Background and Objectives: Type 1 and type 2 diabetes are associated with an elevated incidence of cardiovascular disease. An early indicator of cardiovascular disease is endothelial dysfunction wherein there is a blunted blood flow response following activation of the endothelium. The elevated blood glucose associated with diabetes is thought to be a key factor associated with endothelial dysfunction and, in particular, the development of microvascular disease. Elevated blood glucose also has a negative effect on endothelial cell survival and thus enhances the ageing effect of diabetes on cardiovascular function. Clinical data suggests that metformin, a widely used orally effective hypoglycaemic drug, has an endothelial cell protective action. Metformin may also be beneficial in preventing endothelial cell death via a cellular pathway(s) that involves the activation of AMP-activated kinase (AMPK) - a master metabolic sensor for glucose and lipid metabolism. However, a link between metformin and AMPK and a protective action against high glucose-induced microvascular endothelial cell death has not been established. Methods: In the current study, we designed experimental protocols utilizing cell cultures of mouse microvascular endothelial cells (MMECs) that were exposed to high glucose, 40 mM, equivalent to those observed in the db/db mouse model of type 2 diabetes and in the absence and presence of metformin. Results: Exposure of the MMECs to high glucose for 48 h decreased the phosphorylation of AMPK and activated the endoplasmic reticulum (ER) stress and caspase-dependent apoptotic pathways. The presence of metformin (100 micromole/l) enhanced the phosphorylation of AMPK and prevented the activation by high glucose of the ER stress and caspase-dependent apoptotic pathways. Conclusion: Taken together, these data indicate that metformin, in addition to it's well known hypoglycaemic action, may also be beneficial for the improvement of endothelial cell survival via the up-regulation of AMPK and the down-regulation of ER stress and caspase-dependent apoptotic pathways. Further studies are required to fully elucidate the cellular pathways involved and determine the clinical implications. Supported by NPRP 5-149-3-040 and NPRP 4-910—3-244


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