Effects of long-term nitrate supplementation on carbohydrate metabolism, lipid profiles, oxidative stress, and inflammation in male obese type 2 diabetic rats.

PURPOSE: Supplementation with inorganic nitrate to boost the nitrate-nitrite-nitric oxide (NO) pathway, may act as a potential therapeutic agent in diabetes. The aim of this study was to determine the effects of nitrate on carbohydrate metabolism, lipid profiles, oxidative stress, and inflammation in obese type 2 diabetic rats.

METHODS: Male Wistar rats were divided into 4 groups: Control, control + nitrate, diabetes, and diabetes + nitrate. Diabetes was induced using a high-fat diet and low-dose of streptozotocin. Sodium nitrate (100 mg/L in drinking water) was administered simultaneously for two months. Serum levels of fasting glucose, insulin, and lipid profiles were measured every 2-weeks. Glycated hemoglobin (HbA1c) was measured monthly. Serum thiobarbituric reactive substances (TBARS) level and catalase activity were measured before and after treatment. At the end of the study, glucose, pyruvate, and insulin tolerance tests were done. Glucose-stimulated insulin secretion (GSIS) and insulin content from isolated pancreatic islets were also assessed; mRNA expression of iNOS as well as mRNA expression and protein levels of GLUT4 in insulin-sensitive tissues, and serum IL-1β were determined.

RESULTS: Nitrate supplementation in diabetic rats significantly improved glucose tolerance, lipid profiles, and catalase activity as well as decreased gluconeogenesis, fasting glucose, insulin, and IL-1β; although it had no significant effect on GSIS, islet insulin content, HbA1c, and serum TBARS. Compared to the controls, in diabetic rats, mRNA expression and protein levels of GLUT4 were significantly lower in the soleus muscle (54% and 34%, respectively) and epididymal adipose tissue (67% and 41%, respectively). In diabetic rats, nitrate administration increased GLUT4 mRNA expression and protein levels in both soleus muscle (215% and 17%, respectively) and epididymal adipose tissue (344% and 22%, respectively). In diabetic rats, nitrate significantly decreased elevated iNOS mRNA expression in both the soleus muscle and epididymal adipose tissue.

CONCLUSION: Chronic nitrate supplementation in obese type 2 diabetic rats improved glucose tolerance, insulin resistance, and dyslipidemia; these favorable effects were associated with increased mRNA and protein expression of GLUT4 and decreased mRNA expression of iNOS in insulin-sensitive tissues, and with decreased gluconeogenesis, inflammation, and oxidative stress.