Peroxisome proliferator-activated receptor (PPAR), are nuclear receptors, increasingly recognised as important therapeutic targets to alleviate insulin resistance and metabolic disease. Drugs targeted at PPARalpha and PPARgamma are in clinical use for hypertriglyceridaemia and insulin resistance, respectively. Recent evidence highlights the importance of the less studied isoform PPAR beta/delta. PPAR delta is highly expressed in skeletal muscle. Physical exercise provides health benefits for people with Type 2 diabetes partly by enhancing skeletal muscle insulin action. To determine how skeletal muscle gene-expression changes relates to exercise-induced clinical improvements in Type 2 diabetes we determined mRNA and protein expression of selected genes following a self-supervised program of walking (>150 minutes per wk/ 4 months). Muscle protein expression of PPARdelta increased significantly after physical exercise in subjects with improved clinical profile, but did not change in subjects who did not show exercise-mediated improvement in clinical profile. To assess the role of PPARdelta in human skeletal muscle we utilised primary cultures of human skeletal muscle. Specific activation of PPAR delta using pharmacological agonists increased glucose uptake independently of insulin, and enhanced subsequent insulin stimulation. PPAR delta agonists increased both phosphorylation and expression of AMPK, ERK1/2 MAP kinase and p38 MAP kinase. Basal and insulin-stimulated PKB/AKT was unaltered in cells pre-exposed to PPAR delta agonists. Using siRNA we provide evidence for a role for AMPK in mediation of PPAR delta ?effects on skeletal muscle glucose metabolism. Current work is directed towards understanding the interplay between PPAR delta ?and skeletal muscle metabolic and insulin response profile.