Co-administration of glutathione and nitric oxide enhances insulin sensitivity in Wistar rats

1 The liver modulates insulin sensitivity through a prandial-dependent mechanism that requires activation of the hepatic parasympathetic nerves, hepatic nitric oxide (NO) and hepatic glutathione (GSH). We tested the hypothesis that co-administration of GSH and NO to the liver enhances insulin sensitivity in a GSH and NO dose-dependent manner. 2 24 h fasted Wistar rats were used. Hepatic GSH was supplemented by administration of glutathione monoethylester (GSH-E; 0.1/0.25/0.5/1/2 mmol kg(-1)) and 3-morpholinosidnonimine (SIN-1; 5/10 mg kg(-1)) was used as a NO donor. The drugs were administered either systemically (i.v.) or intraportally (i.p.v.). Insulin sensitivity was assessed using a transient euglycemic clamp. 3 Neither GSH-E nor SIN-1 increased insulin sensitivity when administered alone, both i.v. and i.p.v. Moreover, changes in insulin sensitivity were not observed when GSH-E was administered i.v. followed by either i.v. or i.p.v. SIN-1 at any of the doses tested. However, i.p.v. administration of GSH-E followed by i.p.v. SIN-1 10 mg kg(-1) significantly increased insulin sensitivity in a GSH-E dose-dependent manner: 26.1 +/- 9.4% after 0.1 mmol kg(-1) GSH-E; 44.6 +/- 7.9% after 0.25 mmol kg(-1) GSH-E; 59.4 +/- 15.1% after 0.5 mmol kg(-1) GSH-E; 138.9 +/- 12.7% after 1 mmol kg(-1) GSH-E and 117.3 +/- 29.2% after a dose of 2 mmol kg(-1) (n = 23, P < 0.005). 4 Our results confirm that insulin sensitivity is enhanced in a dose-dependent manner by coadministration of NO and GSH donors to the liver.