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Diabetes Mellitus

By: Pharma Tips | Views: 5971 | Date: 01-May-2011

Diabetes mellitus is a common metabolic disease worldwide affecting approx. 150 million people in 2000, which is predicted to rise to 220 million in 2010. Diabetes and its associated complications have become a public health problem of considerable magnitude. Cardiovascular disease causes most of the excess morbidity and mortality in diabetes mellitus.Adults with diabetes are at a 2- to 4 fold increased risk of cardiovascular events relative to those without diabetes .


                Diabetes mellitus is a common metabolic disease worldwide affecting approx. 150 million people in 2000, which is predicted to rise to 220 million in 2010. Diabetes and its associated complications have become a public health problem of considerable magnitude. Cardiovascular disease causes most of the excess morbidity and mortality in diabetes mellitus.Adults with diabetes are at a 2- to 4 fold increased risk of cardiovascular events relative to those without diabetes . Cardiovascular disease accounts for up to 80% of premature excess mortality in diabeticpatients. Because of the huge premature morbidity and mortality associated with this disease, prevention of complications is a key issue. Vascular complications can be caused by micro- and macro-angiopathy. Retinal and renal microangiopathy cause diabetic retinopathy and nephropathy and microangiopathy of the vasa nervorum is important in the pathogenesis of neuropathy. Macroangiopathy in diabetesn consists mainly of an accelerated form of atherosclerosis and affects the coronary, carotid and peripheral arteries, thus increasing the risk of myocardial infarction, stroke and diabetic foot disease.(1)

Diabetes Mellitus

                     Large clinical trials in both Type I and Type II diabetes have demonstrated that hyperglycaemia plays an important role in the pathogenesis of microvascular complications. Although diabetic patients with the most severe hyperglycaemia have the highest risk of microangiopathy, hyperglycaemia, however, is a necessary, but not a sufficient, cause of clinically important microangiopathy. Hypertension, smoking, hypercholesterolaemia, dyslipidaemia, obesity and hyperhomocysteinaemia are additional major causes of microangiopathy. Risk of macroangiopathy does not appear to be strongly related to hyperglycaemia, but is related to general risk factors for atherothrombosis, such as age, smoking, hypertension, hypercholesterolaemia, dyslipidaemia, obesity and hyperhomocysteinaemia. The cardiovascular risk factors hypertension, dyslipidaemia, obesity, insulin resistance, hyperinsulinaemia and impaired fibrinolysis cluster in the metabolic syndrome. All of the above-mentioned factors create a state of constant and progressive damage to the vascular wall, manifested by a low-grade inflammatory process and endothelial dysfunction.

                     Dysfunction of the vascular endothelium is regarded as an important factor in the pathogenesis of micro- and macro-angiopathy and endothelial function has gained increasing attention in the study of vascular disease. This review will explore how endothelial dysfunction in diabetes relates to the pattern of disease occurrence described above and what current biochemical mechanisms have been proposed as an explanation for the development of endothelial dysfunction in diabetes.


             The endothelium is the biological active inner layer of the blood vessels, which serves as an important locus of control of vascular and thus organ functions.
The endothelium actively regulates vascular tone and permeability, the balance between coagulation and fibrinolysis, the composition of the subendothelial matrix, the adhesion and extravasation of leucocytes, and inflammatory activity in the vessel wall. It also affects the functions of other cell types, such as vascular smooth muscle cells, platelets, leucocytes, retinal pericytes, renal mesangial cells and large artery macrophages. On the other hand, these cells can affect endothelial cells. To carry out its above-mentioned functions, the endothelium produces components of the extracellular matrix such as collagen and a variety of regulatory mediators, including NO (nitric oxide), prostanoids, ET-1 (endothelin-1), Ang II (angiotensin II), t-PA (tissue-type plasminogen activator), PAI-1 (plasminogen activator inhibitor-1), vWF (von Willebrand factor), adhesion molecules and cytokines. The production of these moieties is responsive to various stimuli.

                       Normally, the endothelium actively decreases vascular tone, limits leucocyte adhesion and thus inflammatory activity in the vessel wall, maintains vascular permeability to nutrients, hormones, other macromolecules and leucocytes, inhibits platelet adhesion and aggregation by producing prostacyclin and NO, limits activation of the coagulation cascade by the thrombomodulin/protein C, heparin sulphate/antithrombin and tissue factor/tissue factor pathway inhibitor interactions, and regulates fibrinolysis by producing t-PA and its inhibitor PAI-1.
                        Among important molecules synthesized by endothelial cells is NO, which is a particularly important endothelium-derivedmediator, because of its vasodilator, anti-platelet, anti-proliferative, permeability-decreasing and anti-inflammatory properties. NO inhibits leucocyte adhesion and rolling as well as cytokine-induced expression of VCAM-1 (vascular cell adhesion molecule- 1) and MCP-1 (monocyte chemotactic protein-1) , effects that are at least in part attributable to inhibition of the transcription factor NF-κB (nuclear factor κB) . Injury to the endothelium can cause endothelial dysfunction. Dysfunction of the endothelium can be considered.present when its properties, either in the basal state or after stimulation, have changed in a way that is inappropriate with regard to the preservation of organ function. Such alterations do not necessarily occur simultaneously.

                       Furthermore, they may differ according to the nature of the injury and may depend on the intrinsic properties of the endothelium (e.g. venous versus arterial versus microvascular endothelium). Endothelial activation designates one specific set of dysfunctions characterized by increased interactions with blood leucocytes in which adhesion molecules and chemoattractants such as MCP-1 and IL (interleukin)-8 are essential. Endothelial dysfunction is thought to play an important role not only in the initiation of atherosclerosis, but also in its progression and clinical sequelae. Risk factors such as hypercholesterolaemia, dyslipidaemia, smoking and diabetes initiate atherosclerosis through endothelial activation and therefore endothelial dysfunction. Therefore endothelial activation can be conceptualized as a transducer of atherogenic risk factors.

                  In Type I diabetes, patients who have had diabetes for more than 5–10 years and who have normal urinary albumin excretion compared with non-diabetic individuals are characterized by subtle increases in blood pressure and large-artery stiffness and by autonomic dysfunction, and some or perhaps most have impaired endothelial function and increased low-grade inflammation. All these abnormalities are worse in the microalbuminuric stage. It is not clear how they interact or whether impaired endothelial function is a common antecedent or a consequence, but these data illustrate that cardiovascular function, including endothelial function, does become impaired before the onset of microalbuminuria, at least when the latter is defined as 30 mg/24 h. The possibility remains, however, those patients with ‘normal’ urinary albumin excretion who show such cardiovascular abnormalities are those in whom urinary albumin excretion is in fact increased albeit within the normal range as conventionally defined, i.e. the (arbitrary) cut-off of 30 mg/24 h may be too high. This has a parallel in Type II diabetes and in non-diabetic individuals in whom any increase in microalbuminuria appears associated with increased risk of atherothrombosis.

                    Endothelial dysfunction thus occurs before microalbuminuria sets in. However, is endothelial dysfunction a feature of Type I diabetes and is moderate hyperglycaemia sufficient to impair endothelial function. On the one hand, plasma vWF levels are not increased in patients with early uncomplicated and reasonably well-regulated Type I diabetes, suggesting normal endothelial function. On the other hand, it has been argued that NO-mediated endothelium-dependent vasodilation is impaired in short-term uncomplicated diabetes and that hyperglycaemia, in the absence of other factors, acutely impairs endothelium-dependent vasodilation in non-diabetic individuals. Several findings are, however, in conflict with these concepts. First, studies that carefully stratified patients according to the absence or presence of a normal urinary albumin excretion rate have concluded that, in reasonably well-controlled Type I diabetes, endothelium-dependent and -independent vasodilation of resistance and conduit arteries are neither impaired nor enhanced.(9) Secondly, early uncomplicated Type I diabetes is accompanied by dilation, not constriction, of small and large blood vessels and an increase in microvascular blood flow, both in humans and in animal models .Impaired endothelium-dependent vasodilation may occur early in a subset of Type I diabetic patients apparently dependent on other environmental or genetic factors such as the Ang II type I receptor gene polymorphism. In other words, the diabetic state predisposes to the development of endothelial dysfunction, but in and of itself is not a sufficient cause. Other factors, genetic or environmental, are likely to play a role in determining who among Type I diabetic patients go on to develop aggressive angiopathy.(15)

4)  Type II diabetes
                     Endothelial dysfunction indicated by impaired endothelium-dependent vasodilation and increased plasma concentrations of markers of endothelial function is common in early and otherwise uncomplicated Type II diabetes. For example, vWF and soluble VCAM-1 levels are increased and have been found to be associated with an increased risk of cardiovascular mortality and development and progression of microalbuminuria.  Impairment of endothelial function may be especially severe among diabetic women.  Type II diabetes typically occurs in the context of a cluster of cardiovascular risk factors, notably obesity, hypertension, high triacylglycerol (triglyceride) levels, low HDL (high-density lipoprotein)-cholesterol levels, abnormal LDL composition, hyperinsulinaemia, insulin resistance and chronic low-grade inflammation, all of which may impair endothelial function. Endothelial dysfunction in Type II diabetes appears to be independent of that induced by obesity remains to be established. An important contender is increased inflammatory activity. Endothelial dysfunction, inflammation and urinary albumin excretion in Type II diabetes are progressive and closely interrelated.  Nevertheless, as in Type I diabetes, microalbuminuria in Type II diabetes can occur in the absence of severe endothelial dysfunction and then prognosis is relatively good.(21)

5) Mechanisms of Vascular complications of Diabetes Mellitus
The mechanisms of diabetes that may predispose a hastening of the atherosclerotic process.

5.1) Diabetes Mellitus and Cardiovascular Disease Risk
As it relates to cardiovascular risk, notable differences exist between the two types of diabetes, with type II diabetic individuals developing CVD at a younger age, having a higher rate of multi- vessel disease and poorer outcomes post myocardial infarction than their type I.The Multiple Risk Factor Intervention Trial found diabetic men with one, two or three CVD risk factors experienced higher disease mortality than nondiabetic individuals with the same number of risk factors. Diabetes played an additive role when combined with one or more risk factors. The United Kingdom Prospective Study (UKPDS) following newly detected diabetic individuals, found increased risk of CVD was significantly associated with risk factors of increased LDL, decreased HDL increased HGB A1c, elevated systolic blood pressure and smoking when measured at baseline. Despite the undeniable association of established CVD risk factors and diabetes, these risk factors account for only 50 per cent of the excess CVD in the diabetic. Hyperglycemia, hyperinsulinemia and insulin resistance, dyslipidemia, increased plasma oxidative stress, enhanced fibrinolysis and abnormal vasodilator function are some of the proposed mechanisms and novel risk factors for the accelerated development of atherosclerosis and diabetes.(25)

5.2) Mechanisms of Vascular Dysfunction in Diabetes
Numerous mechanisms contribute to the pathogenesis of diabetic vascular diseases, many of which are complex, incompletely understood and continue to be intensely investigated. The hallmark of diabetic vascular disease is thickening of the basement membranes, which develop in relation to the duration of diabetes and degree of glycemic control. The contribution of hyperglycemia, hyperinsulemia and dyslipidemia to diabetic vascular complications will be briefly reviewed. Hyperglycemia although still controversial, hyperglycemia has emerged as a leading candidate responsible for the excess of diabetes risk. It is unclear if there is a critical value that exists above which CVD raises. A number of mechanisms have been proposed for the contribution of hyperglycemia in CVD. Suggested mechanisms include: glycation of collagen and other vessel-wall proteins and lipoproteins; accelerated generation of reactive oxygen species; increased oxidative stress on glycated end products, LDL cholesterol, and vascular endothelial cells; alteration in haemorrheological characteristics or changes in vascular reactivity. Extracellular glucose can glycate proteins without enzyme action and generate oxidative by-products. Glycated proteins (Advanced Glycation End-products) accumulate in the extracellular matrix and bind to specific AGE-receptors that are expressed on the cell surface. AGE receptors are being extensively investigated for their contribution to the accelerated vascular complications of diabetes.(26) Cells contain several receptors of AGEs that mediate their biological effects. Exposure to AGE modified proteins can elicit the production of inflammatory cytokines from vascular cells, cause impaired endothelial dependent vasodilator function and increase the expression of various leukocyte adhesion molecules implicated in atherosclerosis.
Although it has been suggested that hyperinsulinemia may be the link between hyperglycemia and CVD. It is thought that insulin resistance and compensatory hyperinsulinemia may contribute to atherogenic risk through several different mechanisms. Insulin resistance commonly precedes hyperglycemia, and insulin resistance has been shown to have a positive correlation with CVD. Diabetes is frequently associated with the risk factors of obesity, dyslipidemia, and hypertension.(28)
Most individuals with this group of disorders also have insulin resistance. This group of disorders has been named syndrome X, the insulin resistance syndrome, and CVD metabolic syndrome. Insulin resistance syndrome includes glucose intolerance, and elevated levels of fasting insulin and triglycerides. In normal conditions, insulin has a protective vasodilatory action that may be mediated by nitric oxide. In insulin resistance states, the ability of insulin to induce vasodilation is low, suggesting an impairment or inactivation of nitric oxide. Increased insulin action is also thought to contribute to atherogenesis through smooth- muscle cell hypertrophy and hyperplasia and increased extracellular proteins. A hypothesis generated to explain data from the Framingham Offspring Study, suggested that the atherogenic effects of hyperglycemia or hyperinsulinemia might be mediated through factors predisposing to acute thrombosis. Markers of decreased fibrinolytic potential include elevated levels of plasminogen activator inhibitor 1 (PAI-1) antigen or tissue-type plasminogen activator (tPA) antigen. These markers are associated with increased risk for CVD among non-diabetic individuals. Elevated levels of PAI-1 appear to increase the formation of acellular, thin-walled plaques susceptible to rupture. Increases of fibrinolytic markers have been shown to correlate with elevated markers of inflammation and endothelial dysfunction. Is fibrinolysis the cause or the effect of hyperinsulinemia.(34)
Dyslipidemia and associated metabolic abnormalities. Dysplipidemia is the most thoroughly studied and established mechanism for the increased risk of atherogenesis identified in type II diabetes. Dyslipidemia and diabetes have been done primarily with individuals with type II diabetes because of the increased incidence of dyslipidemia in this population. In type l patients with good glycemic control, lipids may appear to be better than the average for subjects without diabetes. However lipoproteins may be abnormal in composition and as a result more atherogenic. Numerous studies have also shown that dyslipidemias are more prevalent in diabetic women, and probably a very important contributor to the increased CVD risk in this group. The most common dyslipidemias observed in type II diabetes are high triglycerides and reduced high-density lipoprotein (HDL) cholesterol. Low-density lipoprotein concentration is not usually higher than in individuals without diabetes, but the LDL particles themselves tend to be small and dense. Small dense LDL particles are believed to be more atherogenic because they are more easily glycated and susceptible to oxidation. Interventional studies have shown that the benefit of lowering LDL is similar in the diabetic and non-diabetic population. Central to the pathogenesis of dyslipidemia in diabetes is the increased presentation of free fatty acids to the liver, which provide the substrate for triglyceride-rich lipoproteins - very low density (VLDL) production in the liver. Abdominal obesity, a common finding in type II diabetic men, provides a further source of free fatty acids which in turn fuel production of VLDL.
Contributing to the adverse effect of increased VLDL production is the decreased catabolism of triglyceride-rich lipoproteins. Liprotein lipase, an enzyme that plays a central role in clearing postprandial lipemia (consisting largely of triglyceride-rich particles), is decreased in uncontrolled type ll diabetes. Contiguously, states of higher VLDL are associated with low HDL levels because of the intimate relationship between lipoprotein lipase activity (reduced in DM), cholesterol ester transfer protein activity, and efficient HDL. The protective role of HDL in shielding LDL from oxidation also appears to be diminished in diabetes, suggesting differences in the qualitative as well as quantitative aspects of HDL in diabetes.(19)

Coronary artery, cerebrovascular and peripheral vasculardisease, are the principal causes of morbidity and mortality in type 2diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Advanced glycation end products, glycoxidised and oxidized low-density lipoproteins and reactive oxygen species linked to hyperglycemia have all been identified in type 2 diabetes mellitus and could accelerate macroangiopathy.Hence, the resistance to insulin is an additional independent risk factor, in association with oxidant stress, dyslipidemias, and prothrombic/hypofibrinolytic states. Coronary artery, cerebrovascular and peripheral vascular disease are the principal causes of morbidity and mortality in type 2 diabetes mellitus. The accelerated macrovascular disease in type 2 diabetes mellitus is due partly to the increased incidence of cardiovascular risk factors, such as hypertension, obesity and dyslipidemia. Role of endothelium are described as follows.(38)

6.1) Vasoregulation
The integrity of endothelium is needed to maintain the balance between vasodilation and vasoconstriction, and so preserve a sufficient vascular diameter for the satisfactory perfusion of the cardiovascular system. The endothelium is responsible for the short term regulation of this vascular tone. It produces vasodilatator substances, such as nitric oxide (NO) (which was previously called endothelium-derived relaxing factor (EDRF)), prostacyclin (PGI2) and endotheliumderived hyperpolarizing factor (EDHF). It also produces vasoconstrictor substances, such as endothelin-1, thromboxane A2 (TXA2) and prostaglandin H2 (PGH2). This vasoregulation is under the control of biochemical and mechanical stimuli. (31)

6.2) Nitric oxide (NO)
Endothelium is essential for the relaxation of the isolated rabbit aorta in response to acetylcholine, the biological role of the endothelium and of NO has been extensively investigated in both animals and humans. NO is the best characterized and probably the most important vasodilator. NO is produced in response to a variety of stimuli by the oxidation of L-arginine by the NADPH-dependent enzyme, nitric oxide-synthase (NOS). Its production leads to physiological vasodilation and the relaxation of smooth muscle cells. This effect is mediated by protein G.
There are three isoforms of NOS, all of which transform L-arginine into nitric oxide and L-citrulline; eNOS (endothelial NOS), iNOS (inducible NOS), and nNOS (neuronal NOS). Two of them (eNOS and nNOS) are calcium-dependent. The Enos is located in the plasmalemma caveola of endothelial cells, close to caveolin-1, a protein that inhibits the enzyme activity of eNOS. The nitric oxide acts on smooth muscle cells by stimulating guanylate cyclase and by increasing the intracellular concentration of cyclic guanosine monophosphate (cGMP). The cGMP decreases the intracellular Ca2+ concentration causing vasorelaxation.(32)
Nitric oxide also inhibits platelet aggregation by a mechanism dependent on cGMP, having an antithrombotic effect. Finally, NO also inhibits the proliferation of smooth muscle cells, the synthesis of adhesion molecules, and antagonizes endothelin-1 (ET1) . Nitric oxide has a low molecular weight, diffuses rapidly and has a very short half life (a few seconds). It is thus an ideal tool for adapting the vasculature to changes in blood flow and allows instant changes in arterial diameter to cope with blood flow and shear stress.

6.3) Prostacyclin
Another major vasodilator is prostacyclin, which is produced from arachidonic acid by the enzymes cyclooxygenase (COX) and prostacyclin synthase. Its release may be stimulated by bradykinin and adenine nucleotides. Prostacyclin acts by stimulating adenylate cyclase and by increasing intracellular cyclic adenosine monophosphate (cAMP). Like nitric oxide, prostacyclin is a potent vasodilator with a short half life, and acts in both the systemic and pulmonary circulations. Finally, prostacyclin plays a key role in the interaction between the endothelium and platelets by limitating the development of thrombi.(35)

6.4) Endothelium-derived hyperpolarizing factor (EDHF)
Hyperpolarization of the underlying smooth muscle cells hence vasorelaxation. This diffusible relaxing and hyperpolarizing substance, distinct from nitric oxide or prostacyclins and designated endothelium-derived hyperpolarizing factor (EDHF), is secreted by the endothelium, and contributes to endothelium-dependent relaxations by opening K+/ATP dependent channels in the vascularsmooth muscle.(34)

7) Vasoconstrictors secreted by the endothelium
7.1) Endothelin
Endothelin contains 21 amino acids peptide is an extremely powerful vasoconstrictor. There are three isoforms of endothelin, but isoform 1 (ET1) only, is released from human endothelial cells. The production of endothelin-1 from big-endothelin is catalysed by endothelin-converting enzyme (ECE); it is released in response to hypoxia and noradrenalin. The biological actions of endothelin are mediated by two distinct G-protein-coupled receptor subtypes (ETA and ETB), located in smooth muscle cells. Such activation causes an increase in intracellular calcium leading to contraction. ET1 can also interact with ETB receptors on endothelial cells, triggering the release of vasodilators (NO, PGI2). ET1 has a short half life and is present in healthy subjects at low concentrations. ET1 is involved in counter-regulation for preserving peripheral resistance.(34)

7.2) Endothelium-derived contracting factors (EDCFs)

The endothelium also synthesizes and releases EDCFs, causing endotheliumdependent contractions. These EDCFs include vasoconstrictor prostanoids such as prostaglandin H2 and thromboxane A2, which activate specific receptors on the vascular smooth muscle. Superoxide anions may act as contracting factor by scavenging NO. The stimuli for EDCFs production are hypoxia, blood pressure, and variety of neurohumoral mediators.(29)

7.3) Stimuli
A) Neurohumoral factors
The neurohumoral mediators (acetylcholine, bradykinin and histamine), hormones (catecholamines, vasopressin), and substances derived from platelets (adenosine diphosphate and serotonin) and thrombin (T) cause the release of endothelium-derived relaxing or contracting factors by activating specific endothelial receptors, inducing changes in the vascular tone.Vasodilators and vasoconstrictors secreted by the endothelium. NO: nitric oxide, NOS: nitric oxide synthase, ET1: endothelin-1, ECE: endothelin-converting enzyme, PGI2: prostacyclin, COX: cyclooxygenase, L-Arg: L-arginine, EDHF: endothelium-derived hyperpolarizing factor, X?: unknown, cGMP: cyclic guanosine monophosphate, cAMP: cyclic adenosine monophosphate, PGH2: prostaglandin.H2, TXA2: thromboxane A2, AT-I: angiotensin I, AT-II: angiotensin II, ACE: angiotensin-converting enzyme, Ca: calcium, K: potassium, AC: adenylate cyclase, GC: guanylate cyclase. protein G, enzyme, receptor (ET: endothelin, TX: thromboxane, PG: prostaglandins).(30) In healthy subjects, the muscarinic receptors on the endothelium are activated by acetylcholine (Ach), a neurotransmitter which sets off nitric oxide production. Platelets release substances such as adenosine diphosphate (ADP), adenosine triphosphate (ATP) and 5-hydroxytryptamine (serotonin: 5-HT) which trigger the release of NO and prostacyclin from the endothelium. Thrombin, the major enzyme of the coagulation cascade, also activates the formation of NO by endothelium. The endothelium is also stimulated by substances such as histamine, catecholamines (adrenaline, noradrenaline), substance P (neurotransmitter and neuromodulator from the central nervous system), Calcium gene-related peptide. Bradykinin can also stimulate the production of EDHF by the endothelial cells. Hence, when platelets and the coagulation cascade are activated, intact endothelial cells release NO which acts as a negative feed-back by causing vasodilation and thus preventing vasoconstriction, but also by inhibiting platelet activation to prevent thrombus formation. In contrast, the production of EDCFs can be increased by vasopressin (VP) and thrombin (T) through activation of their specific endothelial receptors. In particular, the effects of ET1 produced by endothelial cells can be amplified by the components of the reninangiotensin system, after transformation of angiotensin I (AT-I) to angiotensin II (AT-II) by angiotensin-converting enzyme (ACE). Activation of the endothelial receptors, such as serotoninergic receptors, can stimulate the enzyme COX in certain blood vessels, with the production of PGH2 and TXA2, leading to contraction.(30)

B) Wall shear stress
In addition to receptor-biochemical mechanisms, mechanical factors cause endothelium-dependent vasodilation.
The blood flow exerts a physical force on the vessel wall which can be resolved into two principal vectors; 1) shear stress, which is parallel to the vessel wall and represents the friction between the flowing blood and the endothelial surface of the vessel wall, 2) tensile stress, which is perpendicular to the vessel wall and is due to the dilating force of blood pressure. The whole vessel wall, including the endothelium, smooth muscle cells and the extracellular matrix is exposed to it. In contrast, only the inner surface of the vessel wall composed of the endothelial cell is exposed to the frictional force of shear stress. This force passed to the vascular wall and moves the endothelium and subintimal layer towards the underlying layers in the direction of the blood flow, so explaining the minimal change in blood vessel diameter, related to the activation of mecanoreceptors by shear stress. There are two broad mechanisms underlying the interaction between blood flow and the endothelium. One is activation of a calcium/ calmodulin complex dependent receptor (shear stress receptor), leading to a rapid post-translational activation of eNOS. This signal is based on potassium channels and G-protein coupling. The other is the release of NO by an as-yet-unknown direct effect on the endothelial cells. This action is independent of intracellular calcium, but is probably due to phosphorylation of MAP kinases and/or tyrosine kinase activity.(26)

C) Stretch force
The shear stress effect, the stretch force applied on the endothelium can modulate the production of vasoactive substances by endothelial cells, particularly vasoconstrictors factors, by activating the ionic channels-mecanoreceptor pathway (stretch activated channels).

7.4) Hypoxia and ischemia
They can stimulate the production of NO and secretion of prostacyclins and cause endotheliumdependent vasodilation. Selective luminal hypoxia can cause a 11% dilatation in segments of femoral artery or aorta from rabbits. This hypoxia-induced dilation of intact segments is significantly inhibited by nitric oxide inhibitors. But hypoxia is associated with increases in plasma endothelin-1 or other EDCR factors, particularly at high altitudes, and can cause endothelium-dependent contraction

8) Other functions of the endothelium in Diabetes

8.1) Permeability
The process of adhesion is necessary for a variety of cell functions, including differentiation, growth, migration and the response of the cell to its external milieu. New adhesion molecules have been placed in the selectin family (particularly selectin-E), and in a superfamily of immunoglobulins, including intercellular cell adhesion molecules (ICAMs: include ICAM-1 and ICAM-2), vascular cell adhesion molecule (VCAM-1), and platelet/endothelial cell adhesion molecule (PECAM-1). ICAMs and VCAMs play an important role in the adhesion of circulating blood cells to vascular tissue, as in the inflammatory response to vascular injury. Selections are produced by stimulated endothelial cells: they mediate the loose contacts between leucocytes and endothelial cells that allow the “tank-treading” of leucocytes over the endothelium. The integrins derived from activated leukocytes interact with ICAMs and regulate leukocyte adhesion. Nuclear factor-kappa B (NF-kB) is a transcription factor that has a pivotal role in inducing genes involved in physiological processes as well as in the response to injury and infection. This factor is important in the phenotypic changes of the endothelium, as it promotes the release of proinflammatory interleukins (interleukin-1 (IL-1)) and growth factors, 428 B.
Activation of monocyte chemotactic protein (MCP-1), and the synthesis of adhesion proteins (VCAM-1, ICAM-1). The adhesion molecules are produced upon stimulation of endothelial cells by tumor necrosis factor-α (TNFα), and other cytokines, such as IL-1 or interferon γ. These stimulations occur in several clinical and biological conditions such as smoking, hypercholesterolemia and oxidized LDL production.(41)

8.2) Thrombosis and hemostatic factors
Intact endothelial cells are important for the interaction between cells and the blood stream. In vivo, endothelial cells have pronounced antithrombotic properties. The endothelium secretes the tissue-type plasminogen activator (t-PA), a potent thrombolytic substance,in response to stimulation by noradrenaline, thrombin, vasopressin and stasis. The cyclooxygenase pathway may also play a role in coagulation balance by producing prostacyclin PGI2 or thromboxane A2, but under physiological conditions, endothelial cells have antithrombotic properties due to a favourable PGI2/TXA2 ratio. However, endothelial cells can produce the prothrombotic and procoagulant von Willebrand factor (vWF), and the profibrinolytic factor plasminogen activator inhibitor-1 (PAI-1) in response to inflammation, or stimuli such as IL-1, TNFα, lipopolysaccharide, and oxidized LDL.The platelet activating factor (PAF) can also be produced by endothelial cells in response to these stimulations, and this allows to platelets activatation and aggregation, causing vasoconstriction. In summary, the endothelium plays a key role in the complex relationship between the container (artery) and its contents (blood). This is why the endothelium is considered to be the “brain” of the artery.(41)

9) Generalized endothelial dysfunction, chronic low-grade inflammation, microalbuminuria and atherothrombosis
Although a majority of diabetic patients will develop vascular complications, a substantial fraction will never develop severe vascular complications. Thus, within the group of diabetic patients, a subgroup exists with a relatively normal compared with a very high risk of cardiovascular complications. In both types of diabetes, patients with advanced nephropathy, i.e. macroalbuminuria, have very high risk of developing severe complications. The pattern of increased risk for vascular complications can be observed even in early nephropathy, i.e. microalbuminuria, in Type II diabetes and also in non-diabetic subjects, which has raised the question of what common mechanisms may be at work. Because micro- and macro-albuminuria are often associated with classic risk factors for microangiopathy and atherothrombosis, notably poor glycaemic control, hypertension, obesity, dyslipidaemia and smoking, an obvious possibility is that such risk factors cause both (micro)albuminuria and atherothrombosis and thus explain their association.
Many studies have investigated this and have concluded that common risk factors explain at most a small part of the association between (micro) albuminuria and atherothrombosis. Other mechanisms must therefore be at work, which may include severe generalized endothelial dysfunction and chronic low-grade inflammation. Indeed, in both types of diabetes, micro- and macroalbuminuria are accompanied by a variety of markers of endothelial dysfunction.
In Type II diabetes, increased urinary albumin excretion and endothelial dysfunction develop in parallel, progress with time, and are strongly and independently associated with risk of death. Prospective studies using markers such as plasma Vwf have shown that high vWF concentrations are associated with an increased risk of developing microalbuminuria, an increased progression of microalbuminuria, the occurrence of diabetic retinopathy and neuropathy and an increased risk of cardiovascular events and death. Endothelial dysfunction in Type I and II diabetes complicated by micro- or macro-albuminuria is generalized in that it affects many aspects of endothelial function and occurs both in the kidney and elsewhere. Such data, together with more limited data showing that microalbuminuria is also associated with endothelial dysfunction in the absence of diabetes, have led to the concept that microalbuminuria itself is a marker of generalized renal and extrarenal endothelial dysfunction. It is less clear how endothelial dysfunction would cause (micro) albuminuria. Theoretically, endothelial dysfunction could contribute to the pathogenesis of albuminuria both directly, by causing increased glomerular pressure and the synthesis of a leaky glomerular basement membrane, and indirectly, by influencing glomerular mesangial and epithelial cell function in a paracrine fashion. Importantly, the molecular pathways by which endothelial dysfunction causes (micro) albuminuria have yet to be worked out.
Chronic low-grade inflammation is another candidate to explain the association between (micro) albuminuria and extrarenal complications. Indeed, regardless of the presence of diabetes, chronic low-grade inflammation is associated with the occurrence and progression of (micro) albuminuria and with risk of atherothrombotic disease. In addition, chronic low-grade inflammation can be both cause and consequence of endothelial dysfunction, and the two appear tightly linked . Nevertheless, recent data indicate that the association between (micro) albuminuria and atherothrombotic disease cannot be explained entirely bymarkers of endothelial dysfunction and chronic inflammation. One possibility is that such markers do not fully capture the processes they are meant to reflect; an alternative or additional explanation is that there are other pathways that link (micro) albuminuria to extrarenal complications, such as autonomic neuropathy or prothrombotic mechanisms.(19)

Assessment of blood flow, vascular reactivity and several markers of endothelial dysfunction have been shown to be associated with an adverse cardiovascular prognosis regardless of the presence of diabetes. In diabetes, the close link between endothelial dysfunction and (micro) albuminuria is an attractive explanation for the fact that microalbuminuria is a riskmarker for atherothrombosis. Although endothelial dysfunction predicts the occurrence of microalbuminuria, causality needs to be determined. In diabetes, hyperglycaemia and components of the metabolic syndrome cause endothelial dysfunction directly or indirectly. A common mechanism underlying endothelial dysfunction relates to an increase in oxidative stress. New insights into mechanisms of endothelial dysfunction may lead to novel important strategies of treatment. Since microvascular endothelial dysfunction is closely associated with and may contribute to insulin resistance, hypertension andmicroalbuminuria, improvement of microvascular function should be one of the first targets.


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