Insulin resistance drives GGT elevation in MASLD with diabetes: evidence from clinical cohorts, mendelian randomization and functional genomics

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) commonly occur together and are linked by shared factors like insulin resistance and excess liver fat. While enzymes such as ALT and AST are routinely measured in these conditions, the clinical significance of gamma-glutamyl transferase (GGT) remains less well understood.

Objective

To investigate the relationship between GGT, insulin resistance, and MASLD using integrative approaches combining clinical data, Mendelian Randomization (MR), and functional genomics.

Method

A hospital-based cohort (N = 498) was analyzed for MASLD and T2D status alongside liver enzymes and insulin resistance (HOMA-IR). Findings were validated in the NHANES 2017–2020 dataset (N = 2586). Univariable and multivariable MR analyses were performed using GWAS summary statistics for fasting insulin, glycemic traits, and percentage liver fat to assess their potential causal effects on GGT. Functional annotation of GGT-associated variants was conducted using FUMA.

Results

Individuals with both MASLD and T2D exhibited significantly elevated GGT and HOMA-IR levels compared to those with either condition alone. MR analyses demonstrated a potential causal effect of genetically predicted fasting insulin on GGT, independent of other metabolic traits. Functional enrichment analysis revealed involvement of insulin signaling and lipid metabolism pathways. Tissue expression highlighted predominant liver and pancreatic expression of GGT-associated genes.

Conclusion

These findings suggest that insulin resistance may contribute more strongly to GGT elevation in MASLD than hepatic fat accumulation, though the comparatively weak instrument strength for liver fat in the multivariable model warrants cautious interpretation of this comparison. Genetically predicted fasting insulin showed a potential causal effect on GGT independent of other metabolic traits. GGT appears to reflect underlying metabolic dysfunction, particularly insulin resistance; however, further prospective and interventional studies are required before its role as a predictive or clinically actionable biomarker can be established.