Glp-1 mimetic of sitagliptin improved oxidative stress and liver function tests via suppressing NOX-4 enzyme in hepatic tissues of diabetic rats

Abstract

Background and aim

Oxidative stress acts as a major underlying cause of liver dysfunction in individuals with uncontrolled diabetes mellitus. However, the role of NOX-4 (nicotinamide adenine dinucleotide phosphate oxidase-4) enzymes remains poorly understood. Furthermore, the potential benefits of Sitagliptin in addressing this issue are unclear. Therefore, this experimental study aimed to explore the role of the NOX-4 enzyme and evaluate the potential benefits of Sitagliptin in diabetes-associated impaired liver tests.

Methods

Male Wistar rats were randomly assigned to four groups: normal, normal-treated, diabetic, and diabetic-treated. Diabetes was induced by a single dose of Streptozotocin (45 mg/kg). Treated animals received Sitagliptin (20 mg/day, orally) for five weeks. Blood and tissue samples were collected at the end of the five-week period, and the required data were obtained using biochemical and genetic analysis methods.

Results

In untreated rats, STZ-induced diabetes led to increased NOX-4 enzyme expression in the liver and a reduction in the antioxidant enzymes SOD, CAT, and GLT, collectively contributing to heightened oxidative damage, as indicated by elevated MDA levels. These alterations were associated with elevated circulating levels of SGOT, SGPT, and ALP. However, Sitagliptin reversed these alterations in diabetic animals. It enhanced the activity of antioxidant enzymes, reduced NOX-4 enzyme expression and oxidative damage in liver tissues, and subsequently improved liver function test results.

Conclusion

NOX-4 oxidant enzyme appears to play a critical role in diabetes-induced oxidative stress and subsequent liver failure. However, Sitagliptin may offer extra-glycemic benefits by normalizing NOX-4 enzyme activity levels, thereby improving liver function test results.