Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I Hyperglycemia and insulin resistance are key factors in the development of atherosclerosis and its complications. Evidence suggests that metabolic abnormalities lead to increased production of reactive oxygen species (ROS), which contribute to endothelial dysfunction and inflammation, promoting diabetic vascular disease. Understanding ROS-generating pathways may lead to new therapeutic strategies for vascular complications in diabetes. This review focuses on the latest advances in the pathophysiology of vascular disease, including the role of the endothelium in obesity-induced insulin resistance, hyperglycemia-dependent microRNA (miR) regulation, alterations in coagulation and platelet reactivity, and epigenetic regulation of ROS-generating and pro-inflammatory genes. These insights suggest that mechanism-based therapies may help prevent cardiovascular complications in diabetes. Hyperglycemia induces oxidative stress, leading to endothelial dysfunction and vascular inflammation. ROS production is increased by mitochondrial dysfunction and the activation of protein kinase C (PKC), which contributes to vascular inflammation and atherosclerosis. Hyperglycemia also increases the production of endothelin-1, which promotes vasoconstriction and platelet aggregation. ROS also contribute to the activation of inflammatory genes, leading to vascular inflammation and atherosclerosis. Insulin resistance is a major feature of type 2 diabetes and contributes to vascular dysfunction. Insulin resistance leads to reduced NO availability, increased ROS production, and impaired vascular function. Insulin resistance also contributes to a prothrombotic state, increasing the risk of coronary events. The atherogenic effects of insulin resistance are also due to changes in lipid profile, such as high triglycerides, low HDL cholesterol, and increased remnant lipoproteins. MicroRNAs (miRs) play a key role in the pathogenesis of hyperglycemia-induced vascular damage. miRs regulate gene expression at the post-transcriptional level and are involved in angiogenesis, vascular repair, and endothelial homeostasis. miR-320 and miR-221 are involved in vascular damage and dysfunction. miR-503 is involved in hyperglycemia-induced endothelial dysfunction and is up-regulated in diabetic patients. Thrombosis and coagulation are also affected by diabetes. Diabetic patients have an increased risk of coronary events and cardiovascular mortality due to a prothrombotic state. Hyperglycemia and insulin resistance contribute to this prothrombotic state by increasing PAI-1 and fibrinogen levels and reducing tissue plasminogen activator levels. Microparticles (MPs) are increased in diabetic patients and contribute to cardiovascular outcomes. Vascular hyperglycemic memory refers to the persistence of vascular dysfunction despite normalization of blood glucose levels. This phenomenon is likely due to epigenetic changes that affect the expression of pro-oxidant and pro-inflammatory genes. The persistence ofDiabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I Hyperglycemia and insulin resistance are key factors in the development of atherosclerosis and its complications. Evidence suggests that metabolic abnormalities lead to increased production of reactive oxygen species (ROS), which contribute to endothelial dysfunction and inflammation, promoting diabetic vascular disease. Understanding ROS-generating pathways may lead to new therapeutic strategies for vascular complications in diabetes. This review focuses on the latest advances in the pathophysiology of vascular disease, including the role of the endothelium in obesity-induced insulin resistance, hyperglycemia-dependent microRNA (miR) regulation, alterations in coagulation and platelet reactivity, and epigenetic regulation of ROS-generating and pro-inflammatory genes. These insights suggest that mechanism-based therapies may help prevent cardiovascular complications in diabetes. Hyperglycemia induces oxidative stress, leading to endothelial dysfunction and vascular inflammation. ROS production is increased by mitochondrial dysfunction and the activation of protein kinase C (PKC), which contributes to vascular inflammation and atherosclerosis. Hyperglycemia also increases the production of endothelin-1, which promotes vasoconstriction and platelet aggregation. ROS also contribute to the activation of inflammatory genes, leading to vascular inflammation and atherosclerosis. Insulin resistance is a major feature of type 2 diabetes and contributes to vascular dysfunction. Insulin resistance leads to reduced NO availability, increased ROS production, and impaired vascular function. Insulin resistance also contributes to a prothrombotic state, increasing the risk of coronary events. The atherogenic effects of insulin resistance are also due to changes in lipid profile, such as high triglycerides, low HDL cholesterol, and increased remnant lipoproteins. MicroRNAs (miRs) play a key role in the pathogenesis of hyperglycemia-induced vascular damage. miRs regulate gene expression at the post-transcriptional level and are involved in angiogenesis, vascular repair, and endothelial homeostasis. miR-320 and miR-221 are involved in vascular damage and dysfunction. miR-503 is involved in hyperglycemia-induced endothelial dysfunction and is up-regulated in diabetic patients. Thrombosis and coagulation are also affected by diabetes. Diabetic patients have an increased risk of coronary events and cardiovascular mortality due to a prothrombotic state. Hyperglycemia and insulin resistance contribute to this prothrombotic state by increasing PAI-1 and fibrinogen levels and reducing tissue plasminogen activator levels. Microparticles (MPs) are increased in diabetic patients and contribute to cardiovascular outcomes. Vascular hyperglycemic memory refers to the persistence of vascular dysfunction despite normalization of blood glucose levels. This phenomenon is likely due to epigenetic changes that affect the expression of pro-oxidant and pro-inflammatory genes. The persistence of