title: Rac1 signaling is required for insulin-stimulated glucose uptake and is dysregulated in insulin-resistant murine and human skeletal muscle.
abstract: The actin cytoskeleton-regulating GTPase Rac1 is required for insulin-stimulated GLUT4 translocation in cultured muscle cells. However, involvement of Rac1 and its downstream signaling in glucose transport in insulin-sensitive and insulin-resistant mature skeletal muscle has not previously been investigated. We hypothesized that Rac1 and its downstream target, p21-activated kinase (PAK), are regulators of insulin-stimulated glucose uptake in mouse and human skeletal muscle and are dysregulated in insulin-resistant states. Muscle-specific inducible Rac1 knockout (KO) mice and pharmacological inhibition of Rac1 were used to determine whether Rac1 regulates insulin-stimulated glucose transport in mature skeletal muscle. Furthermore, Rac1 and PAK1 expression and signaling were investigated in muscle of insulin-resistant mice and humans. Inhibition and KO of Rac1 decreased insulin-stimulated glucose transport in mouse soleus and extensor digitorum longus muscles ex vivo. Rac1 KO mice showed decreased insulin and glucose tolerance and trended toward higher plasma insulin concentrations after intraperitoneal glucose injection. Rac1 protein expression and insulin-stimulated PAK(Thr423) phosphorylation were decreased in muscles of high fat-fed mice. In humans, insulin-stimulated PAK activation was decreased in both acute insulin-resistant (intralipid infusion) and chronic insulin-resistant states (obesity and diabetes). These findings show that Rac1 is a regulator of insulin-stimulated glucose uptake and a novel candidate involved in skeletal muscle insulin resistance.
authors: Molecular Physiology Group, Department of Nutrition, Exercise, and Sports, August Krogh Centre, University of Copenhagen, Copenhagen, Denmark.
authors: Lykke
authors: L
authors: Sylow
authors: Thomas E
authors: TE
authors: Jensen
authors: Maximilian
authors: M
authors: Kleinert
authors: Kurt
authors: K
authors: Højlund
authors: Bente
authors: B
authors: Kiens
authors: Jørgen
authors: J
authors: Wojtaszewski
authors: Clara
authors: C
authors: Prats
authors: Peter
authors: P
authors: Schjerling
authors: Erik A
authors: EA
authors: Richter
mesh_terms: D000328:Adult; D000818:Animals; D005260:Female; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D020830:rac1 GTP-Binding Protein; D005947:Glucose