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Endothelial dysfunction in diabetes mellitus.

Hadi HA, Suwaidi JA - Vasc Health Risk Manag (2007)

Bottom Line: A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us.Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes.In the present review we provide the up to date details on this subject.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, State of Qatar, UAE. hadi968@hotmail.com

ABSTRACT
Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.

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Related in: MedlinePlus

Pathophysiology of hyperglycemia induced endothelial dysfunction (DeVriese et al 2000).
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fig2: Pathophysiology of hyperglycemia induced endothelial dysfunction (DeVriese et al 2000).

Mentions: Hyperglycemia is the major causal factor in the development of endothelial dysfunction in patients with diabetes mellitus (Figure 2). Clinical trials have identified hyperglycemia as the key determinant in the development of chronic diabetic complications. The formation of advanced glycation end products (AGEs) is an important biochemical abnormality accompanying diabetes mellitus and, likely inflammation in general. Although the mechanisms underlying this phenomenon are likely to be multi-factorial, recent in-vivo and in- vitro studies have indicated a crucial role of the diacylglycerol (DAG)-protein kinase C (PKC) pathway in mediating this phenomenon. PKC may have multiple adverse effects on vascular function, including the activation of superoxide-producing enzymes such as the nicotinamide adenine dinicleotide phosphate (NADPH) oxidase as well as increased expression of a dysfunctional, superoxide-producing, uncoupled endothelial nitric oxide synthase (NOS III). PKC-mediated superoxide production may inactivate NO derived from endothelial NOS III, and may inhibit the activity and/or expression of the NO downstream target, the soluble guanylyl cyclase. The effects of AGEs on vessel wall homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes. Driven by hyperglycemia and oxidant stress, AGEs form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGEs may “trap” plasma proteins, quench NO activity and interact with specific receptors to modulate a large number of cellular properties. On plasma low density lipoproteins (LDL), AGEs initiate oxidative reactions that promote the formation of oxidized LDL. The interaction of AGEs with endothelial, as well as with other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth muscle cells, provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGEs with vessel wall component increases vascular permeability, the expression of procoagulant activity and the generation of reactive oxygen species, resulting in increased endothelial expression of endothelial leukocyte adhesion molecules (Wen et al 2002; Hink et al 2003; Basta et al 2004; Farhangkhoee et al 2006), while acute hyperglycemia and hyperinsulinemia induced vasodilatation is not accompanied by changes in microvascular permeability or endothelial markers (Oomen et al 2002).


Endothelial dysfunction in diabetes mellitus.

Hadi HA, Suwaidi JA - Vasc Health Risk Manag (2007)

Pathophysiology of hyperglycemia induced endothelial dysfunction (DeVriese et al 2000).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2350146&req=5

fig2: Pathophysiology of hyperglycemia induced endothelial dysfunction (DeVriese et al 2000).
Mentions: Hyperglycemia is the major causal factor in the development of endothelial dysfunction in patients with diabetes mellitus (Figure 2). Clinical trials have identified hyperglycemia as the key determinant in the development of chronic diabetic complications. The formation of advanced glycation end products (AGEs) is an important biochemical abnormality accompanying diabetes mellitus and, likely inflammation in general. Although the mechanisms underlying this phenomenon are likely to be multi-factorial, recent in-vivo and in- vitro studies have indicated a crucial role of the diacylglycerol (DAG)-protein kinase C (PKC) pathway in mediating this phenomenon. PKC may have multiple adverse effects on vascular function, including the activation of superoxide-producing enzymes such as the nicotinamide adenine dinicleotide phosphate (NADPH) oxidase as well as increased expression of a dysfunctional, superoxide-producing, uncoupled endothelial nitric oxide synthase (NOS III). PKC-mediated superoxide production may inactivate NO derived from endothelial NOS III, and may inhibit the activity and/or expression of the NO downstream target, the soluble guanylyl cyclase. The effects of AGEs on vessel wall homeostasis may account for the rapidly progressive atherosclerosis associated with diabetes. Driven by hyperglycemia and oxidant stress, AGEs form to a greatly accelerated degree in diabetes. Within the vessel wall, collagen-linked AGEs may “trap” plasma proteins, quench NO activity and interact with specific receptors to modulate a large number of cellular properties. On plasma low density lipoproteins (LDL), AGEs initiate oxidative reactions that promote the formation of oxidized LDL. The interaction of AGEs with endothelial, as well as with other cells accumulating within the atherosclerotic plaque, such as mononuclear phagocytes and smooth muscle cells, provides a mechanism to augment vascular dysfunction. Specifically, the interaction of AGEs with vessel wall component increases vascular permeability, the expression of procoagulant activity and the generation of reactive oxygen species, resulting in increased endothelial expression of endothelial leukocyte adhesion molecules (Wen et al 2002; Hink et al 2003; Basta et al 2004; Farhangkhoee et al 2006), while acute hyperglycemia and hyperinsulinemia induced vasodilatation is not accompanied by changes in microvascular permeability or endothelial markers (Oomen et al 2002).

Bottom Line: A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us.Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes.In the present review we provide the up to date details on this subject.

View Article: PubMed Central - PubMed

Affiliation: Department of Cardiology and Cardiovascular Surgery, Hamad General Hospital, Hamad Medical Corporation, Doha, State of Qatar, UAE. hadi968@hotmail.com

ABSTRACT
Diabetes mellitus is associated with an increased risk of cardiovascular disease, even in the presence of intensive glycemic control. Substantial clinical and experimental evidence suggest that both diabetes and insulin resistance cause a combination of endothelial dysfunctions, which may diminish the anti-atherogenic role of the vascular endothelium. Both insulin resistance and endothelial dysfunction appear to precede the development of overt hyperglycemia in patients with type 2 diabetes. Therefore, in patients with diabetes or insulin resistance, endothelial dysfunction may be a critical early target for preventing atherosclerosis and cardiovascular disease. Microalbuminuria is now considered to be an atherosclerotic risk factor and predicts future cardiovascular disease risk in diabetic patients, in elderly patients, as well as in the general population. It has been implicated as an independent risk factor for cardiovascular disease and premature cardiovascular mortality for patients with type 1 and type 2 diabetes mellitus, as well as for patients with essential hypertension. A complete biochemical understanding of the mechanisms by which hyperglycemia causes vascular functional and structural changes associated with the diabetic milieu still eludes us. In recent years, the numerous biochemical and metabolic pathways postulated to have a causal role in the pathogenesis of diabetic vascular disease have been distilled into several unifying hypotheses. The role of chronic hyperglycemia in the development of diabetic microvascular complications and in neuropathy has been clearly established. However, the biochemical or cellular links between elevated blood glucose levels, and the vascular lesions remain incompletely understood. A number of trials have demonstrated that statins therapy as well as angiotensin converting enzyme inhibitors is associated with improvements in endothelial function in diabetes. Although antioxidants provide short-term improvement of endothelial function in humans, all studies of the effectiveness of preventive antioxidant therapy have been disappointing. Control of hyperglycemia thus remains the best way to improve endothelial function and to prevent atherosclerosis and other cardiovascular complications of diabetes. In the present review we provide the up to date details on this subject.

Show MeSH
Related in: MedlinePlus