S-Nitrosoglutathione Reverts Dietary Sucrose-Induced Insulin Resistance.

Inês Sousa-Lima,Rita S Patarrão,Young-Bum Kim,M Paula Macedo,Ana B Fernandes

doi:10.3390/antiox9090870

Abstract

The liver is a fundamental organ to ensure whole-body homeostasis, allowing for a proper increase in insulin sensitivity from the fast to the postprandial status. Hepatic regulation of glucose metabolism is crucial and has been shown to be modulated by glutathione (GSH) and nitric oxide (NO). However, knowledge of the metabolic action of GSH and NO in glucose homeostasis remains incomplete. The current study was designed to test the hypothesis that treatment with S-nitrosoglutathione is sufficient to revert insulin resistance induced by a high-sucrose diet. Male Wistar rats were divided in a control or high-sucrose group. Insulin sensitivity was determined: (i) in the fast state; (ii) after a standardized test meal; (iii) after GSH + NO; and after (iv) S-nitrosoglutathione (GSNO) administration. The fasting glucose level was not different between the control and high-sucrose group. In the liver, the high-sucrose model shows increased NO and unchanged GSH levels. In control animals, insulin sensitivity increased after a meal or administration of GSH+NO/GSNO, but this was abrogated by sucrose feeding. GSNO was able to revert insulin resistance induced by sucrose feeding, in a dose-dependent manner, suggesting that they have an insulin-sensitizing effect in vivo. These effects are associated with an increased insulin receptor and Akt phosphorylation in muscle cells. Our findings demonstrate that GSNO promotes insulin sensitivity in a sucrose-induced insulin-resistant animal model and further implicates that this antioxidant molecule may act as a potential pharmacological tool for the treatment of insulin resistance in obesity and type 2 diabetes.

Highlights

The prevalence of diabetes, type 2 diabetes (T2D), is increasing worldwide [1].The development of T2D is agreed to be a consequence of both lifestyle and genetic background [2,3].Given that sugar intake has markedly increased in the last decades [4,5,6,7], it is accepted that diet is a primary environmental factor for the onset of T2D
The data presented in this study shows for the first time that administration of GSNO is sufficient to overcome high sucrose-induced insulin resistance in rats
This effect is associated with a positive modulation of the insulin signaling pathway. We found that both nitric oxide and glutathione are fundamental for maintaining normal insulin action, as their levels are impaired in the early stages of insulin resistance

Summary

Introduction

The prevalence of diabetes, type 2 diabetes (T2D), is increasing worldwide [1]. Given that sugar intake has markedly increased in the last decades [4,5,6,7], it is accepted that diet is a primary environmental factor for the onset of T2D. The consumption of refined carbohydrates has deleterious effects in the progression of insulin resistance and several reports show a correlation between exacerbated sugar intake and higher rates of obesity, diabetes, hypertension, and cardiovascular. The detailed mechanism underlying diet-induced insulin resistance is not yet fully understood. The sucrose present in the diet yields equal amounts of glucose and fructose. Rising amounts of glucose consumption are well documented as one of the major causes of insulin resistance [11]

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Conclusion