Cardiovascular disease is a major complication of diabetes mellitus, and improved strategies for prevention and treatment are needed. Endothelial dysfunction contributes to the pathogenesis and clinical expression of atherosclerosis in diabetes mellitus. This article reviews the evidence linking endothelial dysfunction to human diabetes mellitus and experimental studies that investigated the responsible mechanisms. We then discuss the implications of these studies for current management and for new approaches for the prevention and treatment of cardiovascular disease in patients with diabetes mellitus. KeywordsEndothelium; Nitric oxide; Inflammation; Diabetes mellitus; Mitochondria; Protein kinase C Type 2 diabetes mellitus is a growing public health problem [1] and a major cause of cardiovascular disease in the United States [2]. Type 2 diabetes is associated with systemic insulin resistance, which promotes hyperglycemia and dyslipidemia [3], and it has been proposed that these metabolic abnormalities account for increased cardiovascular risk. Endothelial dysfunction contributes to the pathogenesis and clinical expression of atherosclerosis and has been linked to Type 2 diabetes mellitus and insulin resistance in experimental and clinical studies [4]. This article will review the concept of endothelial dysfunction and the evidence linking it to human diabetes mellitus. We will then review © Springer Science+Business Media, LLC 2010 Correspondence to: Joseph A. Vita. NIH Public Access Author ManuscriptRev Endocr Metab Disord. Author manuscript; available in PMC 2010 June 9. What is endothelial dysfunction?Once thought to be simply a passive lining for blood vessels, it is now recognized that the vascular endothelium is a key determinant of vascular health. Broadly speaking, the term "endothelial dysfunction" refers to an impairment of the ability of the endothelium to properly maintain vascular homeostasis [5]. Although the term is often used in reference to a loss of bioavailable nitric oxide (NO), endothelial dysfunction also reflects increased production of vasoconstrictors and disturbed regulation of inflammation, thrombosis, and cell growth in the vascular wall [5,6]. Numerous studies have linked endothelial dysfunction and resultant atherosclerosis with insulin resistant states such as obesity and diabetes [7][8][9][10].The endothelium plays a key role in the regulation of arterial tone and blood flow. In this regard, the endothelium orchestrates the production of vasodilator molecules such as NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF), and vasoconstrictors, including endothelin-1 (ET-1) and angiotensin II [5]. Stimuli for production of endothelium-dependent vasodilators include physiologically relevant factors such as acetylcholine, thrombin, serotonin, angiotensin II, and alpha adrenergic agonists. In general, these factors also promote vasoconstriction via direct effects on vascular smooth muscle. Endothelium-derived NO and other vasodilators oppose such vasocons...

Chronic cranberry juice consumption reduced carotid femoral pulse wave velocity-a clinically relevant measure of arterial stiffness. The uncontrolled pilot study suggested an acute benefit; however, no chronic effect on measures of endothelial vasodilator function was found. This trial was registered at clinicaltrials.gov as NCT00553904.

We observed no effect of grape juice on ambulatory blood pressure in this cohort of relatively healthy individuals with modestly elevated blood pressure. Secondary analyses suggested favorable effects on nocturnal dip and glucose homeostasis that may merit further investigation. This trial was registered at clinicaltrials.gov as NCT00302809.