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Articles in PresS, published online ahead of print December 4, 2002
Am J Physiol Gastrointest Liver Physiol, 10.1152/ajpgi.00423.2002
Submitted on September 26, 2002
Accepted on December 2, 2002
1 Department of Physiology, New University of Lisbon, Faculty of Medical Sciences, Lisbon, Portugal
2 Department of Chemistry and Biochemistry, University of Lisbon, Faculty of Sciences, Center for Studies in Biochemistry and Physiology, Lisbon, Portugal; Superior School of Health Egas Moniz, Lisbon, Portugal; Institute of Scientific Research Bento da Rocha Cabral, Lisbon, Portugal
3 Portuguese Diabetes Association, Lisbon, Portugal
4 Department of Physiology, New University of Lisbon, Faculty of Medical Sciences, Lisbon, Portugal; Portuguese Diabetes Association, Lisbon, Portugal
* To whom correspondence should be addressed. E-mail: mpmacedo.biot{at}fcm.unl.pt.
We tested the hypothesis that both 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 L-NAME (1.0mg/kg, ipv) decreased insulin sensitivity by 45.1±2.1% (from 287.3±18.1 mg glucose/kg in control 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 a NO donor, SIN-1 (5mg/kg, ipv), which promotes GSH nitrosation, but not after sodium nitroprusside (20nmol/kg/min, ipv) which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor BSO (2mmol/kg bw for 20 days, ip), 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 group. These results support our hypothesis that both, NO and GSH, are essential for insulin action.
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