These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.ORIGINAL ARTICLE Diabetes and Cardiovascular Disease James R. Sowers, MD The prevalence of diabetes is increasing in the United States related to the increasing aging, increased obesity, and an increasing percentage of minority people living in our industrialized, Westernized society. Macrovascular disease is the leading cause of mortality in type 2 diabetic patients, who constitute a large portion of the diabetic population and is the population whose numbers are increasing dramatically in this country. This review covers the various metabolic abnormalities in type 2 diabetes and their contributions to the cardiovascular disease (CVD) so prevalent and deadly in this population. These risk factors include hyperglycemia, hypertension, hyperinsulinemia, dyslipidemia, coagulation abnormalities, and platelet and endothelium dysfunction. Mechanisms by which each of these factors may contribute to atherosclerotic disease in people with diabetes are considered in this review. MACROVASCULAR DISEASE IN DIABETES— Macrovascular disease is the major cause of mortality in people with type 2 diabetes (1–8). Many factors contribute to the high prevalence of macrovascular disease in people with diabetes. Hypertension is one such factor. High blood pressure is about twice as frequent in people with diabetes as in those without (7). The recent United Kingdom Prospective Diabetes Study Group data (6) underscore the critical importance of hypertension and good blood pressure control in people with type 2 diabetes. Information from death certificates indicate that hypertension was implicated in 4.4% of deaths coded to diabetes, and diabetes was involved in 10% of deaths coded to hypertension-related disease (7–9). Up to 75% of diabetes-related cardiovascular complications may be attributed to hypertension (7,9). These observations have contributed to recommendations of more aggressive lowering of blood pressure (i.e., to <130/85 mmHg) in people with coexistent diabetes and hypertension (9,10). Indeed, tight blood pressure control in patients with hypertension and type 2 diabetes achieves a clinically important reduction in the risk of deaths related to diabetes, complications related to diabetes, progression of diabetic retinopathy, and deterioration in visual acuity (6). A powerful underlying factor that dramatically contributes to the increasing prevalence of diabetes in industrialized societies is obesity, particularly android or visceral obesity (11–15). Visceral adipose tissue, localized around omental and mesenteric tissues, is relatively resistant to the antilipolytic actions of insulin (11–13). Enhanced lipolytic activity of this fat mass results in an increased entry of free fatty acids (FFAs) into the portal circulation. Resultant increases in circulating fatty acids may, in turn, contribute to skeletal muscle insulin resistance (16) by substrate competition between glucose and FFA in the glucose–fatty acid cycle. Increased FFA inhibits hepatic clearance of circulating insulin and stimulates hepatic glyconeogenesis (11–13). Further, increased delivery of FFA to the liver stimulates hepatic synthesis and release of triglyceride-rich VLDL (4). Because of peripheral insulin resistance, there is reduced activity of endothelial-bound lipoprotein lipase skeletal muscle and adipocytes. This lipoprotein lipase is responsible for normal metabolism of the triglyceride-rich VLDL and chylomicron particles (17). Thus, triglyceride levels rise as a result of increased hepatic production coupled with reduced peripheral metabolism, and HDL levels decrease as a result of the reduction in peripheral metabolism of VLDL (Table 1). In summary, intra-abdominal obesity is associated with increased portal FFA flux, which predisposes to reduced hepatic insulin extraction and enhanced lipoprotein synthesis, which leads to development of insulin resistance leading to type 2 diabetes and atherosclerotic vascular disease (11–17). Visceral obesity, insulin resistance, and type 2 diabetes are associated with an increased proportion of small, dense LDL particles, which have increased atherogenicity, further contributing to accelerated atherosclerosis (18).
HYPERINSULINEMIA IN CVD OF DIABETES— The endogenous hyperinsulinemia that is often present throughout life in some people with type 2 diabetes could potentially contribute to atherosclerotic vascular disease risk (2,6,7,19–26). In this regard, it is important to note that there is no evidence that insulin therapy for glycemic control contributes to increases in atherosclerosis. Increased lipid content within skeletal muscle contributes to insulin resistance and associated hyperinsulinemia (27,28), akin to visceral adiposity (29). Endogenous hyperinsulinemia may potentially promote atherosclerosis by a number of mechanisms. High levels of insulin stimulate mitogenic signaling pathways and increase DNA synthesis in vascular endothelial and smooth muscle cells (20–32). Insulin stimulates the synthesis of both endothelin and plasminogen activator inhibitor (21,33), two atherogenic factors. Much of the effect of insulin on cardiovascular growth and remodeling is likely mediated through actions on an IGF-1 receptor in endothelial/vascular smooth muscle cells (VSMCs) (30–32) or mediated indirectly by stimulating VSMC (31–33) or cardiac (33,34) IGF-1 synthesis. Insulin and IGF-1 are structurally related, share receptors, and have similar postreceptor signaling pathways (32). Unlike insulin, which is not produced by cardiovascular tissue and must traverse the endothelium before acting on VSMC or cardiomyocytes, IGF-1 is synthesized by these cells and is more likely to function in an autocrine/paracrine role (30–35). There is also increasing evidence that enhanced IGF-1 expression/synthesis plays an important role in mesangial hyperplasia and left ventricular hypertrophy, both disease manifestations of diabetes (30–35). Thus, it is likely that many of the atherosclerotic and growth effects attributed to hyperinsulinemia are mediated through an IGF-1 receptor, either directly by IGF-1 or indirectly by high concentrations of insulin (32). COAGULATION ABNORMALITIES IN DIABETES—A procoagulant state often exists in people with diabetes (36–38) (Table 1). There is an increase in a number of coagulation factors—such as plasminogen activator inhibitor 1, von Willebrand's factor, fibrinogen, factor VII, and thrombin-antithrombin complexes—particularly in association with macrovascular and microvascular disease and poor glycemic control (36–42). Levels of these factors, particularly fibrinogen and thrombin-antithrombin complexes, are critical for the survival of the provisional clot matrix upon transformation of fibrinogen to fibrin at the site of the injured endothelium (4). Plasma levels of lipoprotein(a) are elevated in people with diabetes, particularly those with poor glycemic control (39,40). By inhibiting fibrinolysis, increased levels of lipoprotein(a) potentially delay thrombolysis and contribute to plaque progression (41). There is also impaired attenuation of clot formation and fibrinolysis in the diabetic state (36–43). For example, antithrombin III and protein C are decreased in diabetes, particularly diabetes in poor glycemic control, and levels are increased after glycometabolic control (41–43).
PLATELET ABNORMALITIES— Platelet aggregation and adhesion are characteristically accentuated both in people with type 1 diabetes and in those with type 2 diabetes (4,7,44,45) (Table 2). These functional abnormalities appear to be related to exaggerated elevations in platelet intracellular calcium mobilization, phosphoinositide turnover, and myosin light-chain phosphorylation (45–48). Platelets from people with diabetes have reduced membrane fluidity that is thought to be related to membrane cholesterol-to-phospholipid ratios (44). Another process that likely contributes to enhanced platelet aggregation is an increase in glycosylation of platelet membrane proteins (49). Further, the dyslipidemia accompanying diabetes contributes both directly and indirectly to platelet aggregation (50).
OXIDATIVE STRESS (GLYCOOXIDATION)— The generation of reactive oxygen species/free radicals by cardiovascular intimal macrophages, VSMCs, and cardiomyocytes contributes to oxidative modification of lipids and cardiovascular proteins (51–53). Oxidation, which is enhanced in diabetes (51–53), modifies not only the phospholipid content of LDL but also the amino acid side chains of apolipoprotein B, analogous to the modification produced by acetylation (53) (Table 3). Consequently, oxidized LDL (Ox-LDL) is no longer recognized by the classic LDL receptor, but by so-called macrophage scavenger receptors (53). Foam-cell uptake of LDL via the scavenger pathway is enhanced by oxidative modification of LDL. Once taken up by the foam cell, Ox-LDL degradation is impaired, leading to further accumulation in the cell. Ox-LDL is toxic to endothelial cells, altering both structure and function (51). Ox-LDL increases the adhesion of circulating monocytes to damaged endothelium, increasing their migration into the vascular intima (54–56). Ox-LDL also stimulates the production of chemoattractants that enhance this migration. Glycosylation, the nonenzymatic linkage of glucose to proteins, alters the apolipoprotein B that mediates receptor uptake of LDL (53). The glycosylation of apolipoprotein B thus renders the LDL particle more atherogenic (Table 3). The glycooxidized LDL enhances foam-cell formation, platelet aggregation, and adhesion of molecules to the endothelium (53). Glycooxidized LDL is also immunogenic, forming antibody lipoprotein complexes that stimulate foam-cell formation and enhance platelet aggregation compared with normal LDL. Glycooxidized LDL sequestered in the intima has a greater propensity to become bound by glucose-mediated crosslinks to local matrix proteins. Once this occurs, the LDL particles may undergo even more extensive glycative and oxidative modification (53).
ENDOTHELIUM DYSFUNCTION—Functional and anatomical abnormalities of the vascular endothelium are commonly associated with diabetes (56–59) (Table 4). Both hyperglycemia and dyslipidemia contribute to endothelial dysfunction (56–58). Hyperglycemia results in impairment of endothelial cell nitric oxide (NO) production (50,56,58), perhaps via activation of protein kinase C in endothelial cells. Activation of protein kinase C and associated reduced NO production predispose to increased production of vasoconstrictor prostaglandins, endothelia, glycated proteins, endothelium adhesion molecules, and platelet and vascular growth factors, which cumulatively enhance vasomotor tone and vascular permeability, growth, and remodeling (56–59). Endothelial dysfunction also includes accelerated disappearance of capillary endothelium (58), weakening of intercellular junctions (57), altered protein synthesis, and altered expression/production of adhesion glycoproteins on endothelial cells (56–59) promoting attachment of monocytes and leukocytes, as well as their transendothelial migration (57). Further, hyperglycemia enhances endothelial cell matrix production, which may contribute to basement membrane thickening (60). It also increases the enzymes involved in collagen synthesis (60) and specifically enhances endothelial cell collagen IV and fibronectin synthesis (60). In addition, hyperglycemia delays endothelial cell replication and increases cell death, in part by enhancing oxidation and glycation (glycooxidation) (56–60). DIABETES AND CVD IN WOMEN—Diabetes removes the normal sex-related differences in the prevalence of CVD (50, 61,62) and end-stage renal disease (63). In the Framingham population of people aged 50–59 years, diabetes proved to be a greater CVD risk factor in women than in men (61). After correction for diabetes-associated hypertension, dyslipidemia, and obesity, the risk of coronary events in women with diabetes was double that of nondiabetic women (64). An increased mortality in women with CVD and diabetes compared with nondiabetic women was observed in an epidemiological study in California (64). When adjusted for other CVD risk factors, the risk ratio was 2.4 for diabetic men and 3.5 for diabetic women (62,64). Further, diabetic women are more likely to die after a myocardial infarction than are diabetic men or nondiabetic women (64,65). Thus, the presence of diabetes in women appears to eliminate the cardiovascular protective effects afforded premenopausal women (50,66–69). The mechanisms by which diabetes abrogates the cardiovascular protective effects of female sex hormones are not well understood. One recently described mechanism (32,50) involves the interaction between hyperglycemia and estradiol in regulation of endothelial cell NO production. Hyperglycemia reduces the estradiol-mediated production of NO from vascular endothelial cells (32,50), which may contribute to the accelerated atherosclerosis in diabetic women. THE DIABETIC HEART—Many people with diabetes often manifest a diabetic cardiomyopathy (70–72). This entity is characterized by diastolic dysfunction, with associated prolongation of diastolic relaxation and cytosolic calcium removal (71,72). The diabetic heart is characterized by myocardial fibrosis, which may be related to altered NO and intracellular Ca2+ metabolism as well as growth effects mediated by insulin and/or IGF (32,70). Other factors that often coexist with diabetes, such as hypertension and dyslipidemia, seem to accelerate the development of diabetic cardiomyopathy (4,70). The presence of coronary disease and associated ischemia also likely accelerates the development of severe diabetic cardiomyopathy (70). Hyperglycemia also appears to play a major role in the prognosis of the diabetic individual with coronary disease (73,74). In this regard, with ischemia, the myocardium shifts from the use of fatty acids for aerobic metabolism to the use of glucose for anaerobic metabolism (4,70). High levels of stress hormones generate increased levels of FFAs, which interfere with glucose entry into the myocyte, further potentiating the ischemic process (4,70,75). These observations may help explain the increased mortality of diabetic individuals after myocardial infarction (70–75). ANALOGY BETWEEN DIABETIC GLOMERULOSCLEROSIS AND ATHEROSCLEROSIS— Many similarities exist between the function and structure of the renal glomerulus and the vasculature (30). Endothelial cells line both the glomerulus and vasculature, and mesangial cells are modified VSMCs derived from the same progenitor cell line (30). Endothelial cells and mesangial cells account for 85% of glomerular cells, and both cells produce cytokines and growth factors that act in an autocrine/paracrine fashion, as for the vasculature (30). In diabetes, there is altered endothelial/mesangial cell function, including decreased production/release of NO and vasodilatory prostaglandins (8,30). Because both NO and vasodilatory prostaglandins attenuate the growth/remodeling effects of various growth factors—such as IGF-1, angiotensin II, platelet-derived growth factor, vasopressin, and endothelin—these growth factor effects are exaggerated in diabetes glomerulosclerosis (30,32,76–79). The pathophysiological changes that occur with glomerulosclerosis are similar to those of atherosclerosis, including mesangial proliferation/hypertrophy, foam-cell accumulation, appearance of extracellular matrix, deposits of amorphous debris, and evolving sclerosis (30). Mesangial cell abnormalities, including mesangial expansion, are a hallmark of this process. Mesangial expansion is characterized by hypertrophy/hyperplasia and matrix overproduction (30,76–79). Mesangial expansion, leading to diffuse intercapillary sclerosis, typically occurs after 5–15 years of clinical diabetes in those with type 1 diabetes (30,76). Nodular intercapillary sclerosis is seen in ~25% of people with diabetic glomerulosclerosis (30,76). Basement membranes are specialized regions of extracellular matrix composed of proteoglycans, type IV collagen, laminen, and entactin/nitogen, which collectively form a complex mesh-like structure (30). Sieve-like permselectivity is an integral function of basement membrane that is progressively lost in diabetes, with associated progressive proteinuria (30). Nonenzymatic glycosylation of basement membrane collagen IV and laminen and their cross-linkage lead to modification of basement membrane ultrastructure and loss of permselectivity (30). Nonenzymatic glycation results in production of advanced glycation end products, which bind to mesangial cells with resulting increases in fibronectin and other structural proteins. Thus, hyperglycemia, by promoting nonenzymatic glycation, promotes diabetic glomerulosclerosis. SPECIAL TREATMENT CONSIDERATION IN RELATION TO CVD AND RENAL DISEASE ASSOCIATED WITH DIABETES— Several of the newer oral hypoglycemic agents have been demonstrated to have effects on cardiovascular tissues that may ameliorate diabetic CVD. Thiazolidinediones have been shown to decrease VSMC proliferation and decrease vascular contractility (21,80,81). Metformin has been demonstrated to promote VSMC glucose uptake in conjunction with insulin and IGF-1 receptor autophosphorylation (82). These effects can potentially overcome the vascular resistance to the actions of insulin and IGF-1 that exists in type 2 diabetes (32). The thiazolidinedione troglitazone has also been shown to obviate delayed diastolic relaxation in a model of diabetic cardiomyopathy (72). However, prospective controlled trials of morbidity and mortality with these agents need to be done to determine if they impact CVD mortality in diabetes. That therapy with ACE inhibitors may potentially impact CVD and renal disease in people with diabetes is supported by intriguing preliminary information. Polymorphism of the ACE gene has been associated with coronary artery disease, myocardial infarction, left ventricular hypertrophy, and diabetic nephropathy (83–85). ACE inhibitors have been shown to have a number of protective mechanisms opposing cardiovascular growth and remodeling (86,87). However, clinical trials evaluating the impact of ACE inhibitors on CVD mortality are needed to determine if their theoretical vascular protection translates to decreased CVD in diabetic patients. Considering that angiotensin II is a powerful stimulator of mesangial cell hypertrophy (30), it is not surprising that ACE inhibition abrogates this process as well as progression of diabetic glomerulosclerosis (88). A 5-year clinical trial of ACE inhibitor therapy administered to type 2 diabetic subjects in the early stages of diabetic nephropathy resulted in long-term stabilization of renal function and proteinuria, an effect independent of blood pressure lowering (89). Because people with diabetes generally have a more atherogenic LDL particle, a low HDL level, and high triglycerides, it has been recommended that they be treated in a secondary prevention mode, lowering their LDL levels to <100 mg/dl (90,91). There may also be a role for antioxidants, which counteract the high oxidative stress that exists in the diabetic state. For example, probucol, an antioxidant drug, has been reported to reduce oxidation of LDL in type 2 diabetes (92). Supplements of vitamin C for 4 months in older type 2 diabetic patients increased glutathione levels and reduced LDL levels (93). Acute infusion of vitamin C into the forearm of type 2 diabetic subjects resulted in an improvement in endothelium-dependent vasodilator function (94), likely reflecting the immediate free radical scavenging activity of vitamin C. In type 2 diabetic patients, vitamin E supplementation decreases platelet aggregation and reduces the susceptibility of LDL to copper-mediated oxidation (95). 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Scala Moy C, Laporte R, Dorman J: Insulin dependent diabetes mellitus mortality: the risks of cigarette smoking. Circulation 82:37–43, 1990 From the Endocrine, Metabolism, Hypertension and Vascular Biology Programs, Wayne State University School of Medicine, Detroit, Michigan. Address correspondence and reprint requests to: James R. Sowers, MD, Division of Endocrinology, Metabolism and Hypertension, Wayne State University School of Medicine, 4201 St. Antoine, UHC-4H, Detroit, MI 48201. E-mail: sowers@oncgate.roc.wayne.edu. Received for publication 6 July 1998 and accepted in revised form 13 October 1998. J.R.S. has received honoraria and consulting fees from Boehringer Ingelheim and has served on an advisory panel for Marion-Hoescht Roussel. Abbreviations: CVD, cardiovascular disease; FFA, free fatty acid; Ox-LDL, oxidized LDL; VSMC, vascular smooth muscle cell. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. This article is based on a presentation at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
