Several studies revealed that selenium and the long-acting glucagon like peptide-1(GLP-1) analogue, exendin-4 exert anti-diabetic effects through not well defined mechanisms. In this study, we investigated the effects of treatment of diabetic rats with selenium, exendin-4, combined insulin and selenium or combined selenium and exendin-4 for 6 days on the protein expression of the signaling transducers Akt, GLUT2, PI3K and IRS-1 in the liver of diabetic rats. Diabetes was induced by single intraperitoneal injection of 65 mg/kg body weight of streptozotocin. Insulin was injected intravenously twice daily at a dose of 4 U/Kg body weight, selenium was administered at a dosage of 5ppm selenite in drinking water. Exendin-4 was administered by intraperitoneal injections at a dose of 0.03 μg/Kg body weight twice daily. Induction of diabetes resulted in significant increase in the expression of GLUT2 and IRS-1 levels and a significant decrease in the level of Akt protein and nonsignificant decrease in the level of PI3K in the liver of diabetic rats. Insulin treatment of diabetic rats resulted in a significant increase in the levels of Akt and a significant decrease in IRS-1 levels that resulted in normalized levels of both proteins when compared to that in diabetic untreated rats. Selenium treatment for 6 days resulted in significant increase in hepatic protein levels of Akt, GLUT2, PI3K and IRS-1 compared to that of untreated diabetic rats. Treatment of diabetic rats for 6 days with exendin-4 resulted in significant increase in the level of Akt and a nonsignificant increase in the protein level of IRS-1 when compared to that of untreated diabetic rats. A combination of insulin and selenium resulted in significant increase in hepatic protein levels of Akt and GLUT2 as compared to their levels in the untreated diabetic rats. The levels of IRS-1 and GLUT2 in diabetic rats treated with a combination of selenium and insulin were intermediate between their levels in the liver of diabetic rats treated with either selenium or insulin alone indicating their antagonistic effects on hepatic GLUT2 and IRS-1 levels. Finally, the combined treatment of diabetic rats with selenium and exendin-4 resulted in significant increased hepatic protein levels of Akt and GLUT2 and normalized the protein level of IRS-1 compared to untreated diabetic rats. Therefore, the anti-diabetic effects of selenium, exendin-4 or their combination may result from their effects on the protein levels of Akt, IRS-1 and the glucose transporter GLUT2 in the liver.