Manganese supplementation as an adjuvant therapy for preventing endothelial dysfunction in type 2 diabetes

Hyperglycemia, dyslipidemia, oxidative stress, and vascular inflammation all play a role in endothelial dysfunction and accelerated atherosclerosis observed in diabetes. Manganese (Mn), an essential micronutrient, is reported to be low in the blood and certain tissues of type 2 diabetic (T2D) and atherosclerosis patients. Previous studies have reported that Mn supplementation has beneficial effects on insulin secretion and lipid and glucose metabolisms in various animal and cell culture models; however, the mechanisms of these effects are unknown. The studies in this dissertation investigate the effects of Mn supplementation on markers of endothelial dysfunction in different models of T2D to determine whether Mn supplementation is a good candidate for adjuvant therapy for T2D.;The second part of this study was mainly performed on cultured endothelial cells: Human Umbilical Vein Endothelial Cells. Results showed that Mn supplementation reduces monocyte adhesion to endothelial cells, monocyte chemoattractant protein-1 (MCP-1), reactive oxygen species (ROS), and intracellular adhesion molecule-1 (ICAM-1) levels, all key players in the development of atherosclerosis. To investigate the underlying mechanisms, we performed silencing studies, which included knocking down manganese superoxide dismutase (MnSOD), an antioxidant enzyme that uses Mn as a cofactor, and disulfide bond A-like (DsbA-L), a chaperone protein for adiponectin, an adipokine exhibiting anti-diabetic effects. Our results show that Mn supplementation maintains its beneficial effects on endothelial cells when MnSOD is knocked down; however, the effects are abolished when DsbA-L expression is silenced.;These studies demonstrate that DsbA-L mediates the beneficial effects of Mn and provide evidence for a novel mechanism by which Mn supplementation reduces biomarkers of vascular inflammation in diabetes. Our results also show for the first time that Mn can have beneficial effects on endothelial cells independently of MnSOD. Thus, Mn supplementation should be further explored as an adjuvant therapy in T2D patients to assess its ability to lower the risks of endothelial dysfunction and atherosclerosis.;The first part of this study was conducted in an animal model of T2D: Zucker diabetic fatty rats. These studies showed that Mn supplementation improves blood markers of vascular inflammation, reduces oxidative stress, and downregulates expression of enzymes involved in gluconeogenesis.