Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action

• Published in: American journal of physiology: Gastrointestinal and liver physiology Vol. 284; no. 4; pp. G588 - G594
• Main Authors: Guarino, Maria P., Afonso, Ricardo A., Raimundo, Nuno, Raposo, João F., Macedo, M. Paula
• Format: Journal Article
• Language: English
• Published: United States 01.04.2003
• Subjects: Animals; Buthionine Sulfoximine - pharmacology; Diabetes Mellitus, Type 2 - metabolism; Enzyme Inhibitors - pharmacology; Glutathione - metabolism; Injections, Intravenous; Insulin - metabolism; Insulin Resistance; Liver - innervation; Liver - metabolism; Male; Molsidomine - analogs & derivatives; Molsidomine - pharmacology; NG-Nitroarginine Methyl Ester - pharmacology; Nitric Oxide - metabolism; Nitric Oxide Donors - pharmacology; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitroprusside - pharmacology; Parasympathetic Nervous System - physiology; Portal System; Rats; Rats, Wistar
• ISSN: 0193-1857; 1522-1547
• DOI: 10.1152/ajpgi.00423.2002

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 nmol · kg −1 · min −1 ), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor l-buthionine-[ S,R]-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.