Experimental Evaluation of the Dose-Dependent Pharmacological Effects of Metformin on Glycemic Control, Oxidative Stress, and Insulin Sensitivity in Streptozotocin-Induced Diabetic Wistar Rats

Abstract

Background: Diabetes Mellitus is a chronic metabolic condition characterized by persistent hyperglycemia, insulin resistance, and increased
oxidative stress, leading to severe systemic complications. Metformin is widely used as a first-line therapy; however, its dose-dependent
pharmacological effects on glycemic control, oxidative stress, and insulin sensitivity require further investigation.
Objective: To evaluate the dose-dependent effects of metformin on glycemic control, oxidative stress, and insulin sensitivity in Streptozotocininduced diabetic Wistar rats.
Methods: Experimental diabetes was induced in Wistar rats using a single intraperitoneal injection of streptozotocin (50 mg/kg). Animals were
divided into five groups (n = 6–8): normal control, diabetic control, and three metformin-treated groups (100, 200, and 300 mg/kg). Metformin
was administered orally for 28 days. Key parameters assessed included fasting blood glucose, oral glucose tolerance test (OGTT), HbA1c, serum
insulin levels, HOMA-IR index, and oxidative stress markers (MDA, SOD, CAT, and GSH). Histopathological examination of pancreatic tissue
was also performed. Statistical analysis was conducted using one-way ANOVA followed by Tukey’s post hoc test.
Results: Metformin treatment significantly improved glycemic control in a dose-dependent manner, as evidenced by reductions in fasting blood
glucose, improved OGTT response, and decreased HbA1c levels (p < 0.05–0.001). Insulin sensitivity was enhanced, with increased serum insulin
levels and reduced HOMA-IR values. Oxidative stress was markedly reduced, demonstrated by decreased MDA levels and increased antioxidant
enzyme activities (SOD, CAT, GSH). Histopathological analysis revealed dose-dependent protection and regeneration of pancreatic β-cells, with
the high-dose group showing near-normal architecture.
Conclusion: Metformin exhibits significant dose-dependent antidiabetic and antioxidant effects in streptozotocin-induced diabetic rats. Higher
doses provide superior improvements in glycemic control, insulin sensitivity, and oxidative stress. These findings support the importance of dose
optimization in enhancing the therapeutic efficacy of metformin and warrant further clinical investigations for translational application.