Exercise training decreases insulin resistance and increases glucose tolerance in pre-diabetes and type 2 diabetes. However, the adaptive responses in skeletal muscle at the molecular and genetic level for these effects of exercise training have not been clearly established in an animal model of pre-diabetes. The present study identifies alterations in muscle gene expression that occur with exercise training in pre-diabetic, insulin-resistant obese Zucker rats and insulin-sensitive lean Zucker rats and are associated with a well-defined metabolic outcome. Treadmill running for up to 4 weeks caused significant enhancements of glucose tolerance as assessed by the integrated area under the curve for glucose (AUCg) during an oral glucose tolerance test. Using microarray analysis, a set of only 12 genes was identified as both significantly altered by exercise training (>1.5-fold change; p<0.05) and significantly correlated (p<0.05) with the AUCg. Two genes, peroxisome proliferator-activated receptor- coactivator 1 (PGC-1) and the protein kinase C- (PKC-), are involved in the regulation of muscle glucose transport, and we provide the first evidence that PKC- gene expression is enhanced by exercise training in insulin-resistant muscle. Protein expression of PGC-1 and PKC- were positively correlated with mRNA expression for these two genes. Overall, we have identified a limited number of genes in soleus muscle of lean and obese Zucker rats that are associated with both decreased insulin resistance and increased glucose tolerance following endurance exercise training. These findings could guide the development of pharmaceutical "exercise mimetics" in the treatment of insulin-resistant, pre-diabetic or type 2 diabetic individuals.