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Minimal Model-Based Insulin Sensitivity Has Greater Heritability and a Different Genetic Basis Than Homeostasis Model Assessment or Fasting Insulin

¹ Keck School of Medicine, University of Southern California, Los Angeles, California
² Wake Forest University School of Medicine, Winston-Salem, North Carolina
³ University of Texas Health Sciences Center at San Antonio, San Antonio, Texas
⁴ University of California at Los Angeles, Los Angeles, California
⁵ University of Colorado Health Sciences Center, Denver, Colorado
⁶ Cedars-Sinai Medical Center, Los Angeles, California

Insulin resistance is an important risk factor for development of type 2 diabetes as well as other chronic conditions, including hypertension, cardiovascular disease, and colon cancer. To find genes for insulin resistance it is necessary to assess insulin action in large populations. We have previously measured insulin action in a large cohort of subjects (Insulin Resistance and Atherosclerosis Study [IRAS] Family Study) using the minimal model approach. In this study, we compare sensitivity from the minimal model (insulin sensitivity index [S_I]) with the measure of insulin resistance emanating from the homeostasis model assessment (HOMA) approach. The former measure emerges from the glycemic response to endogenous and exogenous insulin; the latter is based solely on fasting measures of glucose and insulin. A total of 112 pedigrees were represented, including 1,362 individuals with full phenotypic assessment. Heritability of S_I was significantly greater than that for HOMA (0.310 vs. 0.163) and for fasting insulin (0.171), adjusted for age, sex, ethnicity, and BMI. In addition, correlation between S_I and either HOMA or fasting insulin was only 50% accounted for by genetic factors, with the remainder accounted for by environment. Thus S_I, a direct measure of insulin sensitivity, is determined more by genetic factors rather than measures such as HOMA, which reflect fasting insulin.

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