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Therapy: Part I
Mark A. Creager, Thomas F. Lscher, prepared with the assistance of, Francesco Cosentino and
Joshua A. Beckman
Circulation. 2003;108:1527-1532
doi: 10.1161/01.CIR.0000091257.27563.32
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Copyright 2003 American Heart Association, Inc. All rights reserved.
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iabetes 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 (noninsulin-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).
cells.4 In addition, NO protects the blood vessel from endogenous injuryie, atherosclerosis by mediating molecular
signals that prevent platelet and leukocyte interaction with the
vascular wall and inhibit vascular smooth muscle cell proliferation and migration.57 Conversely, the loss of endothelium-derived NO permits increased activity of the proinflammatory transcription factor nuclear factor kappa B (NF-),
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.1316
Similarly, many, but not all, clinical studies have found that
endothelium-dependent vasodilation is abnormal in patients
with type 1 or type 2 diabetes.1720 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
Hyperglycemia and NO
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, endotheliumdependent relaxation is impaired.25 Similarly, endotheliumdependent vasodilation is reduced in healthy subjects during
hyperglycemic clamping.26 Hyperglycemia induces a series
of cellular events that increase the production of reactive
From the Cardiovascular Division, Brigham and Womens Hospital, Harvard Medical School, Boston, Mass (M.A.C., J.A.B.); Cardiology,
CardioVascular Center, University Hospital and Cardiovascular Research, Institute of Physiology, University Zrich, Switzerland (T.F.L., F.C.); and
Cardiology, II Faculty of Medicine, University La Sapienza, Rome & IRCCS Neuromed, Pozzilli, Italy (F.C.).
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 Lscher has served as a consultant on clopidogrel for
Servier.
Correspondence to Mark A. Creager, MD, Brigham and Womens Hospital, Cardiovascular Division, 75 Francis St, Boston, MA 02115. E-mail
mcreager@partners.org
(Circulation 2003;108:1527-1532.)
2003 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org
DOI: 10.1161/01.CIR.0000091257.27563.32
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by guest on October 20, 2014
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Figure 1. Hyperglycemia and endotheliumderived 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; NF, nuclear factor kappa ;
TNF, tumor necrosis factor; ILs, interleukins; and COX-2, cyclooxygenase-2.
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Conclusions
Vascular diseases, particularly atherosclerosis, are major
causes of disability and death 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 Womens
Hospital.
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