title: Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action.
abstract: 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 x kg(-1) x 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.
authors.affiliation: Department of Physiology, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Guarino
authors.forename: Ricardo A
authors.initials: RA
authors.lastname: Afonso
authors.forename: Nuno
authors.initials: N
authors.lastname: Raimundo
authors.forename: João F
authors.initials: JF
authors.lastname: Raposo
authors.forename: M Paula
authors.initials: MP
authors.lastname: Macedo
mesh_terms: D000818:Animals; D019328:Buthionine Sulfoximine / Q000494:pharmacology; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005978:Glutathione / Q000378:metabolism*; D007275:Injections, Intravenous; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000294:innervation / Q000378:metabolism*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D010275:Parasympathetic Nervous System / Q000502:physiology; D011168:Portal System; D051381:Rats; D017208:Rats, Wistar
chemical_list: D004791:Enzyme Inhibitors; D007328:Insulin; D020030:Nitric Oxide Donors; D009599:Nitroprusside; D009569:Nitric Oxide; D019328:Buthionine Sulfoximine; C002385:linsidomine; D008981:Molsidomine; D019001:Nitric Oxide Synthase; D005978:Glutathione; D019331:NG-Nitroarginine Methyl Ester