Cardiovascular risk factors in children and adolescents with type 1 diabetes mellitus: the role of insulin resistance and associated genetic variants

Introduction: Type 1 diabetes (T1D) is associated with increased risk of cardiovascular disease. Insulin resistance is an important cardiovascular risk factor (CVRF), also in subjects with T1D, but the influence of the genetic predisposition of insulin resistance on cardiovascular risk is still unknown in T1D. We aimed to determine whether a genetic score composed of six variants, previously associated to insulin resistance and type 2 diabetes (T2D) risk, associates with insulin sensitivity and known CVRFs in children and adolescents with T1D.Materials and Methods: 330 children and adolescents (174 males; mean age 15.7 +/- 3.5 years) with T1D were genotyped for the following genetic variants: rs1801278 (IRS1), rs1044498 (ENPP1), rs2295490 (TRIB3), rs1801282 (PPARG), rs780094 (GCKR), and rs35767 (IGF1). An additive genetic risk score (GRS) and cardiovascular risk score (CVRS) were calculated. Anthropometric, glycemic control, insulin sensitivity, blood pressure, and biochemical parameters were assessed. Multivariate regression between evaluated phenotypes and GRS were performed. Results: We found a significant association between the GRS and estimated insulin sensitivity [beta=-0.027 (-0.040 to -0.013), R2=0.86, p=<0.001], diastolic blood pressure [beta=0.68 (0.08-1.27), R2=0.20, p=0.026], triglycerides [beta=4.26 (1.74-6.77), R2=0.13, p=0.001], waist to height ratio [beta=0.003 (0.001-0.006), R2=0.75, p=0.010], non-HDL-cholesterol [beta=3.63 (1.39-5.87), R2=0.12, p=0.002], and CVRS [beta=0.063 (0.008-0.118), R2=0.19, p=0.025], independent of age, sex, BMI, pubertal stage, diabetes duration, HbA1c, type of treatment and total insulin requirement. The addition of the GRS to established clinical risk factors significantly improved the discriminatory capability of the regression model for predicting subjects with more CVRFs (C-statistic 0.89 [95%CI 0.84-0.95] vs. 0.83 [0.73-0.93]; p = 0.037).Conclusions: Insulin resistance and T2D risk-associated genetic variants influence insulin sensitivity and known cardiovascular risk factors in children and adolescents with T1D.