Hydrogen sulfide potentiates the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats

Abstract

Objective: Decreased nitric oxide (NO) bioavailability and hydrogen sulfide (H₂S) deficiency have been linked with the pathophysiology of type 2 diabetes (T2D). Restoration of NO levels by nitrite have been associated with favorable metabolic effects in T2D. Moreover, H₂S can potentiate the effects of NO in the cardiovascular system. The aim of this study was to determine the effects of long-term co-administration of sodium nitrite and sodium hydrosulfide (NaSH) on carbohydrate metabolism in type 2 diabetic rats.

Methods: T2D was induced using chronic high fat diet (HFD) feeding combined with low dose streptozotocin (STZ) regimen. Rats were divided into 5 groups (N = 10/group): Control, T2D, T2D + nitrite, T2D + NaSH, and T2D + nitrite + NaSH. Nitrite (50 mg/L in drinking water) and NaSH (0.28 mg/kg, daily i. p. injection) were administered for 9 weeks. Fasting serum glucose, insulin, lipid profile, liver function tests, and oxidative stress indices were measured. Intraperitoneal glucose tolerance test (GTT) was performed at the end of the eighth week, and three days later, intraperitoneal pyruvate tolerance test (PTT) was done. Protein levels and mRNA expression of glucose transporter type 4 (GLUT4) in soleus muscle and epididymal adipose tissue as well as mRNA expression of H₂S-producing enzymes in the liver, soleus muscle, and epididymal adipose tissue were measured at the end of the study.

Results: Compared to the controls, HFD and STZ treated rats developed metabolic dysfunction. Nitrite treatment improved carbohydrate metabolism, liver function, and oxidative stress indices whereas NaSH treatment per se had no significant effects. However, co-administration of NaSH and nitrite resulted in further improvement in serum insulin level, GTT, PTT, liver function, oxidative stress, protein level and mRNA expression of GLUT4, as well as mRNA expression of H₂S-producing enzymes in diabetic rats.

Conclusion: Low dose of NaSH per se had no effect on carbohydrate metabolism while it potentiated the favorable metabolic effects of inorganic nitrite in type 2 diabetic rats. These favorable effects were associated with decreased oxidative stress and increased GLUT4 expression in insulin-sensitive tissues as well as improvement of liver function.

Keywords: Diabetes; Hydrogen sulfide; Insulin resistance; Liver function; Nitric oxide; Oxidative stress.