Minimal model-based insulin sensitivity has greater heritability and a different genetic basis than homeostasis model assessment or fasting insulin.
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 approximately 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.
Bergman
Richard N
RN
Keck School of Medicine, University of Southern California, Los Angeles, California, USA. rbergman@usc.edu
Zaccaro
Daniel J
DJ
Watanabe
Richard M
RM
Haffner
Steven M
SM
Saad
Mohammed F
MF
Norris
Jill M
JM
Wagenknecht
Lynne E
LE
Hokanson
James E
JE
Rotter
Jerome I
JI
Rich
Steven S
SS
D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000453:epidemiology / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics*; D005215:Fasting; D005260:Female; D020022:Genetic Predisposition to Disease / Q000453:epidemiology; D018149:Glucose Intolerance / Q000453:epidemiology / Q000235:genetics*; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D007328:Insulin / Q000097:blood*; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008954:Models, Biological; D010641:Phenotype; D012307:Risk Factors
D007328:Insulin