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(Circulation. 2003;108:1527.)
© 2003 American Heart Association, Inc.

Review: Clinical Cardiology: New Frontiers

Diabetes and Vascular Disease

Pathophysiology, Clinical Consequences, and Medical Therapy: Part I

Mark A. Creager, MD; Thomas F. Lüscher, MD, FRCP; and prepared with the assistance of Francesco Cosentino, MD, PhD; Joshua A. Beckman, MD

From the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass (M.A.C., J.A.B.); Cardiology, CardioVascular Center, University Hospital and Cardiovascular Research, Institute of Physiology, University Zürich, Switzerland (T.F.L., F.C.); and Cardiology, II Faculty of Medicine, University "La Sapienza", Rome & IRCCS Neuromed, Pozzilli, Italy (F.C.).

Correspondence to Mark A. Creager, MD, Brigham and Women’s Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. E-mail mcreager{at}partners.org

Key Words: diabetes mellitus • cardiovascular diseases • nitric oxide • atherosclerosis • insulin

	Introduction

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Diabetes mellitus affects approximately 100 million persons worldwide.¹ Five to ten percent have type 1 (formerly known as insulin-dependent) and 90% to 95% have type 2 (non–insulin-dependent) diabetes mellitus. It is likely that the incidence of type 2 diabetes will rise as a consequence of lifestyle patterns contributing to obesity.² Cardiovascular physicians are encountering many of these patients because vascular diseases are the principal causes of death and disability in people with diabetes. The macrovascular manifestations include atherosclerosis and medial calcification. The microvascular consequences, retinopathy and nephropathy, are major causes of blindness and end-stage renal failure. Physicians must be cognizant of the salient features of diabetic vascular disease in order to treat these patients most effectively. The present review will focus on the relationship of diabetes mellitus and atherosclerotic vascular disease, highlighting pathophysiology and molecular mechanisms (Part I) and clinical manifestations and management strategies (Part II).

	Pathophysiology of Diabetic Vascular Disease

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Abnormalities in endothelial and vascular smooth muscle cell function, as well as a propensity to thrombosis, contribute to atherosclerosis and its complications. Endothelial cells, because of their strategic anatomic position between the circulating blood and the vessel wall, regulate vascular function and structure. In normal endothelial cells, biologically active substances are synthesized and released to maintain vascular homeostasis, ensuring adequate blood flow and nutrient delivery while preventing thrombosis and leukocyte diapedesis.³ Among the important molecules synthesized by the endothelial cell is nitric oxide (NO), which is constitutively produced by endothelial NO synthase (eNOS) through a 5-electron oxidation of the guanidine-nitrogen terminal of L-arginine.⁴ The bioavailability of NO represents a key marker in vascular health. NO causes vasodilation by activating guanylyl cyclase on subjacent vascular smooth muscle cells.⁴ In addition, NO protects the blood vessel from endogenous injury—ie, atherosclerosis—by mediating molecular signals that prevent platelet and leukocyte interaction with the vascular wall and inhibit vascular smooth muscle cell proliferation and migration.^5–7 Conversely, the loss of endothelium-derived NO permits increased activity of the proinflammatory transcription factor nuclear factor kappa B (NF-B), resulting in expression of leukocyte adhesion molecules and production of chemokines and cytokines.⁸ These actions promote monocyte and vascular smooth muscle cell migration into the intima and formation of macrophage foam cells, characterizing the initial morphological changes of atherosclerosis.^8–12 Endothelial dysfunction, as represented by impaired endothelium-dependent, NO-mediated relaxation, occurs in cellular and experimental models of diabetes.^13–16 Similarly, many, but not all, clinical studies have found that endothelium-dependent vasodilation is abnormal in patients with type 1 or type 2 diabetes.^17–20 Thus, decreased levels of NO in diabetes may underlie its atherogenic predisposition.

The bioavailability of NO reflects a balance between its production via NOS and its degradation, particularly by oxygen-derived free radicals.^20–22 Many of the metabolic derangements known to occur in diabetes, including hyperglycemia, excess free fatty acid liberation, and insulin resistance, mediate abnormalities in endothelial cell function by affecting the synthesis or degradation of NO (Figure 2).²³

View larger version (55K): [in this window] [in a new window]   Figure 2. The metabolic abnormalities that characterize diabetes, particularly hyperglycemia, free fatty acids, and insulin resistance, provoke molecular mechanisms that alter the function and structure of blood vessels. These include increased oxidative stress, disturbances of intracellular signal transduction (such as activation of PKC), and activation of RAGE. Consequently, there is decreased availability of NO, increased production of endothelin (ET-1), activation of transcription factors such as NF-B and AP-1, and increased production of prothrombotic factors such as tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)

	Hyperglycemia and NO

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
The intracellular glucose concentration of endothelial cells mirrors the extracellular environment.²⁴ Experimental evidence supports the notion that hyperglycemia decreases endothelium-derived NO (Figure 1). When normal aortic rings are incubated in a hyperglycemic milieu, endothelium-dependent relaxation is impaired.²⁵ Similarly, endothelium-dependent vasodilation is reduced in healthy subjects during hyperglycemic clamping.²⁶ Hyperglycemia induces a series of cellular events that increase the production of reactive oxygen species (such as superoxide anion) that inactivate NO to form peroxynitrite.^27,28 Hyperglycemia may initiate this process by increasing superoxide anion production via the mitochondrial electron transport chain.²⁸ Superoxide anion then promotes a cascade of endothelial processes that engage increasing numbers of cellular elements to produce oxygen-derived free radicals. For example, superoxide anion activates protein kinase C (PKC),²⁸ or visa versa, activation of PKC may contribute to superoxide generation.^29,30 Activation of PKC by glucose has been implicated in the regulation and activation of membrane-associated NAD(P)H-dependent oxidases and subsequent production of superoxide anion.²⁹ Indeed, the activity of NAD(P)H oxidase and levels of its protein subunits are increased in internal mammary arteries and saphenous veins of patients with diabetes.³¹ Peroxynitrite, resulting from the interaction of NO and superoxide anion, oxidizes the NOS co-factor tetrahydrobiopterin.^32,33 This uncouples the enzyme, which then preferentially increases superoxide anion production over NO production.^34,35 Hence, a cascade effect occurs that results in ever-increasing production of superoxide anion and inactivation of NO.

View larger version (35K): [in this window] [in a new window]   Figure 1. Hyperglycemia and endothelium-derived vasoactive substances. Hyperglycemia decreased the bioavailability of nitric oxide (NO) and prostacyclin (PGI2), and increased the synthesis of vasoconstrictor prostanoids and endothelin (ET-1) via multiple mechanisms, as discussed in the text. PLC indicates phospholipase C; DAG, diacylglycerol; PKC, protein kinase C; eNOS, endothelial nitric oxide synthase; Thr, thrombin; NAD(P)H Ox, nicotinamide adenine dinucleotide phosphate oxidase; O2-, superoxide anion; ONOO-, peroxynitrite; MCP-1, monocyte chemoattractant protein-1; NFß, nuclear factor kappa ß; TNF, tumor necrosis factor; ILs, interleukins; and COX-2, cyclooxygenase-2.

Mitochondrial production of superoxide anion also increases intracellular production of advanced glycation end products (AGEs).²⁸ These glycated proteins adversely affect cellular function both by affecting protein function and by activation of the receptor for AGEs (RAGE).^36,37 AGEs, per se, increase production of oxygen-derived free radicals, and RAGE activation increases intracellular enzymatic superoxide oxide production.^38–40 In addition, increased superoxide anion production activates the hexosamine pathway, which diminishes NOS activation by protein kinase Akt.⁴¹ These processes likely recruit extracellular xanthine oxidase, which further augments the oxidative stress.⁴² Hyperglycemia-induced oxidative stress also may increase levels of asymmetric dimethylarginine, a competitive antagonist of NOS, by impairing the ability of dimethylarginine dimethylaminohydrolase to metabolize asymmetric dimethylarginine.⁴³ The concept that hyperglycemia-induced oxidative stress mediates endothelial dysfunction in patients with diabetes is supported by the observations that intra-arterial infusion of ascorbic acid, a water-soluble antioxidant capable of scavenging superoxide anion,⁴⁴ restores endothelium-dependent vasodilation in healthy subjects exposed to a hyperglycemic clamp and in patients with type 1 or type 2 diabetes.^27,45,46

Hyperglycemia also increases the production of the lipid second messenger diacylglycerol, which causes the membrane translocation and activation of PKC.^47,48 Activation of PKC inhibits the activity of the phosphatidylinositol 3 kinase pathway, thereby limiting activation of Akt kinase and subsequent phosphorylation of NOS, which results in less NO production. Diminished endothelium-dependent relaxation of rabbit aorta exposed to elevated glucose levels is restored by PKC inhibition.²⁵ Administration of a PKC_ß isoform inhibitor to healthy subjects prevents abnormal endothelium-dependent vasodilation caused by hyperglycemia, which confirms the contribution of PKC to endothelial dysfunction.⁴⁹

	Free Fatty Acid Liberation and Endothelial Function

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Circulating levels of free fatty acids are elevated in diabetes because of their excess liberation from adipose tissue and diminished uptake by skeletal muscle.^50–52 Free fatty acids may impair endothelial function through several mechanisms, including increased production of oxygen-derived free radicals, activation of PKC, and exacerbation of dyslipidemia.^53–55 Infusion of free fatty acids reduces endothelium-dependent vasodilation in animal models and in humans in vivo.⁵⁶ Co-infusion of the antioxidant ascorbic acid improves endothelium-dependent vasodilation in humans treated with free fatty acids, which indicates that oxidative stress mediates the abnormality.⁵⁷ Elevation of free fatty acid concentrations activate PKC and decrease insulin receptor substrate-1–associated phosphatidylinosital-3 kinase activity.^53,58 These effects on signal transduction may decrease NOS activity as discussed above.

The liver responds to free fatty acid flux by increasing very-low-density lipoprotein production and cholesteryl ester synthesis.⁵⁹ This increased production of triglyceride-rich proteins and the diminished clearance by lipoprotein lipase results in hypertriglyceridemia, which is typically observed in diabetes.⁶⁰ Elevated triglyceride concentrations lower HDL by promoting cholesterol transport from HDL to very-low-density lipoprotein.⁵⁹ These abnormalities change LDL morphology, increasing the amount of the more atherogenic, small, dense LDL.^61,62 Both hypertriglyceridemia and low HDL have been associated with endothelial dysfunction.^63,64

	Insulin Resistance and NO

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Type 2 diabetes mellitus is characterized by insulin resistance. Insulin stimulates NO production from endothelial cells by increasing the activity of NOS via activation of phosphatidylinositol-3 kinase and Akt kinase.^65–67 Thus, in healthy subjects, insulin increases endothelium-dependent (NO-mediated) vasodilation. In insulin-resistant subjects, endothelium-dependent vasodilation is reduced.⁶⁸ Furthermore, insulin-mediated glucose disposal correlates inversely with the severity of the impairment in endothelium-dependent vasodilation.⁶⁹ Drug therapies that increase insulin sensitivity, such as metformin and the thiazolidinediones, improve endothelium-dependent vasodilation.^70,71 Abnormal endothelium-dependent vasodilation in insulin-resistant states may be explained by alterations in intracellular signaling that reduce the production of NO. Specifically, insulin signal transduction via the phosphatidylinositol-3 kinase pathway is impaired, and insulin is less able to activate NOS and produce NO.^53,55,72 Insulin signaling via the mitogen-activated protein kinase pathway remains intact.^55,72 Mitogen-activated protein kinase activation is associated with increased endothelin production and a greater level of inflammation and thrombosis.^73,74

Also, insulin resistance is associated with elevations in free fatty acid levels. Abdominal adipose tissue, the type found prominently in type 2 diabetes, is more insulin resistant and releases more free fatty acids compared with the type of adipose in other locations. Activating lipoprotein lipase to metabolize these free fatty acids increases insulin sensitivity.^75,76 Thus, free fatty acid–induced alterations in intracellular signaling, as discussed previously, may also contribute to decreased NOS activity and reduced production of NO in insulin-resistant states such as type 2 diabetes.

	Endothelial Production of Vasoconstrictors

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
In diabetes, endothelial cell dysfunction is characterized not only by decreased NO but also by increased synthesis of vasoconstrictor prostanoids and endothelin.^77–80 Hyperglycemia increases the expression of cyclooxygenase-2 mRNA and protein levels but not the expression of cyclooxygenase-1 mRNA in cultured human aortic endothelial cells.³⁰ In rabbit arteries exposed to a hyperglycemic milieu in vitro, the production of vasoconstrictor prostanoids is increased, and both cyclooxygenase inhibitors and prostaglandin H₂/thromboxane A₂ receptor antagonists restore endothelium-dependent relaxation.¹³

Endothelin may be particularly relevant to the pathophysiology of vascular disease in diabetes because endothelin promotes inflammation and causes vascular smooth muscle cell contraction and growth.⁸¹ Insulin increases endothelin-1 immunoreactivity in endothelial cells. Also, plasma endothelin-1 concentration increases after administration of insulin to healthy subjects and patients with type 2 diabetes mellitus.^73,74,82,83 In healthy subjects, blockade of endothelin A and B receptors increases forearm blood flow after intra-arterial administration of insulin, which indicates that insulin may affect vascular tone via stimulation of endothelin.⁸⁴ Blockade of endothelin A receptors also increases forearm blood flow in patients with type 2 diabetes mellitus, implicating enhanced activity of endogenous endothelin-1 in resistance vessels of these patients.⁸⁵

	Diabetes and Vascular Smooth Muscle Function

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
The impact of diabetes mellitus on vascular function is not limited to the endothelium. In patients with type 2 diabetes mellitus, the vasodilator response to exogenous NO donors is diminished.¹⁸ Moreover, vasoconstrictor responsiveness to exogenous vasoconstrictors, such as endothelin-1, is reduced.⁸⁶ Dysregulation of vascular smooth muscle function is exacerbated by impairments in sympathetic nervous system function.⁸⁷ Diabetes increases PKC activity, NF-B production, and generation of oxygen-derived free radicals in vascular smooth muscle, akin to these effects in endothelial cells.^55,88 Moreover, diabetes heightens migration of vascular smooth muscle cells into nascent atherosclerotic lesions, where they replicate and produce extracellular matrix—important steps in mature lesion formation.⁸⁹ Vascular smooth muscle cell apoptosis in atherosclerotic lesions is also increased, such that patients with diabetes tend to have fewer smooth muscle cells in the lesions, which increases the propensity for plaque rupture.⁹⁰ In persons with diabetes, elaboration of cytokines diminishes vascular smooth muscle synthesis of collagen and increases production of matrix metalloproteinases, yielding an increased tendency for plaque destabilization and rupture.^91,92

	Diabetes, Thrombosis, and Coagulation

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Platelet function is abnormal in diabetes as well. Expression of both glycoprotein Ib and IIb/IIIa is increased, augmenting both platelet–von Willebrand factor and platelet–fibrin interaction (Figure 3).⁹³ The intracellular platelet glucose concentration mirrors the extracellular environment and is associated with increased superoxide anion formation and PKC activity and decreased platelet-derived NO.^93,94 Hyperglycemia further changes platelet function by impairing calcium homeostasis and thereby alters aspects of platelet activation and aggregation, including platelet conformation and release of mediators.⁹⁵

View larger version (31K): [in this window] [in a new window]   Figure 3. Platelet function and plasma coagulation factors are altered in diabetes, favoring platelet aggregation and a propensity for thrombosis. There is increased expression of glycoprotein Ib and IIb/IIIa, augmenting both platelet–von Willebrand (vWF) factor and platelet–fibrin interaction. The bioavailability of NO is decreased. Coagulation factors, such as tissue factor, factor VII, and thrombin, are increased; plasminogen activator inhibitor (PAI-1) is increased; and endogenous anticoagulants such as thrombomodulin are decreased.

In diabetes, plasma coagulation factors (eg, factor VII and thrombin) and lesion-based coagulants (eg, tissue factor) are increased, and endogenous anticoagulants (eg, thrombomodulin and protein C) are decreased.^96–98 Also, the production of plasminogen activator inhibitor-1, a fibrinolysis inhibitor, is increased.^{87–90,93,96,99–101} Thus, a propensity for platelet activation and aggregation, coupled with a tendency for coagulation, is relevant to a risk of thrombosis complicating plaque rupture.

	Conclusions

Top Introduction Pathophysiology of Diabetic... Hyperglycemia and NO Free Fatty Acid Liberation... Insulin Resistance and NO Endothelial Production of... Diabetes and Vascular Smooth... Diabetes, Thrombosis, and... Conclusions References

 
Vascular diseases, particularly atherosclerosis, are major causes of disability and death in patients with diabetes mellitus. Diabetes mellitus substantially increases the risk of developing coronary, cerebrovascular, and peripheral arterial disease. The pathophysiology of vascular disease in diabetes involves abnormalities in endothelial, vascular smooth muscle cell, and platelet function. The metabolic abnormalities that characterize diabetes, such as hyperglycemia, increased free fatty acids, and insulin resistance, each provoke molecular mechanisms that contribute to vascular dysfunction. These include decreased bioavailability of NO, increased oxidative stress, disturbances of intracellular signal transduction, and activation of receptors for AGEs. In addition, platelet function is abnormal, and there is increased production of several prothrombotic factors. These abnormalities contribute to the cellular events that cause atherosclerosis and subsequently increase the risk of the adverse cardiovascular events that occur in patients with diabetes and atherosclerosis. A better understanding of the mechanisms leading to vascular dysfunction may unmask new strategies to reduce cardiovascular morbidity and mortality in patients with diabetes.

	Acknowledgments

 
This work is supported by grants from the National Institutes of Health (HL-56607 and HL-04169), the Swiss National Research Foundation (31-68 118.02; 32-67202.01), the Italian Ministry of Health (ICS 030.6/RF00-49), the Swiss Heart Foundation, and the Roche Research Foundation. Dr Creager is the Simon C. Fireman Scholar in Cardiovascular Medicine at Brigham and Women’s Hospital.

	Footnotes

 
This article is part I of a 2-part article. Part II will appear in the September 30, 2003 issue of Circulation.

Dr Creager has served on the scientific advisory boards of Bristol Myers Squibb, KOS, Pfizer, and Sanofi-Synthelabo; and the speakers’ bureau of Merck, Inc; he has received research grants from Bristol Myers Squibb, Eli Lilly, and Pfizer. Dr Lüscher has served as a consultant on clopidogrel for Servier.

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