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1 Human Genomics Laboratory, Pennington Biomedical Research Center, Baton Rouge, LA, USA
2 Division of Biostatistics, Washington University School of Medicine, St. Louis, MO, USA
* To whom correspondence should be addressed. E-mail: bouchac{at}pbrc.edu.
The beneficial effects of regular physical activity on insulin sensitivity (SI) and glucose tolerance are well-documented, with considerable heterogeneity in responsiveness to exercise-training (ET). To find novel candidate genes for ET-induced improvement in SI we used microarray technology. Total RNA was isolated from vastus lateralis before and after 20 weeks of exercise from individuals participating in the HERITAGE Family Study. SI index was derived from a frequently sampled intravenous glucose tolerance test using the MINMOD Millennium software. Sixteen subjects were selected: eight showing no changes in SI(low responders; LSIR) and eight displaying marked improvement in SI (high responders; HSIR) with ET. The SI increase was ~4 times greater in HSIR compared to LSIR (+3.6 ± 0.5 vs. -1.2 ± 0.5 µU/ml/min, mean ± SE), whereas age, BMI, % body fat, and baseline SI was similar between the groups. Triplicate microarrays were performed, comparing pooled RNA from HSIR and LSIR individuals for differences in gene expression before (pre) and after (post) -ET using in situ generated microarrays (18,861 genes). Array data was validated by QRT-PCR. Almost twice as many genes showed 
2-fold differences between HSIR and LSIR after training compared to pre-training. We identified differentially expressed genes involved in energy metabolism and signaling, novel structural genes, and transcripts of unknown function. Genes of interest upregulated in HSIR include V-Ski oncogene, Four and half LIM domain 1, and Titin. Further study of these novel candidate genes should provide a better understanding of the molecular mechanisms involved in the improvement in insulin sensitivity in response to regular exercise.
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