Heritability and genetic correlations of insulin sensitivity measured by the euglycaemic clamp

Aims: Studies investigating genetic factors influencing insulin sensitivity/insulin resistance have measured this phenotype using a variety of methods. In this study, genetic correlations and heritability of insulin sensitivity measured using the euglycaemic hyperinsulinaemic clamp and related phenotypes were examined. Methods: The study population included 818 non-diabetic individuals from 297 nuclear families. Genetic correlations and heritability estimates were calculated using variance components methods. Results: Homeostasis model of insulin resistance (HOMA-IR) and fasting insulin were very highly phenotypically and genetically correlated (r = 0.99 and r = 0.99). HOMA-IR and insulin sensitivity measured with the euglycaemic clamp were only moderately genetically correlated (r = -0.53), suggesting that the two traits may be influenced, at least in part, by different genes. Heritabilities for fasting insulin (h² = 0.36) and HOMA-IR (h² = 0.38) were consistent with the published literature, but heritability for insulin sensitivity measured by the euglycaemic clamp was slightly lower than other published estimates (h² = 0.24). Conclusions: Because HOMA-IR (or fasting insulin) and insulin sensitivity measured with the euglycaemic clamp are not highly genetically correlated, they should not be used interchangeably in genetic studies. Given the very high correlations between fasting insulin and HOMA-IR, HOMA-IR does not offer any advantage over fasting insulin in analyses of insulin sensitivity in this population.