Hypoadiponectinemia Is Closely Associated with Impaired Nitric Oxide Synthase Activity in Skeletal Muscle of Type 2 Diabetic Subjects

Objective: In vitro studies suggest that adiponectin plays an important role in nitric oxide (NO) generation. We studied the relationship between plasma adiponectin and skeletal muscle nitric oxide synthase (NOS) activity in type 2 diabetic (T2DM) patients. Methods: We determined NOS activity in skeletal muscle of 7 T2DM and 8 nondiabetic control subjects under basal conditions and after a 4-h euglycemic insulin (80mU/m(2) . min) clamp. Results: Insulin-stimulated glucose disposal (Rd) (5.2 +/- 0.4 vs. 9.0 +/- 0.9 mg/kg-min, P < 0.01) and basal NOS activity (107 +/- 45 vs. 459 +/- 100 pmol/min-mg protein, P < 0.05) were reduced in T2DM versus controls. In response to hyperinsulinemia, NOS activity increased approximately two-fold in controls (757 +/- 244, P < 0.05 vs basal) but failed to increase in T2DM (105 +/- 38, P < 0.01 vs. T2DM). Basal NOS protein content was similar in controls and T2DM and did not change following insulin. Plasma adiponectin was decreased in T2DM (4.5 +/- 0.8 vs. 7.0 +/- 1.0 mg/mL, P < 0.02) and correlated with insulin-stimulated NOS activity (r = 0.49, P < 0.05) and with Rd (r = 0.50, P < 0.05). In controls and T2DM collectively, Rd correlated with insulin-stimulated NOS activity (r = 0.48, P < 0.05). Conclusion: Decreased plasma adiponectin correlates with impaired insulin-stimulated NOS activity and severity of insulin resistance in T2DM. Because impaired NO generation plays a central role in endothelial dysfunction and development of atherosclerosis, our results may provide a link between reduced plasma adiponectin levels and accelerated atherosclerosis in T2DM.