Article Title

IGF1R Pathway is Related to Enhanced Insulin Sensitivity Following Exercise Training


1Barberio, M., 2Huffman, K. 1Hoffman, E., 2Kraus, W. FACSM, 1Hubal, M. FACSM. 1Children’s National Medical Center, Washington, D.C., 2Duke University Medical Center, Durham, NC

Purpose: Skeletal muscle insulin resistance is a hallmark of Type 2 diabetes development and a precursor to cardiovascular disease. Insulin resistance is a complex trait, driven by both intrinsic (i.e. inherited) and extrinsic (i.e. environmental) factors. Exercise training is known to ameliorate insulin resistance, but this response is highly variable among individuals. The purpose of this study was to identify molecular adaptations in skeletal muscle associated with variable changes in insulin sensitivity (Si) following structured endurance training. Methods: Global gene expression (N=32; M= 15, F= 17) from vastus lateralis biopsies and blood Si (via intravenous glucose tolerance test (IVGTT)) were determined prior to and following 6 months of endurance exercise training. Subjects were stratified based on change in Si post-training as responders (top 2/3; n=21) and non-responders (bottom 1/3; n=11). mRNA profiles were analyzed using ANCOVA (gender, age, and group covariates; Partek Genomic Suite) for each responder group. Resultant mRNA lists were filtered at P < 0.01 and fold change > |1.2|, then uploaded into biological pathway analysis software (Ingenuity Pathway Analysis). Results: ANCOVA detected 2878 and 8602 transcripts affected by training in non-responders and responders respectively. Biological pathway analysis of 317 annotated genes that were uniquely dysregulated in high responders (i.e. transcripts specifically related to Si improvement) highlighted the insulin like growth factor 1 receptor (IGF1R) pathway as a potential mediating mechanism. Transcripts related to IGF1R included estrogen receptor 1 (ESR1; FC = +1.4 from pre to post training), mitogen activated protein kinase 8 (MAPK8; FC = -1.3), and cyclic ADP ribose hydrolase (CD38; FC = -1.2). Conclusion: Global gene expression coupled with pathway analysis suggests a role for the IGF1R pathway in modifying the varied response of Si to structured endurance training. Increased expression of ESR1, along with down regulation IGF1R and multiple related genes, were associated with the greatest improvements in Si. These data present a new pathway target to manipulate in order to maximize insulin sensitivity improvements with exercise.

Study supported by NIH (HL057354, DK081559, AR052596).

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