Objective: The metabolic phenotype of youth-onset type 2 diabetes (T2D) differs from that of adult-onset T2D, but little is known about genetic contributions. We aimed to evaluate the association between a T2D genetic risk score (GRS) and traits related to glucose-insulin homeostasis among healthy youth.
Research design and methods: We used data from 356 youth (mean age 16.7 years; 50% female) in the Exploring Perinatal Outcomes Among Children (EPOCH) cohort to calculate a standardized weighted GRS based on 271 single nucleotide polymorphisms associated with T2D in adults. We used linear regression to assess associations of the GRS with log-transformed fasting glucose, 2-h glucose, HOMA of insulin resistance (HOMA-IR), oral disposition index, and insulinogenic index adjusted for age, sex, BMI z score, in utero exposure to maternal diabetes, and genetic principal components. We also evaluated effect modification by BMI z score, in utero exposure to maternal diabetes, and ethnicity.
Results: Higher weighted GRS was associated with lower oral disposition index (β = -0.11; 95% CI -0.19, -0.02) and insulinogenic index (β = -0.08; 95% CI -0.17, -0.001), but not with fasting glucose (β = 0.01; 95% CI -0.01, 0.02), 2-h glucose (β = 0.03; 95% CI -0.0004, 0.06), or HOMA-IR (β = 0.02; 95% CI -0.04, 0.07). BMI z score and in utero exposure to maternal diabetes increased the effect of the GRS on glucose levels.
Conclusions: Our results suggest that T2D genetic risk factors established in adults are relevant to glucose-insulin homeostasis in youth and that maintaining a healthy weight may be particularly important for youth with high genetic risk of T2D.
© 2021 by the American Diabetes Association.