Medicine » Endocrinology and Metabolism » "Recent Advances in the Pathogenesis, Prevention and Management of Type 2 Diabetes and its Complications", book edited by Mark B. Zimering, MD, PhD, ISBN 978-953-307-597-6, Published: August 29, 2011 under CC BY-NC-SA 3.0 license. © The Author(s).

Chapter 10

Effects of Type 2 Diabetes on Arterial Endothelium

By Arturo A. Arce-Esquivel, Aaron K. Bunker and M. Harold Laughlin
DOI: 10.5772/23502

Article top

Effects of Type 2 Diabetes on Arterial Endothelium

Arturo A. Arce-Esquivel1, Aaron K. Bunker1 and M. Harold Laughlin1

1. Introduction

The endothelium, the innermost layer of blood vessels, has many important biological functions which are responsible for regulating vascular tone and structure. One of the major functions of a healthy endothelium is to ensure adequate blood supply to the different tissues. This particular process is regulated by the release and interaction of different vasoactive substances (i.e. vasodilators and vasoconstrictors), which are under tight balance. On the other hand, it is well known that the chronic exposure to certain stresses (e.g. inflammation, oxidative stress, and hyperglycemia) promotes changes in the endothelium leading to endothelial dysfunction.

Type 2 diabetes mellitus (T2DM) is among those chronic diseases that are associated with endothelial dysfunction which may contribute to limited glucose uptake in skeletal muscle. In fact, diabetes-related endothelial dysfunction has been reported to lead to morphologic and structural vascular changes present throughout the course of diabetes (Taylor and Poston, 1994). There are around 17 million people in the United States who have diabetes, of whom close to 95% have T2DM. Cardiovascular disease (CVD) is the major cause of morbidity and mortality in people with T2DM (Ness et al., 1999), and coronary heart disease is the most common cause of death among those individuals. For instance, people with T2DM are two to four times more likely to develop CVD compared with people without the condition (Stamler et al., 1993).

Interestingly, physical activity is an important therapeutic tool to maintain endothelial function. In fact, regular physical exercise has been reported to be effective in the prevention and delay of onset of T2DM (Bassuk and Manson, 2005; Sanz et al., 2010; Stewart, 2002). Thus the primary purpose of this chapter is to summarize the current available literature concerning the effects of T2DM on arterial endothelium. In addition, this chapter is intended to summarize evidence of the beneficial effects of physical activity on the untoward cardiovascular effects of T2DM and/or the apparent ability of physical activity to prevent progression of diabetes-induced CVD.

2. Vascular endothelial function

2.1. Role of the endothelium in vasoregulation

All blood vessels in the systemic and pulmonary circulations are lined by a continuous single cell layer of endothelium. This layer of endothelial cells continues throughout the cardiac chambers as well. As a result of research over the past 30 years it is established that the endothelium constitutes a very important and exciting organ. The endothelium plays an important role in hemostasis, inflammation, lipid metabolism, vascular growth, cell migration, formation of (and interactions with) extracellular matrix molecules, as well as control of vascular permeability and vascular resistance (both vasodilator and vasoconstrictor responses) (Furchgott and Vanhoutte, 1989; Ganz and Vita, 2003). The endothelium can detect chemical substances within the blood and physical forces imparted to blood vessel walls (i.e. shear stress and distention) and initiate responses to these chemical and/or physical signals by releasing substances that modulate vascular tone and/or blood vessel structure (Adair et al., 1990; Furchgott and Vanhoutte, 1989). The vascular endothelium releases a variety of vasoactive substances, including vasodilator and vasoconstrictor substances such as endothelin, which contribute to vasomotor control in tissues throughout the body. As described below, the most common measure of the functional capacity of the endothelium is to measure endothelium-dependent dilation (EDD) primarily because of the potential to assess the health of the endothelium non-invasively. Usually, EDD is the result of release of endothelium-derived relaxing factors (EDRFs).

There appear to be at least three EDRF substances, two of which have been identified; prostacyclin (PGI2) and nitric oxide (NO) (Furchgott and Vanhoutte, 1989; Palmer et al., 1988a; Palmer et al., 1987; Palmer et al., 1988b). The other EDRF, often referred to as endothelium-derived hyperpolarizing factor (EDHF) may not actually be a factor but perhaps represents electrical communication through the gap junctions between endothelial and vascular smooth muscle cells (Cohen and Vanhoutte, 1995; Feletou and Vanhoutte, 2004; Fichtlscherer et al., 2004; Triggle et al., 2003). The relative importance of endothelium-dependent control differs among the tissues of the body at least in part because the endothelial lining is not a homogeneous compartment. Rather the endothelium is characterized by significant structural and functional heterogeneity among tissues and within tissues (Aird, 2007a, 2007b; Laughlin et al., 2008). Even within the vascular bed of a given skeletal muscle, the relative importance of endothelium-dependent vascular control mechanisms changes along the length of the arteriolar network (Laughlin et al., 2008; Laughlin et al., 2001; Laughlin et al., 2003; Laughlin et al., 2004).

NO is produced in endothelial cells by endothelial nitric oxide synthase (eNOS) from L-arginine and oxygen. In its role in vascular control, NO diffuses to the underlying smooth muscle cells, where it activates soluble guanylyl cyclase, resulting in production of cyclic guanosine monophosphate (cGMP) and activation of protein kinase G (PKG), which leads to vasodilation. eNOS is activated by phopshorylation stimulated by shear stress, chemical mediators, and/or by binding of calcium-calmodulin following increases in intracellular calcium signalled by mechanical forces (i.e. an increase in shear stress exerted by the blood flow on the endothelium, referred to as flow-induced dilation) and/or by a host of chemical factors (acetylcholine, bradykinin, substance P, noradrenaline)(Balligand et al., 2009; Barnes and Liu, 1995; Furchgott and Vanhoutte, 1989; Vanhoutte, 1989) acting on their respective receptors on the endothelium (Furchgott and Vanhoutte, 1989; Ganz and Vita, 2003). Flow-induced dilation has been demonstrated in conduit and resistance arteries in various vascular beds (Drexler et al., 1989; Miura et al., 1999; Miura et al., 2001; Sinoway et al., 1989). The weight of evidence suggests that an increase in wall shear stress, secondary to the increased flow, is the physical force that initiates dilation (Pohl et al., 1991). Selective removal or destruction of the endothelium typically abolishes the response (Hull et al., 1986; Lie et al., 1970; Rubanyi et al., 1986) implicating the production and/or release of endogenous, transferable vascular smooth muscle relaxing factor(s) from endothelial cells (Kuo et al., 1991).

Prostanoid EDRFs are metabolites of arachidonic acid produced by the cyclooxygenase pathway. Arachidonic acid itself can produce vasoconstriction or vasodilation in some vascular beds such as the pulmonary vascular bed, depending on concentration and tone at the time of administration (Barnes and Liu, 1995; Furchgott and Vanhoutte, 1989; Vanhoutte, 1989). These effects of arachidonic acid on the vasculature are largely due to formation of prostanoids and/or thromboxane A2 (Barnes and Liu, 1995; Furchgott and Vanhoutte, 1989; Palmer et al., 1988a; Palmer et al., 1987; Selig et al., 1986; Vanhoutte, 1989). There is evidence that the chemical identity of EDHF may vary across vascular beds (Laurindo et al., 1994; Miura et al., 2003; Sorop et al., 2003). The five leading candidates for the identity of EDHF include extracellular potassium (Edwards et al., 1998), hydrogen peroxide and/or superoxide anion, epoxygenase/cytochrome P450 metabolites, and electrical conduction of hyperpolarization through myoendothelial gap junctions (Feletou and Vanhoutte, 2004; Fichtlscherer et al., 2004; Fisslthaler et al., 1999; Triggle et al., 2003).

Endothelins are vasoactive peptides produced by vascular endothelial cells (Korth et al., 1999). Three different isoforms of endothelins (ET) have been identified, namely, ET-1, ET-2 and ET-3 (Haynes and Webb, 1998; Masaki, 2004). ET-1 is the most abundant isoform expressed and secreted in endothelial cells and it is one of the most potent vasoconstrictor agents described to date (Haynes and Webb, 1998). ET-1 is constitutively released by endothelial cells with the majority (~80%) released luminally towards vascular smooth muscle (Wagner et al., 1992). Thus ET-1 appears to act primarily in a local paracrine, rather than circulating endocrine, manner. ET receptors are expressed on endothelial and vascular smooth muscle cells of both arteries and veins throughout the pulmonary and systemic vascular trees (Loesch, 2005; Rubanyi and Polokoff, 1994). Binding of ET to the Gq-protein coupled endothelin type A (ETA) and to endothelin type B (ETB) receptors on vascular smooth muscle leads to vasoconstriction whereas activation of ETB receptors on the endothelium leads to production of NO and prostacyclin, which induce vasodilation (Rubanyi and Polokoff, 1994; Schiffrin and Touyz, 1998; Webb and Haynes, 1995). Although the role of ET-1 in determination of regional blood flow remains unclear, it appears that ET-1 contributes to the control of blood flow to the heart, lungs, kidneys, visceral organs and skeletal muscle but likely not to the brain under normal conditions (Koedel et al., 1998; Maeda et al., 2002; Merkus et al., 2003). Also, there is evidence that alterations in the ET-1 system contribute to vascular dysfunction in T2DM (Lam, 2001; Schneider et al., 2007).

2.2. Endothelial function assessment

2.2.1. Non-invasive techniques

These techniques are mainly used to evaluate the vasomotor response to physical and/or pharmacological stimuli of the endothelium. For instance, flow-mediated vasodilation (FMD), using ultrasonography, is the classic technique used to detect changes in superficial arteries (e.g. brachial, radial or femoral), allowing the measurement of blood flow, blood flow velocity and vascular diameter changes (Corretti et al., 1995). The vasodilatory response, after a period of transient ischemia (~ 5 min), is dependent upon a series of neurologic, myogenic and chemical intermediates, which includes the release of NO. There is a good correlation between this post-ischemic vasodilation observed in the forearm (i.e. FMD) and the coronary vasodilation caused by acetylcholine (Anderson et al., 1995). Thus FMD is used as a surrogate of endothelial health. In addition, strain gauge plethysmography is also used to determine blood flow.

2.2.2. Invasive in vivo techniques

These techniques are used to evaluate endothelial function of arteries and to determine the probable changes in their diameter, by ultrasonograhpy, or blood flow, by plethysmography, after cardiac catheterization to access the coronary circulation. These methods allow also the intra-arterial infusion of different drugs and/or neurohumoral factors to study the endothelial-dependent or independent properties. Finally, it is worth noting that the use of in vitro direct methods. For instance, cell culture allows the evaluation of the different vasoactive substances that can be secreted by the endothelium in response to changes in blood flow and/or shear stress (Malek et al., 1999). Isolated arteries, from different vascular beds, can be used to determine the specific responses to diverse endothelial-dependent dilators and/or inhibitors (Luscher and Noll, 1996).

3. Link between endothelial dysfunction and T2DM: Pathophysiology

3.1. Vascular inflammation

Endothelial dysfunction is characterized by a chronic, systemic pro-inflammatory state, reduced vasodilation (reduction in relaxing factors and an increase in contracting factors), and a pro-thrombotic state. T2DM is among the multiple diseases and conditions that are initiated or associated with endothelial dysfunction (Beckman et al., 2003; Laight et al., 1999; Schofield et al., 2002). In fact, it has been suggested that endothelial dysfunction is an important factor in the pathogenesis of vascular disease observed in patients with diabetes (De Caterina, 2000; Schalkwijk and Stehouwer, 2005). There is evidence that inflammatory states are associated with T2DM, obesity, and insulin resistance (Hotamisligil et al., 1993; Lehrke and Lazar, 2004).

The plasma concentrations of C-reactive protein (CRP), fibrinogen, interleukin-6, interleukin-1, and tumor necrosis factor alpha (TNFα) are increased in diabetes (Grau et al., 1996; Shurtz-Swirski et al., 2001). Hotamisligil et al. (Hotamisligil et al., 1993) reported that the expression of TNFα, a pro-inflammatory cytokine, was markedly increased in obese mice; and when TNFα was counterbalanced insulin resistance improved. Interestingly, the increased levels of CRP would mediate opposite actions on the vasculature. It promotes the increase of adhesion molecules (intracellular adhesion molecule; ICAM-1, vascular cell adhesion molecule; VCAM-1), E-selectin, monocyte chemotactic protein-1 (MCP-1), and ET-1. On the other hand it decreases eNOS expression, NO and prostacyclin bioavailability, and elevates the expression of angiotensin receptor type 1 in the vessel wall (Pasceri et al., 2000; Schalkwijk and Stehouwer, 2005; Venugopal et al., 2002). Insulin exerts anti-inflammatory effects at the cellular and molecular levels in vitro and in vivo. It has been shown that low-dose infusion of insulin reduces reactive oxygen species generation, and suppresses NADPH oxidase expression and plasma ICAM-1 and MCP-1 concentrations. Conversely, long-term insulin infusion (~ 4 hours) in healthy subjects was associated with an induction of endothelial dysfunction (Hartge et al., 2006).

Clearly, the increased levels of these inflammatory cytokines resulted in increased vascular permeability, change in the vasoregulatory responses, and increase in the adhesion of leucokytes to the endothelium. The diabetes-associated alterations on the endothelium that lead to endothelial dysfunction can be summarized as follows; a) impairment of NO production and/or bioavailability, b) reduced NO responsiveness, c) elevated expression and plasma levels of different vasoconstrictors, d) increased adhesion molecule expression, and e) associated enhanced adhesion of vascular cells (e.g. platelets and monocytes) to the endothelium.

3.2. The metabolic syndrome: Obesity and cardiovascular disease

The metabolic syndrome is a collection of risk factors for CVD, typically characterized by endothelial dysfunction. Metabolic syndrome is diagnosed if there are three of the five following components; a) increased abdominal adiposity, b) atherogenic dyslipidemia, c) elevated blood pressure, d) insulin resistance and/or glucose intolerance (i.e. T2DM), and e) a proinflammatory and prothrombotic state (Grundy et al., 2005; Kahn et al., 2005). Incidence of metabolic syndrome has been on the rise over the last decade both in the United States (Ford et al., 2002; Park et al., 2003) and world-wide (Gupta et al., 2004; Magi et al., 2005). Individuals with identified metabolic syndrome are at increased risk for CVD (Malik et al., 2004; Mottill o et al., ; Wilson et al., 2005), an observation independent of age (Ferreira et al., 2007; Lakka et al., 2002; McNeill et al., 2006). The key findings of these studies were that metabolic syndrome leads to a 2-fold increase in CVD and a 1.5-fold increase in all-cause mortality (Mottill o et al.), that increased risk for CVD is not gender specific (Wilson et al., 2005), and that children with metabolic syndrome possess high levels of multiple risk factors (e.g. hypertension, dyslipidemia, and glucose intolerance) for CVD (Ferreira et al., 2007; Taha et al., 2009).

Obesity and/or adipose tissue disorders are also recognized as a potential primary etiological origin for metabolic syndrome. However, independent of the metabolic syndrome, obesity has been increasing in incidence in both adults and children (Klein et al., 2004; Poirier et al., 2006), and is a risk factor for CVD (Hubert et al., 1983; Larsson et al., 1984). It is also well established that metabolic syndrome and obesity linked with metabolic syndrome promote endothelial dysfunction in adults and children (Aggoun, 2007; Singhal, 2005). More current studies over obesity have elucidated that adipose tissue is not just a simple reservoir for energy storage and thermoregulation but rather a complex, indispensable, active metabolic and endocrine organ (Rosito et al., 2008; Sacks and Fain, 2007). Recent studies have demonstrated that adipose tissue possesses the potential to undergo a phenotypic switch in inflammatory and obese-like environments leading it to secrete “adipokines” that increase risk for CVD (Chatterjee et al., 2009; Payne et al., 2010; Sacks and Fain, 2007) and negatively impact endothelial function (Bunker and Laughlin, 2010; Ketonen et al., 2010; Ma et al., 2010; Payne et al., 2009).

3.3. Insulin resistance

In addition to possessing metabolic actions, it is also established that insulin exerts influence over vascular function via; a) stimulation NO production from endothelium, leading to vasodilation; b) increased skeletal muscle blood flow; and c) augmentation of glucose disposal in skeletal muscle (Baron and Clark, 1997). Insulin resistance is typically defined as decreased responsiveness to insulin’s actions that stimulate glucose uptake in the tissues (Lebovitz, 2001). Endothelial dysfunction and insulin resistance often co-exist, however at present it remains unclear as to which one leads to/causes the other. A key characteristic of T2DM, insulin resistance is also an independent risk factor for endothelial dysfunction associated with various forms of CVD (Arcaro et al., 2002; Campia et al., 2004; Williams et al., 1996). Cross-sectional studies indicate endothelial dysfunction can independently predict incidence of insulin resistance/diabetes in humans (Meigs et al., 2004; Meigs et al., 2006; Thorand et al., 2006). Additionally, studies examining rodent models of endothelial dysfunction have demonstrated that even partial defects in endothelial function are sufficient to cause insulin resistance (Cook et al., 2004; Duplain et al., 2001). Taken together current evidence supports a causal role for endothelial dysfunction in the development of insulin resistance.

On the other hand a very recent study, the Women's Health Initiative Observational Study (WHIOS), was conducted calling into question the utility of using endothelial dysfunction biomarkers for insulin resistance and T2DM prediction (Chao et al., 2010). The WHIOS involved 1,584 incident T2DM cases and 2,198 matched controls to evaluate the utility of plasma markers of inflammation and endothelial dysfunction for T2DM risk prediction. Results indicated that none of the inflammatory and endothelial dysfunction markers improved T2DM prediction in a multiethnic cohort of postmenopausal women. Other recent studies have also shown that in humans with insulin resistance, a subsequent impairment occurs in insulin’s ability to induce endothelium dependent vasodilation that is dramatically improved with insulin therapy (Franklin et al., 2008; Rask-Madsen et al., 2001; Vehkavaara et al., 2000). It was also demonstrated recently in rat model of T2DM that insulin resistance manifested prior to a dramatic (20-35%) progressive decline in endothelial function concurrent with T2DM disease development (Bunker et al., 2010). Collectively these studies suggest a potential causal role of insulin resistance in the development of endothelial dysfunction.

Whichever pathology manifests first, endothelial dysfunction or insulin resistance, it is demonstrably clear that development of either pathology rarely occurs without the subsequent development of the other pathology.

3.4. Hyperglycemia

Generally speaking, hyperglycemia can be divided into two broad categories; a) impaired fasting glucose, and b) impaired glucose tolerance. The latter is commonly characterized by 2-hour post-prandial hyperglycemic spikes of 140mg/dl to ≥200mg/dl (Node and Inoue, 2009). These post-prandial spikes in plasma glucose are known to contribute to endothelial dysfunction and CVD in humans, independent of the metabolic syndrome (Ceriello et al., 2002; Su et al., 2008; Title et al., 2000). Indeed, hyperglycemia is the major causal factor in the development of endothelial dysfunction in diabetes. Results from these studies and many others suggest that endothelial dysfunction is mediated through mechanisms that primarily involve generation of oxidative stress that subsequently lowers NO bioavailability.

Impaired fasting glucose is defined by an elevated fasting plasma glucose concentration of ≥100mg/dl and <126 mg/dl (Genuth et al., 2003), which is also an indication of chronically elevated plasma glucose levels. Evidence from recent human studies suggests that fasting hyperglycemia, independent of diabetes and the metabolic syndrome, contributes to endothelial dysfunction and CVD (Rodriguez et al., 2005; Su et al., 2008). However, evidence is slowly mounting from human and animal studies that suggest oscillating glucose levels seen with impaired glucose tolerance can have more deleterious effects than the constant high glucose levels seen with impaired fasting glucose on endothelial function and oxidative stress (Ceriello et al., 2008; Horvath et al., 2009; Monnier et al., 2006).

3.5. Oxidative stress

Elevated production of reactive oxide species (ROS) has been implicated in the development of T2DM (Avogaro et al., 2006; Irani, 2000; Liu et al., 2005; Tesfamariam and Cohen, 1992; Yang et al., 2010). The molecular basis for excessive mitochondrial ROS in diabetes has been extensively reviewed elsewhere (Irani, 2000; Yang et al., 2010; Avogaro et al., 2006). These free radicals also play a critical role in the pathogenesis of diabetes-associated vascular complications (macro-and microangiopathy) (Giugliano et al., 1996; Spitaler and Graier, 2002). In T2DM, the endothelium, due to glucose oxidation, promotes the increase of free radicals (e.g. superoxide and hydrogen peroxide) leading to enhanced intracellular production of hydroxyl radical which has been linked to diabetes-induced endothelial dysfunction (Giugliano et al., 1996; Pieper et al., 1997; Shi and Vanhoutte, 2009; Spitaler and Graier, 2002; Tesfamariam and Cohen, 1992). In that regard, animal models of diabetes have been associated not only with reduced NO bioavailability but also with impaired EDD (Durante et al., 1988; Rosen et al., 1995; Tesfamariam, 1994) as the result of the hyperproduction of superoxide and hydrogen peroxide. In addition, there is evidence that indicates that increased ROS plays an important role in the development of diabetic complications. Maejima et al. (Maejima et al., 2001) reported that the decrease EDD observed in patients with T2DM is linked to NO inactivation resulting from increased oxidative stress, and that abnormal NO metabolism is related to advanced diabetic microvascular complications. Furthermore, endothelial cells in patients with T2DM are not able to produce sufficient amount of NO and therefore fail to vasodilate in response to vasodilators (e.g. acetylcholine, bradykinin, shear stress) (Avogaro et al., 2006).

The increased glucose levels (“hyperglycemia”) also promote mitochondrial formation of ROS. It has been reported that in aortic endothelial cells hyperglycemia induced increased superoxide production which prevents eNOS activity and expression (Srinivasan et al., 2004). The formation of peroxynitrite (superoxide and NO interaction) promotes blunted NO-mediated vasodilatory response and further induces cellular damage through depletion of tetrahydrobiopterin (BH4), an important co-factor for eNOS activity (Pannirselvam et al., 2002). In addition, there are reports indicating that glucose variability (“intermittent low and high glucose levels”) is associated with an excessive production of ROS (Monnier et al., 2006; Piconi et al., 2004) which promotes even more detrimental effects to the endothelium (Ceriello et al., 2008; Piconi et al., 2004). Shi et al. (Shi et al., 2007; Shi and Vanhoutte, 2009) reported that elevated levels of ROS not only reduce NO bioavailability, but also facilitate the production and/or action of EDCFs in the course of T2DM. Finally, the augmented production of ROS in T2DM can also promote the inactivation of antioxidant proteins and therefore reduce the antioxidant defense mechanisms (Laight et al., 1999; Shi et al., 2007).

3.6. Dyslipidemia

T2DM promotes elevated total cholesterol, high levels of oxidized lipoproteins, especially low density lipoptotein (LDL), high triglycerides levels, and decreased high-density lipoprotein (HDL) (Watkins, 2003). It has been suggested that abnormal lipids and lipoproteins play a role in endothelial dysfunction in T2DM (McVeigh et al., 1992). For instance, endothelium-dependent vasodilation was negatively and significantly correlated with elevated triglyceride, LDL and low HDL cholesterol concentrations (Watts et al., 1996). In the same manner, it has been shown that only LDL size was inversely correlated with the acetylcholine-induced brachial EDD (Makimattila et al., 1999). Clearly, we can infer from the above studies that LDL is one of the chief factors involved in endothelial dysfunction.

LDL and other lipoproteins are able to cross the endothelial cells layer by vascular transport, and later they are oxidatively modified at the sub-endothelial space into reactive oxygen species generated by macrophages, endothelial cells and smooth muscles (Steinberg, 1997). The accumulation of oxidized-LDL is toxic to endothelial cells, which in turn alters the function and structure of the endothelium (McVeigh et al., 1992; Tribe and Poston, 1996). Oxidized-LDL decreases NO production by reduction of NOS (Tribe and Poston, 1996) or by stimulating the synthesis of caveolin-I (Bist et al., 1997), consequently contributing to defective vasodilatation. In addition, there are indications that oxidized-LDL could also enhance the release of ET-1, a main endothelial constrictor peptide (Boulanger et al., 1992).

3.7. Mechanisms of endothelial dysfunction in T2DM

Over 170 million people in the world were affected by diabetes in 2000 and this is expected to increase to over 360 million by the year 2030 (Bakker et al., 2009; Ostergard et al., 2007). Type 1 diabetes is characterized by an absence of insulin while T2DM is characterized by insulin resistance followed in time with decreased plasma insulin. Vascular disease is the major cause of death in individuals with T2DM. The vascular complications of T2DM take two major forms; a) atherosclerosis in conduit arteries and b) microvascular dysfunction in skeletal muscle vascular beds. The vasodilatory effects of insulin account for up to 40% of insulin-mediated glucose disposal in skeletal muscle following a meal. In obesity and T2DM, the vasodilatory action of insulin is impaired. Insulin-stimulated NO production via the insulin-receptor substrate-1 (IRS-1) pathway is diminished, while vasoconstriction through the mitogen-activated protein kinase (MAPK) pathway, endothelin-converting enzyme (ECE) and subsequent secretion of the vasoconstrictor ET-1 may be augmented. As a result, microvascular blood flow and delivery of glucose to muscle tissue are diminished, contributing to reduced skeletal muscle glucose uptake and peripheral insulin resistance. Insulin resistance in T2DM appears to be the result of abnormal insulin-induced glucose uptake by skeletal muscle and microvascular dysfunction in skeletal muscle (blunted insulin-induced vasodilation).

Control of blood flow to skeletal muscle is abnormal in diabetes as muscle blood flow is less than normal during exercise in forearms of obese women (Hodnett and Hester, 2007), obese children (Ribeiro et al., 2005), in legs of diabetes subjects during cycle exercise (Hodnett and Hester, 2007; Kingwell et al., 2003), and in obese Zucker rats (Frisbee, 2003; Frisbee et al., 2006; Xiang et al., 2005). The abnormal control of vascular resistance in diabetes is associated with decreased arterial compliance, decreased microvascular density, altered smooth muscle dependent vascular reactivity and endothelial dysfunction (Frisbee et al., 2006; Hodnett and Hester, 2007). Local metabolic control of blood flow is abnormal and myogenic control of vascular smooth muscle tone is affected in diabetes as well. For instance, arterioles isolated from obese Zucker rat skeletal muscle exhibit increased spontaneous tone due to changes in vascular smooth muscle and to changes in an endothelium-derived factor (Frisbee et al., 2006). The endothelium of both conduit arteries and resistance arteries is dysfunctional in diabetes (Hodnett and Hester, 2007). Endothelial dysfunction in conduit arteries appears to be associated with decreased bio-availability of NO with sustained (or normal) eNOS content, decreased phospho-eNOS, deceased BH4 and cytochrome P450 expression as well as increased thromboxane (TXA2) content. In the conduit arteries, endothelial dysfunction is believed to contribute to development of atherosclerosis while in the resistance arteries endothelial dysfunction leads to disruptions in the control of blood flow as well as blunted angiogenesis and structural vascular remodeling (rarefaction)(Frisbee et al., 2006). In normal skeletal muscle insulin-mediated EDD-induced increases in blood flow are responsible for 25-50 % of the increase in glucose clearance stimulated by insulin administration (Kim et al., 2006). Thus, it appears that endothelial dysfunction of resistance arteries in muscle tissue includes blunted insulin-stimulated vasodilation (Mikus et al., 2010).

Endothelial dysfunction in T2DM is associated with glucotoxicity, lipotoxicity, and inflammation which impair insulin signaling (i.e. endothelial cell insulin resistance). These effects may be the result of cytokine signaling and/or increased ROS in the arteries. There are at least two sources of ROS believed to cause endothelial dysfunction in diabetes; a) hyperglycemia, and b) vascular inflammation (Kim et al., 2006; Luscher and Steffel, 2008). Kim et al (Kim et al., 2007) concluded that nutrient excess (excess glucose/lipid) stimulates cellular inflammatory responses that produce insulin resistance leading to decreased Akt and eNOS phosphorylation and increased NF-kB expression leading to expression of inflammatory cytokines in endothelial cells. For instance, Romero et al. (Romero et al., 2008) concluded that hyperglycemia plays a key role in increasing ROS in diabetes through stimulation of arginase activity/expresson in vascular cells. Insulin binding to its receptor signals through two distinct pathways in endothelial cells; a) activation of the IRS-1/phosphatidylinositol 3-kinase (PI3-kinase)/phosphor- Akt/phosphor-eNOS causing release of NO and EDD; b) increased release of ET-1through the mitogen-activated protein kinase (MAPK) pathway. Evidence indicates that T2DM produces an imbalance in the production of NO and ET-1 in response to insulin so that ET-1 release is up-regulated (Kim et al., 2006). It appears that when endothelium is insulin resistant, due to blunted signaling through the IRS-1/Akt/p-eNOS signaling pathway, ET-1 induced constriction leads to decreased muscle blood flow during insulin stimulation (Eringa et al., 2007).

4. Physical activity and type 2 diabetes: Focus on the endothelium

4.1. Benefits of physical activity

Physical activity may be beneficial in slowing the initiation and progression of T2DM and its cardiovascular sequelae through favorable effects on body weight, insulin sensitivity, glycemic control, blood pressure, lipid profile, fibrinolysis, inflammatory defense systems, and endothelial function. More comprehensive reviews regarding the beneficial effects and/or recommendations of physical activity in patients with T2DM have been previously published (Bassuk and Manson, 2005; Sanz et al., 2010; Stewart, 2002; Colberg, 2010). The following section is intended to present the available evidence of the beneficial effects of physical activity focusing on endothelial function. For instance, in clinical trials of patients with diabetes, physical activity (e.g. aerobic exercise) has been shown to increase vasodilator bioavailability (e.g. NO and prostacyclin) and to improve EDD (Moyna and Thompson, 2004; Roberts et al., 2002).

4.2. Acute effects of exercise

4.2.1. Aerobic exercise

Studies examining the acute effects of aerobic exercise training on endothelial function in T2DM are somewhat limited. A series of experiments examining the effects of a single bout of maximal (Colberg et al., 2003) and moderate (Colberg et al., 2006b) aerobic cycling exercise training found that baseline skin blood flow following local heating significantly increased following the exercise in subjects with T2DM (Colberg et al., 2003; Colberg et al., 2006b) and that this effect was independent of interstitial subcutaneous NO levels (Colberg et al., 2006b).

A study by Kingwell et al. (Kingwell et al., 2003) demonstrated that leg blood flow during aerobic cycling exercise and in response to acetylcholine infusion was significantly impaired in T2DM. Infusions of sodium nitroprusside were not different between diabetic subjects and weight-matched controls, suggesting that the impaired leg blood flow during aerobic exercise in T2DM was a result of endothelial dysfunction.

4.2.2. Resistance exercise

Even more limited are studies examining the acute effects of resistance exercise training on endothelial function in T2DM. Currently only one study has examined the acute effects of resistance exercise training on endothelial function in subjects with T2DM. Indeed, Colberg et al. (Colberg et al., 2006a) investigated whether 8-weeks of cycle-ergometery resistance exercise would affect cutaneous perfusion following local heating in T2DM subjects. Their results indicated that resistance exercise training does not significantly affect cutaneous perfusion, either at baseline or following local heating. This finding was independent of unchanged interstitial NO levels. More studies are needed in this area for a better understanding of how resistance exercise training affects the endothelium in T2DM.

4.3. Chronic effects of exercise training

4.3.1. Aerobic exercise

Very few studies exist examining the effects of chronic aerobic exercise training alone on endothelial function in T2DM. A positive association between aerobic status, skin blood flow, and endothelial function has been demonstrated in patients with T2DM (Colberg et al., 2002); however further studies from this same group revealed that 10 weeks of aerobic exercise training intervention does not improve impaired cutaneous perfusion (i.e. endothelial function) in patients with T2DM (Colberg et al., 2005).

Several human studies exist examining the combined effects of chronic aerobic and resistance exercise training on endothelial function in T2DM, but yield conflicting results. For instance, Mairoana et al. (Maiorana et al., 2001) found that 8 weeks of combined aerobic and resistance exercise training exerted a significant positive effect on conduit (i.e. brachial artery FMD) and resistance artery (i.e. forearm plethysmography) endothelial function in patients with diagnosed T2DM. Okada et al. (Okada et al., 2010) also found very recently that 3 months of combined chronic aerobic and resistance exercise training improved brachial FMD in patients with T2DM.

However, the study by Miche et al. (Miche et al., 2006) found that 4 weeks of combined aerobic and resistance exercise training had no effect on brachial artery endothelial function in patients with severe T2DM. Lastly Middlebrooke et al. (Middlebrooke et al., 2006) demonstrated in elderly patients with T2DM (60+ years of age) that 6 months of regular aerobic exercise training does not improve microvascular function (i.e. skin blood flow) or aerobic fitness. It should be noted that the patients in the Colberg et al. (Colberg et al., 2005), Miche et al. (Miche et al., 2006), and Middlebrooke et al. (Middlebrooke et al., 2006) studies had numerous other co-morbidities in addition to T2DM, thereby underscoring the importance of starting exercise training programs before the disease manifests into a complex, multidimensional condition that is difficult to treat. Further studies in humans are needed at this time to know whether chronic aerobic exercise training alone exerts beneficial effects on endothelial function during T2DM.

Current studies using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of T2DM and obesity have revealed that chronic aerobic exercise training alone maintains endothelial function in conduit (i.e. aortic EDD) (Bunker et al., 2010) and resistance arteries (i.e. skeletal muscle arterioles) (Mikus et al., 2010) during the progression of T2DM. Other OLETF studies demonstrated the positive effect of chronic aerobic exercise training alone as a preventative measure for endothelial function (thoracic aorta and mesentery artery EDD) at single time-points during T2DM progression (Minami et al., 2002; Sakamoto et al., 1998). It is worth noting that the experimental design of the OLETF studies was such that aerobic exercise training served as a preventative measure for endothelial dysfunction associated with T2DM, whereas in the human studies discussed above it served as an interventional measure for endothelial dysfunction associated with T2DM. The findings thus far from long-term studies of aerobic exercise training alone collectively suggest that alterations in vascular NO bioavailability, due to direct or indirect changes in eNOS activity/expression, are contributing in part to endothelial dysfunction associated with T2DM.

4.3.2. Resistance exercise

The effects of chronic resistance exercise training on endothelial function are equally unclear at present. Chronic resistance exercise training alone has been shown to have little to no effect on skin blood flow and endothelial function in patients with T2DM (Colberg et al., 2006a). This study observed in ten individuals with T2DM and nine similar non-diabetic controls that 8 weeks of moderate-intensity resistance training did not enhance baseline skin blood perfusion or interstitial NO levels. Results from this study are in agreement with the studies by Miche et al. (Miche et al., 2006) and Middlebrooke et al. (Middlebrooke et al., 2006), discussed in the previous section (i.e. aerobic exercise), which showed that combined aerobic and resistance exercise training had no effect on endothelial function in T2DM.

However they conflict with a recent study conducted by Cohen et al. (Cohen et al., 2008) where 14-months of resistance exercise training alone significantly improved endothelial function in the skin of men and women with diagnosed T2DM. They also conflict with the

Mairoana et al. (Maiorana et al., 2001) and Okada et al. (Okada et al., 2010) studies, discussed in the previous section, where combined aerobic and resistance exercise training was found to positively influence endothelial function in T2DM. At present it remains very unclear as to the effect of chronic resistance exercise training alone on endothelial function in T2DM and more studies are warranted in this area.

4.4. Physical activity: Mechanisms for its vascular benefits

The mechanisms responsible for the beneficial effects of physical activity on endothelium in T2DM are under intense investigation at this time. As for other forms of CVD, it is possible that exercise has beneficial effects on endothelial function directly due to the effects of shear stress or other hemodynamic effects of each exercise bout on the vascular wall or through effects of physical activity on systemic risk factors. For instance, exercise bouts influence circulating cytokines released by skeletal muscle and adipose tissues and can alter circulating lipid profiles. However, most in the field seem to consider that physical activity positively impacts the vascular wall directly via episodic increases in shear stress and indirectly via reduction of comorbidities often associated with insulin resistance (i.e., hyperglycemia, hypercholesterolemia) (Joyner and Green, 2009).

It is known that endurance and interval sprint training enhance vascular function of the gastrocnemius, but not soleus, vasculature of healthy animals (Laughlin et al., 2004; McAllister, 2005) and that daily wheel running is sufficient to prevent the declines/changes in endothelial function associated with insulin resistance in feed arteries of skeletal muscles but effects in the aorta are less clear (Bunker et al, 2010). Physical activity also sustains insulin induced EDD (Mikus et al, 2010). Beneficial effects could also be the result of exercise-induced improvements in antioxidant systems in the vascular cells of the arteries, either endothelium or smooth muscle. It is important for research to establish the exact mechanisms so that exercise protocols can be designed to maximize these benefits.

media/image2.png

Figure 1.

Factors that participated in the pathogenesis of endothelial dysfunction in T2DM. NO; nitric oxide, ROS; reactive oxygen species.

5. Conclusion

Clearly, the information presented in this chapter emphasizes the major role of endothelial dysfunction in the development and/or progression of T2DM. However, the relationship of endothelial dysfunction and the many independent factors associated with T2DM (e.g. hyperglycemia, inflammation, hyperlipidemia, oxidative stress, insulin resistance, hypertension, obesity), presented in figure 1, is not completely understood. Furthermore, the precise mechanisms responsible for the beneficial effects of physical activity on the endothelium of individuals with T2DM are still under intense investigation. Obviously, more research is needed in this area, but we could speculate that the beneficial effects of exercise on endothelial function are due to the effects of shear stress and/or other hemodynamic effects acting directly on the vascular wall or through effects of physical activity on systemic risk factors.

Acknowledgements

This work was supported by National Institutes of Health Grant HL-35088.

References

1 - T. H. Adair, W. J. Gay, J. P. Montani, 1990Growth regulation of the vascular system: evidence for a metabolic hypothesis. Am J Physiol 259, R393404
2 - Y. Aggoun, 2007Obesity, metabolic syndrome, and cardiovascular disease. Pediatr Res 61653659
3 - W. C. Aird, 2007aPhenotypic heterogeneity of the endothelium: I. Structure, function, and mechanisms. Circ Res 100158173
4 - W. C. Aird, 2007bPhenotypic heterogeneity of the endothelium: II. Representative vascular beds. Circ Res 100174190
5 - T. J. Anderson, A. Uehata, M. D. Gerhard, I. T. Meredith, S. Knab, D. Delagrange, E. H. Lieberman, P. Ganz, M. A. Creager, A. C. Yeung, et al.1995Close relation of endothelial function in the human coronary and peripheral circulations. J Am Coll Cardiol 2612351241
6 - G. Arcaro, A. Cretti, S. Balzano, A. Lechi, M. Muggeo, E. Bonora, R. C. Bonadonna, 2002Insulin causes endothelial dysfunction in humans: sites and mechanisms. Circulation 105576582
7 - A. Avogaro, G. P. Fadini, A. Gallo, E. Pagnin, S. de Kreutzenberg, 2006Endothelial dysfunction in type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 16 Suppl 1, S3945
8 - W. Bakker, E. C. Eringa, P. Sipkema, V. W. van Hinsbergh, 2009Endothelial dysfunction and diabetes: roles of hyperglycemia, impaired insulin signaling and obesity. Cell and tissue research 335165189
9 - J. L. Balligand, O. Feron, C. Dessy, 2009eNOS activation by physical forces: from short-term regulation of contraction to chronic remodeling of cardiovascular tissues. Physiol Rev 89481534
10 - P. J. Barnes, S. F. Liu, 1995Regulation of pulmonary vascular tone. Pharmacol Rev 4787131
11 - A. D. Baron, M. G. Clark, 1997Role of blood flow in the regulation of muscle glucose uptake. Annu Rev Nutr 17487499
12 - S. S. Bassuk, J. E. Manson, 2005Epidemiological evidence for the role of physical activity in reducing risk of type 2 diabetes and cardiovascular disease. J Appl Physiol 9911931204
13 - J. A. Beckman, A. B. Goldfine, M. B. Gordon, L. A. Garrett, J. F. Keaney, Jr , M. A. Creager, 2003Oral antioxidant therapy improves endothelial function in Type 1 but not Type 2 diabetes mellitus. Am J Physiol Heart Circ Physiol 285, H23922398
14 - A. Bist, P. E. Fielding, C. J. Fielding, 1997Two sterol regulatory element-like sequences mediate up-regulation of caveolin gene transcription in response to low density lipoprotein free cholesterol. Proc Natl Acad Sci U S A 941069310698
15 - C. M. Boulanger, F. C. Tanner, M. L. Bea, A. W. Hahn, A. Werner, T. F. Luscher, 1992Oxidized low density lipoproteins induce mRNA expression and release of endothelin from human and porcine endothelium. Circ Res 7011911197
16 - A. K. Bunker, A. A. Arce-Esquivel, R. S. Rector, F. W. Booth, J. A. Ibdah, M. H. Laughlin, 2010Physical activity maintains aortic endothelium-dependent relaxation in the obese type 2 diabetic OLETF rat. Am J Physiol Heart Circ Physiol 298, H18891901
17 - A. K. Bunker, M. H. Laughlin, 2010Influence of exercise and perivascular adipose tissue on coronary artery vasomotor function in a familial hypercholesterolemic porcine atherosclerosis model. J Appl Physiol 108490497
18 - U. Campia, G. Sullivan, M. B. Bryant, M. A. Waclawiw, M. J. Quon, J. A. Panza, 2004Insulin impairs endothelium-dependent vasodilation independent of insulin sensitivity or lipid profile. Am J Physiol Heart Circ Physiol 286, H7682
19 - A. Ceriello, K. Esposito, L. Piconi, M. A. Ihnat, J. E. Thorpe, R. Testa, M. Boemi, D. Giugliano, 2008Oscillating glucose is more deleterious to endothelial function and oxidative stress than mean glucose in normal and type 2 diabetic patients. Diabetes 5713491354
20 - A. Ceriello, C. Taboga, L. Tonutti, L. Quagliaro, L. Piconi, B. Bais, Ros. R. Da, E. Motz, 2002Evidence for an independent and cumulative effect of postprandial hypertriglyceridemia and hyperglycemia on endothelial dysfunction and oxidative stress generation: effects of short- and long-term simvastatin treatment. Circulation 10612111218
21 - C. Chao, Y. Song, N. Cook, C. H. Tseng, J. E. Manson, C. Eaton, K. L. Margolis, B. Rodriguez, L. S. Phillips, L. F. Tinker, S. Liu, 2010The lack of utility of circulating biomarkers of inflammation and endothelial dysfunction for type 2 diabetes risk prediction among postmenopausal women: the Women’s Health Initiative Observational Study. Arch Intern Med 17015571565
22 - T. K. Chatterjee, L. L. Stoll, G. M. Denning, A. Harrelson, A. L. Blomkalns, G. Idelman, F. G. Rothenberg, B. Neltner, S. A. Romig-Martin, E. W. Dickson, S. Rudich, N. L. Weintraub, 2009Proinflammatory phenotype of perivascular adipocytes: influence of high-fat feeding. Circ Res 104541549
23 - N. D. Cohen, D. W. Dunstan, C. Robinson, E. Vulikh, P. Z. Zimmet, J. E. Shaw, 2008Improved endothelial function following a 14-month resistance exercise training program in adults with type 2 diabetes. Diabetes research and clinical practice 79405411
24 - R. A. Cohen, P. M. Vanhoutte, 1995Endothelium-dependent hyperpolarization. Beyond nitric oxide and cyclic GMP. Circulation 9233373349
25 - S. R. Colberg, A. L. Albright, B. J. Blissmer, B. Braun, L. Chasan-Taber, B. Fernhall, J. G. Regensteiner, R. R. Rubin, R. J. Sigal, 2010Exercise and type 2 diabetes: American College of Sports Medicine and the American Diabetes Association: joint position statement. Exercise and type 2 diabetes. Medicine and science in sports and exercise 4222822303
26 - S. R. Colberg, H. K. Parson, D. R. Holton, T. Nunnold, A. I. Vinik, 2003Cutaneous blood flow in type 2 diabetic individuals after an acute bout of maximal exercise.Diabetes Care2618831888
27 - S. R. Colberg, H. K. Parson, T. Nunnold, M. T. Herriott, A. I. Vinik, 2006aEffect of an 8-week resistance training program on cutaneous perfusion in type 2 diabetes. Microvasc Res 71121127
28 - S. R. Colberg, H. K. Parson, T. Nunnold, D. R. Holton, D. P. Swain, A. I. Vinik, 2005Change in cutaneous perfusion following 10 weeks of aerobic training in Type 2 diabetes. J Diabetes Complications 19276283
29 - S. R. Colberg, H. K. Parson, T. Nunnold, D. R. Holton, A. I. Vinik, 2006bEffect of a single bout of prior moderate exercise on cutaneous perfusion in type 2 diabetes. Diabetes Care 2923162318
30 - S. R. Colberg, K. B. Stansberry, P. M. Mc Nitt, A. I. Vinik, 2002Chronic exercise is associated with enhanced cutaneous blood flow in type 2 diabetes. J Diabetes Complications 16139145
31 - S. Cook, O. Hugli, M. Egli, B. Menard, S. Thalmann, C. Sartori, C. Perrin, P. Nicod, B. Thorens, P. Vollenweider, U. Scherrer, R. Burcelin, 2004Partial gene deletion of endothelial nitric oxide synthase predisposes to exaggerated high-fat diet-induced insulin resistance and arterial hypertension. Diabetes 5320672072
32 - M. C. Corretti, G. D. Plotnick, R. A. Vogel, 1995Technical aspects of evaluating brachial artery vasodilatation using high-frequency ultrasound. Am J Physiol 268, H13971404
33 - R. De Caterina, 2000Endothelial dysfunctions: common denominators in vascular disease. Curr Opin Lipidol 11923
34 - H. Drexler, A. M. Zeiher, H. Wollschlager, T. Meinertz, H. Just, T. Bonzel, 1989Flow-dependent coronary artery dilatation in humans. Circulation 80466474
35 - H. Duplain, R. Burcelin, C. Sartori, S. Cook, M. Egli, M. Lepori, P. Vollenweider, T. Pedrazzini, P. Nicod, B. Thorens, U. Scherrer, 2001Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase. Circulation 104342345
36 - W. Durante, A. K. Sen, F. A. Sunahara, 1988Impairment of endothelium-dependent relaxation in aortae from spontaneously diabetic rats. Br J Pharmacol 94463468
37 - G. Edwards, K. A. Dora, M. J. Gardener, C. J. Garland, A. H. Weston, 1998K+ is an endothelium-derived hyperpolarizing factor in rat arteries. Nature 396269272
38 - E. C. Eringa, C. D. Stehouwer, M. H. Roos, N. Westerhof, P. Sipkema, 2007Selective resistance to vasoactive effects of insulin in muscle resistance arteries of obese Zucker (fa/fa) rats. Am J Physiol Endocrinol Metab 293, E11341139
39 - M. Feletou, P. M. Vanhoutte, 2004EDHF: new therapeutic targets? Pharmacol Res 49565580
40 - A. P. Ferreira, C. E. Oliveira, N. M. Franca, 2007Metabolic syndrome and risk factors for cardiovascular disease in obese children: the relationship with insulin resistance (HOMA-IR). J Pediatr (Rio J) 832126
41 - S. Fichtlscherer, S. Dimmeler, S. Breuer, R. Busse, A. M. Zeiher, I. Fleming, 2004Inhibition of cytochrome 450C9 improves endothelium-dependent, nitric oxide-mediated vasodilatation in patients with coronary artery disease. Circulation 109, 178-183.
42 - B. Fisslthaler, R. Popp, L. Kiss, M. Potente, D. R. Harder, I. Fleming, R. Busse, 1999Cytochrome 450C is an EDHF synthase in coronary arteries. Nature 401, 493-497.
43 - E. S. Ford, W. H. Giles, W. H. Dietz, 2002Prevalence of the metabolic syndrome among US adults: findings from the third National Health and Nutrition Examination Survey. JAMA 287356359
44 - V. L. Franklin, F. Khan, G. Kennedy, J. J. Belch, S. A. Greene, 2008Intensive insulin therapy improves endothelial function and microvascular reactivity in young people with type 1 diabetes. Diabetologia 51353360
45 - J. C. Frisbee, 2003Impaired skeletal muscle perfusion in obese Zucker rats. American journal of physiology 285, R11241134
46 - J. C. Frisbee, J. B. Samora, J. Peterson, R. Bryner, 2006Exercise training blunts microvascular rarefaction in the metabolic syndrome. Am J Physiol Heart Circ Physiol 291, H24832492
47 - R. F. Furchgott, P. M. Vanhoutte, 1989Endothelium-derived relaxing and contracting factors. FASEB J 320072018
48 - P. Ganz, J. A. Vita, 2003Testing endothelial vasomotor function: nitric oxide, a multipotent molecule. Circulation 10820492053
49 - S. Genuth, K. G. Alberti, P. Bennett, J. Buse, R. Defronzo, R. Kahn, J. Kitzmiller, W. C. Knowler, H. Lebovitz, A. Lernmark, D. Nathan, J. Palmer, R. Rizza, C. Saudek, J. Shaw, M. Steffes, M. Stern, J. Tuomilehto, P. Zimmet, 2003Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 2631603167
50 - D. Giugliano, A. Ceriello, G. Paolisso, 1996Oxidative stress and diabetic vascular complications. Diabetes Care 19257267
51 - A. J. Grau, F. Buggle, H. Becher, E. Werle, W. Hacke, 1996The association of leukocyte count, fibrinogen and C-reactive protein with vascular risk factors and ischemic vascular diseases.Thromb Res 82245255
52 - S. M. Grundy, J. I. Cleeman, S. R. Daniels, K. A. Donato, R. H. Eckel, B. A. Franklin, D. J. Gordon, R. M. Krauss, P. J. Savage, S. C. Smith Jr, J. A. Spertus, F. Costa, 2005Diagnosis and management of the metabolic syndrome. An American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Executive summary. Cardiol Rev 13322327
53 - R. Gupta, P. C. Deedwania, A. Gupta, S. Rastogi, R. B. Panwar, K. Kothari, 2004Prevalence of metabolic syndrome in an Indian urban population. Int J Cardiol 97257261
54 - M. M. Hartge, U. Kintscher, T. Unger, 2006Endothelial dysfunction and its role in diabetic vascular disease. Endocrinol Metab Clin North Am 35551560viii-ix.
55 - W. G. Haynes, D. J. Webb, 1998Endothelin as a regulator of cardiovascular function in health and disease. J Hypertens 1610811098
56 - B. L. Hodnett, R. L. Hester, 2007Regulation of muscle blood flow in obesity. Microcirculation 14273288
57 - E. M. Horvath, R. Benko, L. Kiss, M. Muranyi, T. Pek, K. Fekete, T. Barany, A. Somlai, A. Csordas, C. Szabo, 2009Rapid ‘glycaemic swings’ induce nitrosative stress, activate poly(ADP-ribose) polymerase and impair endothelial function in a rat model of diabetes mellitus. Diabetologia 52952961
58 - G. S. Hotamisligil, N. S. Shargill, B. M. Spiegelman, 1993Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 2598791
59 - H. B. Hubert, M. Feinleib, P. M. Mc Namara, W. P. Castelli, 1983Obesity as an independent risk factor for cardiovascular disease: a 26-year follow-up of participants in the Framingham Heart Study. Circulation 67968977
60 - S. S. Hull, Jr , L. Kaiser, M. D. Jaffe, H. V. Sparks, Jr , 1986Endothelium-dependent flow-induced dilation of canine femoral and saphenous arteries. Blood Vessels 23183198
61 - K. Irani, 2000Oxidant signaling in vascular cell growth, death, and survival : a review of the roles of reactive oxygen species in smooth muscle and endothelial cell mitogenic and apoptotic signaling. Circ Res 87179183
62 - M. J. Joyner, D. J. Green, 2009Exercise protects the cardiovascular system: effects beyond traditional risk factors. The Journal of physiology 58755515558
63 - R. Kahn, J. Buse, E. Ferrannini, M. Stern, 2005The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2822892304
64 - J. Ketonen, J. Shi, E. Martonen, E. Mervaala, 2010Periadventitial adipose tissue promotes endothelial dysfunction via oxidative stress in diet-induced obese C57Bl/6 miceCirc J 7414791487
65 - F. Kim, M. Pham, I. Luttrell, D. D. Bannerman, J. Tupper, J. Thaler, T. R. Hawn, E. W. Raines, M. W. Schwartz, 2007Toll-like receptor-4 mediates vascular inflammation and insulin resistance in diet-induced obesity. Circ Res 10015891596
66 - J. A. Kim, M. Montagnani, K. K. Koh, M. J. Quon, 2006Reciprocal relationships between insulin resistance and endothelial dysfunction: molecular and pathophysiological mechanisms. Circulation 11318881904
67 - B. A. Kingwell, M. Formosa, M. Muhlmann, S. J. Bradley, G. K. Mc Conell, 2003Type 2 diabetic individuals have impaired leg blood flow responses to exercise: role of endothelium-dependent vasodilation. Diabetes Care 26899904
68 - S. Klein, L. E. Burke, G. A. Bray, S. Blair, D. B. Allison, X. Pi-Sunyer, Y. Hong, R. H. Eckel, 2004Clinical implications of obesity with specific focus on cardiovascular disease: a statement for professionals from the American Heart Association Council on Nutrition, Physical Activity, and Metabolism: endorsed by the American College of Cardiology Foundation. Circulation 11029522967
69 - U. Koedel, S. Lorenzl, C. Gorriz, R. M. Arendt, H. W. Pfister, 1998Endothelin B receptor-mediated increase of cerebral blood flow in experimental pneumococcal meningitis. J Cereb Blood Flow Metab 186774
70 - P. Korth, R. M. Bohle, P. Corvol, F. Pinet, 1999Cellular distribution of endothelin-converting enzyme-1 in human tissues. J Histochem Cytochem 47447462
71 - L. Kuo, W. M. Chilian, M. J. Davis, 1991Interaction of pressure- and flow-induced responses in porcine coronary resistance vessels. Am J Physiol 261, H17061715
72 - D. W. Laight, M. J. Carrier, E. E. Anggard, 1999Endothelial cell dysfunction and the pathogenesis of diabetic macroangiopathy. Diabetes Metab Res Rev 15274282
73 - H. M. Lakka, D. E. Laaksonen, T. A. Lakka, L. K. Niskanen, E. Kumpusalo, J. Tuomilehto, J. T. Salonen, 2002The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA 28827092716
74 - H. C. Lam, 2001Role of endothelin in diabetic vascular complications. Endocrine 14277284
75 - B. Larsson, K. Svardsudd, L. Welin, L. Wilhelmsen, P. Bjorntorp, G. Tibblin, 1984Abdominal adipose tissue distribution, obesity, and risk of cardiovascular disease and death: 13 year follow up of participants in the study of men born in 1913. Br Med J (Clin Res Ed) 28814011404
76 - M. H. Laughlin, S. C. Newcomer, S. B. Bender, 2008Importance of hemodynamic forces as signals for exercise-induced changes in endothelial cell phenotype. J Appl Physiol 104588600
77 - M. H. Laughlin, J. S. Pollock, J. F. Amann, M. L. Hollis, C. R. Woodman, E. M. Price, 2001Training induces nonuniform increases in eNOS content along the coronary arterial tree. J Appl Physiol 90501510
78 - M. H. Laughlin, L. J. Rubin, J. W. Rush, E. M. Price, W. G. Schrage, C. R. Woodman, 2003Short-term training enhances endothelium-dependent dilation of coronary arteries, not arterioles. J Appl Physiol 94234244
79 - M. H. Laughlin, C. R. Woodman, W. G. Schrage, D. Gute, E. M. Price, 2004Interval sprint training enhances endothelial function and eNOS content in some arteries that perfuse white gastrocnemius muscle. J Appl Physiol 96233244
80 - F. R. Laurindo, Mde. A. Pedro, H. V. Barbeiro, F. Pileggi, M. H. Carvalho, O. Augusto, Luz. P. L. da, 1994Vascular free radical release. Ex vivo and in vivo evidence for a flow-dependent endothelial mechanism. Circ Res 74700709
81 - H. E. Lebovitz, 2001Insulin resistance: definition and consequences. Exp Clin Endocrinol Diabetes 109 Suppl 2, S135148
82 - M. Lehrke, M. A. Lazar, 2004Inflamed about obesity. Nat Med 10126127
83 - M. Lie, O. M. Sejersted, F. Kiil, 1970Local regulation of vascular cross section during changes in femoral arterial blood flow in dogs. Circ Res 27727737
84 - H. Liu, R. Colavitti, I. I. Rovira, T. Finkel, 2005Redox-dependent transcriptional regulation. Circ Res 97967974
85 - A. Loesch, 2005Localisation of endothelin-1 and its receptors in vascular tissue as seen at the electron microscopic level. Curr Vasc Pharmacol 3381392
86 - T. F. Luscher, G. Noll, 1996Endothelial function as an end-point in interventional trials: concepts, methods and current data.J Hypertens Suppl 14, S111119discussion S119-121.
87 - T. F. Luscher, J. Steffel, 2008Sweet and sour: unraveling diabetic vascular diseaseCirc Res 102911
88 - Ma L. , Ma S. , H. He, D. Yang, X. Chen, Z. Luo, D. Liu, Z. Zhu, 2010Perivascular fat-mediated vascular dysfunction and remodeling through the AMPK/mTOR pathway in high-fat diet-induced obese rats. Hypertens Res 33446453
89 - S. Maeda, T. Miyauchi, M. Iemitsu, T. Tanabe, Y. Irukayama-Tomobe, K. Goto, I. Yamaguchi, M. Matsuda, 2002Involvement of endogenous endothelin-1 in exercise-induced redistribution of tissue blood flow: an endothelin receptor antagonist reduces the redistribution. Circulation 10621882193
90 - K. Maejima, S. Nakano, M. Himeno, S. Tsuda, H. Makiishi, T. Ito, A. Nakagawa, T. Kigoshi, T. Ishibashi, M. Nishio, K. Uchida, 2001Increased basal levels of plasma nitric oxide in Type 2 diabetic subjects. Relationship to microvascular complications. J Diabetes Complications 15135143
91 - L. Magi, C. Stramenga, P. Morosini, 2005Prevalence of the metabolic syndrome among Italian adults. Findings from the SIMAP study]. Recenti Prog Med 96280283
92 - A. Maiorana, G. O’Driscoll, C. Cheetham, L. Dembo, K. Stanton, C. Goodman, R. Taylor, D. Green, 2001The effect of combined aerobic and resistance exercise training on vascular function in type 2 diabetes. J Am Coll Cardiol 38860866
93 - S. Makimattila, M. L. Liu, J. Vakkilainen, A. Schlenzka, S. Lahdenpera, M. Syvanne, M. Mantysaari, P. Summanen, R. Bergholm, M. R. Taskinen, H. Yki-Jarvinen, 1999Impaired endothelium-dependent vasodilation in type 2 diabetes. Relation to LDL size, oxidized LDL, and antioxidants. Diabetes Care 22973981
94 - A. M. Malek, S. L. Alper, S. Izumo, 1999Hemodynamic shear stress and its role in atherosclerosis. JAMA 28220352042
95 - S. Malik, N. D. Wong, S. S. Franklin, T. V. Kamath, G. J. L’Italien, J. R. Pio, G. R. Williams, 2004Impact of the metabolic syndrome on mortality from coronary heart disease, cardiovascular disease, and all causes in United States adults. Circulation 11012451250
96 - T. Masaki, 2004Historical review: Endothelin. Trends Pharmacol Sci 25219224
97 - R. M. Mc Allister, J. L. Jasperse, M. H. Laughlin, 2005Nonuniform effects of endurance exercise training on vasodilation in rat skeletal muscle. J Appl Physiol 98753761
98 - A. M. Mc Neill, R. Katz, C. J. Girman, W. D. Rosamond, L. E. Wagenknecht, J. I. Barzilay, R. P. Tracy, P. J. Savage, S. A. Jackson, 2006Metabolic syndrome and cardiovascular disease in older people: The cardiovascular health study. J Am Geriatr Soc 5413171324
99 - G. E. Mc Veigh, G. M. Brennan, G. D. Johnston, B. J. Mc Dermott, L. T. Mc Grath, W. R. Henry, J. W. Andrews, J. R. Hayes, 1992Impaired endothelium-dependent and independent vasodilation in patients with type 2 (non-insulin-dependent) diabetes mellitus. Diabetologia 35771776
100 - J. B. Meigs, F. B. Hu, N. Rifai, J. E. Manson, 2004Biomarkers of endothelial dysfunction and risk of type 2 diabetes mellitus. JAMA 29119781986
101 - J. B. Meigs, C. J. O’Donnell, G. H. Tofler, E. J. Benjamin, C. S. Fox, I. Lipinska, D. M. Nathan, L. M. Sullivan, R. B. D’Agostino, P. W. Wilson, 2006Hemostatic markers of endothelial dysfunction and risk of incident type 2 diabetes: the Framingham Offspring Study. Diabetes 55530537
102 - D. Merkus, B. Houweling, A. Mirza, F. Boomsma, Meiracker. A. H. van den, D. J. Duncker, 2003Contribution of endothelin and its receptors to the regulation of vascular tone during exercise is different in the systemic, coronary and pulmonary circulation. Cardiovasc Res 59745754
103 - E. Miche, G. Herrmann, M. Nowak, U. Wirtz, M. Tietz, M. Hurst, B. Zoller, A. Radzewitz, 2006Effect of an exercise training program on endothelial dysfunction in diabetic and non-diabetic patients with severe chronic heart failure. Clin Res Cardiol 95 Suppl 1, i117124
104 - A. R. Middlebrooke, L. M. Elston, K. M. Macleod, D. M. Mawson, C. I. Ball, A. C. Shore, J. E. Tooke, 2006Six months of aerobic exercise does not improve microvascular function in type 2 diabetes mellitus. Diabetologia 4922632271
105 - C. R. Mikus, R. S. Rector, A. A. Arce-Esquivel, J. L. Libla, F. W. Booth, J. A. Ibdah, M. H. Laughlin, J. P. Thyfault, 2010Daily physical activity enhances reactivity to insulin in skeletal muscle arterioles of hyperphagic Otsuka Long-Evans Tokushima Fatty rats. J Appl Physiol 10912031210
106 - A. Minami, N. Ishimura, N. Harada, S. Sakamoto, Y. Niwa, Y. Nakaya, 2002Exercise training improves acetylcholine-induced endothelium-dependent hyperpolarization in type 2 diabetic rats, Otsuka Long-Evans Tokushima fatty rats. Atherosclerosis 1628592
107 - H. Miura, J. J. Bosnjak, G. Ning, T. Saito, M. Miura, D. D. Gutterman, 2003Role for hydrogen peroxide in flow-induced dilation of human coronary arterioles. Circ Res 92, e3140
108 - H. Miura, Y. Liu, D. D. Gutterman, 1999Human coronary arteriolar dilation to bradykinin depends on membrane hyperpolarization: contribution of nitric oxide and Ca2+-activated K+ channels. Circulation 9931323138
109 - H. Miura, R. E. Wachtel, Y. Liu, F. R. Loberiza, Jr , T. Saito, M. Miura, D. D. Gutterman, 2001Flow-induced dilation of human coronary arterioles: important role of Ca(2+)-activated K(+) channels. Circulation 10319921998
110 - L. Monnier, E. Mas, C. Ginet, F. Michel, L. Villon, J. P. Cristol, C. Colette, 2006Activation of oxidative stress by acute glucose fluctuations compared with sustained chronic hyperglycemia in patients with type 2 diabetes. JAMA 29516811687
111 - S. Mottillo, K. B. Filion, J. Genest, L. Joseph, L. Pilote, P. Poirier, S. Rinfret, E. L. Schiffrin, M. J. Eisenberg, metabolic. The, syndrome, risk. a. cardiovascular, review. systematic, meta-analysis, J., Joseph, L., Pilote, L., Poirier, P., Rinfret, S., Schiffrin, E.L., Eisenberg, M.J., The metabolic syndrome and cardiovascular risk a systematic review and meta-analysis. J Am Coll Cardiol 5611131132
112 - N. M. Moyna, P. D. Thompson, 2004The effect of physical activity on endothelial function in man. Acta Physiol Scand 180113123
113 - J. Ness, D. Nassimiha, M. I. Feria, W. S. Aronow, 1999Diabetes mellitus in older African-Americans, Hispanics, and whites in an academic hospital-based geriatrics practice. Coron Artery Dis 10343346
114 - K. Node, T. Inoue, 2009Postprandial hyperglycemia as an etiological factor in vascular failure. Cardiovasc Diabetol 8, 23 EOF
115 - S. Okada, A. Hiuge, H. Makino, A. Nagumo, H. Takaki, H. Konishi, Y. Goto, Y. Yoshimasa, Y. Miyamoto, 2010Effect of exercise intervention on endothelial function and incidence of cardiovascular disease in patients with type 2 diabetes. Journal of atherosclerosis and thrombosis 17828833
116 - T. Ostergard, N. Jessen, O. Schmitz, L. J. Mandarino, 2007The effect of exercise, training, and inactivity on insulin sensitivity in diabetics and their relatives: what is new? Applied physiology, nutrition, and metabolism = Physiologie appliquee, nutrition et metabolisme 32541548
117 - R. M. Palmer, D. S. Ashton, S. Moncada, 1988aVascular endothelial cells synthesize nitric oxide from L-arginine. Nature 333664666
118 - R. M. Palmer, A. G. Ferrige, S. Moncada, 1987Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327524526
119 - R. M. Palmer, D. D. Rees, D. S. Ashton, S. Moncada, 1988bL-arginine is the physiological precursor for the formation of nitric oxide in endothelium-dependent relaxation. Biochem Biophys Res Commun 15312511256
120 - M. Pannirselvam, S. Verma, T. J. Anderson, C. R. Triggle, 2002Cellular basis of endothelial dysfunction in small mesenteric arteries from spontaneously diabetic (db/db-/-) mice: role of decreased tetrahydrobiopterin bioavailability. Br J Pharmacol 136255263
121 - Y. W. Park, S. Zhu, L. Palaniappan, S. Heshka, M. R. Carnethon, S. B. Heymsfield, 2003The metabolic syndrome: prevalence and associated risk factor findings in the US population from the Third National Health and Nutrition Examination Survey, 1988-1994. Arch Intern Med 163427436
122 - V. Pasceri, J. T. Willerson, E. T. Yeh, 2000Direct proinflammatory effect of C-reactive protein on human endothelial cells. Circulation 10221652168
123 - G. A. Payne, H. G. Bohlen, U. D. Dincer, L. Borbouse, J. D. Tune, 2009Periadventitial adipose tissue impairs coronary endothelial function via PKC-beta-dependent phosphorylation of nitric oxide synthase. Am J Physiol Heart Circ Physiol 297, H460465
124 - G. A. Payne, L. Borbouse, S. Kumar, Z. Neeb, M. Alloosh, M. Sturek, J. D. Tune, 2010Epicardial perivascular adipose-derived leptin exacerbates coronary endothelial dysfunction in metabolic syndrome via a protein kinase C-beta pathway. Arterioscler Thromb Vasc Biol 3017111717
125 - L. Piconi, L. Quagliaro, Ros. R. Da, R. Assaloni, D. Giugliano, K. Esposito, C. Szabo, A. Ceriello, 2004Intermittent high glucose enhances ICAM-1, VCAM-1, E-selectin and interleukin-6 expression in human umbilical endothelial cells in culture: the role of poly(ADP-ribose) polymerase. J Thromb Haemost 214531459
126 - G. M. Pieper, P. Langenstroer, W. Siebeneich, 1997Diabetic-induced endothelial dysfunction in rat aorta: role of hydroxyl radicals. Cardiovasc Res 34145156
127 - U. Pohl, K. Herlan, A. Huang, E. Bassenge, 1991EDRF-mediated shear-induced dilation opposes myogenic vasoconstriction in small rabbit arteries. Am J Physiol 261, H20162023
128 - P. Poirier, T. D. Giles, G. A. Bray, Y. Hong, J. S. Stern, F. X. Pi-Sunyer, R. H. Eckel, 2006Obesity and cardiovascular disease: pathophysiology, evaluation, and effect of weight loss: an update of the 1997 American Heart Association Scientific Statement on Obesity and Heart Disease from the Obesity Committee of the Council on Nutrition, Physical Activity, and Metabolism. Circulation 113898918
129 - C. Rask-Madsen, N. Ihlemann, T. Krarup, E. Christiansen, L. Kober, Kistorp. C. Nervil, C. Torp-Pedersen, 2001Insulin therapy improves insulin-stimulated endothelial function in patients with type 2 diabetes and ischemic heart disease. Diabetes 5026112618
130 - M. M. Ribeiro, A. G. Silva, N. S. Santos, I. Guazzelle, L. N. Matos, I. C. Trombetta, A. Halpern, C. E. Negrao, S. M. Villares, 2005Diet and exercise training restore blood pressure and vasodilatory responses during physiological maneuvers in obese children. Circulation 11119151923
131 - C. K. Roberts, N. D. Vaziri, R. J. Barnard, 2002Effect of diet and exercise intervention on blood pressure, insulin, oxidative stress, and nitric oxide availability. Circulation 10625302532
132 - C. J. Rodriguez, Y. Miyake, C. Grahame-Clarke, M. R. Di Tullio, R. R. Sciacca, B. Boden-Albala, R. L. Sacco, S. Homma, 2005Relation of plasma glucose and endothelial function in a population-based multiethnic sample of subjects without diabetes mellitus. Am J Cardiol 9612731277
133 - M. J. Romero, D. H. Platt, H. E. Tawfik, M. Labazi, A. B. El -Remessy, M. Bartoli, R. B. Caldwell, R. W. Caldwell, 2008Diabetes-induced coronary vascular dysfunction involves increased arginase activity. Circ Res 10295102
134 - P. Rosen, T. Ballhausen, W. Bloch, K. Addicks, 1995Endothelial relaxation is disturbed by oxidative stress in the diabetic rat heart: influence of tocopherol as antioxidant. Diabetologia 3811571168
135 - G. A. Rosito, J. M. Massaro, U. Hoffmann, F. L. Ruberg, A. A. Mahabadi, R. S. Vasan, C. J. O’Donnell, C. S. Fox, 2008Pericardial fat, visceral abdominal fat, cardiovascular disease risk factors, and vascular calcification in a community-based sample: the Framingham Heart Study. Circulation 117605613
136 - G. M. Rubanyi, M. A. Polokoff, 1994Endothelins: molecular biology, biochemistry, pharmacology, physiology, and pathophysiology. Pharmacol Rev 46325415
137 - G. M. Rubanyi, J. C. Romero, P. M. Vanhoutte, 1986Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 250, H11451149
138 - H. S. Sacks, J. N. Fain, 2007Human epicardial adipose tissue: a review. Am Heart J 153907917
139 - S. Sakamoto, K. Minami, Y. Niwa, M. Ohnaka, Y. Nakaya, A. Mizuno, M. Kuwajima, K. Shima, 1998Effect of exercise training and food restriction on endothelium-dependent relaxation in the Otsuka Long-Evans Tokushima Fatty rat, a model of spontaneous NIDDM. Diabetes 478286
140 - C. Sanz, J. F. Gautier, H. Hanaire, 2010Physical exercise for the prevention and treatment of type 2 diabetes. Diabetes Metab 36346351
141 - C. G. Schalkwijk, C. D. Stehouwer, 2005Vascular complications in diabetes mellitus: the role of endothelial dysfunction. Clin Sci (Lond) 109143159
142 - E. L. Schiffrin, R. M. Touyz, 1998Vascular biology of endothelin. J Cardiovasc Pharmacol 32 Suppl 3, S213
143 - M. P. Schneider, E. I. Boesen, D. M. Pollock, 2007Contrasting actions of endothelin ET(A) and ET(B) receptors in cardiovascular disease. Annu Rev Pharmacol Toxicol 47731759
144 - I. Schofield, R. Malik, A. Izzard, C. Austin, A. Heagerty, 2002Vascular structural and functional changes in type 2 diabetes mellitus: evidence for the roles of abnormal myogenic responsiveness and dyslipidemia. Circulation 10630373043
145 - W. M. Selig, T. C. Noonan, D. F. Kern, A. B. Malik, 1986Pulmonary microvascular responses to arachidonic acid in isolated perfused guinea pig lung. J Appl Physiol 6019721979
146 - Y. Shi, K. F. So, R. Y. Man, P. M. Vanhoutte, 2007Oxygen-derived free radicals mediate endothelium-dependent contractions in femoral arteries of rats with streptozotocin-induced diabetes. Br J Pharmacol 15210331041
147 - Y. Shi, P. M. Vanhoutte, 2009Reactive oxygen-derived free radicals are key to the endothelial dysfunction of diabetes. J Diabetes 1151162
148 - R. Shurtz-Swirski, S. Sela, A. T. Herskovits, S. M. Shasha, G. Shapiro, L. Nasser, B. Kristal, 2001Involvement of peripheral polymorphonuclear leukocytes in oxidative stress and inflammation in type 2 diabetic patients. Diabetes Care 24104110
149 - A. Singhal, 2005Endothelial dysfunction: role in obesity-related disorders and the early origins of CVD. Proc Nutr Soc 641522
150 - L. I. Sinoway, C. Hendrickson, W. R. Davidson, Jr , S. Prophet, R. Zelis, 1989Characteristics of flow-mediated brachial artery vasodilation in human subjects. Circ Res 643242
151 - O. Sorop, J. A. Spaan, T. E. Sweeney, E. Van Bavel, 2003Effect of steady versus oscillating flow on porcine coronary arterioles: involvement of NO and superoxide anion. Circ Res 9213441351
152 - M. M. Spitaler, W. F. Graier, 2002Vascular targets of redox signalling in diabetes mellitus. Diabetologia 45476494
153 - S. Srinivasan, M. E. Hatley, D. T. Bolick, L. A. Palmer, D. Edelstein, M. Brownlee, C. C. Hedrick, 2004Hyperglycaemia-induced superoxide production decreases eNOS expression via AP-1 activation in aortic endothelial cells. Diabetologia 4717271734
154 - J. Stamler, O. Vaccaro, J. D. Neaton, D. Wentworth, 1993Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 16434444
155 - D. Steinberg, 1997Low density lipoprotein oxidation and its pathobiological significance. J Biol Chem 2722096320966
156 - K. J. Stewart, 2002Exercise training and the cardiovascular consequences of type 2 diabetes and hypertension: plausible mechanisms for improving cardiovascular health. JAMA 28816221631
157 - Y. Su, X. M. Liu, Y. M. Sun, Y. Y. Wang, Y. Luan, Y. Wu, 2008Endothelial dysfunction in impaired fasting glycemia, impaired glucose tolerance, and type 2 diabetes mellitus. Am J Cardiol 102497498
158 - D. Taha, O. Ahmed, Sadiq. B. bin, 2009The prevalence of metabolic syndrome and cardiovascular risk factors in a group of obese Saudi children and adolescents: a hospital-based study. Ann Saudi Med 29357360
159 - P. D. Taylor, L. Poston, 1994The effect of hyperglycaemia on function of rat isolated mesenteric resistance artery. Br J Pharmacol 113801808
160 - B. Tesfamariam, 1994Free radicals in diabetic endothelial cell dysfunction. Free Radic Biol Med 16383391
161 - B. Tesfamariam, R. A. Cohen, 1992Free radicals mediate endothelial cell dysfunction caused by elevated glucose. Am J Physiol 263, H321326
162 - B. Thorand, J. Baumert, L. Chambless, C. Meisinger, H. Kolb, A. Doring, H. Lowel, W. Koenig, 2006Elevated markers of endothelial dysfunction predict type 2 diabetes mellitus in middle-aged men and women from the general population. Arterioscler Thromb Vasc Biol 26398405
163 - L. M. Title, P. M. Cummings, K. Giddens, B. A. Nassar, 2000Oral glucose loading acutely attenuates endothelium-dependent vasodilation in healthy adults without diabetes: an effect prevented by vitamins C and E.J Am Coll Cardiol 3621852191
164 - R. M. Tribe, L. Poston, 1996Oxidative stress and lipids in diabetes: a role in endothelium vasodilator dysfunction? Vasc Med 1195206
165 - C. R. Triggle, M. Hollenberg, T. J. Anderson, H. Ding, Y. Jiang, L. Ceroni, W. B. Wiehler, E. S. Ng, A. Ellis, K. Andrews, J. J. Mc Guire, M. Pannirselvam, 2003The endothelium in health and disease--a target for therapeutic intervention. J Smooth Muscle Res 39249267
166 - P. M. Vanhoutte, 1989Endothelium and control of vascular function. State of the Art lecture. Hypertension 13658667
167 - S. Vehkavaara, S. Makimattila, A. Schlenzka, J. Vakkilainen, J. Westerbacka, H. Yki-Jarvinen, 2000Insulin therapy improves endothelial function in type 2 diabetes. Arterioscler Thromb Vasc Biol 20545550
168 - S. K. Venugopal, S. Devaraj, I. Yuhanna, P. Shaul, I. Jialal, 2002Demonstration that C-reactive protein decreases eNOS expression and bioactivity in human aortic endothelial cells.Circulation10614391441
169 - O. F. Wagner, G. Christ, J. Wojta, H. Vierhapper, S. Parzer, P. J. Nowotny, B. Schneider, W. Waldhausl, B. R. Binder, 1992Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem 2671606616068
170 - P. J. Watkins, 2003Cardiovascular disease, hypertension, and lipids. BMJ 326874876
171 - G. F. Watts, S. F. O’Brien, W. Silvester, J. A. Millar, 1996Impaired endothelium-dependent and independent dilatation of forearm resistance arteries in men with diet-treated non-insulin-dependent diabetes: role of dyslipidaemia. Clin Sci (Lond) 91567573
172 - D. J. Webb, W. G. Haynes, 1995The role of endothelin-1 in cardiovascular physiology and pathophysiology. Scott Med J 406971
173 - S. B. Williams, J. A. Cusco, M. A. Roddy, M. T. Johnstone, M. A. Creager, 1996Impaired nitric oxide-mediated vasodilation in patients with non-insulin-dependent diabetes mellitus. J Am Coll Cardiol 27567574
174 - P. W. Wilson, R. B. D’Agostino, H. Parise, L. Sullivan, J. B. Meigs, 2005Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 11230663072
175 - L. Xiang, J. Naik, R. L. Hester, 2005Exercise-induced increase in skeletal muscle vasodilatory responses in obese Zucker rats. American journal of physiology 288, R987991
176 - G. Yang, R. Lucas, R. Caldwell, L. Yao, M. J. Romero, R. W. Caldwell, 2010Novel mechanisms of endothelial dysfunction in diabetes. J Cardiovasc Dis Res 15963