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Am J Physiol Gastrointest Liver Physiol 284: G588-G594, 2003. First published December 4, 2002; doi:10.1152/ajpgi.00423.2002
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Vol. 284, Issue 4, G588-G594, April 2003

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

Maria P. Guarino1, Ricardo A. Afonso1, Nuno Raimundo2,3,4, João F. Raposo5, and M. Paula Macedo1,5

1 Department of Physiology, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria 130, 1169-056 Lisbon; 2 Department of Chemistry and Biochemistry, Center for Studies in Biochemistry and Physiology, Faculty of Sciences, University of Lisbon, Campo Grande, 1749-016 Lisbon; 3 Superior School of Health Egas Moniz, Quinta da Granja, Monte da Caparica, 2829-511 Caparica; 4 Institute of Scientific Research Bento da Rocha Cabral, Calçada Bento da Rocha Cabral No. 14, 1250-047 Lisbon; and 5 Portuguese Diabetes Association, 1250-203 Lisbon, Portugal

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 NG-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.

hepatic nitric oxide synthase; hepatic parasympathetic nerves; type 2 diabetes


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