A transcriptional signature of exercise resistance in skeletal muscle of individuals with type 2 diabetes mellitus

Aims/Hypothesis. Exercise benefits most, but not all, individuals with type 2 diabetes mellitus (T2DM). The aim of this study was to determine whether a proportion of individuals with T2DM would fail to demonstrate exercise-induced metabolic improvements. We hypothesized that this lack of response would be related to their skeletal muscle transcriptional profile. Methods. 42 participants with T2DM from the previously reported HART-D study underwent a 9-month supervised exercise intervention. We performed a principal components analysis to distinguish Responders from Non-Responders (n = 9 each) based on: decreases in (1) HbAic, (2) %fat (3) BMI and (4) increase in skeletal muscle mtDNA. mRNA expression patterns in muscle tissue at baseline were assessed by microarray and qRT-PCR analysis in both groups. Results. Of 186 genes identified by microarray analysis, 70% were up-regulated in Responders and down-regulated in Non-Responders. Several genes involved in substrate metabolism and mitochondrial biogenesis were significantly different (fold-change > 1.5, p < 0.05) between the groups at baseline, indicating a blunted oxidative capacity at baseline in Non-Responders. Conclusions/Interpretations. These data suggest that a unique baseline expression pattern of genes involved in muscle fuel metabolism may predict an individual's lack of exercise response in metabolic outcomes, thus allowing exercise interventions to be targeted to these individuals and aid in the identification of novel approaches to treat Non-Responders in the future. (C) 2015 Elsevier Inc. All rights reserved.