Diabetes Mellitus: A Fundamental and Clinical Text
3rd Edition

Macrovascular Complications of Diabetes Mellitus
Helaine E. Resnick
Robert S. Lindsay
Barbara V. Howard
Macrovascular diseases, including coronary heart disease, stroke, and peripheral vascular disease, are the major causes of morbidity and mortality in individuals with diabetes mellitus (DM) (1), accounting for around 50% of deaths in persons with either type 1 or type 2 diabetes. This chapter discusses the occurrence of these complications and their relationships to known risk factors for arteriosclerosis, and mechanisms for the increased incidence of cardiovascular disease (CVD) among individuals with diabetes.
Mortality from coronary heart disease (CHD) among individuals with type 1 DM is significantly higher than that for the general population, with rates up to 9 times higher for men and 14 times higher for women (2). In people with type 2 DM, there is a 1.5- to 3-fold increase in CHD mortality compared with the general population. In most studies, CHD has a greater impact on diabetic women (3,4,5,6,7,8,9,10,11,12,13,14). Furthermore, individuals with diabetes have worse clinical outcomes. They are more likely to present with cardiac shock, congestive cardiac failure, and sudden death. Acute myocardial infarction (MI) is more likely to be fatal, and risk of reinfarction is higher compared with nondiabetic individuals (15,16,17).
Increasing duration of diabetes is associated with elevated risk of both fatal and nonfatal MI, CHD, and peripheral arterial disease (PAD) (18,19,20). Although mortality rates from stroke have decreased in the United States in recent years (21), diabetes is a key risk factor for stroke. Importantly, mortality rates from stroke are higher among diabetic compared with nondiabetic individuals (22,23). Data from the First National Health and Nutrition Examination Survey (NHANES I) (24) indicated 2.5-fold higher rates of stroke among diabetic men and women, both white and African American. However, stroke mortality is higher in African Americans compared with whites (25).
Findings for the effect of diabetes on stroke for men in the Multiple Risk Factor Intervention Trial (MRFIT) study were similar to those from NHANES I: a 2.8-fold stroke risk. But the Nurses’ Health Study reported a diabetes-associated stroke risk of 4.1 for women, a much larger effect than reported from national data (26,27). The relationship between diabetes and atherosclerosis in multiple vessels was highlighted by the Framingham Study, which showed elevated risk for stroke among diabetic women with absent pedal pulses (28). These findings underscore the importance of ankle-brachial index (ABI) as a clinically meaningful measure of subclinical CVD (29).
Peripheral Arterial Disease
The prevalence of peripheral vascular disease in both sexes, as measured by ankle/arm blood pressure ratios, is 22% to 34% among those with type 1 DM (30,31) and 22% among those with type 2 DM (32). Other population studies of diabetic and nondiabetics have reported PAD prevalence in the range of 4% to 6% (20,33,34). Studies of PAD conducted in exclusively diabetic populations ranging in size from 70 to 1,018 persons report PAD prevalence ranging from 5.1% to 38.9% (35,36,37,38,39,40,41,42). However, in both population-based studies and clinic populations, PAD is consistently higher in diabetic than in nondiabetic patients (36,37,38,43).
Variability in prevalence estimates of PAD is due to different methods for ascertaining this condition. Use of the Rose Questionnaire for intermittent claudication often identifies only advanced disease, thereby yielding a high false-negative rate. Use of Doppler blood pressures to calculate the ABI results in higher PAD prevalence due to its ability to identify subclinical disease. This was shown in the Strong Heart Study, in which only 33% of participants with ABI-defined PAD had absent posterior tibial pulses and only 1.8% had intermittent claudication by the Rose Questionnaire.
There are few data on progression of PAD. Data from the Mayo Clinic, however, suggest that progression of PAD did not differ between diabetic and nondiabetic individuals (44). One prospective study of PAD showed that 8.2% of people with baseline claudication had an amputation or vascular surgery over 5 years of follow-up (45).
Finally, it is important to note that genetic polymorphisms may interact with environmental/behavioral factors such as

smoking to increase risk of PAD among people with diabetes, a hypothesis supported by data from the Honolulu Asia Aging Study (19). Results of this report, along with other studies (46) showing the deleterious effects of smoking on PAD, highlight the need to eliminate modifiable CVD risk factors.
In large studies in which atherosclerosis has been evaluated directly in diabetic subjects, diabetes is associated with an increase in the extent of atherosclerotic lesions (47). Moreover, evaluations of angiographic data show that diabetic patients have greater occlusion of the coronary arteries and a greater prevalence of multivessel disease (48,49), and ultrasonography of carotid arteries shows greater intima-medial thickness in individuals with diabetes (50). In people with diabetes, restenosis after interventional procedures is more common (51).
Risk Factors for Atherosclerosis in Diabetic Individuals
The increased prevalence of atherosclerotic vascular disease among diabetic individuals appears to be partly explained by increases in diabetes-associated CVD risk factors.
Elevated blood pressure levels have been observed consistently in people with diabetes, independent of age, obesity, and renal disease (52,53,54,55,56,57). The prevalence of hypertension increases with duration of diabetes (58) and is greatly exacerbated in the presence of diabetic nephropathy (59,60,61,62). In type 1 DM, the prevalence of hypertension has been reported to approach 50% among patients over 50 years of age (63). NHANES data show that hypertension is more than twice as prevalent among people with type 2 DM compared with those with normal glucose tolerance (64).
The mechanisms of increased hypertension in diabetic individuals are not well understood. Blood pressure is higher in a number of states also characterized by resistance to glucose uptake in response to glucose infusion and altered function of the vascular endothelium, notably obesity and type 2 diabetes. In addition, lean hypertensive subjects are also relatively insulin resistant on euglycemic hyperinsulinemic clamp (65). The reasons underpinning these associations are as of yet unclear. However, it has become apparent that insulin has a variety of potentially important actions that might impact on blood pressure. Insulin acts as a peripheral vasodilator, acting by endothelial nitric oxide–dependent pathways. Insulin also has central actions resulting in sympathetic activation and acts as a trophic factor to vascular smooth muscle cells. Finally insulin also acts to increase sodium retention in the kidney. One possible cause is the increase in exchangeable sodium and enhanced cardiovascular reactivity, which occur in both type 1 and type 2 DM. Alternatively, increased intracellular calcium and decreased magnesium have been reported among diabetic hypertensive patients. Furthermore, the insulin resistance syndrome, with accompanying hyperinsulinemia, may contribute to hypertension in individuals with type 2 DM (65,66,67).
Several studies have demonstrated that hypertension is a significant risk factor for development of vascular disease in diabetic individuals. Mortality rates among diabetics have been shown to be four times greater in those with elevated blood pressures (68), and the Whitehall Study revealed an increased relative risk of death among diabetic individuals with systolic hypertension (69). In the recent WHO multinational study, systolic blood pressure acted as a risk factor for both coronary heart disease and stroke in subgroups of men and women and in both type 1 and type 2 diabetes (70). When it accompanies diabetes, hypertension is a key risk factor for development of cerebral vascular disease: Diabetic patients with hypertension are twice as likely as normotensive patients to develop cerebrovascular disease (71). There also is a close relationship between systolic hypertension and peripheral vascular disease among individuals with diabetes (72,73). Lowering blood pressure results in a reduction in macrovascular disease in patients with type 2 diabetes (74).
Altered Lipoprotein Concentrations
Lipoprotein alterations occur in and are associated with atherogenesis, both in type 1 and type 2 DM. Foremost among these are hypertriglyceridemia and low circulating levels of high- density lipoprotein (HDL).
Hypertriglyceridemia, which is represented by increased levels of very-low-density lipoprotein (VLDL) and remnants of VLDL and chylomicron metabolism, is very common among individuals with type 1 and type 2 DM (75,76,77). Elevations in VLDL in diabetic subjects may result from several possible mechanisms:
  • Increased free fatty acid and glucose availability to the hepatocyte lead to overproduction of VLDL.
  • Abnormalities of lipoprotein lipase result in decreased clearance both of chylomicrons and VLDL.
  • Prolonged postprandial hypertriglyceridemia leads to accumulation of chylomicron remnants.
Although there has been conflicting evidence concerning the relationship between hypertriglyceridemia and atherosclerotic CVD in the nondiabetic population (78), several studies have demonstrated that elevated triglycerides are a risk factor for atherosclerotic disease among individuals with type 2 diabetes, even after adjustment for other risk factors (79,80,81,82,83,84). Triglycerides have not emerged as an independent predictor of CVD in individuals with type 1 diabetes (69,85). Other studies have highlighted the causative role of hypertriglyceridemia in diabetes-associated peripheral vascular disease (86,87).
Although it is not clear why hypertriglyceridemia predisposes diabetic patients to atherosclerosis, hypertriglyceridemia is associated with increased concentrations of chylomicron remnants (88) and smaller VLDL remnant-like particles (89). This increase in remnants, which contain a higher proportion of cholesterol than does LDL (90) and are known to be atherogenic (91), may impart the increased CVD risk via remnant uptake

by macrophages and subsequent lipid accumulation in the vessel wall (92).
Decreased High-Density Lipoprotein Concentrations
Decreased concentrations of HDL cholesterol are observed uniformly in type 2 DM patients and in type 1 DM patients with poor glycemic control. There are several possible mechanisms for decreased HDL. In diabetic patients, the impaired metabolism of triglyceride-rich lipoproteins, with decreased activity of lipoprotein lipase, impairs transfer of materials to the HDL compartment (93). In addition, levels of hepatic lipase are higher among diabetic patients (94). Finally, insulin resistance may be a direct cause of decreased HDL concentrations (95).
HDL is protective against vascular disease, and a strong association has been observed between low HDL levels and CHD risk in both type 2 and type 1 DM (96,97). Although it is not clear how low HDL predisposes diabetic individuals to atherosclerosis, it is likely that, as in nondiabetic persons, HDL mediates critical steps in lipoprotein transport that influence the flux of cholesterol to and from the arterial wall (98,99). HDL is thought to interact with a cell surface receptor; free cholesterol is transferred from the cell to the core of HDL, and then exchanged with triglycerides during the metabolism of triglyceride-rich lipoproteins (83,84). This creates a cholesterol transport process that theoretically results in removal of cholesterol from the vessel wall and excretion through the liver. Another possibility is that the HDL decrease reflects the impaired catabolism of triglyceride-rich lipoproteins and the presence of their atherogenic remnants.
Levels of Total and Low-Density Lipoprotein Cholesterol
Elevation of total or LDL cholesterol is a strong risk factor for coronary artery disease in both nondiabetic and diabetic persons (100). Concentrations of LDL are only modestly higher (101,102) or the same (103) in individuals with type 2 diabetes compared with nondiabetic individuals. Nevertheless, treatments designed to lower LDL cholesterol reduce risk for vascular death, including MI and stroke in both individuals with type 2 diabetes as in the general population (104,105).
The Insulin Resistance Syndrome
In three prospective population-based studies, hyperinsulinemia was shown to be a precursor of CHD, independent of other risk factors (106,107,108). It is not clear, however, whether it is the elevated insulin concentrations or the insulin resistance that contributes to atherosclerosis. Results from the Diabetes Control and Complications Trial indicate that increased insulin administration is not associated with increased CHD among patients with type 1 DM (109). It is likely that insulin level predicts atherosclerosis because hyperinsulinemia is a component of the insulin resistance syndrome and indeed in one small study clamp measures of insulin resistance were predictive (110). This syndrome, which is characterized by a constellation of metabolic disorders accelerating the progression of atherosclerosis, is associated with central intraabdominal adiposity, dyslipidemia, and hypertension (111,112). Although the insulin resistance syndrome was linked with increased risk of CVD as early as 1965 (113), this risk is probably not mediated by elevated insulin concentrations per se; it is likely associated with the increase in CVD risk factors that accompanies insulin resistance and also may result from adverse effects on endothelial and vascular function, cardiovascular hemodynamics, and inflammation (114).
Extensive recent literature suggests that inflammation is important in the development of vascular disease. Inflammatory processes are involved in the development of atherosclerotic plaque, in plaque rupture, and in thrombotic events (115). C-reactive protein, an acute-phase reactant, is predictive of development of atherosclerosis (116,117). Part of the beneficial effect of statins to reduce the risk for cardiovascular events has been ascribed to antiinflammatory actions of these drugs. These findings may have great relevance to the relationship of obesity and type 2 diabetes to increased vascular risk. Notably, both obesity and type 2 diabetes are associated in cross-sectional studies with endothelial dysfunction and markers of inflammation (118).
More recently it has been demonstrated that markers of inflammation and endothelial dysfunction act as predictors of the development of type 2 diabetes (119,120,121). In addition, animal models support the hypothesis that inflammatory pathways may be central to the development of insulin resistance (particularly in relation to obesity) and type 2 diabetes (122,123). It is hypothesized that activation of inflammatory pathways may underpin the “common soil” in which genetic and environmental risk factors increase risk of both vascular disease and type 2 diabetes (124) and underpin the greatly increased vascular risk seen in patients with type 2 diabetes. A further, important observation is that the adipose cell is likely to be key to these relationships. Adipocytes are active in secreting a variety of mediators, most notably tumor necrosis factor-α, leptin, and adiponectin, which potentially modulate both insulin sensitivity and inflammatory pathways. Adiponectin is of particular interest because it is negatively related to adiposity (125) and insulin resistance in human studies (126), and also improves glycemia (127) and stimulates β-oxidation of fats in animal models (128). In human studies, adiponectin is negatively associated with the presence of vascular disease (129) and protective against development of new vascular events (130) and of type 2 diabetes (131). It is therefore possible that adiponectin, along with other products of the adipocyte, may be central mediators of increased metabolic and vascular risk.
Cardiovascular Disease Risk Factors of Particular Importance in Diabetes
Data from several prospective studies suggest that increased CHD risk among diabetics cannot be explained fully by increases in known CHD risk factors (1). Thus, the diabetic state

itself appears to increase the risk for atherosclerosis, in addition to its potentiating effect on known risk factors. This was demonstrated in the Multiple Risk Factor Intervention Trial (132) and the Framingham Study (3), in which, for varying levels of each major risk factor analyzed, diabetics had a higher risk than nondiabetics at the same level of each risk factor. These findings may be explained in part by changes in CVD risk factors that are either unique to DM or that may have enhanced impact among persons with DM.
Alterations in Lipoprotein Composition
Diabetes not only changes lipoprotein concentrations but induces a number of alterations in lipoprotein composition that may influence the atherosclerotic process. Many of these changes involve LDL, the most important lipoprotein in the atherogenic process. A primary alteration in LDL composition is the presence of small, dense LDL particles. This shift in distribution of LDL particle size toward the subtype B pattern defined by Austin and colleagues (133) has been associated with several markers of CVD in studies of nondiabetic patients. A greater proportion of small, dense LDL particles has been demonstrated to be associated with the insulin resistance syndrome (112) and to be more prevalent among diabetic patients (134,135). In addition, these particles have been shown to be more susceptible to glycation and oxidation, thus enhancing the damaging cycle of oxidation and glycation.
In diabetes, the single apoprotein in LDL, apo B, is glycated (136). Glycated LDL has been shown to interact abnormally with macrophages (137). Recognition of glycated LDL by the classic LDL receptor is impaired; however, it is recognized by the receptor on macrophages and other scavenger cells that recognize modified LDL (138). The glycated LDL is recognized by a high-capacity, low-affinity pathway on monocyte-derived macrophages, which accelerates its uptake by these cells and thus enhances foam cell formation. A second modification observed in diabetic LDL is increased extent of oxidation. Oxidatively modified LDL is believed to play an important role in atherogenesis because it (a) stimulates the production of foam cells by macrophages (139,140), (b) induces adhesion of monocytes to endothelial cells (141), (c) stimulates monocyte chemotaxis (142), and (d) can be cytotoxic to endothelial cells (143). Furthermore, it has been shown that glycated LDL is more susceptible to oxidation (90,144). Thus, the processes of glycation and oxidation are closely interwoven and may produce a vicious cycle of vascular injury (83,84).
Glycated (145) and oxidized (146) LDL also may stimulate the production of circulating antibodies, which suggests that these modified lipoprotein species can be immunogenetic (84,90). Circulating lipoprotein immune complexes may accelerate atherosclerosis (84,147,148) via stimulation of (a) macrophage foam cell formation by immune complex uptake or (b) atherogenetic immune mechanisms in arterial wall cells.
Alterations in HDL composition also are associated with diabetes. Diabetic individuals have a smaller proportion of the larger HDL2 subfraction and a greater proportion of HDL3, a distribution known to be associated with atherosclerosis. Additionally, glycation of HDL also has been reported in diabetic subjects, which could interfere further with the metabolic actions of HDL. Glycation hastens HDL clearance from plasma (149) and impairs stimulation of cholesterol efflux from arterial cells (150,151).
Glycated Proteins
In addition to the effects of glycation on lipoproteins, the process of glycation may influence other macromolecules that play a role in atherogenesis. Increased glycation of antithrombin III has been shown to impair its inhibition of the coagulation cascade (152). In diabetes, longer-lived proteins are increasingly likely to undergo excessive glycation (90). Collagen, for example, has been shown to have an increased rate of glycation in diabetics (153), which may facilitate atherogenesis by trapping lipoproteins in the extracellular matrix. Glycated collagen also stimulates platelet aggregation (154). The initial glycation process leads to further chemical changes and subsequent formation of advanced glycation end products (155,156), which serve as a catalyst for the transendothelial migration of monocytes and the expression of growth factors by macrophages, mechanisms that could stimulate the atherogenetic process (156,157).
Increasing excretion of albumin (and other proteins) in the urine is an early and progressive marker of renal dysfunction in diabetes. Albuminuria has now been shown in multiple population-based studies to be a strong, independent predictor of CVD in diabetes (158,159,160,161,162). Renal disease may be related to CVD because of its influence on lipoproteins, blood pressure, and other metabolic factors. In the Strong Heart Study, albuminuria was a significant correlate of CVD in the multivariate analysis after adjustment for these factors, as well as for the presence of diabetes (13). This suggests that the association between diabetes and CHD may share common determinants with microvascular disease in other organs, of which albuminuria is a marker.
Disturbed Endothelial Function
Endothelial function is impaired in patients with diabetes (163,164,165,166). Hyperglycemia attenuates endothelium-dependent relaxation and thus impairs vasodilation and blood flow. Endothelial-derived nitric oxide synthase, a key regulator of vascular tone, is impaired (167). This may be mediated by activation of protein kinase C, which can cause vascular dysfunction (168). In addition, regulation of endothelial products such as endothelium, cytokines, and adhesion molecules is disrupted (169), thus enhancing vascular dysfunction.
Diabetes is associated with an increased propensity for thrombosis, as indicated by in vitro measurements (170). Abnormalities of platelet adherence and aggregation in diabetes have been reported, as have increased levels of several clotting factors and

the plasminogen activation inhibitor-1, which may lead to a procoagulant state (171). Fibrinogen levels also are elevated (172). Platelets can contribute to vascular disease by releasing factors that can modify the vessel wall and by forming thrombi.
There is evidence of enhanced platelet adhesion in diabetic subjects (173). Hypersensitivity to aggregating agents, and subsequent increased sensitivity to the release of their granular contents, is associated with type 1 and type 2 DM (174). This is thought to be caused by (a) increased arachidonate mobilization, (b) fibrinogen binding to platelets, (c) alterations in nonarachidonate pathways, or (d) alterations in the platelet membrane lipid fluidity (174).
Diabetic Cardiomyopathy
In addition to the enhanced atherosclerotic process, it has been proposed that additional cardiac dysfunction is associated with diabetes. The small and medium vessels that penetrate the ventricular wall may be altered in individuals with diabetes, perhaps because of the presence of microangiopathy (175,176). This appears to be associated with left ventricular dysfunction (177), diffuse subendocardial fibrosis, and glycoprotein deposits. Altered substrate utilization by myocytes also has been proposed as a mechanism (178).
The autonomic nervous system also seems to be involved in diabetic cardiomyopathy. Diabetics have altered autonomic dysfunction, resulting in tachycardia, postural hypertension, and silent ischemia. This may involve destruction of the cardiac sympathetic fibers (179) and hence cardiac dysfunction. Nerve dysfunction, which influences heart rate, has been demonstrated in diabetic patients (180,181). In addition, sympathetic nerve dysfunction also can cause dysfunction in the peripheral circulation, thus exacerbating peripheral arterial disease.
Both type 1 and type 2 diabetes act as risk factors for development of vascular disease independent of other known risk factors. However, a causative role for hyperglycemia in vascular disease remains controversial. In both the DCCT (in type 1 diabetic individuals) and UKPDS (in type 2 diabetic individuals) tighter control of glycemia did not convincingly reduce macrovascular end points. In the UKPDS, tighter glycemic control resulted in an improvement with marginal significance (p = 0.052 in UKPDS) in MI and no significant improvement in stroke (p = 0.52) (182). Similarly, in the DCCT improvement in the incidence of combined macrovascular events dependent on intensive treatment was of marginal significance (p = 0.08), although the number of macrovascular events in the DCCT was small, and this may represent a type 2 error (183). Furthermore, their relevance to clinical practice may be moot. In both trials intensive glycemic control was markedly successful in reducing onset of nephropathy, which as previously noted is a powerful risk factor for development of vascular disease in both type 1 and type 2 diabetes (69). Because intensive glycemic control is associated with improvements in lipids, control of glycemia plays a key indirect role in preventing vascular disease.
Increased atherosclerotic vascular disease involving vessels of the heart, brain, and periphery has been well established in the diabetic population and is responsible for a large proportion of diabetes-associated morbidity and mortality. Part of the increased propensity for atherosclerosis appears to be related to the effect of diabetes-induced increases of known risk factors: hypertension, dyslipidemia, and insulin resistance. However, diabetes also appears to be associated with increased risk for atherosclerosis, even when the classic risk factors are taken into account. There are multiple possible explanations for the independent effect of diabetes on enhancing atherosclerosis. Many alterations in lipoprotein composition, especially small dense LDL, glycation, and oxidation, are known to accelerate the atherosclerotic process. In addition, endothelial function in diabetic patients is altered. These alterations may be induced as a result of the glycation process or through the secretion or alteration of cytokine activity. There is ample evidence for increased rates of thrombosis among diabetics, and there is increasing evidence that chronic inflammation plays a key role in development of both DM and CVD.
Although our knowledge of the mechanisms leading to macrovascular disease in diabetes is not complete, there is much information to guide atherosclerosis prevention strategies. These strategies must be aimed toward reducing the prevalence and impact of modifiable CVD risk factors. Thus, blood pressure should be carefully controlled, dyslipidemia appropriately treated (including aggressive lowering of LDL), and smoking cessation required. Efforts to increase weight loss and physical activity will contribute to reducing these risk factors (control of plasma glucose will decrease the rate of glycation, thus potentially reversing some of the abnormalities of lipoprotein composition and cellular dysfunction). Further work must be done to improve our understanding of the mechanisms of diabetic vascular disease so that we can design more specific and successful strategies for its prevention and control.
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