title: Insulin resistance is associated with impaired nitric oxide synthase activity in skeletal muscle of type 2 diabetic subjects.
abstract: Type 2 diabetes is an insulin-resistant state characterized by hyperinsulinemia and accelerated atherosclerosis. In vitro and in vivo studies in rodents have suggested that nitric oxide generation plays an important role in glucose transport and insulin action. We determined nitric oxide synthase (NOS) activity in skeletal muscle of 10 type 2 diabetic (hemoglobin A(1C) = 6.8 +/- 0.1%) and 11 control subjects under basal conditions and during an 80 mU/m(2).min euglycemic insulin clamp performed with vastus lateralis muscle biopsies before and after 4 h of insulin. In diabetics, insulin-stimulated glucose disposal (Rd) was reduced by 50%, compared with controls (5.4 +/- 0.3 vs. 10.4 +/- 0.5 mg/kg.min, P < 0.01). Basal NOS activity was markedly reduced in the diabetic group (101 +/- 33 vs. 457 +/- 164 pmol/min.mg protein, P < 0.05). In response to insulin, NOS activity increased 2.5-fold in controls after 4 h (934 +/- 282 pmol/min.mg protein, P < 0.05 vs. basal), whereas insulin failed to stimulate NOS activity in diabetics (86 +/- 28 pmol/min.mg protein, P = NS from basal). Basal NOS protein content in muscle was similar in controls and diabetics and did not change following insulin. In controls, insulin-stimulated NOS activity correlated inversely with fasting plasma insulin concentration (r = -0.58, P = 0.05) and positively with Rd (r = 0.71, P = 0.03). In control and diabetic groups collectively, Rd correlated with insulin-stimulated NOS activity (r = 0.52, P = 0.02). We conclude that basal and insulin-stimulated muscle NOS activity is impaired in well-controlled type 2 diabetic subjects, and the defect in insulin-stimulated NOS activity correlates closely with the severity of insulin resistance. These results suggest that impaired NOS activity may play an important role in the insulin resistance in type 2 diabetic individuals.
authors.affiliation: The University of Texas Health Science Center at San Antonio, Diabetes Division, Texas 78229, USA.
authors.forename: Sangeeta R
authors.initials: SR
authors.lastname: Kashyap
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Roman
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lamont
authors.forename: Bettie Sue S
authors.initials: BS
authors.lastname: Masters
authors.forename: Mandeep
authors.initials: M
authors.lastname: Bajaj
authors.forename: Swangjit
authors.initials: S
authors.lastname: Suraamornkul
authors.forename: Renata
authors.initials: R
authors.lastname: Belfort
authors.forename: Rachele
authors.initials: R
authors.lastname: Berria
authors.forename: Dean L
authors.initials: DL
authors.lastname: Kellogg
authors.forename: Yanjuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Ralph A
authors.initials: RA
authors.lastname: DeFronzo
mesh_terms: D001706:Biopsy; D001786:Blood Glucose / Q000378:metabolism; D015992:Body Mass Index; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology*; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005260:Female; D015309:Glucose Clamp Technique; D006801:Humans; D007328:Insulin / Q000097:blood / Q000494:pharmacology; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000201:enzymology* / Q000473:pathology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D012016:Reference Values; D013599:Systole / Q000502:physiology
chemical_list: D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D007328:Insulin; D019001:Nitric Oxide Synthase