Abstract
Glucose transport into skeletal muscle is essential for maintaining whole-body glucose homeostasis and accounts for the majority of glucose disposal in response to insulin. The group I p21-activated kinase (PAK) isoforms PAK1 and PAK2 have been shown to be activated in response to insulin in skeletal muscle. Moreover, PAK1/2 signalling is impaired in insulin-resistant mouse and human skeletal muscle and PAK1 has been suggested to be required for insulin-stimulated GLUT4 translocation. However, the relative contribution of PAK1 and PAK2 to insulin-stimulated glucose uptake in mature skeletal muscle is unresolved. The aim of the present investigation was to determine the requirement for PAK1 and PAK2 in whole-body glucose homeostasis and insulin-stimulated glucose uptake in skeletal muscle. Glucose uptake was measured in isolated skeletal muscle incubated with a pharmacological inhibitor (IPA-3) of group I PAKs and in muscle from whole-body PAK1 knockout (KO), muscle-specific PAK2 (m)KO and double whole-body PAK1 and muscle-specific PAK2 knockout mice. The whole-body respiratory exchange ratio, indicative of substrate utilization, was largely unaffected by lack of PAK1 and/or PAK2. Whole-body glucose tolerance was mildly impaired in PAK2 mKO, but not PAK1 KO mice. In contrast to a previous study of GLUT4 translocation in PAK1 KO mice, PAK1 KO muscles displayed normal insulin-stimulated glucose uptake in vivo and in isolated muscle. On the contrary, glucose uptake was slightly reduced (-12-18%) in response to insulin in glycolytic extensor digitorum longus muscle lacking PAK2. In conclusion, group I PAKs are largely dispensable for the regulation of whole-body glucose homeostasis and skeletal muscle glucose uptake. Thus, the present study challenges that group I PAKs, and especially PAK1, are necessary regulators of insulin-stimulated glucose uptake in skeletal muscle.
Footnotes
Addition of new data. Removal of data on the involvement of group I PAKs in contraction-stimulated glucose uptake which will be included in a different manuscript.
Non-standard abbreviations
- 2DG
- 2-Deoxyglucose
- AUC
- Area under the curve
- BCA
- Bicinchoninic acid
- BW
- Body weight
- dKO
- Double knockout
- EDL
- Extensor digitorum longus
- FM
- Fat mass
- GLUT4
- Glucose transporter 4
- GTT
- Glucose tolerance test
- HFD
- High-fat diet
- HOMA-IR
- Homeostatic Model Assessment of Insulin Resistance
- ITT
- Insulin tolerance test
- i.p.
- Intraperitoneal
- KO
- Knockout
- L6-GLUT4myc
- Rat L6 skeletal muscle cells overexpressing myc-tagged GLUT4
- LBM
- Lean body mass
- mKO
- Muscle-specific knockout
- NOX
- NADPH oxidase
- PAK
- p21-activated kinase
- PI3K
- Phosphoinositide 3-kinase
- RER
- Respiratory exchange ratio
- r.o.
- Retro-orbital
- VO2
- Oxygen uptake