The role of p-21 activated kinases (PAKs) in glucose homeostasis and skeletal muscle glucose uptake

Skeletal muscle glucose transport is essential for maintaining whole body glucose homeostasis and skeletal muscle accounts for the majority of glucose disposal in response to insulin. Glucose transport into skeletal muscle can be induced by several stimuli, such as insulin and muscle contraction, which all have been shown to activate group I p-21 activated kinases (PAKs). Skeletal muscle expresses two group I PAK isoforms but the role of these in muscle glucose uptake has not been determined. Recent evidence suggests that p-21 activated kinase (PAK) 1 may play a role in insulin-stimulated GLUT4 translocation and that PAK1/2 signaling is markedly impaired in insulin resistant skeletal muscle. To elucidate the role for group I PAKs in skeletal muscle glucose uptake, we determined glucose uptake in mature skeletal muscle from mice treated with a pharmacological inhibitor of group I PAKs, IPA-3, or knockout (KO) of either PAK1, PAK2, or joint KO of both PAK1 and PAK2 (d1/2KO). In contrast with our hypothesis, we found that lack of PAK1 did not affect glucose uptake in response to insulin or contraction. Lack of PAK2 protein only mildly reduced insulin-stimulated glucose transport. We conclude that PAK1/2 proteins are not major regulators of skeletal muscle glucose uptake but that PAK2 may play a minor role.