Effects of GW 501516 treatment on insulin-stimulated glucose transport in rodent skeletal muscle

Cresser, Justin Hugh Bain
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University of Guelph

Increased levels of reactive lipid species, such as diacylglycerols (DAGs) and ceramides, in the intracellular milieu of skeletal muscle are thought to play a major role in the development of insulin resistance and type 2 diabetes. Agents that increase LCFA oxidation in skeletal muscle have been the focus of much research as they may be able to attenuate the development of insulin resistance in this tissue via decreased lipid accumulation. PPAR-[delta] is a ligand-activated transcription factor that has been implicated as a profound regulator of LCFA transport and oxidation in skeletal muscle and is an attractive target for the pharmacological treatment of type 2 diabetes. Treatment with the PPAR-[delta] agonist, GW 501516 has been shown to increase whole body insulin sensitivity, but information regarding its direct effects on glucose metabolism in skeletal muscle are lacking. Furthermore, there is evidence to suggest that GW 501516 treatment may exhibit fiber-type specific effects. We determined the effects of 2 weeks of treatment with the PPAR-[delta] agonist, GW 501516, on insulin-stimulated glucose transport in soleus (oxidative) and epitrochlearis (glycolytic) muscles in high fat-fed rats. High fat feeding significantly decreased insulin-stimulated glucose transport in soleus but not epitrochlearis muscles, and was associated with increased skeletal muscle DAG and ceramide content. Interestingly, treatment with GW 501516 led to a significant reduction in insulin-stimulated glucose transport in both soleus and epitrochlearis muscles, and was independent of diet. The observed reductions in insulin-stimulated glucose transport induced by GW 501516 treatment were associated with increased whole muscle FAT/CD36 protein content, but not DAG or ceramide contents. Importantly, treatment with GW 501516 did not alter PPAR-[delta], insulin signalling proteins (IRS-1, PI3-K, Akt/PKB) or adipo-R1 protein expression. Additionally, agonist treatment led to a small but significant increase in oxidative capacity in glycolytic but not oxidative muscle. We conclude that chronic treatment with the PPAR-[delta] agonist GW 501516 may induce or worsen insulin resistance in rodent skeletal muscle by increasing the capacity for LCFA transport across the sarcolemma with a subsequent increase in the accumulation of reactive lipids other than DAGs and ceramides.

GW 501516, treatment, insulin-stimulated glucose transport, rodent, skeletal muscle, receptor, agonist