Blockade of hepatic nitric oxide synthase causes insulin resistance

The hypothesis was tested that insulin sensitivity, previously shown to dep end on a functional hepatic parasympathetic reflex, was mediated by hepatic production of nitric oxide (NO). Insulin sensitivity was measured using th e rapid insulin sensitivity test. N-nitro-L-arginine methyl ester (L-NAME, 2.5 and 5.0 mg/kg iv) and N-monomethyl-L-arginine (L-NMMA, 0.73 mg/kg), nit ric oxide synthase (NOS) antagonists, caused insulin resistance in rats. In traportal administration of L-NAME at a dose of 1.0 mg/kg significantly red uced the response to insulin (54.9 +/- 5.2%); however, administration of th e same dose of L-NAME intravenously did not cause a significant decrease in insulin response. Intraportal, but not intravenous, administration of 3-mo rpholinosydnonimine (SIN-1, 5.0 mg/kg), a NO donor partially reversed the i nsulin resistance caused by L-NMMA. Intraportal administration of SIN-1 (10 .0 mg/kg) completely restored insulin sensitivity after L-NMMA or surgical denervation of the liver. Insulin resistance produced by denervation was no t further increased by NOS blockade. These results suggest that blockade of NOS causes peripheral insulin resistance secondary to blockade of the hepa tic parasympathetic reflex release of hepatic insulin-sensitizing substance in response to insulin.