1651-P: Low Leg Fat and Ethnicity Are Predictors for Genetic Insulin Resistance in a Multiethnic Sample of Early Pubertal Children

In the United States, Hispanic- and African-Americans (HA and AA, respectively) have been shown to have a higher prevalence of type 2 diabetes than their European-American (EA) counterparts. A recent genome-wide association study revealed that genetic variants linked to insulin resistance (IR) phenotypes were associated with lower levels of leg fat mass. We investigated whether leg fat deposition and genetic risk for IR differed by ethnicity in a cross-sectional study of 82 AA, 75 HA, and 83 EA children aged 7-12 years. Participants were genotyped with the Metabochip array for 46 single nucleotide polymorphisms (SNPs) associated with IR, and a genetic risk score (GRS) was developed using the weighted sum of the risk alleles. An intravenous glucose tolerance test and minimal modeling were used to derive the insulin sensitivity index (S_I), while body composition was measured by DXA. Multiple linear regression was used to compare differences among ethnicity after adjustment for sex, age, Tanner stage, and socioeconomic status. Leg fat models were also adjusted for total body fat and BMI percentile, while S_I models were adjusted for adiposity. Mean leg fat deposition relative to total body fat was significantly lower in HA compared to EA and AA (P < 0.001 for both comparisons). Additionally, GRS independently predicted both leg fat (β = -0.34 (0.13), P = 0.012) and S_I (β = -1.33 (0.59), P = 0.027) in HA. In contrast, GRS was not an independent predictor of either outcome in AA or EA. These results suggest that HA may have a genetically impaired ability to store lipid in peripheral adipose tissue depots, consequently leading to deposition in ectopic regions and IR. Our findings highlight a potential mechanism contributing to the higher rate of type 2 diabetes observed in Hispanic-American populations.