title: In vivo activation of ROCK1 by insulin is impaired in skeletal muscle of humans with type 2 diabetes.
abstract: To determine whether serine/threonine ROCK1 is activated by insulin in vivo in humans and whether impaired activation of ROCK1 could play a role in the pathogenesis of insulin resistance, we measured the activity of ROCK1 and the protein content of the Rho family in vastus lateralis muscle of lean, obese nondiabetic, and obese type 2 diabetic subjects. Biopsies were taken after an overnight fast and after a 3-h hyperinsulinemic euglycemic clamp. Insulin-stimulated GDR was reduced 38% in obese nondiabetic subjects compared with lean, 62% in obese diabetic subjects compared with lean, and 39% in obese diabetic compared with obese nondiabetic subjects (all comparisons P < 0.001). Insulin-stimulated IRS-1 tyrosine phosphorylation is impaired 41-48% in diabetic subjects compared with lean or obese subjects. Basal activity of ROCK1 was similar in all groups. Insulin increased ROCK1 activity 2.1-fold in lean and 1.7-fold in obese nondiabetic subjects in muscle. However, ROCK1 activity did not increase in response to insulin in muscle of obese type 2 diabetic subjects without change in ROCK1 protein levels. Importantly, insulin-stimulated ROCK1 activity was positively correlated with insulin-mediated GDR in lean subjects (P < 0.01) but not in obese or type 2 diabetic subjects. Moreover, RhoE GTPase that inhibits the catalytic activity of ROCK1 by binding to the kinase domain of the enzyme is notably increased in obese type 2 diabetic subjects, accounting for defective ROCK1 activity. Thus, these data suggest that ROCK1 may play an important role in the pathogenesis of resistance to insulin action on glucose disposal in muscle of obese type 2 diabetic subjects.
authors.affiliation: Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02216, USA.
authors.forename: Kwang-Hoon
authors.initials: KH
authors.lastname: Chun
authors.forename: Kang-Duk
authors.initials: KD
authors.lastname: Choi
authors.forename: Dae-Ho
authors.initials: DH
authors.lastname: Lee
authors.forename: Yoonshin
authors.initials: Y
authors.lastname: Jung
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.forename: Young-Bum
authors.initials: YB
authors.lastname: Kim
mesh_terms: D051339:Actin Depolymerizing Factors / Q000378:metabolism; D000328:Adult; D001711:Biotransformation / Q000187:drug effects; D015153:Blotting, Western; D015992:Body Mass Index; D003598:Cytoskeletal Proteins / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D005260:Female; D005947:Glucose / Q000378:metabolism; D015309:Glucose Clamp Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000494:pharmacology*; D055504:Insulin Receptor Substrate Proteins / Q000096:biosynthesis / Q000235:genetics; D007333:Insulin Resistance; D007700:Kinetics; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism; D010766:Phosphorylation; D014443:Tyrosine / Q000378:metabolism; D020741:rho GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D054460:rho-Associated Kinases / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism; D000099149:Ezrin
chemical_list: D051339:Actin Depolymerizing Factors; D003598:Cytoskeletal Proteins; D005947:Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D014443:Tyrosine; D020741:rho GTP-Binding Proteins; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D000099149:Ezrin; C066737:RHOA protein, human; C515851:ROCK1 protein, human; C508705:RND3 protein, human