Higher triglyceride-glucose index is linked to increased risk of diabetic microvascular complications

Methodology

This was a prospective cohort study using data from the UK Biobank, a nationwide study that recruited over 500,000 volunteers aged 40-69 years across the United Kingdom beginning in 2006. The analysis included 19,512 participants with type 2 diabetes who did not have diabetic microvascular complications at baseline. Type 2 diabetes was defined using physician diagnosis, baseline diabetes medication use, HbA1c ≥48 mmol/mol, or elevated random blood glucose levels.

The triglyceride-glucose index was calculated at baseline using fasting blood glucose and triglyceride levels with the formula: TyG = Ln[TG (mg/dL) × FBG (mg/dL)/2]. The primary outcomes were first diabetic microvascular complication (DMC) and DMC multimorbidity, defined as coexistence of two or more complications. Individual complications included diabetic retinopathy, neuropathy, and nephropathy, identified through ICD-9 and ICD-10 codes in hospital admission records. Participants were followed until onset of complications, death, or October 31, 2022, with a median follow-up of 12.9 years.

Statistical analysis used multivariable Cox proportional hazards models adjusted for age, sex, ethnicity, socioeconomic status, smoking and drinking status, physical activity, sleep duration, diet quality, blood pressure, lipid levels, HbA1c, diabetes duration, medication use, and polygenic risk score for type 2 diabetes. Multistate models examined transitions from no complications to first complication, multimorbidity, and death. Restricted cubic splines assessed dose-response relationships. Sensitivity analyses tested robustness by varying time intervals for same-day events and excluding early outcome events.

Interventions

This study examined the triglyceride-glucose (TyG) index as an exposure or risk factor rather than as an intervention. The TyG index is a calculated biomarker derived from routine laboratory measurements (fasting glucose and triglycerides) that serves as a surrogate marker of insulin resistance. It was measured at baseline and participants were categorized by TyG index tertiles for analysis.

The study also incorporated polygenic risk scores (PRS) for type 2 diabetes as a measure of genetic susceptibility. The PRS was generated using the PRS-CS Bayesian regression framework with genome-wide association study data from the DIAMANTE consortium, and participants were categorized into low, intermediate, and high genetic risk groups. The combination of metabolic risk (TyG index) and genetic risk was examined to identify subgroups at particularly high risk for microvascular complications.

Key Findings

Among 19,512 participants with type 2 diabetes followed for a median of 12.9 years, 5,875 (30.1%) developed at least one microvascular complication and 1,314 (22.4% of those with complications) progressed to multimorbidity. Each standard deviation increase in the TyG index was associated with a 19% increased risk of first microvascular complication (HR 1.19, 95% CI 1.14-1.24) and a 38% increased risk of multimorbidity (HR 1.38, 95% CI 1.27-1.51) after comprehensive adjustment. The association was strongest for diabetic neuropathy (HR 1.54, 95% CI 1.38-1.70), followed by diabetic retinopathy (HR 1.20, 95% CI 1.13-1.27) and diabetic nephropathy (HR 1.16, 95% CI 1.10-1.23). Multistate modeling demonstrated that elevated TyG index predicted progression from first complication to multimorbidity (HR 1.25, 95% CI 1.15-1.37), particularly among those initially diagnosed with retinopathy (HR 1.39) or nephropathy (HR 1.14). A J-shaped dose-response relationship was observed, and individuals with both high TyG index and high genetic risk showed the greatest risk of complications in a stepwise fashion, though no statistical interaction was detected.

Comparison with other Studies

Previous cross-sectional and short-term studies have linked elevated TyG index to individual diabetic microvascular complications, but few have examined its role in predicting disease progression or multimorbidity. A meta-analysis by Li et al. (2019) of 26 cross-sectional studies found strong correlations among microvascular complications, with retinopathy significantly associated with nephropathy (OR 4.64) and neuropathy (OR 2.22), supporting the concept of multimorbidity. Liu et al. (2021) found associations between TyG and diabetic nephropathy in a cross-sectional study, while Neelam et al. (2023) reported associations with diabetic retinopathy in a Singaporean population.

The current study extends this literature by demonstrating that TyG predicts not just incident complications but also transitions between disease states over an extended 13-year period. The finding that TyG remains predictive after adjusting for multiple lifestyle factors addresses a gap in prior research. The multistate modeling approach provides novel insights into progression pathways, showing that retinopathy and nephropathy serve as particularly high-risk states for developing multimorbidity. The incorporation of polygenic risk scores represents an advance in understanding how metabolic and genetic factors jointly influence complication risk, though the lack of statistical interaction suggests these operate as independent risk factors rather than synergistically.

Regarding mortality, prior studies including Bjerg et al. (2019) and Garofolo et al. (2019) demonstrated that microvascular complication burden substantially increases mortality risk in type 1 diabetes. The current study's finding that TyG predicts mortality only among those who have already developed complications (HR 1.10) rather than from baseline (HR 1.04) aligns with this literature and suggests microvascular disease acts as a mortality accelerator. This contrasts with the more direct association typically seen between metabolic markers and macrovascular outcomes, highlighting distinct pathways by which metabolic dysfunction affects different complication types.

Journal Reference

Yuan X, Peng M, Shi X, Yang D, Wang F, Hou C, Xu G. Triglyceride-glucose index, genetic susceptibility, and trajectory of microvascular multimorbidity in type 2 diabetes. Sci Rep. 2026;16:8230. doi:10.1038/s41598-026-39777-w