Insulin Sensitivity and Insulin Clearance are Heritable and Have Strong Genetic Correlation in Mexican Americans

OBJECTIVE: We describe the GUARDIAN (Genetics UndeRlying DIAbetes in HispaNics) consortium, along with heritability estimates and genetic and environmental correlations of insulin sensitivity and metabolic clearance rate of insulin (MCRI). DESIGN AND METHODS: GUARDIAN is comprised of seven cohorts, consisting of 4336 Mexican-American individuals in 1346 pedigrees. Insulin sensitivity (S(I)), MCRI, and acute insulin response (AIRg) were measured by frequently sampled intravenous glucose tolerance test in four cohorts. Insulin sensitivity (M, M/I) and MCRI were measured by hyperinsulinemic-euglycemic clamp in three cohorts. Heritability and genetic and environmental correlations were estimated within the family cohorts (totaling 3925 individuals) using variance components. RESULTS: Across studies, age and gender-adjusted heritability of insulin sensitivity (S(I), M, M/I) ranged from 0.23–0.48 and of MCRI from 0.35–0.73. The ranges for the genetic correlations were 0.91 to 0.93 between S(I) and MCRI; and −0.57 to −0.59 for AIRg and MCRI (all P<0.0001). The ranges for the environmental correlations were 0.54 to 0.74 for S(I) and MCRI (all P<0.0001); and −0.16 to −0.36 for AIRg and MCRI (P <0.0001−0.06). CONCLUSIONS: These data support a strong familial basis for insulin sensitivity and MCRI in Mexican Americans. The strong genetic correlations between MCRI and S(I) suggest common genetic determinants.