We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are involved in the synthesis of a putative hormone referred to as hepatic insulin-sensitizing substance HISS. Insulin action was assessed in Wistar rats using the rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)-nitro-L-arginine methyl ester (L-NAME, 1.0 mg/kg intraportal) decreased insulin sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3 +/- 10.1 mg glucose/ kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/- 44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not after intraportal. sodium nitroprusside (20 mnol.kg(-1).min(-1)), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor 1-buthionine-[S,]sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by 39.1%. Insulin sensitivity after L-NAME was not significantly different between BSO- and sham-treated animals. SIN-1 did not reverse the insulin resistance induced by L-NAME in the BSO-treated group. These results support our hypothesis that NO and GSH are essential for insulin action.
|Journal||American Journal Of Physiology-Gastrointestinal And Liver Physiology|
|Publication status||Published - 1 Jan 2003|