African Americans (AA) are at greater risk for type 2 Diabetes (T2D) compared to European Americans (EA). This greater risk may derive in part from genetic factors. The genetic risk for insulin resistance (IR) has been linked to the failure to expand adipose tissue and is reflected in a genetic risk score (GRS) that is inversely associated with adiposity. In this study, we investigated whether associations between the GRS and measured insulin sensitivity (IS) differ by BMI status and/or race in a sample of 107 EA and AA adults without diabetes. IS was measured with the euglycemic clamp with an insulin dose of 120 µU/m²/min/kg lean body mass. In addition, surrogate indices of IS were calculated using glucose and insulin values obtained from an oral glucose tolerance test. Participants were classified as “high” or “low” BMI using the sample median (25.9 kg/m^2) as the cut-point. GRS were derived from imputed genotypes and weighted for clamp-derived IS. Multiple linear regression models were used to assess interactions between BMI status and GRS on measures of IS. Models were stratified by race and adjusted for percent body fat, sex, and age. In EA, associations of GRS with HOMA-IR and Matsuda differed by BMI status (pint=0.024 and pint=0.007, respectively), where GRS was inversely associated with IS in the high BMI group only (p=0.027 and p=0.010, respectively), suggesting that genetic risk for IR in EA is driven by greater adiposity. Conversely in AA, associations of GRS with IS from the clamp differed by BMI status (pint=0.083), but an inverse association was observed only in the low BMI group (p=0.035), suggesting that in AA, genetic risk for IR is associated with lower adiposity. Our results indicate that obesity status may differentially impact the link between genetic risk for IR and measured IS within and between races. Further, these results suggest that with a larger sample, a distinct phenotype may exist in AA where higher adiposity permits greater IS.


M. L. Yurchishin: None. L. A. Fowler: None. V. Parcha: None. P. Arora: None. W. Garvey: Advisory Panel; Boehringer-Ingelheim, Novo Nordisk, Eli Lilly and Company, Merck & Co., Inc., Alnylam Pharmaceuticals, Inc., Fractyl Health, Inc. Research Support; Novo Nordisk, Eli Lilly and Company, Epitomee, Pfizer Inc. Advisory Panel; Inogen. Research Support; Neurovalens. B. Gower: Consultant; Abbott.

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