Endothelial Dysfunction in Diabetes: Pathogenesis, Significance, and Treatment

Abstract

■ AbstractType 2 diabetes (T2D) markedly increases the risk of cardiovascular disease. Endothelial dysfunction (ED), an early indicator of diabetic vascular disease, is common in T2D and independently predicts cardiovascular risk. Although the precise pathogenic mechanisms for ED in T2D remain unclear, at inception they probably involve uncoupling of both endothelial nitric oxide synthase activity and mitochondrial oxidative phosphorylation, as well as the activation of vascular nicotinamide adenine dinucleotide phosphate oxidase. The major contributing factors include dyslipoproteinemia, oxidative stress, and inflammation. Therapeutic interventions are designed to target these pathophysiological factors that underlie ED. Therapeutic interventions, including lifestyle changes, antiglycemic agents and lipid-regulating therapies, aim to correct hyperglycemia and atherogenic dyslipidemia and to improve ED. However, high residual cardiovascular risk is seen in both research and clinical practice settings. Well-designed studies of endothelial function in appropriately selected volunteers afford a good opportunity to test new therapeutic interventions, paving the way for clinical trials and utilization in the care of the diabetic patient. However, based on the results from a recent clinical trial, niacin should not be added to a statin in individuals with low high-density lipoprotein cholesterol and very well controlled low-density lipoprotein cholesterol.

Pancreatic perfusion and subsequent response to glucose in healthy individuals and patients with type 1 diabetes

“…It is therefore likely that the pancreatic perfusion increase observed in this study did not only reflect an islet blood flow increase, as seen in rodents [4,5], but may also have occurred as a result of general blood flow increase, caused by parasympathetic signalling through the vagal nerve [12]. In line with this, the absence of an increase in pancreatic perfusion in diabetic individuals may be explained by autonomic neuropathy or endothelial dysfunction [13], albeit the type 1 diabetic participants involved in this study were chosen based on good metabolic control and absence of known microvascular complications. Additionally, the lack of an increase in arterial hepatic perfusion could be explained by the hepatic arterial buffer response to increased portal flow.…”

oxLDL induces injury and defenestration of human liver sinusoidal endothelial cells via LOX1

“…Endothelial dysfunction is a major cause of diabetic microangiopathy (Cameron & Cruickshank 2007, Renier et al 2007, and oxidative damage is a critical step in this process (Hink et al 2001, Hamilton & Watts 2013. Hepatic sinusoid endothelial dysfunction is an early event implicated in the progression to NAFLD (Pasarín et al 2012).…”

Early drug development: assessment of proarrhythmic risk and cardiovascular safety

“…Cardiac valve dysfunction, presumed due to 5-hydroxytryptamine 2B agonists, has been noted on two-dimensional Doppler color flow cardiac sonography with anorexigenic-and ergotamine-derived drugs [53]. Antidiabetic agents have been shown to have important off-target effects on nitric oxide-mediated endothelial function as measured by flowmediated dilation that may presage systemic hypertension and atherosclerosis [54]. Increased thrombogenicity due to thromboxane effects on platelet aggregation leading to stroke and heart attack assessed by platelet aggregometry has been controversially linked to cycloogenase-2 inhibitors prompting more intense scrutiny of this class of agents including the withdrawal of rofecoxib(Vioxx) from the market in 2004 [55].…”