Associations Between Type 2 Diabetes-Related Genetic Scores and Metabolic Traits, in Obese and Normal-Weight Youths

Context: Young-onset obesity is strongly associated with the early development of type 2 diabetes (T2D). Genetic risk scores (GRSs) related to T2D might help predicting the early impairment of glucose homeostasis in obese youths. Objective: Our objective was to investigate the contributions of four GRSs (associated with: T2D [GRS-T2D], beta-cell function [GRS-β], insulin resistance [GRS-IR], and body mass index) to the variation of traits derived from oral glucose tolerance test (OGTT) in obese and normal-weight children and young adults. Design: This was a cross-sectional association study. Patients: A total of 1076 obese children/adolescents (age = 11.4 ± 2.8 years) and 1265 normalweight young volunteers (age = 21.1 ± 4.4 years) of European ancestry were recruited from pediatric obesity clinics and general population, respectively. Intervention: Standard OGTT was the intervention in this study. Main Outcome Measures: Associations between GRSs and OGTT-derived traits including fasting glucose and insulin, insulinogenic index, insulin sensitivity index, disposition index (DI) and associations between GRSs and pre-diabetic conditions were measured. Results: GRS-β significantly associated with fasting glucose (β = 0.019; P = 3.5 × 10-4) and DI (β =-0.031; P = 8.9 × 10-4, last quartile 18%lower than first) in obese children, and nominally associated with fasting glucose (β = 0.009; P = 0.017) and DI (β =-0.030; P = 1.1 × 10-3, last quartile 11%lower than first) in normal-weight youths. GRS-T2D showed weaker contribution to fasting glucose and DI compared to GRS-β, in both obese and normal-weight youths. GRS associated with insulin resistance and GRS associated with body mass index did not associate with any traits. None of the GRSs associated with prediabetes, which affected only 4%of participants overall. Conclusion: Single nucleotide polymorphisms identified by genome-wide association studies to influence beta-cell function were associated with fasting glucose and indices of insulin secretion in youths, especially in obese children. (J Clin Endocrinol Metab 101: 4244-4250, 2016).