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. 2006 Apr;147(8):959-65.
doi: 10.1038/sj.bjp.0706691.

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

Maria P Guarino  1 , M Paula Macedo
Affiliations

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

Maria P Guarino et al. Br J Pharmacol. 2006 Apr.

Abstract

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.

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Figures

Figure 1
Figure 1
RIST index after a 24 h-fast, followed by a RIST after co-administration of i.p.v. GSH-E 1 mmol kg−1 and i.v. (n=5) or i.p.v. (n=5) SIN-1 10 mg kg−1. I.v. SIN-1 after i.p.v. GSH-E did not change insulin sensitivity while i.p.v. SIN-1 after i.p.v. GSH-E significantly increased insulin sensitivity. Values are means±s.e.m. ***P<0.001.
Figure 2
Figure 2
RIST after SIN-1 as a function of the dose of GSH-E administered intravenously, n=12 or intraportally, n=23. Insulin sensitivity is dependent on the dose of GSH-E. GSH-E is more potent and more efficient when administered intraportally than systemically.
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