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.
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We have recently shown that meal-induced insulin sensitization (MIS) occurs after feeding and decreases progressively to insignificance after 24 h of fasting and is caused by action of a hepatic insulin sensitizing substance (HISS). In order to carry out quantitative studies of MIS, some standardized meal intake is required. Our objective was to establish animal models to be tested in both the conscious and anaesthetized state using intragastric injection of liquid meals in order to quantify MIS. Insulin sensitivity was assessed before and 90 min after the meal using the rapid insulin sensitivity test (RIST) which is a transient euglycaemic clamp. Rats tested in the conscious state were instrumented under anaesthesia 6-9 d prior to testing with catheters in the carotid artery, jugular vein and stomach. Meals, injected into the stomach, consisted of a liquid mixed meal, sucrose, glucose or water. The glucose sequestration in response to insulin increased by 90 % and 61 % following the liquid mixed meal (10 ml/kg) in conscious and anaesthetized rats, respectively. Glucose, sucrose and water did not effectively activate MIS. MIS was completely reversed in the conscious model by atropine and completely prevented from developing in the anaesthetized model that had previously undergone hepatic denervation. Gastric administration of a liquid mixed meal but not glucose or sucrose is capable of activating MIS for purposes of mechanistic studies and quantification of the MIS process. The feeding signal is mediated by the hepatic parasympathetic nerves.
In animal studies, the whole-body glucose disposal effect of insulin is low in the fasted state or after atropine infusion, but doubles after a meal, consistent with the hepatic insulin-sensitizing substance (HISS) hypothesis. We tested how a standardized test meal and atropine affected the dynamic response to insulin in humans. Insulin sensitivity was assessed in healthy male subjects (aged 28.9 +/- 1.9 years, body mass index 23.3 +/- 0.8 kg.m-2) by using the rapid insulin sensitivity test (RIST), which is a transient euglycemic clamp. After a 24-hour fasting period, dynamic insulin sensitivity was assessed and then repeated 100 min after the test meal. In a second protocol, the volunteers were fed the standardized test meal and intravenous atropine (0.5 mg) or saline (control group) was administered 50 min before insulin sensitivity assessment. Insulin sensitivity increased in the fed state (232.1% +/- 46.3%, n = 7) in comparison with the 24-hour fasted state. In the atropine protocol, the drug partially blocked (56.5% +/- 11.6%, n = 6) insulin sensitivity. In humans, feeding resulted in increased insulin sensitivity. The low dose of atropine in humans lead to a partial HISS-dependent decrease in insulin sensitivity. Meal-induced insulin sensitization occured in humans by a similar mechanism as that reported in other species. The sensitization process was regulated by a cholinergic 'feeding signal.'
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