Block by Nitrate Tolerance of Meal-Induced Insulin Sensitization in Conscious Rabbits

Abstract

Aims: Hemodynamic nitrate tolerance has been shown to result in an insulin resistant state.We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits.Methods: Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate tolerant and non-tolerant animals.In a separate series of experiments with anaesthetized rabbits with or without nitrate tolerance, the hyperinsulinaemic euglycaemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole body insulin sensitivity. Results:Rabbits with normal feeding exhibited a 46 ± 6 % increase in insulin sensitivity as compared to their matching fasting control. A 7-day period of treatment with patches releasing 0.07 mg nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3-3.0 μg/kg over 20 min) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate tolerant fasted anaesthetized animals. Conclusions:Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin sensitizing effect of intraportal cholecystokinin. We studied whether nitrate tolerance induced by a 7-day continuous exposure to transdermal nitroglycerin influenced the meal-induced insulin sensitization phenomenon in rabbits.Methods: Changes in insulin sensitivity in response to feeding in conscious rabbits were determined by rapid insulin sensitivity test, in both nitrate tolerant and non-tolerant animals.In a separate series of experiments with anaesthetized rabbits with or without nitrate tolerance, the hyperinsulinaemic euglycaemic glucose clamping methods was used to study the effect of intraportal infusion of cholecystokinin (CCK) on whole body insulin sensitivity. Results:Rabbits with normal feeding exhibited a 46 ± 6 % increase in insulin sensitivity as compared to their matching fasting control. A 7-day period of treatment with patches releasing 0.07 mg nitroglycerin per hour yielded nitrate tolerance and a state of insulin resistance and no increase in insulin sensitivity in response to food. Intraportal infusion of CCK8 (0.3-3.0 μg/kg over 20 min) resulted in a dose-dependent increase in insulin sensitivity in normal but not in nitrate tolerant fasted anaesthetized animals. Conclusions:Nitrate tolerance blocks both the meal-induced insulin sensitization phenomenon and the insulin sensitizing effect of intraportal cholecystokinin.

Effect of Transdermal Nitroglycerin on Insulin Resistance in Healthy Young Men

“…Piatti, et al study also indicating long term application of L-arginine as a precursor of nitric oxide synthesis caused improve in insulin sensitivity in diabetic patients and decreased blood pressure [13]. Bajza, et al in another study performing in rabbits reported tolerance to nitroglycerine decreased the effect of food on enhancement of insulin sensitivity [14]. Saydow, et al also in a study reported a positive correlation between inhibition of NO production and insulin resistance in normotensive, nondiabetic healthy humans [15,16].…”