Fat mass mediating effect on the association of worsening insulin resistance with increased left ventricular mass in 1595 adolescents: a 7-Year Longitudinal and Mediation Study

Abstract

Abstract Background Fat mass-insulin resistance vicious cycle has been established in the young population and late adolescence has been identified as the critical time when the pathologic cycle begins. However, the independent and synergistic effect of fat mass in the relationship of insulin resistance with cardiac structure remains unexamined in a large cohort of adolescents, possibly due to the scarcity of repeated echocardiography measures. Mounting effective prevention strategies relies on strong evidence of the timing of the earliest cardiovascular alteration induced by insulin resistance. Purpose To investigate the longitudinal association of insulin resistance with left ventricular mass (LVM) and the mediating effect of fat mass in adolescents. Methods From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1595 adolescents aged 17 years who had fasting glucose and insulin measured at 17- and 24-year clinic visits were included. Homeostatic model assessment for insulin resistance (HOMA-IR) was calculated from fasting insulin x fasting glucose/22.5 at ages 17 and 24 years. Repeated echocardiography measured LVM indexed for height2.7 (LVMI2.7) was available at baseline and follow-up. Fat mass was repeatedly measured with dual-energy Xray absorptiometry at both time points. Multivariable adjusted association was examined using generalized linear mixed-effect models and adjusted for sex, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, and time-varying covariates measured at both baseline and follow-up such as age, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, fat mass, lean mass, smoking status, sedentary time, light physical activity, moderate-to-vigorous physical activity, low-density lipoprotein cholesterol, triglyceride, and high-density lipoprotein cholesterol. Mediation analysis was conducted with a structural equation model adjusting for same covariates, except fat mass. Results Among 1595 adolescents (mean [SD] age at baseline, 17.74 [0.38] years; 955 [59.8%] females]) median insulin resistance increased from 1.46 to 1.74, median fat mass increased from 15.6kg to 19.2kg and the mean LVMI increased from 35.4g/m2.7 to 38.1g/m2.7, over 7 years. In a fully adjusted model, increased insulin resistance from adolescence through young adulthood was significantly associated with increased LVMI (effect estimate 1.01g/m2.7 [95% CI, 0.63 – 1.57], p<0.001) across the 7-year observation period. Increased fat mass mediated (62.3% mediation effect) the longitudinal association between insulin resistance and LVMI from ages 17 – 24 years. Conclusion Worsening insulin resistance from adolescence through young adulthood was associated with increased cardiac mass, contributing 37% to the total increase in LVMI between ages 17 to 24 years but increased fat mass explained two-thirds of the relationship.