Insulin Resistance and the Endothelium Manuel J. Quiñones, MD,* Susanne B. Nicholas, MD, PhD, and Christopher J. Lyon, PhD

Address *David Geffen School of Medicine at UCLA, University of California Los Angeles, 900 Veteran Avenue, Suite 24-130, Los Angeles, CA 90095, USA. E-mail: [email protected] Current Diabetes Reports 2005, 5:246–253 Current Science Inc. ISSN 1534–4827 Copyright © 2005 by Current Science Inc.

Type 2 diabetes is a cardiovascular disease equivalent that is associated with accelerated atherosclerosis and significant mortality. However, the metabolic syndrome and prediabetes are associated with increased cardiovascular mortality, indicating that atherogenic vascular changes begin prior to the onset of overt diabetes. At the core of diabetes and the metabolic syndrome is insulin resistance (IR), which sets the stage for dyslipidemia, hypertension, and inflammation. Endothelial dysfunction is the first stage of the atherosclerosis process and results from exposure to cardiovascular risk factors, such as IR and diabetes. IR and atherosclerosis follow parallel paths as they progress in severity. Thiazolidinediones, angiotensin-converting enzyme inhibitors, angiotensin receptor-AT1 blockers, and statins are widely used in the treatment of diabetes. Emerging evidence indicates that these pharmacologic agents have added mechanisms of action, especially on the endothelium and in the prevention of diabetes.

Introduction We are in an epidemic with regard to obesity. In the United States alone, it is estimated that over 31% of the adult population is obese and more than 65% is overweight [1]. In turn, the high prevalence of obesity has resulted in dramatic increases in the prevalence of type 2 diabetes. In the United States, over 18 million people suffer from diabetes; these numbers are expected to escalate to over 25 million by the year 2025 [2]. Diabetes is associated with accelerated atherosclerosis and mortality. At the core of type 2 diabetes (T2D) are insulin resistance (IR) and the metabolic syndrome, which themselves are significant cardiovascular disease (CVD) risk factors even in the absence of carbohydrate intolerance [3].

Diabetes Is a Cardiovascular Disease Type 2 diabetes is associated with a number of chronic microvascular (retinopathy and nephropathy) and macro-

vascular (cardiovascular) complications that result in significant morbidity and mortality. Results from the UKPDS (United Kingdom Prospective Diabetes Study) reveal that intensive glucose lowering significantly reduced microvascular, but not macrovascular, complications. The lack of significant reduction in atherosclerosis with improvements in glycemic control infers that other forces, besides elevated glucose levels, are critical for the atherosclerotic process in the diabetic patient. Over the past 40 years, CVD mortality has progressively declined in both men and women. Unfortunately, diabetic patients have not experienced the same beneficial decline in mortality. In fact, diabetic women have actually experienced an increase in CVD mortality over this same period [4]. Risk for a first cardiovascular event in T2D is equal to the risk for reinfarction in patients with established CVD [5]. Further, diabetic patients with no previous cardiovascular disease have the same long-term morbidity and mortality as nondiabetic patients with established CVD [6]. Finally, carotid artery intima-media thickness (CIMT), a surrogate for subclinical atherosclerosis, is greater in T2D with or without clinical coronary artery disease (CAD) compared to non-T2D individuals with established CAD [7]. Therefore, as a result of the strong association between T2D and CVD and mortality, the NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) recently reclassified diabetes from a “classical risk factor” to a “cardiovascular disease equivalent,” and emphasized the urgent need for aggressive clinical management of T2D [8].

Endothelial Function: A Balancing Act The endothelium is a dynamic endocrine organ with paracrine and autocrine activity. It produces both vasodilators and vasoconstrictors (Table 1) that, through a delicate physiologic balance, modulate vascular tone, coagulation, and the interaction of the vessel wall with circulating substances and blood cells. The generation and secretion of nitric oxide (NO) and other vasodilators by the endothelium is critical for maintaining a favorable balance away from atherosclerosis. NO is a potent vasodilator and is vasculoprotective. It inhibits inflammation and oxidation, circulating monocyte recruitment and adhesion, vascular smooth muscle cell (VSMC) growth and migration, and platelet aggregation and thrombosis. In contrast, vasoconstrictors, such as angiotensin II (AII) and endothelin, promote vascular damage.

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Table 1. Endothelial vasoactive substances Vasodilators

Vasoconstrictors

Nitric oxide Endothelial-derived hyperpolarizing factor Prostacyclin Kinins

Angiotensin II Endothelin Thromboxane A2

Table 2. Components of the metabolic syndrome Risk factor Abdominal obesity (waist circumference) Men Women Triglycerides High-density lipoprotein cholesterol Men Women Blood pressure Fasting glucose

Defining level

> 102 cm (> 40 inches) > 88 cm (> 35 inches) ≥ 150 mg/dL < 40 mg/dL < 50 mg/dL ≥ 130/ ≥ 80 mm Hg ≥ 110 mg/dL

The development of CVD risk factors, such as T2D, results in the generation of reactive oxygen species with resultant increases in oxidative stress. Oxidative stress alters the critical balance between vasodilators and vasoconstrictors, resulting in endothelial dysfunction, decreased NO bioavailability, activation of vascular angiotensin-converting enzyme (ACE), and increased production of AII in the vessel wall. AII is a powerful vasoconstrictor that also activates the potent membrane NADPH oxidase to produce superoxide radicals that further increase oxidative stress levels. In addition, AII enhances monocyte adhesion and migration into the vessel wall by increasing endothelial expression of monocyte chemoattractant protein-1 (MCP-1), intracellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1); mediates vascular remodeling via increased production of transforming growth factor-β; and promotes a prothrombotic environment by inducing transcriptional activation of plasminogen activator inhibitor-1 (PAI-1) and platelet aggregation. AII also enhances production of endothelin-1 (ET-1) from endothelial cells and VSMCs, an action that is blocked by NO in healthy arteries [9]. In healthy arteries ET-1 stimulates NO release. In injured vessels, however, ET-1 is a potent vasoconstrictor, is proinflammatory, stimulates production of MCP-1, and is mitogenic to VSMCs [10]. Also, it has been suggested that ET-1 mediates, at least in part, AII-induced vascular damage [11].

Insulin Resistance and the Endothelium Insulin resistance can be defined as an impairment of normal biological responses to insulin, resulting in impaired insulin-stimulated glucose uptake by normally insulin-

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sensitive (IS) tissues and overproduction of glucose by the liver. Genetics, aging, and certain medications (eg, thiazides, β blockers, steroids) are key risk factors for IR. However, the driving force for IR in our generation is a combination of obesity and physical inactivity [12]. Current evidence indicates that this major public health burden will only worsen as obesity prevalence in children continues to rapidly grow, which will invariably translate into a rise in CVD morbidity and mortality [13]. A hallmark of obesity is overloaded fat cells with resultant elevated circulating levels of triglycerides and free fatty acids (FFAs) that induce both IR and endothelial dysfunction [14]. IR is associated with a cluster of CVD risk factors, collectively referred to as the metabolic syndrome, and these risk factors have all independently been associated with abnormal endothelial function [15]. Further, accumulation of these risk factors increases CVD risk to the degree that the metabolic syndrome confers a greater overall risk than any of its individual components [16,17]. In 2001, the NCEP ATP III provided a clinical definition for the metabolic syndrome (Table 2) and recognized it as a therapeutic target for the prevention of CVD [8]. In the United States, the prevalence of metabolic syndrome has been reported to be 24% in the adult population; 43% of adults are affected by age 60 [18]. The nearly 85% prevalence of the metabolic syndrome in patients with T2D is possibly even more critically relevant [16]. Obesity activates the adipocyte and other stromal cells in adipose tissue to secrete a number of cytokines (“adipokines”), such as tumor necrosis factor-α (TNF-α), PAI-1, angiotensinogen, interleukin-6, and others, which further reduce insulin sensitivity and promote systemic and vascular inflammation [19]. Through these insulin desensitizing and proinflammatory factors, the adipocyte is able to directly or indirectly influence IR and atherogenesis. TNF-α activates the transcription factor nuclear factor-κB and interferes with insulin receptor tyrosine kinase activity. PAI-1 reduces fibrinolysis, is elevated in obesity, T2D, and atherosclerosis, and plays an important role in vascular disease and thrombosis. Interleukin-6 stimulates C-reactive protein (CRP) production in the liver. CRP levels reflect systemic inflammation and highly predict CVD mortality [20]. Of note, recent evidence indicates that CRP may have a more direct role in the atherosclerotic process [21]. Adiponectin, also an adipocytederived endocrine factor, has insulin sensitizing and antiatherogenic properties [22]. In contrast to other adipokines, circulating levels are reduced in obesity, T2D, and CAD. Women generally have higher circulating levels; however, this putative protection is lost in IR [23]. Adiponectin improves IR, reduces liver fat content, and has anti-inflammatory effects on the endothelium, VSMCs, and macrophages [22]. Therefore, adiponectin appears to confer protection against both T2D and atherosclerosis. Insulin resistance results in a compensatory hyperinsulinemia to maintain euglycemia. Insulin activates two

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Endothelial Dysfunction Figure 1. Insulin resistance and atherosclerosis follow parallel paths. IFG—impaired fasting glucose; IGT—impaired glucose tolerance.

major signaling pathways: insulin receptor substrate-1/ phosphatidylinositol-3-kinase/Akt (IRS-1/PI3K/Akt) and mitogen-activated protein kinase (MAPK) [24]. The former mediates both insulin-stimulated glucose transport and NO production, whereas the latter mediates VSMC growth and migration and MCP-1, ICAM-1, and PAI-1 production. Therefore, insulin can have either protective or damaging actions. In the normal IS state, the IRS-1/PI3K/Akt pathway dominates and NO production and vasculoprotection are enhanced. Conversely, in IR, IRS-1/PI3K/Akt activity is diminished, therefore blunting NO production. Further, the MAPK pathway remains virtually unaffected in IR and compensatory hyperinsulinemia could preferentially drive the MAPK mitogen pathway, contributing to proatherogenic vascular changes [24]. Therefore, in this latter setting, insulin promotes inflammation, MCP-1 and ICAM-1 expression, monocyte adhesion, and VSMC mitogenesis and migration [24]. In the normal IS state, insulin acutely stimulates endothelium-dependent vasodilation; however, in IR and hyperinsulinemia, insulin blunts endothelial function in humans [25].

Insulin Resistance and Atherosclerosis Follow Parallel Paths Insulin resistance can be considered as a spectrum that progresses from obesity/hyperinsulinemia, to the metabolic syndrome, prediabetes, and eventually overt T2D (Fig. 1). T2D is associated with functional endothelial abnormalities of the peripheral and coronary circulations [26,27]. However, atherogenesis begins prior to the onset of overt diabetes because the metabolic syndrome and prediabetes are associated with increased CVD mortality [28]. Therefore, other pathophysiologic mechanisms, besides hyperglycemia, are critical for early atherogenic vascular changes. A major question is where in the spectrum of IR do vascular changes for atherosclerosis begin? Obesity is a risk factor for IR, T2D, and atherosclerosis and it is associated with endothelial abnormalities [29]. It has been suggested that obesity-induced atherosclerosis

may actually start in childhood [30]. Tounian et al. [31] reported that severely obese children had significantly greater carotid artery stiffness and reduced brachial artery endothelial-dependent vasodilation compared with normal weight children. Two independent studies have evaluated the effect of family history of T2D on endothelial function. Caballero et al. [32] reported abnormalities in brachial artery endothelium-dependent and -independent blood flow responses in normoglycemic children of parents with T2D; Balletshofer et al. [33] reported brachial artery endothelial dysfunction in normoglycemic insulinresistant but not IS relatives of patients with diabetes. Collectively, these reports indicate that IR–associated endothelial functional abnormalities, as measured in peripheral vessels, are present in the absence of T2D. Using positron emission tomography (PET) and sympathetic stimulation, our group recently reported that IR, in the absence of other CVD risk factors, is associated with significantly reduced coronary endothelial function [34]. Mexican-American subjects with no risk factors for CVD were divided into IS and insulin-resistant groups based on hyperinsulinemic-euglycemic clamp measurements. Myocardial blood flow was measured noninvasively in response to cold pressor test (CPT; primarily endothelial-dependent vasodilation) and dipyridamole (mostly endothelial-independent vasodilation) by PET using N-13-ammonia tracer. We found that the insulin-resistant and IS subjects had similar total vasodilator capacity in response to dipyridamole stimulation [34]. However, the insulin-resistant subjects had 70% blunting of coronary endothelial function compared with the IS group, despite having no other CVD risk factors [34]. In fact, the observed reduction in endothelial function was similar to that previously reported in chronic smokers [35]. More recently, we evaluated whether progression of IR severity would parallel worsening coronary endothelial functional abnormalities [26]. Using PET and N-13 ammonia, myocardial blood flow was measured in response to CPT and either dipyridamole or adenosine (mostly NO-independent vasodilatation). We evaluated a total of 140 MexicanAmerican patients who were either IS or insulin-resistant, had

Insulin Resistance and the Endothelium • Quiñones et al.

impaired glucose tolerance (IGT), or had T2D, the latter with and without hypertension. Our results demonstrated that total vasodilator capacity (mostly vascular smooth muscle mediated) was preserved in the IS, insulin-resistant, and IGT groups. However, there were significant reductions in total vasodilator capacity in normotensive (-17%) and hypertensive (-34%) patients with T2D. Compared with IS subjects, we found that endothelium-dependent coronary vasomotion progressively worsened as subjects progressed through the spectrum of IR: IR (-56%), IGT (-85%), normotensive T2D (-91%), and hypertensive T2D (-120%) [26]. Some of the insulin-resistant subjects with and without carbohydrate abnormalities demonstrated negative or paradoxical flow responses to CPT, as previously observed with intracoronary flow velocity measurements in patients with known CAD or T2D [36,37]. These results add to prior evidence that there appears to be a parallel progression of increased atherosclerosis incidence and mortality with progressively worsening IR (Fig. 1) [38,39].

Reversing Endothelial Dysfunction Current treatment strategies for T2D employ thiazolidinediones (TZDs), inhibitors of the renin-angiotensin system, and the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). Emerging data suggest that these pharmacologic agents may have effects that extend beyond their originally defined mechanism of action, especially in regard to vascular inflammatory processes. Recent evidence indicates that these agents may be beneficial in improving endothelial functional abnormalities in diabetic and nondiabetic patients and could be effective tools in the prevention of diabetes.

Thiazolidinediones The TZDs are a group of insulin-sensitizing antidiabetic agents (rosiglitazone and pioglitazone) that have had a major impact on the treatment of T2D. TZDs are peroxisome proliferator-activated receptor-γ (PPAR-γ ) ligands that interact with their nuclear receptor to enhance insulin action by improving insulin sensitivity in IS tissues (skeletal muscle, liver, and adipose tissue). Therefore, TZDs target the core of T2D, namely IR. PPAR-γ regulates adipose differentiation and expression of a number of genes involved in lipid and carbohydrate metabolism. TZDs have been demonstrated to efficiently decrease glucose levels as monotherapy or in combination with other oral agents or exogenous insulin. However, growing data indicate that TZDs have important nonglycemic effects, especially on adipose tissue, inflammation, and the vascular wall. Insulin resistance and T2D are atherogenic states that are associated with increased subclinical atherosclerosis, and endothelial dysfunction and TZDs have been demonstrated to have beneficial effects on both. Xiang et al. [40] reported that normoglycemic young women at high risk for T2D (previous history of gestational diabetes) who

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were treated with troglitazone for up to 4 years had a 31% reduction in CIMT progression compared with placebo. Other studies have demonstrated that TZDs may actually decrease CIMT, independent of glucose control [41]. TZDs have also been demonstrated to improve endothelial dysfunction in the peripheral vasculature of subjects with T2D. Caballero et al. [42] reported that 12 weeks of troglitazone significantly improved flow-mediated vasodilation in recently diagnosed T2D that had no clinical evidence for macrovascular disease. More recently, Pistrosch et al. [43] reported that rosiglitazone improved both insulin sensitivity and brachial artery responses to acetylcholine infusion in recently diagnosed T2D. Similarly, these agents improved endothelial function in obese nondiabetic subjects and women with polycystic ovary syndrome (an insulin-resistant condition) [44,45]. We recently reported that the beneficial effects of TZDs on endothelial function extend to the coronary circulation. Nondiabetic, but highly insulin-resistant subjects with no risk factors for CVD were found to have significant blunting of coronary endothelial responses to sympathetic stimulation compared with IS subjects [34]. Subgroups of the insulin-resistant subjects were treated with either 8 mg of rosiglitazone or 600 mg of troglitazone for 3 months. After treatment, both groups significantly improved insulin sensitivity, decreased circulating insulin and FFA levels, and normalized coronary endothelial functional abnormalities. Repeat measurements taken at least 3 months after TZD treatment was discontinued revealed that endothelial function had deteriorated to pretreatment levels [34]. The precise mechanisms by which TZDs improve or normalize endothelial function have not been well defined. Obesity results in dysregulated release of FFAs, and elevated levels of FFAs have been shown to decrease circulating levels of L-arginine (substrate for NO production), directly inhibit NO synthesis, and induce endothelial dysfunction [46]. TZDs effectively decrease circulating levels of FFAs, a proposed mechanism for improving insulin sensitivity, which may also have a beneficial effect on the endothelium. Visceral obesity results in the release of a number of adipokines that increase inflammation and aversely affect the vascular wall [19]. TZDs have been shown to increase adiponectin while decreasing TNF-α levels; inhibit the expression of MCP-1, ICAM-1, and VCAM-1 in endothelial cells and VSMCs; decrease VSMC proliferation and migration; and decrease vascular lesion formation in animal models of atherosclerosis [47]. The antiinflammatory effects of TZDs have also been demonstrated in human studies where troglitazone or rosiglitazone has been reported to decrease circulating levels of CRP, TNF-α, PAI-1, and matrix metalloproteinase-9 in patients with T2D [48,49]. In our own studies with normoglycemic insulin-resistant subjects with no other risk factors for CVD, 3 months of treatment with rosiglitazone reduced circulating levels of CRP and PAI-1 and more than doubled those of adiponectin [23]. Recently, IR has been associated with increased concentrations of asymmetric dimethylarginine (ADMA), which

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Endothelial Dysfunction

correlated with the degree of IR [50]. ADMA, produced from the hydrolysis of methylated proteins, is an endogenous inhibitor of endothelial NO synthase, and is strongly associated with impaired endothelial function in humans [51]. Treatment of insulin-resistant hypertensive subjects with rosiglitazone improved insulin sensitivity and significantly decreased ADMA concentrations [50]. In summary, TZDs improve insulin sensitivity and decrease glucose levels, but also appear to have beneficial effects on the vascular wall and endothelial function. In addition, because TZDs improve insulin sensitivity, the core of T2D, they have been suggested as potential tools for the prevention of T2D. The ability of the TZD rosiglitazone to reduce the incidence of T2D is currently being evaluated in the prospective DREAM (Diabetes Reduction Assessment with Ramipril and Rosiglitazone) trial [52].

ACE inhibitors and ARBs Pharmacologic inhibition of AII action by ACE inhibitors or selective AII type 1 (AT1) receptor blockers (ARBs) has had a major impact on the treatment of hypertension, and has provided unique benefits in progression of diabetic nephropathy. In addition, large randomized clinical trials have demonstrated the effectiveness of these drugs in reducing CVD morbidity and mortality in high-risk patients with and without diabetes. An interesting and unexpected finding from secondary analysis in these studies has been the consistent reporting of reductions in the development of T2D [53]. The first clinical trial to report that ACE inhibition reduces new-onset T2D was CAPP (Captopril Prevention Project), where patients treated with captopril had significantly fewer new cases of diabetes than those treated with comparator drugs (diuretics or β blockers). These results were confirmed in the HOPE (Heart Outcomes Prevention Evaluation) study where ramipril, as monotherapy or in combination with other antihypertensives, had a 35% greater reduction in diabetes development compared with placebo. These effects have not been limited to ACE inhibitors because three independent cardiovascular clinical trials that employed ARBs reported similar findings [53]. The LIFE (Losartan Intervention for Endpoint) reduction in hypertension study compared the effects of losartan and the β-blocker atenolol on cardiovascular outcomes and found that those treated with losartan had 25% fewer cases of newly diagnosed T2D compared with the atenolol group. The CHARM (effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction)-Preserved Trial and VALUE (Valsartan Antihypertensive Long-term Use Evaluation) have recently reported similar findings [54,55]. However, it should be noted that none of the abovementioned studies were designed to evaluate diabetes prevention as a primary outcome. In response to this, there currently are two prospective studies underway that will evaluate diabetes prevention as a primary outcome: the DREAM trial (mentioned earlier) and the NAVIGATOR

(Nateglinide and Valsartan in Impaired Glucose Tolerance Outcomes Research) trial. The latter will determine if valsartan and/or nateglinide will lower the incidence of diabetes and cardiovascular events in patients with IGT. The mechanisms by which ACE inhibitors and/or ARBs improve the insulin-resistant metabolic milieu and reduce the development of T2D are not completely clear. Recently, several ARBs have been demonstrated to have PPAR-γ activity independent of AT1-blocking actions. In two independent studies, telmisartan was shown to induce PPAR-γ activity by interaction with the PPAR-γ ligand-binding dom ain an d pr omo t ed adip oc yte d if f er e nt i a ti on [56••,57••]. In one of these studies, irbesartan and losartan were demonstrated to have similar effects [56••]. In addition, both telmisartan and irbesartan have been demonstrated to improved insulin sensitivity in animal models of obesity and IR [57••,58]. Our group recently investigated whether valsartan would have favorable effects on insulin sensitivity or endothelial function in subjects with IGT. Twenty Mexican-American subjects with IGT but no other risk factors for CVD underwent baseline measurements of insulin sensitivity and coronary endothelial function. At baseline, subjects were severely insulin resistant and had significant coronary endothelial functional abnormalities. Twelve weeks of treatment with valsartan 160 mg/d significantly improved insulin sensitivity and normalized coronary endothelial abnormalities [59]. Glucose disposal rate, as measured by euglycemic clamp, improved by 31%, an appreciable finding when compared with the 59% increase that we previously reported in similar subjects treated with the insulin sensitizers troglitazone and rosiglitazone [34]. Increasing the dose of valsartan to 320 mg/d further increased insulin sensitivity and had a 50% additive beneficial effect on coronary flow measurements [59]. In summary, ACE inhibitors and ARBs have a clear and defined role in the treatment of hypertension, especially in diabetes, and in the prevention of cardiovascular events in high-risk patients. More recently, these agents have been demonstrated to improve insulin sensitivity in animal and human studies and, therefore, may also be effective in reducing the development of T2D. For these reasons, we look forward to the results of the DREAM and NAVIGATOR trials.

Statins Statins are widely used in diabetic and nondiabetic populations. Clinical trials have clearly demonstrated that they are effective in lipid reduction and primary and secondary prevention of cardiovascular mortality [60]. In addition, clinical trials have demonstrated that diabetic patients appear to have higher response rates compared to nondiabetic patients [61]. However, clinical trials involving the use of statins have indicated that observed reductions in CVD events occur to a greater degree than can be explained by just low-density lipoprotein cholesterol (LDLC) reduction [60]. Therefore, there is considerable scientific interest in

Insulin Resistance and the Endothelium • Quiñones et al.

their potential “pleiotropic” effects that could provide added cardiovascular protection. Evidence for pleiotropic effects of statins include the following: 1) clinical benefits are apparent earlier than can be accounted for by simple reductions in cholesterol levels; 2) similar beneficial cardiovascular effects have been observed in individuals with normal range cholesterol levels; and 3) beneficial effects have been observed in noncardiovascular areas, such as dementia, tumor growth, and osteoporosis [60,62,63]. Elevated LDLC is associated with impaired endothelial function, and statins have been shown to both decrease LDLC and improve endothelial dysfunction in peripheral and coronary circulations [64,65]. However, beneficial effects on endothelial function have been reported within days or even after only a single dose, indicating that endothelial improvements occurred prior to appreciable lipid-lowering effects [66]. In addition, although all statins effectively reduce lipid levels, there may be drug-specific endothelial effects. Yokoyama et al. [67] found a significant improvement in coronary endothelial abnormalities in a group treated with simvastatin but not with pravastatin, although both treatment groups had similar lipid-lowering effects. More recently, Landmesser et al. [68••] reported that 4 months of treatment with simvastatin, but not ezetimibe (a cholesterol absorption inhibitor), significantly improved endothelialdependent vasodilation of the radial artery despite similar reductions in LDLC by both medications. They further reported that simvastatin abolished vitamin C–mediated improvement of endothelial function and increased levels of endothelium-bound extracellular superoxide dismutase, suggesting that simvastatin-induced improvements on endothelial function resulted from reduced vascular oxidative stress [68••]. In this same study, simvastatin increased the number of functionally active endothelial progenitor cells. This is an interesting finding because recent studies have suggested that endothelial progenitor cells have the potential to increase endothelial regeneration [69]. These results give further evidence to the pleiotropic effects of statins and are especially important because both medications reduced lipid levels comparably but only simvastatin improved oxidative stress and endothelial function. Finally, further insight on the pleiotropic effects of statins will be forthcoming with the results of the ongoing trials of the CORONA (Controlled Rosuvastatin Multinational Study in Heart Failure) and GISSI-HF (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarcto myocardio Heart Failure) studies.

Conclusions Type 2 diabetes is a CVD equivalent whose atherogenic vascular changes begin early in the IR spectrum and, therefore, years prior to overt diabetes. As IR progresses in severity, atherosclerosis follows a similar path of progression. Obesity/IR is associated with dyslipidemia, hypertension, and endothelial dysfunction; however, coronary endothelial dysfunction is present at this stage even in the

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absence of other CVD risk factors. Elevated levels of oxidative stress and local generation of AII are key players in vascular inflammatory processes that propagate atherosclerosis progression. TZDs, ACE inhibitors, ARBs, and statins have all been demonstrated to reduce these vascular inflammatory processes, improve or normalize endothelial dysfunction, and serve as potential tools for the prevention of T2D.

Acknowledgments This work was supported, in part, by National Institutes of Health grants HL6003, HL076771, and MO1-RR00865. The authors would like to thank Preethi Srikanthan, MD, for her helpful suggestions and Ms. Roxana De La Rosa for her assistance with the preparation of this manuscript.

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