Type 2 Diabetes Genetic Risk and Type 1 Diabetes Heterogeneity and Progression.

Summary

In 4,324 autoantibody-positive individuals in TrialNet, higher type 2 diabetes genetic risk was associated with higher C-peptide AUC, insulin resistance, and faster progression to clinical type 1 diabetes in most subgroups, whereas type 1 diabetes GRS predicted progression across all groups. These data indicate that T2D genetic burden modulates metabolic heterogeneity and disease trajectory in preclinical T1D.

Key Findings

• T2D-GRS and T1D-GRS2 varied significantly across five C-peptide AUC-defined subgroups.
• Higher T2D-GRS associated with higher C-peptide AUC, higher BMI z-score, greater insulin resistance, and older age.
• Progression to stage 3 T1D was associated with T1D-GRS2 across all groups and with T2D-GRS in all but the lowest C-peptide subgroup.

Clinical Implications

Integrating T2D-GRS with T1D-GRS2 and metabolic phenotyping may refine staging, risk communication, and selection for prevention trials, including targeting insulin resistance pathways in autoantibody-positive individuals.

Limitations

• Observational design precludes causal proof of T2D-GRS effects on progression
• Follow-up duration and event adjudication details not specified in the abstract

Future Directions

Test whether insulin resistance–targeted interventions slow progression in autoantibody-positive individuals with high T2D-GRS; integrate multi-omic predictors to improve individualized prevention.