diabetes or impaired glucose regulation, dyslipidemia (hypertriglyceridemia and/or low high-density lipoprotein cholesterolemia), hypertension and insulin resistance (1). MetS can increase the incidence of atherosclerotic cardiovascular disease (ASCVD) and is an independent influence on cardiovascular events and the rate of death from all-cause mortality. With the development of urbanization and improvement in living standards, the prevalence of MetS has steadily increased and become a serious threat to human health (2). In China, the prevalence of MetS increased from 24.2% in 2015 to 31.1% in 2017, with 25.2% of those screened positive for one abnormal MetS component, in which the majority had diabetes or were at high risk of diabetes (1). Therefore, further research is urgently needed to identify MetS in high-risk populations and help clinicians take early action.

With the increased prevalence of diabetes, studies have reported a reciprocal effect between diabetes and MetS (3). Therefore, MetS is common in the population with diabetes. The CCMR-3B study showed that the prevalence of MetS in Chinese patients with type 2 diabetes (T2DM) was 57.4%. Of which 71.7% of diabetic patients were positive for at least one abnormal MetS component other than glucose abnormalities (4). In a UK cohort study, more than two-thirds of people with diabetes were found to have one or more components of the metabolic syndrome such as hyperlipidemia and hypertension (5). Despite the discrepancies in the results of the above studies, which are based on the different population characteristics of the study population. It is undeniable that diabetic patients are at high risk for MetS and therefore it becomes urgent to explore a simpler, easier, and more effective tool to screen diabetic patients for MetS to avoid cardiometabolic complications.

Anthropometric indicators have been a convenient predictor of MetS for a long time (6–8). However, anthropometric indicators are subject to many instabilities and often change after the body has reacted pathologically, whereas biochemical indicators are more likely to change in response to changes in the body size and composition and before the onset of disease. Objective indicators have rarely been explored between MetS.

Insulin resistance (IR) is a major pathophysiological mechanism in MetS and diabetes. Therefore, early and accurate identification of IR is clinically important for implementing prevention strategies and optimizing syndrome management. There are many methods available for estimating insulin resistance, ranging from complex techniques to simple indices. Methods for assessing IR fall into three broad categories, namely dynamic tests, simple indices, and biochemical indices (9, 10). Each method has its own strengths and limitations. High insulin clamp test (HEC), Frequent Sampling Intravenous Glucose Tolerance Test (FSIVGTT) are the gold and silver standards for assessing IR. However, they are expensive, time consuming, invasive and non-physiologic methods (10). Biochemical markers (e.g., fasting insulin, insulin-like growth factor-binding protein-1 (IGFBP-1), sex hormone-binding globulin (SHBG)), while providing useful information on IR status, cannot be interpreted alone and need to be combined with the other tests (9). Relatively simple alternatives have been proposed, such as homeostasis modeling assessment (HOMA-IR). HOMA-IR is the most commonly used indirect indicator to assess IR, however is vulnerable to the accuracy of insulin testing equipment (11). Compared to health systems in high-income countries, health systems in middle- and low-income countries have limited resources for laboratory facilities, which are not available in all health systems, HOMA-IR reproducibility is poor. As widespread measurement of insulin resistance or circulating insulin levels is not feasible in clinical practice, a simpler, accurate, practical and more cost-effective index of assessment is sought in a context of enhanced use of existing resources rather than the introduction of entirely new methods. To address this limitation, researchers have developed the triglyceride-glucose (TyG) index which is considered to be a reliable index for assessing IR (12, 13), and is better than the HOMA-IR (14).

The GGT/HDL-C ratio, a new metric proposed in a recent study, is not only less susceptible to interference, but is also readily available and has been shown to be a good predictor of risk for T2DM, non-alcoholic fatty liver disease (NAFLD) and is strongly associated with IR (15–17). Liver is one of the main target organs for insulin and liver dysfunction is closely associated with the development of MetS (18). Gamma-glutamyl transferase (GGT) is a common marker of liver dysfunction. Numerous studies have demonstrated that GGT is a predictive biomarker for MetS and that the risk of MetS increases with increasing GGT levels (19–21). In addition, The Framingham Heart Study has shown that GGT is positively associated with BMI, blood pressure, triglycerides and glucose (22). High-density lipoprotein cholestero (HDL-C) is a multifunctional structural protein with anti-inflammatory, antioxidant and cholesterol efflux effects, long considered the ‘good’ cholesterol (23). HDL-C stimulates glucose uptake and improves β-cell function (24). Studies have shown that lower HDL-C is associated with IR, dyslipidemia and obesity; and that IR is a potential mechanism for dyslipidemia, characterized by lower HDL-C and increased TG in the MetS component (25).

Given the correlation between GGT and HDL-C and MetS, it is crucial to study the association between GGT/HDL-C ratio and MetS. However, there is still a lack of studies reporting the association between GGT/HDL-C ratio and MetS. The aims of this study (1) were to assess the association between GGT/HDL-C ratio and MetS in subjects with T2DM and its predictive performance, (2) were to compare which of the three indexes, GGT/HDL-C ratio, TyG index and HOMA-IR, could more accurately screening for MetS in subjects with T2DM.

In this study, the GGT/HDL-C ratio, TyG index and HOMA-IR were used to determine the optimal cut-off values for screening for MetS in subjects with T2DM. The GGT/HDL-C ratio is a relatively accurate indicator for identifying MetS in subjects with T2DM and has a higher and more discriminatory value than the TyG index and HOMA-IR. Based on the results of the ROC analysis, GGT/HDL-C ratio, TyG index and HOMA-IR cut-off values were 19,94 (AUC=0.779), 1.82 (AUC=0.765) and 3.31 (AUC=0.702) respectively.

IR is an independent risk factor for the development of MetS and diabetes. Therefore, it is important to identify IR in a clinically significant way. Methods of assessing IR fall into three broad categories, namely dynamic tests, simple indices and biochemical indices (9, 10). Among the dynamic tests such as HEC is considered a reference technique. However, HEC has limitations including technical demands, laboriousness, time consumption, expense, and non-physiologic methods. Due to the complexity of HEC, FSIVGTT was preferred as an alternative option. Unlike HEC, FSIVGTT relies on dynamic glucose and insulin data obtained before and after intravenous glucose administration. Nonetheless, it is time-consuming and limited by the availability of appropriate software, and it does not provide results in diabetic subjects (10). In addition, measurement of biochemical markers (e.g., fasting insulin, IGFBP-1, SHBG) can provide useful information about IR status. However, the results of these indices should not be interpreted in isolation and need to be interpreted in the context of other findings, including anthropometric measures such as BMI and WC as well as biochemical measures. Age, sex, and race should also be considered. More importantly, biological variability needs to be considered (9). HOMA-IR is the most used measure of insulin resistance for epidemiological studies. Compared to the high glucose clamp test, HOMA-IR requires only insulin and glucose testing and has the advantage of being less invasive, less costly, and simpler to perform (30, 31). Previous studies have reported that the HOMA-IR index is a good indicator for defining MetS and IR in adults. Research conducted in different countries has reported that the threshold for HOMA-IR to predict adult MetS ranges from 1.70-2.83 (AUC=0.68-0.82) (32, 33). Our study found a higher threshold for HOMA-IR than the above-mentioned studies, based on the fact that we studied T2DM, and our results were similar to those of a diabetic population study in Iran (34). However, there are limitations to this indicator, which is based on fasting glucose and insulin levels, as previously mentioned; one of these is that the measurement of insulin levels is not only expensive. It is also difficult to measure insulin levels in laboratories and health facilities in many developing countries or low-income areas, and there are problems with standardization. On the other hand, diabetic patients receiving insulin therapy or subjects with severely impaired or lost pancreatic beta-cell function can seriously interfere with the measurement results. In contrast, the TyG index and GGT/HDL-C ratio is measured without the need for fasting insulin levels. These tests have the advantage of being able to review lipid parameters and GGT levels, are less expensive than insulin, and can be done by all clinical laboratories.

TyG index is a simple and effective alternative marker for identifying insulin resistance by combining fasting glucose and triglycerides (12, 35). A series of clinical studies have confirmed the close association between TyG index and MetS (27, 33, 36). This study determined that TyG index (AUC=0.765) was a valid marker for diagnosing MetS superior to HOMA-IR (AUC=0.707). The findings are consistent with those of Primo David et al. (TyG index (AUC= 0.746), HOMA-IR (AUC= 0.682)) (37). TyG index is also associated with other diseases. A real-world single-centre study reported that TyG index was more strongly associated with atherosclerosis in T2DM patients compared to HOMA-IR (38). It is important to note that TyG index is susceptible to hyperlipidemia and diabetes as it is a composite index consisting of fasting TG and FPG. In most studies, TG and FPG are only examined at baseline and certain acute illnesses, or unexpected events may lead to stress hyperglycemia and affect TyG index. In addition, dietary habits can greatly affect TG levels. In addition, most studies on TyG index use in MetS have been conducted in middle-aged or older adults, and there is a lack of information on the value of TyG index in younger participants (39).

Multivariate logistic regression analysis showed a strong correlation between GGT/HDL-C ratio and MetS after adjusting for all available confounders. Each 1 SD increase in GGT/HDL-C ratio was associated with a 228% increase in the prevalence of MetS. ROC analysis showed that GGT/HDL-C ratio was an accurate indicator of MetS screening (ACU= 0.779, 95% CI: 0.749-0.809), with an optimal threshold of 19.94, which has a high sensitivity and specificity.

GGT/HDL-C ratio has good predictive performance for the risk of T2DM and NAFLD. Xie, Wangcheng et al. found that GGT/HDL-C ratio is an important predictor of T2DM (15), with an AUC of 0.750 and an optimal threshold of 17.92. It is lower than that of the present study. Feng, Guofang et al. explored the predictive performance of GGT/HDL-C ratio for NAFLD risk (17). They discovered that the GGT/HDL-C ratio had an AUC of 0.799 and an optimal threshold of 21.3, which was slightly higher than that of the present study. Compared with T2DM, GGT/HDL-C ratio had the best predictive performance for NAFLD and the second-best predictive ability for MetS. This is because GGT and HDL-C are more strongly correlated with NAFLD, which is either a symptom and cause of MetS (40). Anyway, GGT and HDL-C are routinely tested in clinical laboratories compared to HOMA-IR and TyG indexes. GGT/HDL-C ratio is indeed a convenient and cost-effective indicator for screening the risk of MetS in subjects with T2DM.

Mechanisms underlying the association between high GGT/HDL-C ratios and MetS remain unclear and are currently thought to be related to insulin resistance, dyslipidemia and oxidative stress in MetS pathology (41, 42). Elevated GGT is a marker of intracellular triglyceride accumulation and is associated with overweight/obesity and insulin resistance, not alcohol consumption (43, 44). In addition to its ability to reflect the involvement of insulin resistance in the development and progression of MetS by representing liver dysfunction and intrahepatic lipid accumulation (41). On the other hand GGT is involved in oxidative stress in organisms through the regulation of glutathione, which is linked to the pathophysiological development of MetS. Some investigators suggest that elevated serum GGT reflects oxidative stress and chronic inflammation, which also contributes to the development of MetS (45, 46). GGT not only positively correlates with numerous inflammatory factors such as C-reactive protein and interleukin-6, but also itself mediates the conversion of leukotriene C4 to leukotriene D4, which enhances the development of inflammation (15). Numerous previous studies have demonstrated that GGT is a useful biomarker for predicting MetS and its components, and that the risk of MetS increases with increasing levels of GGT (22).

Dyslipidemia is a risk factor for MetS, and reduced HDL-C is the most common clinical disorder of lipid metabolism. As part of the diagnosis of MetS, HDL-C can improve cellular uptake of glucose in skeletal muscle cells and insulin secretion from beta cells and helps protect β-cells from apoptosis caused by cholesterol accumulation by promoting cholesterol efflux (15, 16). HDL-C also has anti-inflammatory and antioxidant effects, directly increasing beta cell survival by inhibiting apoptosis caused by oxidized LDL-C and inflammatory factors, HDL-C decreased levels may reflect reduced beta cell function and insulin resistance (23). Study demonstrates an independent negative correlation between HDL-C and IR (24, 47). IR may be an underlying mechanism for dyslipidemia, characterized by increased TG and decreased HDL-C in the MetS component. IR leads to increased release of fatty acids from adipose tissue and increased hepatic TG synthesis, contributing to increased plasma TG levels, hypertriglyceridemia contributes to decreased HDL-C through enhanced clearance of TG-rich HDL by hepatic lipase due to enhanced clearance of TG-rich HDL by hepatic lipase (25).

In the context of a high GGT/HDL-C ratio, both elevated GGT levels and reduced HDL-C levels are associated with an increased risk of MetS. The optimal threshold for the GGT/HDL-C ratio is 19.94, which means that when T2DM patients have a GGT/HDL-C ratio above 19.94, we need to pay extra attention to them as they are at high risk of MetS. Clinicians need to urge them to improve their lifestyle and promote healthy eating and physical activity to help them prevent or delay MetS early.

In addition, the heterogeneity of MetS is reflected in alterations in the transcriptome and associated pathways (48, 49). The anti-aging gene Sirtuin 1, whose involvement in glucose, fatty acid, and cholesterol metabolism has been demonstrated, and is involved in the biological processes of oxidative stress and inflammation by activating the transcriptional activity of downstream genes (50, 51). In recent years, Sirtuin 1 has been shown to be associated with insulin resistance and to be important for glucose-dependent insulin secretion and the protection of pancreatic β-cell mass (52). Decreased levels of Sirtuin 1 have been shown to be associated with the diagnosis of diabetes mellitus, nonalcoholic fatty liver disease, and the metabolic syndrome, in which epigenetic modifications may play an important role (49, 51–53). Both GGT and HDL-C are metabolic biochemical indicators associated with MetS. The activity of Sirtuin 1 was found to be negatively correlated with GGT levels; Positive regulation of HDL-C levels (54, 55). Thus, inactivation of Sirtuin 1 may also be associated with the optimal threshold GGT/HDL-C ratio for screening MetS. Studies on the relationship between Sirtuin 1 and GGT and HDL-C are limited, and the mechanisms involved are not fully understood. More studies are needed in the future to explore the role of Sirtuin 1 in the relationship between GGT/HDL-C ratio and MetS, which may help to reduce the risk of MetS in subjects with T2DM, to start treatment early, and to improve the quality of life of patients.

The strengths of this study are as follows. (1) We revealed for the first time an independent positive relationship between MetS in subjects with T2DM and GGT/HDL-C ratio; (2) We performed a series of sensitivity analyses (transformation in the form of target independent variables, subgroup analysis) to ensure the reliability of the results. Limitations of this study are also noteworthy: (1) This was a cross-sectional study and therefore only provides weak evidence of an association between exposure and outcome; it is difficult to distinguish a cause-and-effect relationship. Prospective studies are needed to further validate this relationship, especially in comparison with the TyG index. This will help us to understand the validity of the GGT/HDL-C ratio in predicting MetS and its potential application in early detection and intervention. (2) Our study was conducted in Chinese patients with T2DM, and its applicability to other national and ethnic populations is unknown. Additionally, our study was the lack of subpopulation analysis of the number and the kind of metabolic syndrome components. (3) This study lacked data on NAFLD, although we had adjusted for liver enzymes; therefore, the presence of NAFLD could not be considered in the data analysis. (4) As with other observational studies, there may be certain confounding factors that were not identified or included.

GGT/HDL-C ratio is an independent risk factor for MetS in subjects with T2DM. The risk of MetS in subjects with T2DM increased in conditions with a higher GGT/HDL-C ratio. In the study, GGT/HDL-C ratio was a stronger predictor of MetS than TyG index and HOMA-IR, suggesting as a simple marker for use in underdeveloped and developing countries and in areas with poor laboratory facilities, as well as facilitating large epidemiological studies. For clinical applications, GGT/HDL-C ratios above 19.94 should be used by physicians to guide future medical prophylaxis of MetS in subjects with T2DM to avoid cardiometabolic complications as early as possible.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving humans were approved by Ethics Committee of Changde First People’s Hospital. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin.

SGo, SGa analyzed the data and drafted the manuscript. SGa, HZ organized the database. SGo, QZ performed the statistical analysis. HZ wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.