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Review: Endothelial cell dysfunction, medial arterial calcification and osteoprotegerin in diabetes
Dhruv K Singh, Peter Winocour and Ken Farrington British Journal of Diabetes & Vascular Disease 2010 10: 71 DOI: 10.1177/1474651409355453 The online version of this article can be found at: http://dvd.sagepub.com/content/10/2/71

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Endothelial cell dysfunction, medial arterial calcification and osteoprotegerin in diabetes

DHRUV K SINGH,1, 2 PETER WINOCOUR,1 KEN FARRINGTON2
Abstract

acrovascular complications such as cardiovascular disease and peripheral vascular disease are the leading cause of increased mortality and morbidity, respectively, in patients with diabetes mellitus. The aetiopathogenesis of macrovasculopathy in diabetes is multifactorial and differs in types 1 and 2 diabetes. Endothelial cell dysfunction is an early feature of diabetic vasculopathy and is associated with poor glycaemic control. Chronic hyperglycaemia may promote an adverse vascular milieu leading to early endothelial cell apoptosis, in the long run. The presence of apoptotic cells in the vascular lumen may trigger a cascade of reactions between the promoters and inhibitors of arterial calcification. Medial arterial calcification, a characteristic feature of diabetes, is an important predictor of cardiovascular disease and occurs independently of atherosclerosis. Medial arterial calcification may occur in the presence of normal serum calcium and phosphate levels. Osteoprotegerin is an important modulator of mineral metabolism and manifests its effects in the bone and arteries. It is hypothesised that osteoprotegerin is a key inhibitor of arterial calcification which is released by endothelial cells as a protective measure for survival in adverse conditions. It is a potential risk marker for early identification and monitoring of disturbed mineral metabolism and vasculopathy in diabetes. Br J Diabetes Vasc Dis 2010;10:7177. Key words: diabetic vasculopathy, endothelial cell dysfunction, medial arterial calcification, osteoprotegerin, RANKL Review criteria We searched PubMed, Google and Scopus for articles abstracted in these electronic databases until 2009, containing the terms
1

Abbreviations and acronyms AGE AKT ALP BMP CVC CVD CRP EBCT ECD EDHF eNOS ET HbA1C ICAM IGF1 IL MAC MGP mRNA Msx2 NO OPG PAI PDGF PI3k PPi RANKL ROS TGF TNF TRAIL VCAM VSMC vWF advanced glycation end product serine/threonine protein kinase alkaline phosphatase bone morphogenic protein calcifying vascular cell cardiovascular disease Creactive protein electron beamcomputed tomography endothelial cell dysfunction endotheliumderived hyperpolarising factor endothelial nitric oxide synthase endothelin glycated haemoglobin A1C intercellular adhesion molecule insulinlike growth factor 1 interleukin medial arterial calcification matrix Gla protein messenger ribonucleic acid homeobox, mshlike 2 gene nitric oxide osteoprotegerin plasminogen activator inhibitor plateletderived growth factor phosphatidylinositol3 kinase inorganic pyrophosphate receptor activator for nuclear factor kappa B ligand reactive oxygen species transforming growth factorbeta tumour necrosis factor TNFrelated apoptosis inducing ligand vascular cell adhesion molecule vascular smooth muscle cell von Willebrand factor

Department of Diabetes and Endocrinology, QEII Hospital, Welwyn Garden City, UK. 2 Renal Unit, Lister Hospital, Stevenage, UK. Correspondence to: Dr Dhruv K Singh Renal Unit, Lister Hospital, Coreys Mill Lane, Stevenage, SG1 4AB, UK. Tel: +44 (0)1438781430; Fax: +44 (0)1438781130 Email: dsingh4@nhs.net

diabetes mellitus, endothelial cell dysfunction, diabetic vas culopathy, vascular calcification, medial arterial calcification, Osteoprotegerin, RANKL.

Introduction
Macrovascular complications of diabetes mellitus such as CVD and peripheral vascular disease are the leading cause of incre ased mortality1 and morbidity2 respectively, in such patients.

The Author(s), 2010. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

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The pathogenesis of macrovasculopathy in diabetes is multifac torial and not completely understood. The pathogenetic pro cesses for macrovasculopathy are different in type 13 and type 2 diabetes4 due to different causes of these two conditions. The pathogenetic processes in these two categories may have a common beginning in generalised endothelial dysfunction, which is followed by atherosclerosis and vascular calcification. However, there may be an overlap of the last two stages. Macrovasculopathy in diabetes is associated with structural and functional modulation of the vasculature, resulting in reduced tone and flexibility. In the long run, with onset of vascular cal cification, these changes contribute to the development and progression of CVD in patients.5 The process of vascular calcification incorporates the laying down of calciumphosphate material, usually in the form of hydroxyapatite in the vessel wall. MAC, though traditionally associated with the ageing process, is a characteristic feature of vascular calcification in diabetes. MAC, however, refers to con centric calcification and stiffening of the elastic layer of the arterial wall. In contrast to the eccentric and intimal arterial calcification, as seen in atherosclerosis, MAC does not occlude the arterial lumen.6 MAC is also seen in advanced chronic kid ney disease in association with abnormal mineral metabolism. However, in patients with diabetes, MAC may occur with nor mal serum calcium and phosphate levels.7 The pathogenesis of MAC is multifactorial and poorly understood. This review will discuss the potential roles of (i) ECD in genesis of vasculopathy in type 1 and type 2 diabetes, (ii) the reninangiotensin system and other contributory factors in the progression of vasculopathy, (iii) the OPG/RANKL/TRAIL axis in the genesis and progression of MAC in diabetes.

(ii) procoagulant and anticoagulant mediators, (iii) vascular growthinhibiting and growthpromoting substances. ECD may lead to various pathophysiological complications such as enhanced expression of adhesion molecules resulting in increased leukocyteendothelial cell adhesions, promotion of a procoagulant state as a result of increased activation of plate lets and clotting factors,16 and impaired NO release. This may lead to defective modulation of vascular growth and remodel ling in the vessel wall.17 ECD is usually inferred by observations of surrogate mark ers such as flowmediated vasodilation subsequent to transient ischaemia18 and evaluation of changes in vascular resistance in small or large arteries in response to physiological stimuli.19 These techniques essentially assess the NO releasing capacity of the endothelial cells in response to various stimuli. Other indi rect estimates of ECD include assessment of the vascular per meability of macromolecules,20 measurement of vasoactive (vasoconstrictors/vasodilators) factors,21 of prothrombotic/pro coagulant activity,22 and of inflammatory markers such as adhesion molecules (VCAM1, ICAM1, and Eselectin),13 cyto kines (IL1beta, IL6, and TNFa)23 and CRP.24

Risk factors for ECD in diabetes

The pathogenesis of ECD in type 1 and type 2 diabetes is unclear and the processes leading to ECD may be different in these two groups. However, several risk factors are shared. In the presence of chronic hyperglycaemia, risk factors, such as hypertension, poor glycaemic control, microalbuminuria, dys lipidaemia, poor antioxidant status and smoking play an impor tant role in the pathogenesis of ECD. In addition to these risk factors, patients with diabetes are at an increased risk of ECD in the presence of conventional risk factors for atherosclerosis such as family history of coronary artery disease, poor dietary habits, physical inactivity, excessive alcohol consumption and elevated inflammatory markers (CRP, fibrinogen, PAI1). On this background, the major factors for pathogenesis of ECD in patients with type 1 diabetes are poor glycaemic con trol25 and duration of diabetes.26 Furthermore, patients with type 1 diabetes may manifest features of ECD prior to the onset of microalbuminuria,27 which is considered as a marker of extensive ECD. Microalbuminuria is an independent risk fac tor for atherosclerosis, CVD, and premature mortality due to CVD in patients with hypertension and with type 1 and type 2 diabetes.28 There are reports of a subset of resistant type 1 diabetes patients who may have no evidence of ECD in spite of established microalbuminuria.29 The major risk factors for ECD in type 2 diabetes are obesity and insulin resistance. In fact, all the components of metabolic syndrome may potentially promote ECD.30 Individuals at risk of type 2 diabetes have been demonstrated to have higher levels of biochemical markers of ECD such as ET1, vWF, ICAM and VCAM, even with normoglycaemia,31 supporting the hypothesis that ECD may well precede the development of type 2 diabetes.32 Insulin may modulate ET1 release33 and also has a vasodila tory effect on the skeletal muscle vasculature by promoting

Endothelial physiology
The vascular endothelium is a layer of endothelial cells lining the internal lumen of the blood vessels. It serves as a biological barrier between the blood and VSMCs. The physiological actions of endothelial cells include modulation of vascular tone (vasoconstriction and vasodilation), haemostasis, regulation of growth and differentiation of VSMC and modulation of inflam mation in the vasculature.8 Vascular remodelling is carried out primarily by regulation of growth factors such as IGF1, PDGF,9 fibroblast growth factor, angiotensin II and TGF.10 Endothelial cells modulate vascular tone by regulating the release of vasodilators such as NO and EDHF and vasoconstric tors such as endothelin1, prostaglandin H2,11 ROS, angiotensin II, and thromboxane A2.12 Endothelial cells also express a range of adhesion molecules such as ICAM1, VCAM1, and selectins (E, P and Lselectin).13 These molecules are modulated by the endothelial cells to regulate the dissociation of leukocytes14 and platelets from the vascular bed by release of NO.15

Endothelial cell dysfunction

ECD may be defined as the incapacity of the endothelial cells to regulate some or all their functions. This may lead to an imbalance of (i) vascular relaxing and contracting factors,

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synthesis/release of NO from the endothelial cells.34 Insulin has an antiapoptotic protective effect on the endothelial cells by binding to its receptor and activating the phosphatidylinositol3 kinase (PI3k)/AKT pathway.35 Endothelial insulin receptor knock out mouse model experiments have demonstrated a significant reduction of eNOSmRNA expression potentially resulting in low NO stimulation by insulin.36 Reduced postreceptor endo thelial insulin action may lead to reduced phosphorylation of the AKT pathway, resulting in increased susceptibility of endo thelial cells to apoptosis.37 Insulin resistance is one of the major components in the pathophysiology of ECD in type 2 diabe tes.38 It may lead to functional insulin deficiency and elevated levels of lipids and glucose in the vasculature. All these factors may contribute to impaired NO production,39 and potentially impair the vasodilatory action of endothelial cells. Whether ECD results from insulin resistance or is part of a common soil origin is still debated.38

impaired compensatory remodelling, enhanced plaque progression, reduced lumen size with no difference in the external elastic layer.50 MAC leads to stiffening of the elastic layer in the arterial wall and is seen more commonly in the elderly general popula tion and patients with diabetes.6 MAC is an important predic tor of CVD and occurs independent of atherosclerosis in diabetes.51 Serum OPG levels have been reported to be ele vated early in patients with type 2 diabetes.52 In addition, OPG and TRAIL have been detected in calcified regions of athero sclerosis and MAC along with enhanced apoptosis, suggesting a significant role for the regulators of bone metabolism in the pathogenesis of MAC in patients with diabetes.53

Regulators of vascular calcification

Traditionally, vascular calcification has been assumed to be a passive process of relocalisation of calcium from bone to the vasculature. It is now perceived to be a complex interaction between inhibitors and promoters of vascular calcification act ing in concert (figure 1). In the normal vascular milieu, a diverse group of regulatory factors such as PPi, MGP, fetuin, osteopon tin and OPG overwhelmingly inhibit the process of vascular calcification. However, in the phenotypically altered vascular milieu, these defence mechanisms may be weakened, render ing the vascular milieu susceptible to the actions of promoters of vascular calcification such as glucotoxicity, endothelin1, ALP, BMP2, BMP4, TGF and RANKL.54

Progression of ECD
Hyperglycaemia may modulate several aspects of the function of endothelial cells through activation of various biochemical pathways (sorbitol, diacylglycerol/protein kinase C, hexos amine) of glucose metabolism,8 promotion of procoagulant state (elevated PAI1 and reduced fibrinolytic activity),22 increased blood viscosity,40 enhanced production of basement membrane components (collagen type IV and fibronectin),41 increased proliferation of endothelial cells and VSMCs,42 ele vated inflammatory markers (CRP, haptoglobin and alpha1 acid glycoprotein),43 enhanced adhesion molecule expression44 and apoptosis of endothelial cells.45 In addition, chronic hyperglycaemia may promote ECD by promoting several other abnormalities such as enhanced oxida tive stress,46 increased formation of AGEs,47 disturbed renin angiotensin system,48 abnormal platelet15 and leukocyte function,14 enhanced cytokine activation23 and promotion of dyslipidaemia.4 All these factors may potentially modulate the progression of ECD in patients with diabetes.

Pathogenesis of MAC
Activation of vascular endothelial cells, in response to inflamma tory stimuli, is a key step in the transformation of these cells from a quiescent barrier to a dynamic state.55 Endothelial cells play a key role in bone development and remodelling by modu lating formation and activity of osteoclasts. They also orches trate the inflammatory response and immune mediated

Figure 1. Endothelial cell dysfunction in type 2 diabetes mellitus

ECD and calcification

ECD is an independent marker and a key early step in the pathogenesis of vascular disease and accelerated atherosclero sis in diabetes.8 In nondiabetics, ECD promotes atherosclerosis by facilitating (i) a thrombogenic milieu with fibrin and platelet adhesion on its surface, (ii) deposition of oxidised lipid particles, (iii) adhesion of inflammatory macrophage and T cells, leading to atherosclerotic plaque formation in the intimal layer of the blood vessels and finally calcification of the intima, also termed as vascular calcification.49 In patients with diabetes, atheroscle rotic changes are seen in the intima and the media, along with more pronounced medial sclerotic changes, termed MAC or Mnckebergs sclerosis.6

ENDOTHELIAL CELL DYSFUNCTION

OPG/TRAIL axis and vascular calcification

In comparison to nondiabetics, patients with diabetes have a greater burden of atheroma, more extensive atherosclerosis,

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mechanisms in various vascular diseases such as vascular calcifi cation.56 The evidence for TRAIL induced apoptosis in normal endothelial cells is contradictory. However, TRAIL may activate apoptosis in endothelial cells with altered phenotype.55 Apoptosis of endothelial cells, as a result of prolonged ECD, may compro mise the continuity of the endothelial barrier and expose VSMCs to the hazards of hyperglycaemia and cytokine action.

Calcification of elastic laminae

The deposition of calcium in the vicinity of elastin fibres in the medial arterial layer adversely modulates elastin matrix metab olism, resulting in reduced expression of major elastic fibre components such as tropoelastin, fibrillin1, elastinrelated enzyme and lysyl oxidase. In addition, it may result in reduced formation of new elastic fibres and increased vascular stiff ness.61 The process of calcium deposition starts in lipid vesicles located along and between the elastic fibres of the elastic laminae.53

VSMC dysfunction and apoptosis

VSMCs are multilineage cells and have a huge capacity to undergo phenotypic transformation. A subset of VSMCs, termed CVCs can potentially express chondrogenic, leiomyo genic and stromogenic (osteoblast) markers on activation.54 Glucotoxicity and oxidative stress as a result of chronic hyper glycaemia may play an important role in the activation and transformation of CVC into osteoblastlike cells,57 which pro duce hydroxyapatite mineral for vascular calcification. TRAIL induced apoptosis of endothelial cells and VSMCs serves as a focal point or matrix for initiation of vascular calcification (figure 2).53

Initiation of calcification
PPi is a direct and powerful inhibitor of hydroxyapatite forma tion in vitro and PPi inhibition is a critical step in the initiation of vascular calcification.7 Elevated levels of alkaline phospha tase degrade and inactivate tissue PPi, helping to mobilise cal cium and phosphate ions to the site of calcification. The upregulation of alkaline phosphatase activity is mediated by TNFa and BMP2.58 The calcification process in MAC is similar to that for intramembranous bone formation.49 The activation of the osteo/chondrogenic pathway results in production of a layer of cartilage by the chondrocytes, which, on maturing, degenerates. The CVC differentiated osteoblasts may now supersede and generate a layer of bone matrix on the existing cartilaginous base.62 This mineralised matrix may be subse quently replaced by osteoid, and with osteoblast and osteo clast action, remodelled into mature bone as in endochondrial ossification.56

Figure 2. Emerging mechanism of medial arterial calcification in diabetes

Diabetes Duration Dyslipidaemia Inflammatory Markers Inhibitors of Calcification Adequate Response No Calcification Inadequate Response

Endothelial Cell Dysfunction

Hyperglycaemia Oxidative Stress

Endothelial Cell Apoptosis

Role of calcification regulators

The interaction of inhibitors and promoters of vascular calcifica tion is complex and the underlying mechanisms are still being unravelled. Vascular calcification may be seen as a failure of the inhibitory mechanism in the background of various metabolic and cytokine insults. The inhibitors of calcification try to counter the influence of promoters at every step in the process of calci fication. PPi is a byproduct of intracellular enzymatic reactions and is produced by several celltypes including VSMCs.7 PPi sta bilises VSMCs and a reduction in PPi levels renders the VSMCs susceptible to osteo/chondrogenic transdifferentiation.63 The VSMCs also produce MGP, a calcium binding matrix protein, which inhibits the process of calcification by blocking the production of alkaline phosphatase, antagonising BMP2 and binding to matrix elastin.58 TGF facilitates vascular calci fication by mineralization of extracellular matrix in the vessel wall. Fetuin, a glycoprotein released by liver, is a potent inhibi tor of calcification and it works by blocking the action of pro fibrotic TGF and BMP2.64 The transdifferentiated osteoblastlike cells, from the CVC, express several bone matrix regulatory factors such as alkaline phosphatase, collagen type I, bone sialoprotein, osteocalcin, osteonectin and osteopontin, akin to osteogenesis.65 Osteopontin, a potent inhibitor of vascular calcification is normally not present in the nondiseased vasculature. It has been localised in mineralised matrix in the vasculature, pointing

Cytokines Promoters of Calcification

Medial Arterial Calcification

Inorganic Pyrophosphate

Msx and Wnt Signalling in Vasa Vasorum

Calcification cascade activation

In the background of hyperglycaemia and oxidative stress, apoptosis of vascular cells (endothelial cells and VSMCs) may be a trigger for TNFa to induce the production of BMP2 from surviving endothelial cells.58 BMP2, a potent osteoblastic dif ferentiation factor, in conjunction with TNFa, galvanises the osteo/chondrogenic cascade by activating the homeobox homolog (Msx2) and Wnt signalling pathways. These signals are expressed concentrically in the medial arterial layer through the vasa vasorum the network of small blood vessels that supply large blood vessels.59 The activation of these pathways results in mobilisation of osteogenic enzymes and matrix pro teins to facilitate calcium phosphate mineral deposition.60

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towards its role as an inhibitor of calcification, in the advanced stages.62 The precise mechanisms of action of other suggested regulators of calcification such as bone sialoprotein, osteocal cin, and osteonectin remain elusive. All the abovementioned inhibitors seem to be activated after the initiation of calcifica tion with matrix formation in the vascular apoptotic cells. OPG, expressed by the endothelial cells in response to ECD and TRAILinduced apoptosis,53 seems to be the foremost inhibitor in this sequence.

protective mechanism and facilitate continuing calcification. To counter the progressive calcification, osteoblastlike cells and the vascular cells in the vicinity of the matrix may further boost OPG production. This process of inhibition and promotion may be progressive and continue until the formation of bonelike tissue in the vessel wall.

Assessment of vascular calcification

In the research arena, EBCT is widely used for noninvasive assessment of vascular calcification. EBCT may also be helpful in diagnosis and prognosis of subclinical atherosclerosis in patients with moderate risk of coronary artery disease.69 EBCT assessment of coronary calcification may also help to predict a future coronary event.70 However, there is still no consensus on using EBCT as a screening tool for detection of coronary calci fication in asymptomatic patients.71 In addition, there have been concerns about the cost effec tiveness of EBCT in assessment of coronary calcification arising from the fact that computed tomography screening may miss some patch of vascular disease which may not be calcified yet and this may result in falsenegative observations. Similarly, there may be falsepositive results, given the fact that many patients with calcified vessels may have normal blood flow.71 In view of the current dilemma in the use of EBCT for assessment of calcification, more data are required to justify the use of EBCT for detection of calcification in asymptomatic patients in clinical practice. Unless, indicated for research assessments, in the absence of supportive data EBCT should only be used for assessment of calcification in patients with supportive evidence of widespread vascular disease.

OPG/RANKL axis and MAC

OPG and RANKL are key regulators of bone metabolism and vascular disease and the OPG/RANKL/TRAIL axis plays an impor tant role in the osteogenic modulation of vasculature in diabe tes.56 OPG is produced by a diverse range of tissues including endothelial cells and VSMCs, with high levels in aortic and renal arteries. In contrast, RANKL is not usually detectable in normal vasculature.66 OPG has indirect antiapoptotic and protective effects on the endothelial cells by serving as a decoy receptor for TRAIL and minimising its effect on endothelial cells.67 In the bone milieu, RANKL functions as a major osteoclast maturation factor, promoting osteoclast activity and bone resorption, whereas OPG undermines the action of RANKL by acting as a soluble decoy receptor for RANKL, diminishing its effects.53 RANKL promotes calcification in the vessel wall, while OPG protects against it.56 High OPG levels, as seen in ECD,68 may be a compensatory mechanism by the endothelial cells to protect against TRAIL induced apoptosis. In this regard, high OPG levels may be a sur vival factor for endothelial cells.67 The localisation of OPG/RANKL in MAC and in atherosclerotic calcification points towards an active role of OPG/RANKL axis, in these processes.56 The process of inhibition of vascular calcification therefore appears to be tightly regulated with multiple teleologically protective pathways activated in response to metabolic and inflammatory insults. Despite adverse metabolic milieu, in the context of ECD, these vascular cells may respond by overexpressing OPG, which may serve as a survival factor for these cells by blunting the action of TRAIL, through binding to its receptor on endo thelial cells.67 The overexpression of OPG by the vascular cells may continue through the process of calcification. In fact, OPG levels may rise further, as calcification progresses, by concurrent production of OPG by the newly differentiated osteoblastlike cells from the CVC. The additional OPG expression from these cells may try to counter the calcification promoting actions of RANKL, which at this stage may be expressed at the site of new bone formation in the vessel wall.53 High OPG levels are reported to be positively correlated with inflammatory markers (CRP, IL6 and fibrinogen), HbA1C levels and insulin resistance.68 OPG expression by the vascular cells appears to be a major protective mechanism against vascular calcification and thus MAC. However, an unabated adverse envi ronment comprising hyperglycaemia, oxidative stress, activated cytokine networks and other potent stimuli, may ultimately allow the promoters of vascular calcification to override these

Conclusion
ECD is a primary event in the initiation of vasculopathy in dia betes. The aetiopathogenesis of ECD is different in types 1 and type 2 diabetes. ECD may precede the onset of type 2 diabetes and some features of ECD may be seen in uncontrolled type 1 diabetes. The blood milieu in diabetes, with chronic hypergly caemia, enhanced AGE production, oxidative stress, abnormal leukocytes and platelets, activation of the reninangiotensin system, and an enhanced inflammatory status with an overac tive cytokine network, may all contribute to the progression of vasculopathy. The endothelial cells may be susceptible to cel lular apoptosis as a result of chronic hyperglycaemia or TRAIL activity. Despite the existence of a number of protective endothelial pathways (including increased expression of OPG to counter TRAIL action), the process of calcification may become progres sive in response to immense or persistent metabolic insult. Vascular cell apoptosis may serve as a focal point for matrix formation for calcification initiation. The process is carried for ward with the interplay of various inhibitors and promoters of vascular calcification. In addition to other regulators, OPG plays a major role in modulating the response of endothelial cells and VSMCs to the action of calcification promoters from the stage of ECD, through to the development of MAC.

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Key messages
Endothelial cell dysfunction: is an important complication of chronic hyperglycaemia has a different aetiopathogenesis in type 1 and type 2 diabetes when chronic, may promote endothelial cell apoptosis; providing a focal point for initiation of vascular calcification The OPG/RANKL system may play an important role in the modulation of vascular calcification in patients with diabetes Measurement of OPG level may help in identifying the presence and monitoring the progression of vasculopa thy in patients with diabetes

The enhanced atherosclerotic burden in diabetes coupled with a stiffened elastic layer due to MAC may reduce the size of the overall arterial lumen. In the long term, the decreased arterial lumen together with hyperglycaemia, hypertension, increased arterial stiffness, impaired remodelling, oxidative stress, dyslipidaemia and abnormal leukocyte and platelet func tion may facilitate a hypoxic vascular milieu and promote isch aemic injury. In view of the lack of consensus on the use of EBCT in the assessment of vascular calcification, measurement of OPG levels is a future candidate for identifying the presence and monitoring the progression of vasculopathy in patients with diabetes.

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