Diabetes mellitus (DM) is a major disorder currently affecting 250 million worldwide, including 3 million in the UK. DM can lead to a number of long term complications including nephropathy, retinopathy, neuropathy and cardiomyopathy. These diabetic-induced complications are mainly related to either insulin deficiency or resistance resulting in prolonged hyperglycaemia, hyperlipidaemia and exaggerated levels of reactive oxygen species with impaired antioxidant defense system. Methods which can improve insulin secretion can be of help in the treatment of DM. GLP-1 and its analogue, exenatide are known insulin secretagogues. Adult male Wistar rats (n=20) were rendered diabetic using 60 mg/kg body weight (i.p.) of streptozotocin (STZ) according to Home Office regulations. One week after STZ injection and after DM was confirmed, the rats were divided into two groups of 10 each. One group of diabetic (type 1) rats was treated with exenatide (1 μg/kg body weight, daily intravenously) for 10 weeks compared to age-matched diabetic controls (treated with saline). During, and at the end of the experimental period, blood samples were taken from control and diabetic rats for the measurement of a number of biochemical parameters. Pancreatic tissues were also taken for analysis after the rats were humanely killed according to Home Office regulation. After 10 weeks of exenatide administration, levels of serum insulin increased significantly (3.5±0.2 µIU/ml vs 4.7±0.1 µIU/ml; Student’s t-test; p<0.01) accompanied with a decrease in serum cholesterol (49±2.4 mg/dl vs 44±5.0 mg/dl) and a significant reduction of serum triglyceride (79±6.7 mg/dl vs 48±5.9 mg/dl; p<0.01), for treated rats compared to untreated control. Simultaneously, the percentage (%) of both catalase (66.3±2.9 vs 91.6±0.8; p<0.001) and glutathione reductase (66.2±3.7 vs 86.1±2.1; p<0.01) positive cells was significantly elevated in exenatide treated diabetic rats compared to untreated diabetic rats. At molecular level, the study revealed a significant increase in the gene expression of both glutathione peroxidase (0.97±0.06 to 1.44±0.09 p<0.01) and GLP-1 receptor (1.00±0.07 vs 12.46±0.44 P<0.001) with significant reduction in glucagon gene (1.03±0.06 vs 0.75±0.06 P<0.05) expression in diabetic rats compared to untreated diabetic control. These findings confirmed the protective role of exenatide in enhancing insulin secretion with reduction in blood lipid levels and improving the antioxidant protective system in pancreatic β-cells. These actions may be mediated through enhancement of both glutathione peroxidase and GLP-1, all of which may contribute to the beneficial effect of exenatide on diabetes mellitus.