Exercise training enhances insulin sensitivity (Si) in humans. However, it is to be determined which phenotypic and muscle molecular changes underwrite this change in Si. We sought to understand the mechanisms behind increased Si following 12 weeks of high intensity aerobicinterval (HIIT), resistance (RT), or combined (CT) exercise training in 30 young and 24 old humans. Measurements included Si estimated from a two-stage hyperinsulinemic-euglycemic clamp, and a host of independent variables including VO2 peak, muscle mitochondrial respiration, Liver FWF (Fat-Water-Fraction), visceral and subcutaneous fat, and gene expression from muscle biopsies. We performed a univariate and multivariate analysis of Si vs. phenotypic changes induced by training. After adjusting for age, sex and exercise group, VO2max was positively associated with an increase in Si from pre to post exercise (p=0.032). Interestingly, within the RT group alone, positive association between VO2max and Si (p=0.05) and negative association between liver FWF and Si (p=0.034) were observed. Within the HIIT group, there was a positive association between muscular strength and Si (p=0.04). Separate multivariate models assessed the effect of muscle gene expression changes on Si while adjusting for age, training type, response to training, VO2max, and mitochondrial function. Enrichment Analysis of genes associated with Si showed upregulation of genes in Branched-Chain Amino Acid (BCAA) and Lysine metabolism, although the latter was specifically upregulated with HIIT. Products of lysine metabolism, such as alpha-aminoadipic acid have been implicated in development of insulin resistance and BCAA are involved in signaling of insulin response. A strong positive association of Si with both BCAA (FDR 0) and lysine metabolism (FDR 0.008) following HIIT and a weaker correlation between Si and BCAA metabolism (FDR 0.002) following RT indicates the role of muscle AA metabolism as a common factor contributing to enhanced Si following exercise training.


A. Prabha kumar: None. S. Dasari: None. M. W. Pataky: None. J. Crook: None. C. T. Ball: None. K. Klaus: None. I. R. Lanza: None. M. M. Robinson: Stock/Shareholder; Self; GE Healthcare. K. Nair: None.


National Institutes of Health (R01AG09531)

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