Mice with gene disruption of both endothelial and neuronal nitric oxide synthase exhibit insulin resistance

Studies from our laboratory using acute pharmacologic blockade of nitric ox ide synthase (NOS) activity have suggested that nitric oxide (NO) has an im portant role in regulating carbohydrate metabolism. We now report on insuli n sensitivity in mice with targeted disruptions in endothelial NOS (eNOS) a nd neuronal NOS (nNOS) genes compared with their wild-type (WT) counterpart s. Mice underwent hyrperinsulinemic-euglycemic clamp studies after a 24-h f ast, during an insulin infusion of 20 mU . kg(-1) . min(-1). Glucose levels were measured at baseline and every 10 min during the clamp. Insulin level s were measured at baseline and at the end of the clamp study Glucose infus ion rates (GIRs) during the last 30 min of the clamp study were in a steady state. Tritiated glucose infusion a-as used to measure rates of endogenous glucose output (EGO) both at baseline and during steady-state euglycemia. Glucose disposal rates (GDRs) were computed from the GIR and EGO. Easting a nd steady-state glucose and insulin levels were comparable in the 3 groups of mice. No differences in fasting EGO were noted between the groups, GIR w as significantly reduced (37%, P = 0.001) in the eNOS knockout (KO) mice co mpared with the WT mice, with values for the nNOS mice being intermediate. EGO was completely suppressed in the nNOS and WT mice during insulin infusi on, but not in the eNOS mice. Even so, the eNOS mice displayed significantl y reduced whole-body GDRs compared with those of the WT mice (82.67 +/- 10. 77 vs. 103.67 +/- 3.47 mg . kg(-1) . min(-1), P = 0.03). eNOS KO mice are i nsulin resistant at the level of the liver and peripheral tissues, whereas the nNOS KO mice are insulin resistant only in the latter These data indica te that NO plays a role in modulating insulin sensitivity and carbohydrate metabolism and that the eNOS isoform may play a dominant role relative to n NOS.