European Journal of Cardiovascular Medicine

Diabetes Mellitus (DM) is a chronic metabolic disorder characterized by persistent hyperglycemia resulting from defects in insulin secretion or insulin action, or both. Globally, the prevalence of diabetes mellitus is 10.5% in 2021, projected to rise to 12.2% by 2045.1 Type 2 diabetes mellitus (T2DM) accounts for approximately 90–95% of all diabetes cases and is often associated with high risk of developing metabolic syndrome (MS), a cluster of abnormalities including central obesity, hyperglycemia, dyslipidemia, and hypertension, which significantly elevates cardiovascular disease (CVD) risk, thus contribute to significant morbidity and mortality.2The global prevalence of MS is estimated at 20–25%, while in India it is approximately 31.4% .3

Recent studies have focused on the role of liver enzymes, particularly Gamma Glutamyl Transferase (GGT), in predicting MS and CVD. GGT is a cell surface enzyme predominantly synthesized by the liver, catalyzing the extracellular transfer of gamma-glutamyl groups from glutathione to amino acids or peptides. This reaction plays a critical role in maintaining intracellular glutathione levels, a key antioxidant. Increased oxidative stress in MS results in glutathione depletion, prompting compensatory upregulation of GGT synthesis.4 Evidence indicates that all MS components correlate with elevated GGT levels, suggesting its utility as a biomarker for early detection.

In India, where the prevalence of T2DM and MS is rising rapidly, early identification of high-risk individuals is crucial for implementing timely interventions to prevent cardiovascular complications.5 While traditional risk assessment includes anthropometric measurements, blood pressure, lipid profile, and glycemic indices, the inclusion of GGT measurement may enhance predictive accuracy, particularly in asymptomatic or borderline cases.

Our study was designed to evaluate serum GGT levels in T2DM patients with and without metabolic syndrome, and to compare them with healthy controls. The study also assessed the level of serum GGT in Type 2 diabetes mellitus patients with metabolic syndrome and in healthy controls, and to determine the association between GGT levels and Metabolic syndrome in Type 2 Diabetes mellitus patients. By establishing a clear association between elevated GGT and MS in T2DM, we aim to highlight the potential role of GGT as a cost-effective, widely available biomarker in routine clinical practice for early detection and risk stratification.

Study Design and Setting: This study was conducted as a cross-sectional analytical study at the Government Medical College and Hospital, Tiruppur, Tamil Nadu, a tertiary care teaching hospital catering to a large and diverse patient population from both urban and rural areas. The study was carried out over a period of four months, from April 2024 to July 2024. The hospital provides comprehensive outpatient and inpatient services for patients with diabetes mellitus and related metabolic disorders, making it an appropriate setting to evaluate biochemical markers associated with metabolic syndrome in Type 2 Diabetes Mellitus (T2DM). Study Participants: The study population comprised adults attending the outpatient and inpatient departments of the hospital during the study period. Participants aged 30 to 60 years were enrolled and categorized into three groups based on diabetic status and presence of metabolic syndrome. • Group I (Healthy controls) included apparently healthy individuals without diabetes or metabolic syndrome, matched for age and sex with the study groups. • Group II consisted of patients with known T2DM for more than one year but without features of metabolic syndrome. • Group III included patients with T2DM and metabolic syndrome, diagnosed based on the National Cholesterol Education Program–Adult Treatment Panel III (NCEP-ATP III) criteria, wherein the presence of three or more components confirmed the diagnosis. These components included increased waist circumference (women >35 inches, men >40 inches), serum triglyceride levels >150 mg/dL, reduced HDL cholesterol (<50 mg/dL in women and <40 mg/dL in men), blood pressure ≥130/85 mm Hg, and fasting blood glucose ≥100 mg/dL. Exclusion criteria were strictly applied to minimize confounding factors influencing serum gamma-glutamyl transferase (GGT) levels. Individuals younger than 30 years or older than 60 years were excluded. Pregnant and lactating women, patients with Type 1 Diabetes Mellitus, alcohol consumers, and those with known liver disease, renal disease, or cardiovascular disease under treatment were excluded. Additionally, patients receiving anticonvulsant medications or oral contraceptive pills were not included due to their potential effect on hepatic enzymes. Sample Size and Sampling Technique: The sample size was calculated based on data from a previous study by Vidushi Singh et al. (2020)4, using the formula: Considering a 10% non-response rate, the final sample size was determined to be 35 participants in each group, resulting in a total of 105 study participants. Participants were recruited using a consecutive sampling technique, wherein eligible subjects presenting during the study period were enrolled until the desired sample size for each group was achieved. Study Tools and Measurements: Data collection was performed using a pre-structured proforma, which included demographic details, clinical history, anthropometric measurements, and laboratory parameters. Waist circumference was measured using a non-stretchable measuring tape at the midpoint between the lower margin of the last palpable rib and the iliac crest. Blood pressure was recorded in the sitting position after adequate rest using a calibrated sphygmomanometer. Study Methodology: After obtaining written informed consent, all participants underwent clinical and biochemical evaluation following an overnight fast of at least 8–10 hours. Five milliliters of venous blood was collected under aseptic precautions in a red vacutainer. Serum was separated by centrifugation at 3000 rpm for 10 minutes and analyzed on the same day. Fasting blood glucose and postprandial blood glucose levels were estimated using the glucose oxidase–peroxidase (GOD-POD) method. Serum total cholesterol was measured by the cholesterol oxidase phenol 4-aminoantipyrine peroxidase (CHOD-PAP) method, triglycerides by the glycerol phosphate oxidase phenol 4-aminoantipyrine peroxidase (GPO-PAP) method, and HDL cholesterol by the PEG/CHOD-PAP method. All biochemical estimations were performed using the ERBA XL-640 fully automated analyzer. Serum gamma-glutamyl transferase (GGT) levels were analyzed using an enzymatic colorimetric method on the same analyzer, following standard operating procedures and internal quality control measures. Ethical Considerations: The study protocol was reviewed and approved by the Institutional Ethics Committee of Government Medical College and Hospital, Tiruppur. All procedures were conducted in accordance with the ethical principles outlined in the Declaration of Helsinki. Confidentiality of participant data was strictly maintained, and participation was entirely voluntary, with the option to withdraw from the study at any stage without any impact on clinical care. Statistical Analysis: Data were entered and analyzed using Statistical Package for Social Sciences (SPSS) version 16.0. Continuous variables were expressed as mean ± standard deviation, while categorical variables were presented as frequencies and percentages. Differences in biochemical and clinical parameters among the three groups were assessed using Analysis of Variance (ANOVA). A p value <0.05 was considered statistically significant for all analyses.

The mean age of participants did not differ significantly among the three groups (p = 0.063), indicating effective age matching across controls, patients with Type 2 Diabetes Mellitus (DM), and those with Type 2 Diabetes Mellitus with Metabolic Syndrome (MS). In contrast, waist circumference showed a statistically significant difference between groups (p = 0.001), with progressively higher values observed from controls to DM and MS groups. The highest mean waist circumference was noted among patients with metabolic syndrome, underscoring the central role of abdominal obesity in the clustering of metabolic abnormalities associated with metabolic syndrome (Table 1).

Table 1: Descriptive Statistics of Age and Waist Circumference Across Study Groups.

                                                                                                                                            
Systolic and diastolic blood pressure values differed significantly across the three groups, with the highest mean SBP and DBP observed in the metabolic syndrome group (p < 0.0001 and p = 0.010, respectively), reflecting the hypertensive burden associated with metabolic syndrome. Fasting blood glucose levels were significantly elevated in both diabetic groups compared to controls, with the highest mean value recorded in the DM group (164.52 ± 58.10 mg/dL, p < 0.0001). Similarly, postprandial blood glucose levels were markedly higher in diabetic patients, with the DM group demonstrating the highest PPBS values (224.89 ± 48.08 mg/dL, p < 0.0001). These findings highlight the pronounced glycemic dysregulation in Type 2 Diabetes Mellitus, particularly in patients without metabolic syndrome (Table 2).

Table 2: Comparison of Blood Pressure and Glycemic Parameters Across Study Groups.

Total cholesterol and triglyceride levels demonstrated statistically significant variation across the three groups, with both parameters showing the highest mean values in patients with metabolic syndrome (p = 0.039 and p < 0.0001, respectively). The markedly elevated triglyceride levels in the MS group reflect the characteristic dyslipidemia associated with insulin resistance and central obesity. Although HDL cholesterol levels were lower in the MS group, and LDL cholesterol levels were higher in diabetic groups, these differences did not reach statistical significance (Table 3).

Serum gamma-glutamyl transferase (GGT) levels differed significantly among the three study groups (F = 12.375, p = 0.0001). Patients with metabolic syndrome exhibited markedly elevated mean GGT levels (52.58 ± 48.10 U/L) compared to both controls and diabetic patients without metabolic syndrome. Post-hoc Bonferroni analysis confirmed that the MS group differed significantly from the other two groups, while no significant difference was observed between controls and the DM group. These findings suggest a strong association between elevated serum GGT levels and the presence of metabolic syndrome in patients with Type 2 Diabetes Mellitus, potentially reflecting increased oxidative stress and subclinical hepatic dysfunction (Table 4).

Table 3: Comparison of Lipid Profile Parameters Among Study Groups.

Figure 1: GGT levels in the study participants.

Table 4: Association Between Type 2 Diabetes Mellitus With Metabolic Syndrome and Serum GGT Levels.

Note. Groups with different superscript letters (a, b) differ significantly (p < 0.05), Bonferroni post-hoc test.

The present cross-sectional study assessed serum Gamma-Glutamyl Transferase (GGT) levels among three groups — healthy controls, patients with type 2 diabetes mellitus (T2DM) without metabolic syndrome (MS), and T2DM patients with MS — and demonstrated a statistically significant elevation of GGT in the MS group compared to both the T2DM-only group and healthy controls (p < 0.001). Our results align with the findings of Naidu et al.6, who reported significantly elevated GGT in individuals with MS compared to non-MS subjects, independent of liver disease or alcohol intake.

Similarly, Vidushi Singh et al.4 demonstrated that GGT levels correlated positively with each component of MS — waist circumference, fasting glucose, triglycerides, and blood pressure — even in individuals with normal liver function. A large prospective cohort study by Lee et al.7 found that elevated baseline GGT levels predicted incident MS and T2DM over a 7-year follow-up, with risk estimates remaining significant after adjusting for body mass index (BMI) and alcohol consumption. Thus, GGT is not merely a hepatic enzyme marker but also a potential surrogate biomarker for metabolic and cardiovascular risk.

In an Indian context, Rakesh Sinha et al.8 reported similar trends, suggesting that GGT may serve as a valuable early marker in populations with a high baseline prevalence of T2DM and MS. Our findings are consistent with these reports, reinforcing the applicability of GGT testing in routine metabolic risk screening.

The pathophysiological basis for the association between elevated GGT and MS involves oxidative stress and chronic low-grade inflammation. GGT is integral to glutathione metabolism — catalyzing the breakdown of extracellular glutathione to facilitate the resynthesis of intracellular stores10 . In states of increased oxidative stress, such as obesity, insulin resistance, and dyslipidemia, glutathione turnover is accelerated, leading to compensatory upregulation of GGT expression4.

In addition, GGT is expressed in extrahepatic tissues including the kidney, pancreas, and arterial wall. Local GGT activity in atherosclerotic plaques has been implicated in the generation of reactive oxygen species, contributing to LDL oxidation and endothelial dysfunction — key steps in atherogenesis 11. This mechanistic link between GGT, oxidative stress, and vascular injury may explain its association with both MS and cardiovascular events.

The study is not without limitations. Cross-sectional design limits causal inference, and small sample size obtained from a single center may limit generalizability. Also, potential confounding factors like dietary habits and physical activity were not assessed.

Serum GGT levels are significantly elevated in T2DM patients with metabolic syndrome. As the incidence of metabolic syndrome in Type 2 Diabetes mellitus patients is increasing tremendously in recent years, Incorporating GGT testing into routine assessment for T2DM patients will help in early detection of metabolic syndrome, thus reducing mortality & morbidity due to cardiovascular disease.

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