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

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. 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. 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). Our results confirm that insulin sensitivity is enhanced in a dose‐dependent manner by co‐administration of NO and GSH donors to the liver.British Journal of Pharmacology (2006) 147 , 959–965. doi: 10.1038/sj.bjp.0706691