The triglyceride to HDL‑C ratio explains part of the association between fatty liver and incident type 2 diabetes: a statistical mediation analysis of the NAGALA cohort

BACKGROUND: Fatty liver is associated with an increased risk of type 2 diabetes mellitus (T2DM). However, the mediating role of the triglyceride to high-density lipoprotein cholesterol (HDL-C) ratio (THR) in this association remains unclear. This study aimed to evaluate the impact of fatty liver on diabetes risk and explore the mediating effect and predictive performance of THR. METHODS: This secondary analysis included 15,453 non-diabetic participants from the NAGALA cohort. Fatty liver was diagnosed using ultrasonography, and T2DM was defined as a fasting plasma glucose level ≥ 7 mmol/L, hemoglobin A1c level ≥ 6.5%, or self‑report. THR was calculated as triglycerides (mmol/L) divided by HDL-C (mmol/L). Cox regression, mediation analysis, and receiver operating characteristic (ROC) curve analyses were performed. RESULTS: Over a median follow-up of 5.4 years, 373 (2.4%) participants developed diabetes. Fatty liver was associated with a significantly increased risk of diabetes [adjusted hazard ratio (HR) 2.88; 95% confidence interval (CI) 2.22-3.73; P < 0.001]. The association was more pronounced in women and younger individuals (< 45 years). Fatty liver was also significantly associated with a higher THR (adjusted β 0.35; P < 0.001). Compared with the lowest THR quartile (< 0.30), the highest quartile (> 0.90) showed an adjusted HR of 2.08 (95% CI 1.27-3.40) for diabetes. THR mediated 11.63% (95% CI 6.80-19.58%) of the fatty liver-T2DM association, with significant mediation in men but not in women. THR yielded an area under the curve (AUC) of 0.75 (95% CI 0.72-0.77) for predicting diabetes, with a sensitivity of 69.71% and specificity of 68.58% at an optimal cutoff value of 0.75. CONCLUSIONS: Fatty liver is significantly associated with an increased risk of diabetes, and THR statistically explains part of this association, particularly in men. THR demonstrates moderate predictive value and may serve as a useful biomarker for risk stratification in patients with diabetes.