Ethnic Differences in Hepatic Insulin Clearance Seen since Childhood Suggest a Genetic Basis

African American (AA) adult women (AAw) have 1/3 the hepatic insulin extraction as European American adult women (EAw). Lower hepatic (but not extrahepatic) insulin clearance in AAw contributes to hyperinsulinemia. Our aim was to examine whether hepatic insulin clearance impairment exists in AA since childhood. If so, genetic factors might explain ethnic differences in insulin clearance. The FSIGT was performed on 203 children [55 AAc, 88 EAc, 60 HAc (Hispanic American), ages 7-13 years, mean BMI = 19 kg/m², basal plasma glucose = 99 mg/dL, insulin = 78 pM, C-peptide = 511 pM]. Data were analyzed with a recent mathematical model providing individual estimates of both hepatic fractional insulin extraction (FE_L) and extrahepatic insulin clearance (CL_P). Results are presented as mean (SD). Two-way ANOVA and ANCOVA were done: sex and ethnicity were used as groups for both the analysis, while age, Tanner stage and body fat from DXA were the covariates. FE_L is lower in AAc (19% (20%)) than EAc (33% (20%)), p = 0.0007). Adjusting for the covariates, ethnicity was still associated with lower FE_L in AAc vs. EAc (p = 0.0012); sex had a slight but significant effect (FE_L=24% (10%) in boys vs. 29% (10%) in girls, p = 0.04). FE_L in HAc (28% (21%)) was not significantly different than either AAc or EAc (p>0.05), with or without covariates correction. No correlation between FE_L and age was found in these children. Unlike FE_L, CL_P was not impacted by ethnicity or sex; similar values were observed among the three groups [27 (12), 21 (12), and 24 (28) mL/kg/min for AAc, HAc, and EAc, respectively; p > 0.05]. As the between-group differences in FE_L are seen early in childhood, this suggests genetic factors likely contribute to those, rather than lifestyle, that might have a less evident effect at that age, instead. Playing a more important role than previously realized, the reduced insulin degradation would lead to hyperinsulinemia, insulin resistance, and possibly greater risk for type 2 diabetes in AA, compared to other ethnic groups.