Hepatic glutathione and nitric oxide are critical for hepatic insulin-sensitizing substance action

Abstract

We tested the hypothesis that hepatic nitric oxide (NO) and glutathione (GSH) are involved in the synthesis of a putative hormone referred to as hepatic insulin-sensitizing substance HISS. Insulin action was assessed in Wistar rats using the rapid insulin sensitivity test (RIST). Blockade of hepatic NO synthesis with N(G)-nitro-l-arginine methyl ester (l-NAME, 1.0 mg/kg intraportal) decreased insulin sensitivity by 45.1 +/- 2.1% compared with control (from 287.3 +/- 18.1 to 155.3 +/- 10.1 mg glucose/kg, P < 0.05). Insulin sensitivity was restored to 321.7 +/- 44.7 mg glucose/kg after administration of an NO donor, intraportal SIN-1 (5 mg/kg), which promotes GSH nitrosation, but not after intraportal sodium nitroprusside (20 nmol x kg(-1) x min(-1)), which does not nitrosate GSH. We depleted hepatic GSH using the GSH synthesis inhibitor l-buthionine-[S,R]-sulfoximine (BSO, 2 mmol/kg body wt ip for 20 days), which reduced insulin sensitivity by 39.1%. Insulin sensitivity after l-NAME was not significantly different between BSO- and sham-treated animals. SIN-1 did not reverse the insulin resistance induced by l-NAME in the BSO-treated group. These results support our hypothesis that NO and GSH are essential for insulin action.

Insulin resistance induced by sucrose feeding in rats is due to an impairment of the hepatic parasympathetic nerves

“…Other studies by our groups [34,35] have previously uncovered other steps of the hepatic pathway that lead to HISS release. According to these studies, following a meal, the activation of the hepatic parasympathetic nerves leads to the release of acetylcholine, which binds to muscarinic receptors in the liver.…”

Inhalation of Insulin (Exubera) Is Associated With Augmented Disposal of Portally Infused Glucose in Dogs

“…Recent studies, however, have suggested the possibility that some NO may escape inactivation by traveling in a plasma compartment in the blood and act as an endocrine factor distal to the site of its release (17,18). Furthermore, it has been suggested that under hyperinsulinemic conditions, NO action in the liver can alter the release of a humoral factor, which increases nonhepatic glucose disposal (19,20). This mechanism may involve parasympathetic input as the effect is blocked by surgical liver denervation and atropine and is restored by acetylcholine administration (21,22).…”

The Relationship Between Chronic Alcohol Use and Type 2 Diabetes Mellitus: New Insights into Mechanisms of Appetite-Regulating Peptides

“…Alcohol suppresses the release or action of HISS and meal-induced insulin sensitization in rats [65]. Moreover, in animal models, acute alcohol administration also reduces glutathione [66] which is important for HISS release [67]. As with acute alcohol consumption, hepatic glutathione and HISS seem to be involved.…”