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.
Department of Pathophysiology, Faculty of Medical Sciences, New University of Lisbon, Campo Mártires da Pátria 130, 1169-056 Lisbon, Portugal.
Maria P
MP
Guarino
M Paula
MP
Macedo
D000818:Animals; D004305:Dose-Response Relationship, Drug; D004333:Drug Administration Routes; D004359:Drug Therapy, Combination; D005215:Fasting; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D007333:Insulin Resistance; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar
D009569:Nitric Oxide; C002385:linsidomine; C042431:S-ethyl glutathione; D008981:Molsidomine; D005978:Glutathione