Type 2 Diabetes Genetic Risk and Type 1 Diabetes Heterogeneity and Progression
Year: 2025
Type: other
Abstract: Insulin secretion varies widely in preclinical type 1 diabetes. To understand the pathogenesis of this metabolic heterogeneity, we asked whether genetic predisposition to type 2 diabetes, quantified by a type 2 diabetes genetic risk score (T2D-GRS), modulates beta cell function and disease progression in individuals at risk for type 1 diabetes. We analyzed 4,324 islet-autoantibody-positive TrialNet Pathway to Prevention participants with genome-wide genotyping and oral-glucose-tolerance testing. Both T2D-GRS and the type 1 diabetes genetic risk score-2 (T1D-GRS2) differed significantly across five previously described groups defined by area-under-the-curve (AUC) C-peptide (a measure of insulin secretion). The highest C-peptide group, compared with the lowest, had significantly higher T2D-GRS, lower T1D-GRS2, higher BMI z-score, greater insulin resistance, older age, and lower prevalence of males, multiple islet autoantibody positivity, and IA-2- or insulin-autoantibody positivity. Progression to clinical (Stage 3) type 1 diabetes was significantly associated with T1D-GRS2 across all groups and with T2D-GRS in all but the lowest C-peptide group. In conclusion, type 2 diabetes genetic burden shapes metabolic heterogeneity and accelerates progression in preclinical type 1 diabetes. These results support evaluating type 2 diabetes-related mechanisms as targets to improve the prediction and prevention of type 1 diabetes.
Authors: Taylor M. Triolo, Jay M. Sosenko, David Cuthbertson, Richard A. Oram, Hemang M. Parikh, Andrea K. Steck, Emily K. Sims, Laura M. Jacobsen, Brandon Nathan, Erin L. Templeman, Suna Onengut-Gumuscu, Carmella Evans-Molina, Stephen S. Rich, Mark A. Atkinson, Maria J. Redondo, Type 1 Diabetes TrialNet Study Group
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4417407520
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