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

Maria P. Guarino, Ricardo A. Afonso, Nuno Raimundo, João F. Raposo, M. Paula Macedo

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70 Scopus citations


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 NGnitro-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 1-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.

Original languageEnglish (US)
Pages (from-to)G588-G594
JournalAmerican Journal of Physiology - Gastrointestinal and Liver Physiology
Issue number4 47-4
StatePublished - Apr 1 2003

All Science Journal Classification (ASJC) codes

  • Physiology
  • Hepatology
  • Gastroenterology
  • Physiology (medical)


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