Understanding the in-vivo relevance of S-nitrosothiols in insulin action.
Insulin sensitivity is maximal in the postprandial state, decreasing with a fasting period through a mechanism that is dependent on the integrity of the hepatic parasympathetic nerves/nitric oxide (NO) production and increased hepatic glutathione (GSH) levels. GSH and NO react to form S-nitrosoglutathione (GSNO), an S-nitrosothiol (RSNO) for which the in-vivo effects are still being determined. The goal of this study was to test the hypothesis that in-vivo administration of RSNOs, GSNO, or S-nitroso-N-acetylpenicillamine (SNAP) increases insulin sensitivity in fasted or fed-denervated animals, but not in fed animals, where full postprandial insulin sensitivity is achieved. Fasted, fed, or fed-denervated male Wistar rats were used as models for different insulin sensitivity conditions. The rapid insulin sensitivity test (RIST) was used to measure insulin-stimulated glucose disposal before and after drug administration (GSNO, SNAP, or 3-morpholinosydnonimine (SIN-1), intravenous (i.v.) or to the portal vein (i.p.v.)). Fast insulin sensitivity was not altered by administration of SIN-1 (neither i.v. nor i.p.v.). Intravenous infusion of RSNOs in fasted and fed hepatic denervated rats increased insulin sensitivity by 126.35% ± 35.43% and 82.7% ± 12.8%, respectively. In fed animals, RSNOs decreased insulin sensitivity indicating a negative feedback mechanism. These results suggest that RSNOs incremental effect on insulin sensitivity represent a promising therapeutical tool in insulin resistance states.
CEDOC, Universidade Nova de Lisboa, Campo Mártires da Pátria, Portugal.
Ana B
AB
Fernandes
Maria P
MP
Guarino
M Paula
MP
Macedo
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism; D005215:Fasting / Q000378:metabolism; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008981:Molsidomine / Q000031:analogs & derivatives / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism; D019518:Postprandial Period / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D026422:S-Nitrosoglutathione / Q000494:pharmacology; D026403:S-Nitrosothiols / Q000494:pharmacology*
D001786:Blood Glucose; D007328:Insulin; D026403:S-Nitrosothiols; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; C002385:linsidomine; D026423:S-Nitroso-N-Acetylpenicillamine; D008981:Molsidomine