ab

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Journal of the American College of Cardiology Vol. 53, No. 5, Suppl S, 2009 2009 by the American College of Cardiology Foundation ISSN 0735-1097/09/$36.00Pubtions has remained a difficult, complicated, and to date,gely unsuccessful enterprise. In contrast, tighter glucosetrol does limit microvascular disease. These seemingly

radoxical trends force re-examination of the diabeticcular disease spectrum.

abetic Macrovascular Complications

perglycemia can promote vascular complications by mul-le postulated mechanisms (Table 1). Increased glucosecentrations can activate nuclear factor-B (1), a keydiator that regulates multiple pro-inflammatory and-atherosclerotic target genes in endothelial cells (ECs),cular smooth muscle cells (VSMCs), and macrophages.

zymes implicated in plaque rupture and arterial remodeling,inducing similar responses in VSMC. Glucose may alsostimulate VSMC proliferation, migration, and altered reactiv-ity, for example, through renin-angiotensin activation.

Inflammation has been strongly implicated in both ath-erosclerosis and T2DM (46). Despite this, no singlemechanism yet explains why this pattern is found in diabeticpatients. Monocytes grown in the presence of high glucoseconcentrations or isolated from persons with poorly con-trolled diabetes appear activated (7), with induction of manyinflammatory mediators such as protein kinase C andnuclear factor-B. These targets, as well as others, maypromote oxidative stress (8). In vitro studies suggest similarpro-atherogenic effects of hyperglycemia on T lymphocytes,inflammatory cells also involved in atherosclerosis.

Hyperglycemia Versus Dyslipidemiain the Pathogenesis of Atherosclerosis

m the Cardiovascular Division, Brigham and Womens Hospital, Harvarddical School, Boston, Massachusetts. Dr. Orasanu has no conflict of interest tort. Dr. Plutzky has received grant/research support from sanofi-aventis, andsulting fees or honoraria from Dainippon Sumitomo Pharma America, Inc.,xoSmithKline, Novo Nordisk, Ono Pharmaceutical Co., Ltd., sanofi-aventis,eda Pharmaceuticals North America, Merck & Co., Inc, Amylin PharmaceuticalsThe Pathologic Continuum of Di

Gabriela Orasanu, MD, Jorge Plutzky, MD

Boston, Massachusetts

Hyperglycemia can promote vascular complications by mglycation end products and increased oxidative stress provascular complications. Many of the earliest pathologic recells that directly encounter elevated blood glucose levelscells and vascular smooth muscle cells. In the microvascretinopathy), and podocytes (in renal disease). Additionalmay promote atherosclerotic plaque progression and conmacroangiopathy and microangiopathy. (J Am Coll Cardof Cardiology Foundation

pe 2 diabetes mellitus (T2DM) is diagnosed, and hencegely defined, by hyperglycemia. Although this definitions framed the perspective on T2DM, the pathologicprint of this disease often involves the vasculature, withhyperglycemia promoting both microvascular and mac-ascular complications. Not surprisingly, given complica-ns such as stroke and acute coronary syndromes, muchention has focused on diabetic macrovascular disease.wever, the morbidity associated with diabetic microvas-ar disease, including retinopathy, neuropathy, nephrop-y, and limb ischemia, is staggering. Given the impact ofbetic vascular disease, prodigious effort has been directed

lished by Elsevier Inc.Atglu

F. Hoffmann-La Roche Ltd, and Tethys Bioscience Inc.anuscript received September 15, 2008; accepted September 30, 2008.etic Vascular Disease

e mechanisms, with formation of advancedd to contribute to both macrovascular and micro-ses to hyperglycemia are manifest in the vascularhe macrovasculature, these include endothelialre, these include endothelial cells, pericytes (inovascularization arising from the vasa vasorume to plaque rupture, thereby interconnecting009;53:S3542) 2009 by the American College

evated glucose can foster glycation of proteins, promotingmation of advanced glycation end products (AGEs)tein cross-linking, and reactive oxygen species formation.perglycemia itself can stimulate oxidative stress, which hasn strongly implicated as a driving force in atherosclerosis.Not surprisingly, many early pathologic responses to glucosemanifest in the vascular cells that directly encounter

perglycemia. The loss of the nonadhesive property of theothelium, with monocyte adhesion to ECs, is an earlyerogenic step. Hyperglycemia increases monocyte adhesioncultured ECs (2). Hyperglycemia and AGEs can alsoulate EC production of superoxide (1,3), suggesting links

doi:10.1016/j.jacc.2008.09.055tempts to improve cardiovascular (CV) outcomes throughcose control contrast strikingly with the benefits seen in

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S36 Orasanu and Plutzky JACC Vol. 53, No. 5, Suppl S, 2009most trials with statins in pa-tients with diabetes. Such datachallenge the focus on glucose asthe prime determinant of patho-logic, or at least vascular, out-comes among patients with dia-betes. The relative effects ofhyperglycemia versus dyslipide-mia in atherogenesis have beendifficult to separate. For example,dyslipidemia can be exacerbatedby hyperglycemia. At the sametime, some data suggest possibleindependent effects of hypergly-cemia on atherosclerosis (9,10).Atherosclerosis was found todevelop more rapidly in fat-feddiabetic pigs than in similardyslipidemic fat-fed pigs with-out diabetes (9). In low-densitylipoprotein receptor-deficient micewith a novel form of diabetes

uced by a T-celldirected viral antigen, consumption ofholesterol-free diet resulted in hyperglycemia withoutanges in lipids or lipoproteins (10). Adding increasingounts of dietary cholesterol led to dyslipidemia, whichs the major factor in atherosclerosis progression indepen-nt of hyperglycemia in this model (10).Endoplasmic reticulum (ER) stress may promote athero-erosis among those with diabetes. All secretory andmbrane proteins, many pathogens, and diverse nutrients,luding glucose, pass through the ER. Hyperglycemiane can induce ER stress in multiple tissues, including theer and fat, activating pathways involved in oxidation andammation (11). Thus, ER stress, which can also bemulated by hypoxia, elevated free fatty acids, and othernglucose pathways, may promote both diabetes anderosclerosis (12).

bbreviationsnd Acronyms

GE advanced glycationnd product

PC activated protein C

V cardiovascular

C endothelial cell

R endoplasmiceticulum

EDF pigmentpithelium-derived factor

PAR peroxisomeroliferator-activatedeceptor

2DM type 2 diabetesellitus

EGF vascularndothelial growth factor

SMC vascular smoothuscle cell

Examples of Mechanisms Implicated in Diabetic M

Table 1 Examples of Mechanisms Implicated i

Cellular Players

Endothelium NF-B activati

Decreased NO

Increased reac

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Increased lipid

Impaired endo

Monocyte-derived macrophages Increased IL1

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The Continuum of Diabetic Vascular DiseaseIncreased nonenzym

AGE advanced glycation end products; IL interleukin; MCPmonocyte chemoaIt is of interest to overlay these various postulatedchanisms that promote inflammation and macrovascularease onto microvascular disease. As noted, in contrast tocrovascular disease, the impact of better glycemic controlmicrovascular disease is unequivocal. This divergence inical experience raises fundamental questions about the

ture of microvascular disease, how hyperglycemia modi-s the microvasculature, and the implications of differingcose effects on arterial disease, based on vessel size.

abetic Microvascular Complications

thological changes in the diabetic microvasculature caner organ perfusion, particularly affecting organs heavilypendent on their microvasculature supply, namely theina, kidneys, and peripheral nervous system. The clinicalblems associated with these changesretinopathy, ne-ropathy, and neuropathydrive a large burden ofDM morbidity. Microvascular disease also contributes toripheral vascular disease, reduced myocardium vascular-tion, and poor wound healing (13). To some extent,betic microvascular disease has been overlooked in termsits clinical impact and research attention. Further con-eration of microvascular disease should begin with anrview of the anatomic nature of the microvasculature.

ructural and Functionalfferences: Micro Versus Macro

icrovesselsthe smallest functional unit of the CVtemconsist of arterioles, capillaries, and venules. Thesesels differ significantly from macrovessels with respect tohitecture and cellular components. In contrast to largersels providing blood to organs, microvessels have specifices regulating blood pressure and offering nutrient delivery.e microcirculation also has regulatory systems such asomotion, permeability, and myogenic responses that canpt flow to local metabolic needs (14,15). Disturbances incrovascular function may arise before overt hyperglycemia

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S37JACC Vol. 53, No. 5, Suppl S, 2009 Orasanu and PlutzkyFebvascular pathologic changes (14,15). This timeline under-res the importance of understanding the distinct role of thecrovasculature in the natural history of T2DM.The most consistent structural diabetic microvasculardification is a thickening of the capillary basementmbrane, including arterioles in the glomeruli, retina,ocardium, skin, and muscle, resulting in the classicbetic microangiopathy. This thickening alters vesselction, directly promoting clinical problems like hyper-sion, reduced wound healing, and tissue hypoxia. Ulti-tely, in later stages, a frank loss of microvessels occurs,th microvessel drop-out and pruning classically associatedth T2DM. The possibility that microvascular pathologytributes to systemic diabetic complications, includingcrovascular atherosclerosis, remains an intriguing hy-thesis worthy of further exploration.

chanisms of Diabetic Microvascular Disease

ucose and the microvasculature. A linear relationshipsts between hyperglycemia and microvascular complica-ns. The impact of improved glucose control in preventinglimiting progression of microvascular disease stronglyplicates hyperglycemia in these complications (16). In-ed, the current fasting plasma glucose parameters used tognose diabetes derive largely from diabetes-specific mi-vascular complication data, especially retinopathy (17).ore recently, cross-sectional data from the Blue Moun-ns Eye Study, the Australian Diabetes, Obesity andestyle Study, and the Multi-Ethnic Study of Atheroscle-is showed no uniform glycemic threshold for retinopathyoss different populations (18). These data suggest thatcrovascular complications do not occur at an arbitrarycemic threshold, a notion also raised for macrovascularease (18). Ultimately, the interaction between glucoseels and microvascular disease requires a molecular expla-tion. Interestingly, hyperglycemia-induced molecular re-nses are especially evident in insulin-insensitive cells thatthus unable to regulate glucose handling. Capillary ECsthe retina, mesangial cells in the renal glomerulus, andurons and Schwann cells in peripheral nerves can all beegorized in this way (1921).Various mechanisms have been proposed for diabeticcrovascular complications (Table 2). Of note, as with thecrovasculature, the endothelium is often implicated in

mples of Mechanisms Implicated in Diabetic Microvascular Disea

able 2 Examples of Mechanisms Implicated in Diabetic Microva

Increased AldoseReductase Pathway

Protein KinaseActivation Ox

Sorbitol 1VEGF

smotic cellular damage 1ROS

(Na and K) ATPase activity NF-B activation

NADH/NAD Inhibition of eNOS activity

NADPH 1Endothelin-1

ruary 3, 2009:S3542ase adenosine triphosphatase; eNOS endothelial nitric oxide synthase; NAD nicotinamide adeninine dinucleotide phosphate reduced; PAI plasminogen activator inhibitor; ROS reactive oxygen spebetic microvascular disease pathways. Together, theseta place ECs in the pathologic center of T2DM. Endo-lial cells display remarkable heterogeneity in structured function. The endothelium arising from vessels offerent sizes and from different anatomical compartmentsexpress different phenotypic properties in normal and

eased states (22,23). Recently, DNA microarrays exam-d differences among gene expression profiles of ECs fromge and smaller vessels (24). The differentially expressedes uncovered in this study have diverse, well-establishedes in endothelial biology, including extracellular matrixmation, neuronal signaling and migration, angiogenesis,d lipid metabolism (24).Other specific cell types may also play defined roles incrovascular disease in certain tissue beds. An early,cific retinal change induced by hyperglycemia is theath of microvascular contractile cells known as pericytes.ricytes provide vessel stability and regulate control ofdothelial proliferation and angiogenesis (25). In theney, podocytes and ECs form the glomerular capillary,ich, together with the basement membrane, constitutesglomerular filtration barrier. Podocyte injury and loss,ich also involves apoptosis, are cardinal features ofbetic nephropathy (26). Many of the mechanisms impli-ed in microvascular injury are common to ECs, pericytes,d podocytes. Recent clinical evidence reveals that cerebralcroangiopathy may play a role in promoting vascularmentia, ventricular hypertrophy, lacunar infarcts, hemor-ge, and may be a predisposing factor for Alzheimersease in patients with diabetes (27). It is also worth notingt the heart itself contains a large and extensive micro-culature. Indeed, coronary microangiopathy has beensed as a major complication in diabetics. Compared withtrols, hyperemic myocardial flow was decreased 28% in

tients with T2DM and macrovascular coronary disease,t was even further reduced (57%) among patients withDM who also had evidence of coronary microangiopathy,29). As suggested in other tissue beds, glycemic controly influence the degree of coronary microangiopathy (28).AGEs, strongly implicated in diabetic vascular injury,ve been localized to retinal blood vessels in patients withDM and correlated with the degree of retinopathy (30).tinal vascular ECs exposed to AGEs show abnormaldothelial nitric oxide synthase expression (31) and induc-

condary to Hyperglycemia

r Disease Secondary to Hyperglycemia

asede Stress Protein Glycation

IncreasedHexosamine Pathway

OS 1AGE 1PAI-1

Apoptotic death Inhibition of eNOS activity

NF-B activation

1ROS

The Continuum of Diabetic Vascular Diseasediadatheandifcandisinee dinucleotide; NADH nicotinamide adenine dinucleotide reduced; NADPH nicotinamidecies; VEGF vascular endothelial growth factor; other abbreviations as in Table 1.

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S38 Orasanu and Plutzky JACC Vol. 53, No. 5, Suppl S, 2009n of vascular endothelial growth factor (VEGF) expres-n (32). AGEs reportedly signal via the receptor for AGE.neuronal-associated vessels, the AGE receptor has beenalized with its putative ligand N-epsilon-carboxymethyline and nuclear factor-B, and interleukin-6 (33). Theckade of AGE formation by aminoguanidine improvedral signal transmission in diabetic rats, suggesting this as arapeutic strategy for diabetic vascular complications (34).Oxidative stress has been implicated in both microvascu-and macrovascular disease. Hyperglycemia promotesmation of reactive oxygen species, which can interactth both deoxyribonucleic acid (DNA) and proteins, caus-damage. Mitochondrial DNA may be an especially

evant target (35). Interestingly, reactive oxygen species-diated cellular damage may be a form of pathologicemory in the microvasculature that persists even aftercose normalization, as suggested in human retinal vas-ar ECs (35). The microvasculature may be more sensitivesuch changes simply on the basis of mass. Oxidative stressy also link hyperglycemia with other pathways implicateddiabetic vascular complications, including AGE forma-n, protein kinase C activation, increased polyol flux, andxosamine formation (36,37). For example, oxidative stressresponse to AGE formation may promote diabeticurovascular dysfunction (38,39).Thrombospondin-1, a potent antiangiogenic and pro-erogenic protein, has received some attention as a po-tial mediator linking hyperglycemia to both microvascu-and macrovascular disease (40). Glucose alters both

l- and tissue-specific thrombospondin-1 expression andpost-transcriptional regulation in ECs, VSMCs, androblasts (41). In contrast, thrombospondin-1 levels arematically decreased by high glucose in microvasculars and retinal pigment epithelial cells, making this proteinexample of differences between macrovascular and mi-vascular disease.Recently, thrombomodulin-dependent formation of acti-ed protein C (APC) was identified as a potential mech-ism for hyperglycemia-induced changes in mesangial ECsd podocytes (42). The endothelial thrombomodulin-tein C system is impaired in T2DM, as evident in thereased soluble thrombomodulin and decreased APCels among such patients (43,44). APC may protectmerular ECs against apoptosis and has potent anti-ombotic and other cytoprotective, fibrinolytic, and anti-ammatory properties. The APC modulates the mito-ondrial apoptosis pathway via the protease-activatedeptor-1 and the endothelial protein C receptor incose-stressed cells. Loss of thrombomodulin-dependentC formation interrupts cross-talk between the vascularpartment and podocytes, causing glomerular apoptosis

d diabetic nephropathy (42).Microalbuminuria in T2DM reflects a generalized dis-bance of microvascular function related to endothelium-

The Continuum of Diabetic Vascular Diseasependent mechanisms. Microalbuminuria may be a markerthe risk of retinopathy, nephropathy, and neuropathy.

oxweerestingly, microalbuminuria may also predict CV dis-e (45).e vasa vasorum and neovascularization in diabetes. Thea vasorum is a network of small vessels normally found onlythe adventitia and outer medial layer of larger arteries andaorta (46). Neovascularization arising from the vasa vaso-may promote atherosclerosis and predict plaque rupture

). Neovascularization in atherosclerotic arteries occurs bywth from both the adventitial layer outward and the arterialen inward, toward the intima (46). The vasa vasorum alsovides the arterial wall with a vast absorptive endothelialface that influences lipid metabolism and delivery, andoval of neurohumoral factors (46).

In T2DM, angiogenesis is increased and associated withque rupture (48). Neovasculature microangiopathy mayelerate diabetic atherosclerosis (Fig. 1). The initial an-genic response in the adventitial vasa vasorum appearsmulated by hypoxia and ischemia, perhaps through in-ased hypoxia-induced factor-1 and VEGF action (49).GF also increases vascular permeability to macromole-es, monocyte chemotaxis, and tissue factor production,ssible contributors to microvascular complications,51). VEGF is also associated with diabetic nephropathy). Increased vascular permeability instigates an inflam-tory response, with recruited monocyte-macrophagesving as a source of VEGF (5356). Conversely, VEGFatment may limit diabetic neuropathy by restoring mi-circulation in the vasa nervorum, as suggested by rodentGF gene transfer experiments (57).In the eye, pigment epithelium-derived factor (PEDF)y offset VEGF action, providing another example ofsue-specific settings in microvascular disease. PEDF is aurotrophic factor and a potent angiogenic inhibitor (58).proliferative diabetic retinopathy, VEGF levels are in-ased while PEDF levels are decreased (59). DecreasedDF levels may also contribute to diabetic nephropathy.her growth factors may foster proliferative retinopathy,luding insulin-like growth factor 1, basic fibroblastwth factor, and hepatocyte growth factor (60,61).ditional contributors to diabetic microvascular dis-e. Dyslipidemia is strongly associated with the develop-nt and progression of microvascular disease. Increasedels of dense low-density lipoprotein, as well as low-nsity lipoprotein modified by glycation and oxidation,y foster retinopathy, neuropathy, and nephropathy; andenuated levels and function of high-density lipoproteinve also been linked to retinopathy (6265). T2DM isen characterized by abnormal very-low-density lipopro-n and triglyceride levels. Elevated very-low-density li-protein and triglyceride levels appear involved with reti-pathy and albuminuria. This may be due to changes infunction of lipoprotein lipase, a key enzyme in triglyc-

de hydrolysis, which acts in the microvasculature. Inter-ingly, lipoprotein lipase action can generate natural per-

February 3, 2009:S3542isome proliferator-activated receptor (PPAR) ligands asand others have found (66,67). Perhaps lipoprotein

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S39JACC Vol. 53, No. 5, Suppl S, 2009 Orasanu and PlutzkyFebase dysfunction in T2DM promotes microvascular dis-e through a loss of endogenous PPAR agonists. Poten-lly consistent with this, in the FIELD (Fenofibrateervention and Event Lowering in Diabetes) study, theAR- agonist fenofibrate reduced the need for laseratment for diabetic retinopathy as a tertiary end point). Of note, this effect did not appear to be mediated byproved lipid, glycemic, or blood pressure profiles, leavingmechanism involved unclear. PPAR- agonists inhibitVEGF pathway, which may promote angiogenesis,

ammation, and cell migration (69,70); they also regulateinal EC survival, limit apoptotic cell death (71), andprove vascular reactivity (70). In the DAIS (Diabetesherosclerosis Intervention Study) trial, the improved lipidfiles with fenofibrate in patients with T2DM wereociated with reduced progression to microalbuminuria).In animal studies, thiazolidinediones reportedly de-ased proteinuria or delayed progression to nephropathy;ults were independent of insulin sensitization, glycemictrol, and lipid metabolism, but were associated withuctions in blood pressure (73). In 6 randomized, active-trolled trials up to 12 months in duration with eitherglitazone or rosiglitazone, significant 10% to 30% reduc-ns in albumin-to-creatinine ratio were demonstrated,75).Adiposity may promote microvascular disease. Increasedmass and resistance to insulin-mediated inhibition ofolysis increase elevated free fatty acid levels, which canectly impair microvascular function and increase diabeticcroangiopathy (76). Increased visceral fat is a sourceinflammatory mediators such as tumor necrosis factor-,

igure 1 Intersection of Microangiopathy and Macroangiopathy in

type 2 diabetes mellitus, both angiogenesis and microangiopathy are increased anlaque. Hyperglycemia is a driving force in both large- and small-vessel disease. Indetherosclerosis through processes such as hypoxia and changes in the vasa vasorum

ruary 3, 2009:S3542erleukins, and the pro-coagulant plasminogen activatoribitor-1. In addition to increasing C-reactive protein

inobels and oxidative stress, these mediators also stimulatedothelial degradation and leukocyte adhesion, with thessible obstruction of microvessels (77,78).Inflammation also promotes diabetic retinopathy, ne-ropathy, and neuropathy (79,80). Leukocyte adherenced accumulation within the retinal vasculature is an earlyange in experimental diabetes (81,82). Overexpression ofhesion molecules (83) and certain chemokines (84) maymote diabetic nephropathy. In diabetic retinopathy, thisy result from elevated tumor necrosis factor- levels (85).addition to promoting leukocyte infiltration and activa-n, tumor necrosis factor- may also enhance microvas-ar cell apoptosis (86). In keeping with these observations,or necrosis factor- inhibition decreases leukostasis). Consistent with their opposing roles discussed earlier,GF can also trigger inflammation (87), whereas PEDFpears to limit it (88).

ersection of Diabeticcrovascular and Macrovascular Disease

DM may be best characterized by its complexity. Arisingr decades, T2DM involves multiple pathologic forcesulting in a range of clinical issues. This complexity isdent in the problems of diabetic macrovascular andcrovascular disease. Diabetic subjects with microvascularplications, 25% to 30% of all those with diabetes,

pear particularly prone to accelerated atherosclerosis andmature death. Neovascularization arising from the vasaorum may interconnect macroangiopathy and microan-pathy (Fig. 1).Why the benefits of glycemic control are readily apparent

elerated Atherosclerosis

contribute to accelerated atherosclerosis and the development of vulnerable2 disorders may be interconnected, with microvascular disease promoting

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S40 Orasanu and Plutzky JACC Vol. 53, No. 5, Suppl S, 2009crovascular and macrovascular disease, including differingponses to therapeutic interventions, remain important,resolved issues in the field of T2DM; clarity in these areasld lead to treatments that improve outcomes in patientsth diabetes.The challenge to better understand how all forms ofcular disease occur in T2DM and how to interveneows us to refocus on perhaps the most obvious clinicalue at hand: implementing treatments known to improveDM outcomes. Microvascular disease is significantlyproved by tighter glycemic control, which should beplemented as early as is safely possible and maintained forlong as possible. Such interventions can significantlyuce a large burden of disease. In terms of macrovascularease, diabetic control involves appropriate control ofod pressure as well as lipids. These steps should also been early in the natural history of T2DM. While we waitgreater insight and better therapeutic options in T2DM,se simple steps would have a major impact on improvingtcomes for millions of people.

knowledgmente authors thank Ruzena Tupy for excellent editorialistance.

print requests and correspondence: Dr. Jorge Plutzky,gham and Womens Hospital, 77 Louis Pasteur Avenue, NRB2, Boston, Massachusetts 02115. E-mail: jplutzky@rics.h.harvard.edu.

ERENCES

Piga R, Naito Y, Kokura S, Handa O, Yoshikawa T. Short-term highglucose exposure induces monocyte-endothelial cells adhesion andtransmigration by increasing VCAM-1 and MCP-1 expression inhuman aortic endothelial cells. Atherosclerosis 2007;193:32834.Otsuka A, Azuma K, Lesaki T, et al. Temporary hyperglycaemiaprovokes monocyte adhesion to endothelial cells in rat thoracic aorta.Diabetologia 2005;48:266774.Quagliaro L, Piconi L, Assaloni RG, et al. Intermittent high glucoseenhances ICAM-1, VCAM-1 and E-selectin expression in humanumbilical vein endothelial cells in culture: the distinct role of proteinkinase C and mitochondrial superoxide production. Atherosclerosis2005;183:25967.Hansson GK. Inflammation, atherosclerosis, and coronary arterydisease. N Engl J Med 2005;352:168595.Biddinger SB, Kahn CR. From mice to men: insights into the insulinresistance syndromes. Ann Rev Physiol 2006;68:12358.Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resis-tance. J Clin Invest 2006;116:1793801.Dasu MR, Devaraj S, Jialal I. High glucose induces IL-1 betaexpression in human monocytes: mechanistic insights. Am J PhysiolEndocrinol Metab 2007;293:E33746.Venugopal SK, Devaraj S, Yang T, Jialal I. Alpha-tocopherol de-creases superoxide anion release in human monocytes under hypergly-cemic conditions via inhibition of protein kinase C-alpha. Diabetes2002;51:304954.Gerrity RG, Natarajan R, Nadler JL, Kimsey T. Diabetes-inducedaccelerated atherosclerosis in swine. Diabetes 2001;50:165465.Renard CB, Kramer F, Johansson F, et al. Diabetes and diabetes-associated lipid abnormalities have distinct effects on initiation and

The Continuum of Diabetic Vascular Diseaseprogression of atherosclerotic lesions. J Clin Invest 2004;114:65968.Gregor MF, Hotamisligil GS. Adipocyte stress: the endoplasmicreticulum and metabolic disease. J Lipid Res 2007;48:190514.

35.Gargalovic PS, Gharavi NM, Clark MJ. The unfolded proteinresponse is an important regulator of inflammatory genes in endothe-lial cells. Arterioscler Thromb Vasc Biol 2006;26:24906.He Z, Rask-Madsen C, King GL. Pathogenesis of diabetic microvas-cular complications. In: De Fronzo RA, Ferrannini E, Keen H,Zimmet P, editors. International Textbook of Diabetes Mellitus.Hoboken, NJ: John Wiley & Sons, 2004;2:113559.Wiernsperger NF. In defense of microvascular constriction in diabetes.Clin Hemorheol Microcirc 2001;25:5562.Sheetz MJ, King GL. Molecular understanding of hyperglycemiasadverse effects for diabetic complications. JAMA 2002;288:257988.The Diabetes Control and Complications Trial Research Group. Theeffect of intensive treatment of diabetes on the development andprogression of long-term complications in insulin-dependent diabetesmellitus. N Engl J Med 1993;329:97786.World Health Organization. Definition and diagnosis of diabetes mellitusand intermediate hyperglycaemia. Available at: http://www.who.int/diabetes/publications/Definition%20and%20diagnosis%20of%20diabetes_new.pdf. Accessed August 26, 2008.Wong TY, Liew G, Tapp RJ, et al. Relation between fasting glucoseand retinopathy for diagnosis of diabetes: 3 population-based cross-sectional studies. Lancet 2008;371:73643.Brownlee M. The pathobiology of diabetic complications: a unifyingmechanism. Diabetes 2005;54:161525.Kaiser N, Sasson S, Feener EP, et al. Differential regulation of glucosetransport and transporters by glucose in vascular endothelial andsmooth muscle cells. Diabetes 1993;42:809.Heilig CW, Concepcion LA, Riser BL, Freytag SO, Zhu M, CortesP. Overexpression of glucose transporters in rat mesangial cellscultured in a normal glucose milieu mimics the diabetic phenotype.J Clin Invest 1995;96:180214.Aird WC. Phenotypic heterogeneity of the endothelium: II. Repre-sentative vascular beds. Circ Res 2007;100:17490.Aird WC. Phenotypic heterogeneity of the endothelium: I. Structure,function, and mechanisms. Circ Res 2007;100:15873.Chi J-T, Chang HY, Haraldsen G, et al. Endothelial cell diversityrevealed by global expression profiling. Proc Natl Acad Sci U S A2003;100:106238.Ejaz S, Chekarova I, Ejaz A, Sohail A, Lim CW. Importance ofpericytes and mechanisms of pericyte loss during diabetes retinopathy.Diabetes Obes Metab 2008;10:5363.Wolf G, Chen S, Ziyadeh FN. From the periphery of the glomerularcapillary wall toward the center of disease: podocyte injury comes ofage in diabetic nephropathy. Diabetes 2005;54:162634.Huber JD. Diabetes, cognitive function, and the blood-brain barrier.Curr Pharm Des 2008;14:1594600.Yokoyama I, Yonekura K, Ohtake T, et al. Coronary microangiopathyin type 2 diabetic patients: relation to glycemic control, sex, andmicrovascular angina rather than to coronary artery disease. J NuclMed 2000;41:97885.Schindler TH, Zhang XL, Vincenti G, Mhiri L, Lerch R, SchelbertHR. Role of PET in the evaluation and understanding of coronaryphysiology. J Nucl Cardiol 2007;14:589603.Murata T, Nagai R, Ishibashi T, Inomuta H, Ikeda K, Horiuchi S.The relationship between accumulation of advanced glycation endproducts and expression of vascular endothelial growth factor inhuman diabetic retinas. Diabetologia 1997;40:7649.Chakravarthy U, Hayes RG, Stitt AW, McAuley E, Archer DB.Constitutive nitric oxide synthase expression in retinal vascular endo-thelial cells is suppressed by high glucose and advanced glycation endproducts. Diabetes 1998;47:94552.Lu M, Kuroki M, Amano S, et al. Advanced glycation end productsincrease retinal vascular endothelial growth factor expression. J ClinInvest 1998;101:121924.Kislinger T, Fu C, Huber B, et al. N(epsilon)-(carboxymethyl)lysineadducts of proteins are ligands for receptor for advanced glycation endproducts that activate cell signaling pathways and modulate geneexpression. J Biol Chem 1999;274:317409.Kihara M, Schmelzer JD, Poduslo JF, Curran GL, Nickander KK,Low PA. Aminoguanidine effects on nerve blood flow, vascularpermeability, electrophysiology, and oxygen free radicals. Proc Natl

February 3, 2009:S3542Acad Sci U S A 1991;88:610711.Xie L, Zhu X, Hu Y, et al. Mitochondrial DNA oxidative damagetriggers mitochondrial dysfunction and apoptosis in high glucose-

36.

37.

38.

39.

40.

41.

42.

43.

44.

45.

46.

47.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

70.

71.

72.

73.

74.

75.

76.

77.

78.

79.

80.

S41JACC Vol. 53, No. 5, Suppl S, 2009 Orasanu and PlutzkyFebinduced human retinal vascular endothelial cells. Invest OphthalmolVis Sci 2008;49:12532.Nishikawa T. Normalizing mitochondrial superoxide productionblocks three pathways of hyperglycaemic damage. Nature 2000;404:78790.Brownlee M. Biochemistry and molecular biology of diabetic compli-cations. Nature 2001;414:81320.Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors andmetabolic interactions in the pathogenesis of diabetic neuropathy.Diabetologia 2001;44:197388.Gruden G, Bruno G, Chaturvedi N, et al., for the EURODIABProspective Complications Study Group. Serum heat shock protein 27and diabetes complications in the EURODIAB prospective compli-cations study: a novel circulating marker for diabetic neuropathy.Diabetes 2008;57:196670.Stenina OI, Krukovets I, Wang K, et al. Increased expression ofthrombospondin-1 in vessel wall of diabetic Zucker rat. Circulation2003;107:320915.Bhattacharyya S, Marinic TE, Krukovets I, Hoppe G, Stenina OI.Cell type-specific post-transcriptional regulation of production of thepotent antiangiogenic and proatherogenic protein thrombospondin-1by high glucose. J Biol Chem 2008;283:5699707.Isermann B, Vinnikov IA, Madhusudhan T, et al. Activated protein Cprotects against diabetic nephropathy by inhibiting endothelial andpodocyte apoptosis. Nat Med 2007;13:134958.Borcea V, Morcos M, Isermann B, et al. Influence of ramipril on thecourse of plasma thrombomodulin in patients with diabetes mellitus.Vasa 1999;28:17280.Fujiwara Y, Tagami S, Kawakami Y. Circulating thrombomodulin andhematological alterations in type 2 diabetic patients with retinopathy.J Atheroscler Thromb 1998;5:218.Nathan DM, Cleary PA, Backlund JY, et al., for the Diabetes Controland Complications Trial/Epidemiology of Diabetes Interventions andComplications (DCCT/EDIC) Study Research Group. Intensivediabetes treatment and cardiovascular disease in patients with type 1diabetes. N Engl J Med 2005;353:264353.Hayden MR, Tyagi SC. Vasa vasorum in plaque angiogenesis,metabolic syndrome, type 2 diabetes mellitus, and atheroscleropathy: amalignant transformation. Cardiovasc Diabetol 2004;3:1.Langheinrich AC, Kampschulte M, Buch T, Bohle RM. Vasa vaso-rum and atherosclerosisQuid novi? Thromb Haemost 2007;97:8739.Moreno PR, Fuster V. New aspects in the pathogenesis of diabeticatherothrombosis. J Am Coll Cardiol 2004;44:2293300.Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role ofthe HIF system. Nat Med 2003;9:67784.Dvorak HF, Brown LF, Detmar M, Dvorak AM. Vascular perme-ability factor/vascular endothelial growth factor, microvascular hyper-permeability, and angiogenesis. Am J Pathol 1995;146:102939.Miyamoto K, Khosrof S, Bursell SE, et al. Vascular endothelial growthfactor (VEGF)-induced retinal vascular permeability is mediated byintercellular adhesion molecule-1 (ICAM-1). Am J Pathol 2000;156:17339.Khamaisi M, Schrijvers BF, De Vriese AS, Raz I, Flyvbjerg A. Theemerging role of VEGF in diabetic kidney disease. Nephrol DialTransplant 2003;18:142730.Hayden MR, Tyagi SC. Atherosclerosis: implications of angiotensin IIand the AT-1 receptor. In: Dhalla NS, Zahradka P, Dixon IMC,Beamish RE. Angiotensin II Blockade: Physiological and Clinical Impli-cations. Boston, MA: Kluwer Academic Publishers, 1998:23343.Hayden MR, Tyagi SC. Arterial vascular remodeling: the endothelialcells central role. Mo Med 1998;95:2137.Williamson JR, Kilo C. Hyperglycemia pseudohypoxia and diabeticcomplications. Diabetes 1993;42:80113.Zhang Y, Cliff WJ, Schoefl GI, Higgins G. Immunohistochemicalstudy of intimal microvessels in coronary atherosclerosis. Am J Pathol1993;143:16472.Schratzberger P, Walter DH, Rittig K, et al. Reversal of experimentaldiabetic neuropathy by VEGF gene transfer. J Clin Invest 2001;107:

ruary 3, 2009:S3542108392.Campochiaro PA. Retinal and choroidal neovascularization. J CellPhysiol 2000;184:30110.

81.Gao G, Li Y, Zhang D, Gee S, Crosson C, Ma J. Unbalancedexpression of VEGF and PEDF in ischemia-induced retinal neovas-cularization. FEBS Lett 2001;489:2706.Miller JW, Adamis AP, Aiello LP. Vascular endothelial growth factorin ocular neovascularization and proliferative diabetic retinopathy.Diabetes Metab Rev 1997;13:3750.Shinoda K, Ishida S, Kawashima S, et al. Comparison of the levels ofhepatocyte growth factor and vascular endothelial growth factor inaqueous fluid and serum with grades of retinopathy in patients withdiabetes mellitus. Br J Ophthalmol 1999;83:8347.Lyons TJ, Jenkins AJ, Zheng D, et al. Diabetic retinopathy and serumlipoprotein subclasses in the DCCT/EDIC cohort. Invest Ophthal-mol Vis Sci 2004;45:9108.Jenkins AJ, Lyons TJ, Zheng D, et al., for the DCCT/EDIC ResearchGroup. Lipoproteins in the DCCT/EDIC cohort: associations withdiabetic nephropathy. Kidney Int 2003;64:81728.Song W, Barth JL, Yu Y, et al. Effects of oxidized and glycated LDLon gene expression in human retinal capillary pericytes. Invest Oph-thalmol Vis Sci 2005;46:297482.Lyons TJ, Li W, Wells-Knecht MC, Jokl R. Toxicity of mildlymodified low-density lipoproteins to cultured retinal capillary endo-thelial cells and pericytes. Diabetes 1994;43:10905.Ziouzenkova O, Perrey S, Asatryan L, et al. Lipolysis of triglyceride-rich lipoproteins generates PPAR ligands: evidence for an antiinflam-matory role for lipoprotein lipase. Proc Natl Acad Sci U S A 2003;100:27305.Chawla A, Lee CH, Barak Y, et al. PPARdelta is a very low-densitylipoprotein sensor in macrophages. Proc Natl Acad Sci U S A 2003;100:126873.Keech AC, Mitchell P, Summanen PA, et al., for the FIELD studyinvestigators. Effect of fenofibrate on the need for laser treatment fordiabetic retinopathy (FIELD study): a randomised controlled trial.Lancet 2007;370:168797.Ferrara N. Role of vascular endothelial growth factor in regulation ofphysiological angiogenesis. Am J Physiol Cell Physiol 2001;280:C135866.Malik J, Melenovsky V, Wichterle D, et al. Both fenofibrate andatorvastatin improve vascular reactivity in combined hyperlipidaemia(fenofibrate versus atorvastatin trialFAT). Cardiovasc Res 2001;52:2908.Kim J, Ahn JH, Kim JH, et al. Fenofibrate regulates retinal endothelialcell survival through the AMPK signal transduction pathway. Exp EyeRes 2007;84:88693.Ansquer JC, Foucher C, Rattier S, Taskinen MR, Steiner G, for theDAIS Investigators. Fenofibrate reduces progression to microalbumin-uria over 3 years in a placebo-controlled study in type 2 diabetes:results from the Diabetes Atherosclerosis Intervention Study (DAIS).Am J Kidney Dis 2005;45:48593.Sarafidis PA, Bakris GL. Protection of the kidney by thiazolidinediones:an assessment from bench to bedside. Kidney Int 2006;70:122333.Rohatgi A, McGuire DK. Effects of the thiazolidinedione medicationson micro- and macrovascular complications in patients with diabetes-update 2008. Cardiovasc Drugs Ther 2008;22:23340.Kanda T, Wakino S, Hayashi K, Plutzky J. Cardiovascular disease,chronic kidney disease, and type 2 diabetes mellitus: proceeding withcaution at a dangerous intersection. J Am Soc Nephrol 2008;19:47.de Jongh RT, Sern EH, Ijzerman RG, de Vries G, Stehouwer CD.Free fatty acid levels modulate microvascular function: relevance forobesity-associated insulin resistance, hypertension, and microangiopa-thy. Diabetes 2004;53:287382.Park HS, Park JY, Yu R. Relationship of obesity and visceral adipositywith serum concentrations of CRP, TNF-alpha and IL-6. DiabetesRes Clin Pract 2005;69:2935.Wiernsperger NF, Bouskela E. Microcirculation in insulin resistanceand diabetes: more than just a complication. Diabetes Metab 2003;29:6S7787.Crane IJ, Wallace CA, McKillop Smith S, Forrester JV. Control ofchemokine production at the blood-retina barrier. Immunology 2000;101:42633.Meleth AD, Agron E, Chan C, et al. Serum inflammatory markers in

The Continuum of Diabetic Vascular Diseasediabetic retinopathy. Invest Ophthalmol Vis Sci 2005;46:4295301.Miyamoto K, Khosrof S, Bursell SE, et al. Prevention of leukostasisand vascular leakage in streptozotocin-induced diabetic retinopathy via

intercellular adhesion molecule-1 inhibition. Proc Natl Acad SciU S A 1999;96:1083641.

82. Canas Barouch F, Miyamoto K, Allport JR, et al. Integrin-mediatedneutrophil adhesion and retinal leukostasis in diabetes. Invest Oph-thalmol Vis Sci 2000;41:11538.

83. Sugimoto H, Shikata K, Hirata K, et al. Increased expression ofintercellular adhesion molecule-1 (ICAM-1) in diabetic rat glomeruli:glomerular hyperfiltration is a potential mechanism of ICAM-1upregulation. Diabetes 1997;46:207581.

84. Shikata K, Makino H. Role of macrophages in the pathogenesis ofdiabetic nephropathy. Contrib Nephrol 2001;134:4654.

85. Limb GA, Chignell AH, Green W, LeRoy F, Dumonde DC.Distribution of TNF-alpha and its reactive vascular adhesion mole-cules in fibrovascular membranes of proliferative diabetic retinopathy.Br J Ophthalmol 1996;80:16873.

86. Behl Y, Krothapalli P, Desta T, DiPiazza A, Roy S, Graves DT.Diabetes-enhanced tumor necrosis factor-alpha production promotesapoptosis and the loss of retinal microvascular cells in type 1 and type2 models of diabetic retinopathy. Am J Pathol 2008;172:14118.

87. Lu M, Perez VL, Ma N, et al. VEGF increases retinal vascularICAM-1 expression in vivo. Invest Ophthalmol Vis Sci 1999;40:180812.

88. Zhang SX, Wang JJ, Gao G, Shao C, Mott R, Ma JX. Pigmentepithelium-derived factor (PEDF) is an endogenous antiinflammatoryfactor. FASEB J 2006;20:3235.

Key Words: glucose y atherosclerosis y advanced glycation endproducts y oxidative stress y inflammation.

S42 Orasanu and Plutzky JACC Vol. 53, No. 5, Suppl S, 2009The Continuum of Diabetic Vascular Disease February 3, 2009:S3542

The Pathologic Continuum of Diabetic Vascular DiseaseDiabetic Macrovascular ComplicationsHyperglycemia Versus Dyslipidemia in the Pathogenesis of AtherosclerosisDiabetic Microvascular ComplicationsStructural and Functional Differences: Micro Versus MacroMechanisms of Diabetic Microvascular DiseaseGlucose and the microvasculatureThe vasa vasorum and neovascularization in diabetesAdditional contributors to diabetic microvascular dis-ease

Intersection of Diabetic Microvascular and Macrovascular DiseaseAcknowledgmentREFERENCES