Introduction

Metabolic syndrome (MetS) is a cluster of conditions comprising hypertension, hyperglycemia, central obesity, and dyslipidemia, which are considered risk factors for the future development of type 2 diabetes mellitus (T2DM), cardiovascular disease (CVD), and certain cancers. The global prevalence of MetS is rising (12.5% to 31.4%), depending on the definition used, and is considered one of the major contributors to non-communicable disease mortality in developing countries [1].

25-hydroxyvitamin D (25[OH]D) deficiency (VDD) has arisen as a critical global health challenge, with increasing prevalence rates observed across diverse populations worldwide [2], particularly in South Asian countries like India [3]. Paradoxically, despite abundant sunlight, factors such as increased urbanization, reduced outdoor activities, and darker skin pigmentation aid in widespread VDD in the Indian community [3–5]. Emerging evidence has expanded our understanding of 25(OH)D’s role beyond calcium and phosphate regulation, linking its deficiency to increased risks of mortality, diabetes, thyroid dysfunction, obesity, cancer, and vascular disease [6,7].

Studies have shown inadequate 25(OH)D levels correlate with MetS [8, 9]. Furthermore, a comprehensive systematic review and meta-analysis of randomized controlled trials of T2DM patients revealed a moderate enhancement in insulin sensitivity following 25(OH)D supplementation interventions [10,11]. However, a recent meta-analysis indicates inadequate evidence supporting the advantages of taking 25(OH)D on MetS and its elements among obese and diabetic patients, highlighting the complexity of this relationship [12]. Similarly, a randomized controlled trial in prediabetes shows no effects of 25(OH)D supplements on insulin resistance, emphasizing the inconsistent conclusion about the interplay between 25(OH)D and insulin resistance [13].

However, due to its cost, 25(OH)D is not routinely tested in many hospitals. Further, studies have shown that most 25(OH)D test requests are unnecessary [14,15]. Therefore, it is important to develop a cost-effective screening tool for the detection of patients at risk of VDD. This could help relieve unnecessary financial burdens prior to sending for the test.

The Triglyceride-Glucose (TyG) index, derived from fasting plasma glucose (FPG) and triglyceride concentration, has gained attention as a reliable and cost-effective surrogate marker of insulin resistance [16]. A substantial body of literature has supported the concurrence of the TyG index and standard insulin resistance measurements, such as homeostatic measurement of insulin resistance (HOMA-IR) and hyperglycemic clamp [17,18]. Studies have elucidated its role as a marker for CVD deaths in the general population, mortality in MetS, and renal impairment in hypertensive patients [7,19–22]. Similarly, TyG-body mass index (TyG-BMI) has also shown a significant association with the standard measure of insulin resistance [23].

Despite growing evidence linking insulin resistance indices to metabolic complications, the relationship between triglyceride-glucose indices and 25(OH)D status in MetS remains poorly characterized. Therefore, this study aimed to conduct a retrospective cross-sectional analysis in patients with MetS to examine the associations between TyG and TyG-BMI indices with serum 25(OH)D concentrations, providing valuable insights for clinical practice.

Materials and methods

Study design and setting

This retrospective cross-sectional study investigated the TyG index and TyG-BMI association with 25(OH)D in patients with MetS. Initially, 16,262 patients whose medical records were screened, 1,297 (869 men, 428 women) met the diagnostic criteria for MetS and were evaluated (Fig 1).‌‌

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Fig 1. Study participants’ selection flowchart.

https://doi.org/10.1371/journal.pone.0349683.g001

The TyG index values were stratified into three tertiles: tertile 1 (<9.16), tertile 2 (9.16–9.53), and tertile 3 (≥9.54). 25(OH)D, lipid profile, FPG, urea, creatinine, and albumin were compared across tertiles and genders.

Essential data were retrieved from participants who underwent routine health examinations at a tertiary care hospital from January 1, 2021, through July 14, 2023, and were accessed on January 1, 2024. The Institutional Ethics Committee of Kasturba Medical College and Kasturba Hospital, Manipal, approved the study and waived the consent due to the retrospective nature of the study (numbered IEC1: 276/2023). The Declaration of Helsinki was followed when conducting the study.

Results

Comparison between tertiles

Table 1 shows the comparison among tertiles. Analysis of TyG index tertiles showed significant differences in lipid profile parameters, including TC, triglycerides, and HDL-C (all P < 0.001). Blood glucose indices, FBG, PPBG, and HbA1c also showed significant differences among tertiles (all P < 0.001).

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Table 1. Comparison of variables between the tertiles(T).

https://doi.org/10.1371/journal.pone.0349683.t001

Furthermore, we observed statistically significant disparities in kidney function indicators, including creatinine (p = 0.01) and albumin (p < 0.001). Similarly, the TyG-BMI is significantly higher in tertile 3 (p < 0.001).

Comparisons of gender

Table 2 shows the comparison of genders. Males had significantly higher serum 25(OH)D concentrations than females (P < 0.001). BMI differed significantly between sexes (P < 0.001), with women demonstrating higher BMI values than men. Conversely, men exhibited significantly higher values for the TyG index and triglyceride levels (all P < 0.001) than women. Women participants showed significantly higher values of (HbA1C, TC, and LDL-C (P < 0.001), compared to their male counterparts. TyG-BMI was significantly higher in females compared to males (P = 0.04)

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Table 2. Sex-specific comparison of clinical and biochemical parameters.

https://doi.org/10.1371/journal.pone.0349683.t002

Correlation analysis

Table 3 depicts the correlation analysis. The TyG index demonstrated significant correlations with lipid profile (TC, HDL-C, and TC/HDL-C) and glucose parameters (HbA1c and PPBG) (all P < 0.001) but not with 25(OH)D. However, TyG-BMI shows a significantly weak negative correlation with vitamin D (r = −0.09, P < 0.001). The scatter plot is shown in (Figs 2 and 3).

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Table 3. Correlation analysis.

https://doi.org/10.1371/journal.pone.0349683.t003

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Fig 2. Association between TyG index and serum vitamin D concentration (r = 0.007, p = 0.81): Correlation coefficients were interpreted as follows: r < 0.10 = negligible, 0.10–0.29 = weak, 0.30–0.49 = moderate, ≥ 0.50 = strong association‌‌.

https://doi.org/10.1371/journal.pone.0349683.g002

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Fig 3. Association between TyG-BMI index and serum vitamin D concentration (r = −0.09, p < 0.001): Correlation coefficients were interpreted as follows: r < 0.10 = negligible, 0.10–0.29 = weak, 0.30–0.49 = moderate, ≥ 0.50 = strong association.

https://doi.org/10.1371/journal.pone.0349683.g003

Discussion

This study examined the relationship between 25(OH)D status and TyG-related indices in adults with MetS, revealing limited or no utility for identifying vitamin D deficiency in adults with MetS. Our primary finding is that, while the TyG-BMI showed a statistically significant but weak negative correlation with serum 25(OH)D levels (r = −0.09, P < 0.001), this association is unlikely to be clinically relevant. The TyG index showed no significant association (r = 0.007, P = 0.81). Importantly, this study revealed a high prevalence of VDD and insufficiency in the MetS patients, with only 7% of participants exhibiting normal levels. Significant differences were observed across TyG index tertiles in various metabolic parameters, including lipid profiles, glycemic indices, and markers of kidney function.

Contrary to previous studies suggesting improvements in insulin responsiveness with the dietary addition of 25(OH)D [10,11], the TyG index doesn’t show a significant association with circulating 25(OH)D in our sample; however, the TyG-BMI and 25(OH)D association is consistent with these findings. The very small effect size limits the clinical utility of TyG-BMI as a marker of vitamin D status. Our finding on the TyG index aligns with systematic reviews and meta-analyses of obese and diabetic patients from Brazil, Europe, and the United States, which reported no improvement in insulin resistance after consuming 25(OH)D [12]. Further, a study of Kenyan patients with T2DM also shows no association of insulin resistance with inadequate serum 25(OH)D [27].

The observed widespread VDD underscores the urgent need for a targeted approach to raise 25(OH)D status in this high-risk population. These findings align with previous research documenting a lack of sufficient 25(OH)D among general adults in the Delhi region [3] and MetS patients in northern India [28]. However, the prevalence rate documented in our study exceeded that described in meta-analyses of general adult populations in South Asia [4] and African regions [29]. This inconsistency could be associated with factors such as insulin resistance, a key component of MetS, which has been inversely related to 25(OH)D supplementation [10]. Moreover, MetS patients are usually obese, and it was found that inadequate serum 25(OH)D is linked with higher BMI [10]. Furthermore, a meta-analysis of overweight and obese adults revealed that a lack of 25(OH)D is related to dyslipidemia [30].

The significant variations in lipid profiles across TyG index tertiles are consistent with previous research demonstrating the strong correlation of the index with dyslipidemia [31]. The observed differences in FBG, PPBG, and HbA1c across TyG index tertiles highlight the possible role of the index in identifying individuals with impaired glucose metabolism, consistent with the Simental-Mendía et al. study [16].

Significant differences in kidney function parameters, particularly creatinine and albumin, were observed across TyG index tertiles. These findings indicate a possible connection between insulin resistance, as captured by the TyG index, and initial signs of kidney dysfunction. This association aligns with recent studies reporting correlations between chronic kidney disease (CKD) risk [32] and renal impairment in adults with elevated blood pressure [21] with the TyG index. The underlying mechanisms may involve insulin resistance-mediated pathways, including oxidative stress, inflammation, and endothelial dysfunction [32,33]. However, as the present study is a cross-sectional study, causal inference cannot be established, and the above mechanistic interpretations are purely speculative and require confirmation through longitudinal and interventional studies.

Further, the inverse relationship of the TyG index with BMI contradicts previous findings [34], challenging the conventional understanding of metabolic risk factors. These results imply that the TyG index might capture aspects of metabolic dysfunction independent of, or differently related to, overall adiposity, highlighting the potential limitations of relying solely on BMI as a metabolic risk indicator [35].

The subgroup analysis revealed that women in our study were generally older and had higher BMI than men, consistent with previous research suggesting increased risk for MetS in postmenopausal women [36]. Although the degree of VDD was comparable in both sexes, serum concentrations of 25(OH)D were much higher in men. This finding diverges from a study of adult populations across Latin American countries, which revealed a greater rate of reduced 25(OH)D concentration in men [37]. The decreased 25(OH)D concentrations in women may be attributed to cultural factors in the region, including increased indoor activity, clothing practices that limit sun exposure, and generally higher body fat percentage than men [4,5].

The strengths of this study include its large sample size (n = 1,297) of MetS patients, allowing for robust statistical analysis of various metabolic parameters and sex-specific comparisons. Nonetheless, this study possesses certain drawbacks. Firstly, the cross-sectional approach hinders the capability to determine causal connections. Research spanning an extended period is necessary to evaluate the ability of TyG and TyG-BMI to predict metabolic outcomes and determine whether the temporal variation in the TyG index correlates with changes in the observed parameters. Second, the lack of multivariable adjustment for key confounders such as age, BMI, physical activity, sun exposure, and seasonal variations represents a critical limitation that may substantially affect the observed associations. Furthermore, it was not determined whether subjects were taking medications commonly prescribed for MetS, such as statins or metformin, which are known to influence both lipid profiles and vitamin D metabolism. Future studies should incorporate multivariable-adjusted models to better isolate the independent contribution of TyG-related indices to vitamin D status. Third, this study was conducted on patients with MetS from South India; this may restrict the applicability of our findings to populations from other regions and individuals with different health conditions. Finally, we assessed serum 25-hydroxyvitamin D concentrations, which, while widely accepted as reliable markers of 25(OH)D status, may not fully represent the biochemically active form, 1,25-dihydroxyvitamin D. Furthermore, sensitivity analysis was not conducted in this study. This potential discrepancy could introduce information bias into our results.

Conclusion

This analysis reveals the high prevalence of VDD and insufficiency in MetS. Moreover, given its significant associations with these clinical parameters, the TyG index emerges as a promising biomarker for assessing lipid metabolism disorders, glycemic control, and renal dysfunction in this population. However, the clinically insignificant association between TyG indices and serum 25(OH)D suggests limited utility for identifying VDD risk within MetS patients.

Future research should also address the identified limitations by incorporating data on unmeasured confounders, such as dietary intake, medication use, and detailed sun exposure habits. Further mechanistic studies are needed to elucidate the complex interplay between insulin resistance, 25(OH)D metabolism, and the progression of MetS components. Public health authorities should prioritize proper screening programs and targeted interventions to address the high rate of VDD in MetS patients, especially considering regional and cultural factors.

Acknowledgments

Department of Biochemistry, Medicine and Medical Records, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India-576104, for supporting this study.