Exenatide improves antioxidant capacity and reduces the expression of LDL receptors and PCSK9 in human insulin-secreting 1.1E7 cell line subjected to hyperglycemia and oxidative stress

Abstract Introduction GLP-1 receptor agonists (e.g., exenatide) are novel drugs used in the treatment of diabetes. These drugs, working with other mechanisms of action, improve glycemic control by increasing secretion of insulin and improving survival of pancreatic islet beta cells. Alterations in the oxidative stress level or the expression of proteins associated with cholesterol uptake might be responsible for those findings. Currently, there are few in vitro studies on the impact of exenatide antioxidant capacity in human islet beta cell lines and none that assess the influence of exenatide on LDL receptors and PCSK9 under hyperglycemia and oxidative stress. Therefore, we evaluated the impact of exenatide on antioxidant capacity, insulin secretion, and proteins involved in cholesterol metabolism. Materials and Method An in vitro culture of insulin-secreting cells 1.1E7 was subjected to hyperglycemia and oxidative stress. Assessment was made of the expression of enzymes associated with oxidative stress (NADPH oxidase, catalase, glutathione peroxidase, superoxide dismutase, iNOS) and cholesterol uptake (LDL receptors, PCSK9). Additionally, insulin and nitrite levels in culture media were quantified. Results We showed that exenatide improves expression of catalase and reduces the amount of nitrite in cell cultures in a protein kinase A–dependent manner. Those results were accompanied by a drop in the expression of LDL receptors and PCSK9. Insulin secretion was modestly increased in the culture condition. Conclusions Our findings show potential protective mechanisms exerted by exenatide in human insulin-secreting pancreatic beta cell line (1.1E7), which may be exerted through increased antioxidant capacity and reduced accumulation of cholesterol.