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Section of Endocrinology (V.F., C.D., S.A.), Department of Medicine, Tulane University Medical Center, New Orleans, Louisiana 70112; and Laboratory for Atherosclerosis and Metabolic Research (I.J.), University of California Davis, Sacramento, California 95817
Correspondence: Address all correspondence and requests for reprints to: Vivian A. Fonseca, M.D., Professor of Medicine, Director, Tulane Diabetes Program, Department of Medicine, Section of Endocrinology, Tulane University Medical Center SL53, 1430 Tulane Avenue, New Orleans, Louisiana 70112-2699. E-mail: vfonseca{at}tulane.edu
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Abstract |
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 Top Abstract I. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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I. Introduction |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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) may be important in people with diabetes (4, 5). Several studies have demonstrated the importance of these factors in the pathogenesis of CVD in diabetes. However, very few of them have demonstrated prospectively the associations of nontraditional risk factors in diabetes, independent of traditional risk factors (5). Several therapeutic strategies that are currently used in the management of diabetes can improve these nontraditional risk factors. For example, lipid management with statins reduces markers of inflammation in plasma (6). Similarly, insulin sensitizers have a variety of effects on many of these risk factors (7).
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It is important to recognize that these risk factors do not function in isolation. In fact, they frequently "cluster" in individual patients and possibly interact with each other, although such interactions are hard to quantify. Figure 1 represents a hypothetical model of interaction of various risk factors. Although some of these risk factors cluster, others appear to be independent of each other. Furthermore, studies on these risk factors are usually either epidemiological descriptions of associations with CVD or experimental studies focusing on a single risk factor. We recognize that CVD is a complex multifactorial disease and that many of these processes are functioning simultaneously (8). Nevertheless, in the interest of simplicity, we will consider each risk factor separately.
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Many of these risk factors may be common antecedents for both diabetes and CHD, supporting the hypothesis that both disorders arise separately from "common soil" (9). Possible common antecedents include insulin resistance (IR) and inflammation, which have been shown to be independent risk factors for CHD and are clearly associated with type 2 diabetes. Consistent with the common soil hypothesis, some of these nontraditional risk factors have also predicted incident diabetes in the same studies, suggesting that they are altered in the prediabetic state, during which both IR and inflammation are often present. Inflammation, endothelial dysfunction, and abnormalities of coagulation are all associated with IR and may thereby become common antecedents of both diabetes and CHD (9).
B. Natural history of vascular abnormalities in the pathogenesis of CVD in diabetes
The current concepts with regard to atherosclerosis suggest that the earliest event in atherogenesis is endothelial cell dysfunction manifesting as deficiencies of nitric oxide (NO) and prostacyclin. This can be induced by various noxious insults including dyslipidemia, diabetes, hypertension, smoking, etc. Recent data suggest that the prediabetic state may be associated with endothelial dysfunction possibly due to IR. The next event in atherogenesis is the binding of mononuclear cells, such as monocytes and T lymphocytes, to the endothelium; this binding is mediated by adhesion molecules present on the endothelial surface, such as vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), and E-selectin. Once the monocyte migrates into the subendothelial space, it matures into a resident macrophage, takes up lipid largely through certain scavenger receptors such as SR-A and CD-36, and becomes a foam cell. In the later stages of atherogenesis, smooth muscle cells migrate to the surface and form the fibrous cap of the lesion. Finally, lipid-laden macrophages release matrix metalloproteinases causing plaque rupture and acute coronary syndromes such as myocardial infarction and unstable angina.
Oxidative stress plays a crucial role in atherogenesis, especially in diabetes (10, 11). Several lines of evidence support a proatherogenic role for oxidized low-density lipoprotein (Ox-LDL) and its in vivo existence (12, 13). Ox-LDL is not recognized by the LDL receptor but by the scavenger receptor pathway on macrophages, which results in unregulated cholesterol accumulation, leading to foam cell formation. Factors that may promote increased oxidative stress in diabetes include antioxidant deficiencies, increased production of reactive oxygen species, and the process of glycation and glycooxidation (13).
Direct evidence of increased oxidative stress and lipid peroxidation in diabetes has been reported and recently reviewed (11). Clinical markers include F2-isoprostanes, which are prostaglandin-like compounds formed in vivo from free radical-catalyzed peroxidation of arachidonic acid and have emerged as novel and direct measures of oxidative stress. F2-isoprostane levels are increased in both the urine and plasma of patients with type 2 diabetes (14, 15, 16). Also, patients with type 2 diabetes have elevated plasma levels of nitrotyrosine, another marker of protein oxidation (14, 15), as well as evidence of oxidative damage to DNA (17).
In summary, CVD is increased in diabetes due to a complex interplay of many traditional and nontraditional risk factors. The latter have recently been recognized to have a significant role in the initiation and the progression of atherosclerosis, over its long natural history from endothelial function to clinical events.
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II. Hyperinsulinemia/IR |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Unfortunately, it is difficult to measure IR in epidemiological studies, particularly in patients with advanced type 2 diabetes. Research studies have used complex experimental techniques to quantify insulin sensitivity (SI)/resistance. Epidemiological studies utilize hyperinsulinemia to define IR. Studies use either fasting plasma insulin alone or formulas based on plasma insulin and glucose (such as the homeostasis model assessment, commonly known as HOMA). Because plasma insulin concentrations are a reflection of both ambient glucose and pancreatic ß-cell function (which decreases even before the onset of type 2 diabetes), it is a poor marker of IR. Furthermore, lack of standardization of the insulin assay makes interpretation of plasma insulin concentration difficult. More, recently the World Health Organization (WHO) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP-ATP III) have attempted to define the syndrome for clinicians (NCEP-ATP III internet site http://www.nhlbi.nih.gov/guidelines/cholesterol/atp_iii.htm). Subjects identified using these clinical definitions have been shown to be at increased risk of CVD.
Prospective studies suggest that hyperinsulinemia may be an important risk factor for ischemic heart disease. The Quebec Heart Study studied men who were 45 to 76 yr of age and who did not have ischemic heart disease (22). A first ischemic event occurred in 114 men who were then matched for age, body mass index, smoking habits, and alcohol consumption with a control selected from among the 1989 men who remained free of ischemic heart disease during follow-up. Fasting insulin concentrations at baseline were 18% higher in the study patients than in the controls. High fasting insulin concentrations were an independent predictor of ischemic heart disease in these men after adjustment for systolic blood pressure, family history of ischemic heart disease, plasma triglyceride, apolipoprotein B, LDL cholesterol, and HDL cholesterol concentrations. Similarly, hyperinsulinemia was associated with increased all-cause and cardiovascular mortality in Helsinki policemen independent of other risk factors (23). Because correlations of insulin with other risk factors make interpretation difficult, factor analysis to study the clustering of risk factors in the baseline data of the Helsinki Policemen Study was carried out. Factor analysis including only risk factor variables proposed to be central components of IRS predicted the risk of CHD and stroke independently of other risk factors (24).
Other population studies have supported these studies (25, 26, 27). Nevertheless, it is important to recognize that the relationship between IR and plasma insulin may not be linear (28), and some studies have been negative (29). A recent metaanalysis, however, cautioned that the association was somewhat weak, although statistically significant (25). The metaanalysis resulted in an estimated summary relative risk of 1.18 for differences in insulin level, equivalent to the difference between the 75th and 25th percentiles of the general population. Ethnic background and type of insulin assay modified the relationship between insulin and CVD. Overall, these studies confirm that components of the syndrome are present for several years before the onset of type 2 diabetes and that the "clock for coronary heart disease starts ticking before the onset of clinical diabetes" (27).
B. Proposed mechanisms linking IR with CVD in diabetes
The exact mechanism by which IR causes CVD is not known. However, IR is associated with several other cardiovascular risk factors, some of which are discussed below. Insulin-resistant type 2 diabetic subjects have more atherogenic cardiovascular risk factor profiles than insulin-sensitive type 2 diabetic subjects, and this is only partially related to increased obesity and an adverse body fat distribution (30).
1. Obesity.
Obesity is frequently associated with several of the components of the IRS and may be critical for the development of the syndrome. Several mechanisms have been proposed for the link between obesity and the IRS (31). Cardiovascular morbidity and mortality are increased in obese individuals independently of other risk factors. IR is very common in obese individuals. However, some nonobese individuals demonstrate hyperinsulinemia and the other features of the IRS (32). Thus, obesity may not be essential for the expression of the syndrome, but the presence of obesity or weight gain may accentuate the pathophysiological changes associated with the syndrome.
Body fat distribution rather than body mass may actually be a better predictor of IR and cardiovascular risk (33). IR, type 2 diabetes, and hypertension are more closely associated with a central distribution of adiposity than with general increases in fat mass. Waist circumference serves as a clinical surrogate of intraabdominal fat and correlates with insulin levels and IR.
Adipose tissue is now recognized to be a significant endocrine organ secreting a variety of hormones and cytokines. Data suggest that some of these cytokines arising from adipose tissue may be partly responsible for the metabolic, hemodynamic, and hemostatic abnormalities associated with IR. Studies show a close relationship between obesity and circulating C-reactive protein (CRP), TNF
, and IL-6, and some of these cytokines are predictors of CVD. Plasma CRP is elevated in obese subjects who have other features of the IRS (34). Thus, inflammation originating from excess adipose tissue cytokine production may contribute not only to the development of the IRS but also to the associated CVD.
Increased expression of TNF in adipose tissue has been reported in obese subjects. TNF inhibits the action of lipoprotein lipase and stimulates lipolysis. TNF promotes monocyte adhesion to the endothelium and inhibits endothelial nitric oxide synthase (eNOS). TNF also impairs the function of the insulin-signaling pathway by effects on phosphorylation of both the insulin receptor and insulin receptor substrate-1. IL-6 may also induce endothelial expression of cytokines, thereby contributing to endothelial dysfunction.
2. Dyslipidemia.
Hyperlipidemia is well established as a risk factor in diabetics to the same extent as in nondiabetics. However, certain qualitative abnormalities in the lipoprotein pattern associated with IR appear to convey excess risk and could be classified as nontraditional risk factors. One of the characteristic relationships between IR and a cardiovascular risk factor is with "diabetic dyslipidemia" (35). The hallmark of the syndrome is hypertriglyceridemia and low plasma HDL cholesterol concentration. Plasma LDL cholesterol concentrations in insulin-resistant subjects are no different from those in insulin-sensitive subjects. However, there are qualitative changes in LDL cholesterol resulting in "pattern B" distribution of LDL particles, which consists of smaller LDL particles that are more susceptible to oxidation and thus potentially more atherogenic (36). Small dense LDL particles permeate the arterial wall faster and bind more avidly to proteoglycans than larger LDL particles.
IR at the level of adipose tissue may result in increased activity of hormone-sensitive lipase and therefore increased breakdown of stored triglycerides. Free fatty acids (FFAs) released from adipocytes, particularly intraabdominal adipocytes, can be transported to the liver where they stimulate synthesis of triglycerides and assembly and secretion of very LDL (VLDL). Increased plasma VLDL triglycerides exchange with cholesterol esters from HDL, resulting in a lower plasma HDL cholesterol. On the other hand, an increase in circulating FFA has been proposed as having an etiological role in the development of IR (37). The effect of treatment of IR on dyslipidemia is discussed in Section II.B.3.
3. Hypertension.
Although it is well established that essential hypertension is frequently associated with IR, the impact of this abnormality on blood pressure homeostasis is still a matter of debate. Fasting plasma insulin is frequently higher in hypertensive subjects, and glucose disposal during an euglycemic clamp is decreased. The association between hypertension and IR is more convincing in obese subjects. Significant decreases in blood pressure have been observed in obese subjects who lose modest amounts of weight, correlating closely with the decline in fasting plasma insulin concentrations. Plasma insulin concentrations are higher and insulin-mediated total-body glucose disposal is reduced in young, normal weight individuals with essential hypertension (20). The impairment in insulin-mediated glucose disposal was closely related to the increase in blood pressure. Multiple potential mechanisms by which IR may cause hypertension have been proposed (38). These include resistance to insulin-mediated vasodilation, impaired endothelial function, sympathetic nervous system overactivity, sodium retention, increased vascular sensitivity to the vasoconstrictor effect of pressor amines, and enhanced growth factor activity leading to proliferation of smooth muscle walls. However, some studies do not support the association of metabolic IR with essential hypertension. Clearly, hypertension is itself a complex disorder with many etiologies, and not all subjects with essential hypertension are insulin resistant.
4. Abnormal insulin signaling, hyperinsulinemia, and the vasculature.
As outlined above, IR with resultant hyperinsulinemia is an independent risk factor for CVD. It is important to recognize that although hyperinsulinemia is frequently used as a surrogate marker for underlying IR, it is still controversial whether insulin itself is the culprit, and the specific role of insulin in the pathogenesis of atherosclerosis remains unclear. In fact, insulin has vasodilatory and antiinflammatory properties, which should protect against atherosclerosis. Several mechanistic hypotheses have been proposed to explain this controversy (20, 39). First, insulin is a growth factor that stimulates vascular cell growth and synthesis of matrix proteins. Second, the insulin signaling pathway thought to be responsible for abnormalities in glucose metabolism is also involved in NO production. Thus, the abnormal intracellular signaling that causes hyperglycemia may also be responsible for vascular disease due to loss of insulin’s antiatherogenic properties, whereas hyperinsulinemia continues to stimulate growth-promoting enzymes such as MAPK (39). Although some controversy remains, this hypothesis has been supported by many studies. In addition, imbalances in insulin homeostasis are associated with abnormalities in expression and action of various peptides, growth factors, and cytokines. These include angiotensin II, endothelin-1, and IGF-I (39). Although the exact role of peroxisome proliferator-activated receptors in the pathogenesis of this syndrome is unclear, several studies support the concept that they may have a role in the development of not only IR but also atherosclerosis (40). For example, these receptors are present in vascular tissue, heterozygous mutations in the ligand-binding domain of peroxisomal proliferator-activated receptor-
are occasionally associated with IR, and agonists of these receptors have a significant impact on the syndrome.
In summary, IR is a key abnormality linking type 2 diabetes and CVD. By its clinical definition, it is associated closely with traditional cardiovascular risk factors. As discussed in Section III, it is also significantly related to nontraditional risk factors as well.
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III. Endothelial Dysfunction |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Many of the functions of the endothelium are maintained through paracrine and endocrine regulatory substances secreted from endothelial cells, which may often have opposing actions. For example, endothelial cells secrete NO, the most potent known vasodilator. Endothelial cells also secrete other important vasodilators such as prostacyclin. The vasodilatory actions are opposed by secretion of potent vasoconstrictors such as endothelin 1. Similarly, these and other endothelial products are involved in maintaining the balance between smooth muscle cell growth, promotion and inhibition, thrombosis and fibrinolysis, inflammation, and cell adhesion.
Assessment of endothelial function can be broadly divided into biochemical and functional. Biochemical parameters of endothelial dysfunction have frequently been described as risk factors for CVD and include plasma von Willebrand factor (vWF), thrombomodulin, and several adhesion molecules such as VCAM, ICAM, E-Selectin, and P-Selectin. Functional assessment is dependent on the ability of blood vessels to dilate in response to a number of varied stimuli, such as shear stress and acetylcholine infusion. These stimuli result in the release of NO from the endothelium and therefore measure endothelium-dependent vasodilation. Details of the various methods used to assess endothelial function are beyond the scope of this review.
The ability of blood vessels to dilate in response to stimuli, including ischemia, is called vascular reactivity or flow-mediated dilation (FMD). Brachial artery vascular reactivity is a noninvasive method of assessing arterial endothelial function in vivo. Because endothelial injury is an early event in atherogenesis, it has been suggested that abnormal FMD may precede the development of structural changes in the vessel wall. Abnormal FMD has been shown in several insulin-resistant states and is present in relatives of patients with type 2 diabetes who have normal glucose tolerance. It has even been proposed that endothelial dysfunction may be a precursor of the IRS (43).
Table 2 lists various endothelial abnormalities associated with IR.
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Impaired endothelial function was first associated with CVD when Ludmer et al. (49) injected acetylcholine into coronary arteries and demonstrated paradoxical vasoconstriction, instead of the expected vasodilation. Schachinger et al. (44) assessed coronary endothelial vasomotor function in response to acetylcholine and nitroglycerin infusion in 147 patients undergoing cardiac catheterization. During a 7.7-yr follow-up, 16 patients had a cardiovascular event, and endothelial-dependent and -independent vasodilation was significantly worse in these 16 patients (44, 45). Suwaidi et al. (49A ) tested endothelial function in 157 patients with mild coronary atherosclerosis. During a 28-month follow-up, six patients had cardiovascular events, and all six had prior evidence of severe endothelial dysfunction. A recent large study has demonstrated that epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without coronary artery disease, providing both functional and prognostic information that complements angiographic and risk factor assessment (50).
Finally, impaired brachial artery reactivity independently predicts postoperative cardiac events such as myocardial infarction, unstable angina, stroke, and cardiac death in patients undergoing vascular surgery (51).
It has become clear that among its many actions insulin is also a vasoactive hormone (52, 53, 54, 55, 56). Its effect to cause endothelial-NO-dependent vasodilation is physiological and dose dependent (57). Insulin has been shown to induce expression of the enzyme NO synthase (NOS) (58), and this effect is inhibited by cytokines important in the pathogenesis of IR (59). Importantly, the effect of insulin on NOS is mediated through the same intracellular signaling pathway as the effect of insulin on glucose metabolism (60). Thus, IR in glucose metabolism and in the vasculature can be explained on the basis of a single defect. Recent data suggest that the metabolic and vascular actions of insulin are closely linked. Insulin-resistant states exhibit diminished insulin-mediated glucose uptake into peripheral tissues as well as impaired insulin-mediated vasodilation and impaired endothelium-dependent vasodilation to the muscarinic receptor agonist, acetylcholine. Thus, insulin action in peripheral tissues is probably linked to its action on endothelium.
Basal forearm blood flow in diabetic and nondiabetic subjects is comparable. The forearm blood flow responses to both methacholine chloride and nitroprusside are significantly attenuated in diabetic compared with nondiabetic subjects.
Endothelial dysfunction is also detectable in young normotensive first-degree relatives of subjects with type 2 diabetes (61). There is a significant association between endothelial dysfunction and IR in young relatives of diabetic subjects independent of the classic cardiovascular risk factors (62). Caballero et al. (61) studied vascular reactivity in both the micro- and macrocirculation as well as biochemical markers of endothelial function in four age- and sex-comparable groups: healthy normoglycemic subjects with no family history of type 2 diabetes (controls), healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), subjects with impaired glucose tolerance (IGT), and patients with type 2 diabetes without vascular complications (diabetes). The vasodilatory responses to acetylcholine chloride were reduced in relatives, IGT, and diabetes compared with controls, as were the responses in the brachial artery diameter during reactive hyperemia. Compared with control subjects, endothelin-1 was significantly higher in all groups, vWF was higher only in the diabetic group, and soluble ICAM levels were higher in the IGT and diabetic groups, whereas soluble VCAM concentrations were higher in the relatives and those with diabetes. These results suggest that abnormalities in vascular reactivity and biochemical markers of endothelial cell activation are present early in individuals at risk of developing type 2 diabetes, even at a stage when normal glucose tolerance exists, and that factors in addition to IR, such as genetic factors, may be operative.
B. Proposed mechanisms linking endothelial dysfunction with CVD in diabetes
As discussed above, insulin itself has vasodilatory actions via a NO-dependent mechanism (63). In healthy subjects, insulin dilates arterioles supplying skeletal muscle, probably through enhancement of NO production. Some in vitro studies have documented that insulin regulates NOS, the enzyme that synthesizes NO from arginine. This action may be impaired in insulin-resistant subjects, an abnormality that might be attributable to either impairment in the ability of the endothelium to produce NO or enhanced inactivation of NO (63). Because NO plays a critical role in the maintenance of vascular health (41), this abnormality may explain much of the increased CVD in the IRS. Impairment of insulin action on glucose metabolism assessed by glucose clamp parallels impairment of insulin action on the vasculature. Thus, obesity and type 2 diabetes are associated with resistance to the vascular effects of insulin.
As discussed above, abnormalities in insulin signaling lead not only to IR in glucose metabolism but also abnormalities in the vasculature (39). Recent data suggest that insulin signaling through the phosphatidylinositol 3-kinase pathway is important in NO production in human vascular endothelial cells (64, 65, 66). Disruption of this signaling pathway (which is known to be associated with IR), may lead to a disturbance in NO production and contribute to vascular disease.
Increased levels of asymmetric dimethylarginine (ADMA) are associated with endothelial dysfunction and increased risk of CVD. ADMA is an endogenous and competitive inhibitor of NOS (67). Plasma levels of this inhibitor are elevated in patients with atherosclerosis and in those with risk factors for atherosclerosis (67). In these patients, plasma ADMA levels are correlated with the severity of endothelial dysfunction and atherosclerosis. By inhibiting the production of NO, ADMA may impair blood flow, accelerate atherogenesis, and interfere with angiogenesis. Thus, plasma ADMA may be a novel risk factor for vascular disease (67). Stuhlinger et al. (68) have demonstrated that plasma ADMA concentrations are positively correlated with impairment of insulin-mediated glucose disposal in subjects with the metabolic syndrome, independent of hypertension. Pharmacological intervention with rosiglitazone enhanced SI and reduced ADMA levels (68). Increases in plasma ADMA concentrations may thus contribute to the endothelial dysfunction observed in insulin-resistant patients and also contribute to CVD in diabetes.
Tetrahydrobiopterin (BH4), an essential cofactor for the catalytic activity of eNOS, is depleted during states of oxidative stress because of excessive oxidation (69). Depleted BH4 causes eNOS to uncouple, which results in decreased NO production. IR has been shown to diminish the activity of the enzyme that produces BH4 in human coronary arteries with resultant BH4 depletion and endothelial dysfunction, which is reversed by BH4 administration (70). Treatment with BH4 has been shown to improve endothelial function in experimental diabetes (71).
Disturbances in other functions of the endothelium, such as increased expression of adhesion molecules and suppression of inflammation (discussed in Section IV), also play an important role in diabetes.
In summary, endothelial dysfunction is the earliest abnormality associated with CVD and occurs very frequently in patients with diabetes, often preceding the onset of hyperglycemia.
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IV. Impaired Fibrinolysis and Prothrombotic State |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Impaired fibrinolysis is now recognized as being an important component of the IRS and probably contributes considerably to the increased risk of cardiovascular events (30, 72). Plasma PAI-1 antigen and activity are elevated in a wide variety of insulin-resistant subjects including obese subjects with and without diabetes and women with the polycystic ovarian syndrome. Elevated levels of fasting insulin are associated with impaired fibrinolysis and hypercoagulability in subjects with normal glucose tolerance (78). Hyperinsulinemia is associated primarily with impaired fibrinolysis in subjects with glucose intolerance. Excess risk for CVD associated with hyperinsulinemia and glucose intolerance may be mediated in part by enhanced potential for acute thrombosis. Finally, abdominal fat produces PAI-1 and could contribute to increased plasma PAI-1 concentrations in human obesity associated with IR (79).
Coagulation disorders also play a role in increasing the risk of CHD in patients with type 2 diabetes (80). Platelets from patients with diabetes are more sensitive to several aggregating agents and have increased numbers of glycoprotein receptors and a lower activity of guanylate cyclase (80, 81). These factors may contribute to the documented hyperreactivity of platelets in patients with type 2 diabetes. Other factors in patients with type 2 diabetes include alterations in serum fibrinogen, and factors V, II, and VII, which have all been linked to the risk of myocardial infarction. Increased D-dimer, vWF antigen, A-II antiplasmin, and decreased antithrombin III have also been reported in patients with type 2 diabetes and reviewed elsewhere (80). Many of these abnormalities are nonspecific, and the association of IR with coagulation abnormalities is less robust than that with abnormal fibrinolysis. Serum fibrinogen is an acute phase reactant, and elevated plasma fibrinogen may be a manifestation of inflammation like CRP. Nevertheless, coagulation abnormalities probably play a role in increasing the frequency and severity of thrombotic events in patients with diabetes.
B. Proposed mechanisms linking impaired fibrinolysis and thrombosis with CVD in diabetes
Probably the most important component of disturbed coagulation in diabetes relates to the abnormal fibrinolysis due to changes in the dynamic equilibrium between endogenous tissue plasminogen activator and PAI-1 (82). Insulin, proinsulin, VLDL cholesterol, and various cytokines regulate PAI-1 synthesis and release. The greatest elevations in PAI-1 occur when there is a combination of hyperinsulinemia, hyperglycemia, and increased FFA in obese insulin-resistant subjects (83), and impaired fibrinolysis is closely related to the metabolic syndrome (84).
Basal fibrinolytic activity is decreased in patients with type 2 diabetes; this may accelerate atherosclerosis by exposing vascular luminal wall surfaces to persistent and recurrent thrombi. There is also evidence that PAI-1 content is increased in atherosclerotic lesions of patients with type 2 diabetes (85), suggesting that interventions to reduce IR and improve glycemic control may improve the fibrinolytic response. Diabetes is associated with increased PAI-1 in the arterial wall, which could decrease local fibrinolysis and elevate thrombus formation and the unfavorable evolution of atherosclerotic plaques (86). Insulin also inhibits platelet function, PAI-1, and transcription factors associated with coagulation (87, 88, 89). Dysregulation of these actions may contribute to the hypercoagulability in insulin-resistant states.
Immunohistochemical analysis of coronary lesions from patients with coronary artery disease has demonstrated an imbalance of the local fibrinolytic system with increased coronary artery tissue PAI-1 in patients with type 2 diabetes (85).
In summary, increased PAI-1 and, to a lesser extent, increased coagulation are very closely linked to IR and thereby could contribute to CVD in diabetes.
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V. Inflammation and CVD in Diabetes |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Several markers of inflammation have been used in various studies. Data suggest that plasma CRP, measured using an hs-CRP assay, appears to have a significant predictive value in determining the risk of future coronary events (90). CRP is an acute-phase protein produced by the liver in response to cytokine production (IL-6, IL-1, TNF). Figure 2 summarizes the hypothetical link between cytokines secreted by adipose tissue (adipokines), inflammation, and CVD in diabetes. The standard CRP test determines levels of CRP that increase up to 1000-fold in response to infection or tissue destruction but cannot adequately assess the normal range and thus cannot be used for cardiovascular risk prediction. hs-CRP assays detect changes in levels of CRP within the normal range. High levels in this range have been proven to predict future cardiovascular events. Other inflammatory risk factors, including oxidized lipids, infectious agents, and cytokine produced from adipocytes or other inflammatory cells, stimulate production of IL-6, which serves as a "messenger" cytokine that stimulates the liver to produce inflammatory substances such as CRP (93).
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Several other prospective studies have been published in which hs-CRP has predicted cardiovascular events after correction for various other risk factors (95, 96, 97, 98, 99, 100, 101). In all of these studies, the subjects have been free of clinical CVD at baseline. In 1997, Ridker et al. (94) demonstrated that subjects in the highest quartile of CRP (>2.1 mg/liter) had more than 2.5 increased risk of CVD compared with those in the lowest quartile of CRP (<0.55 mg/liter). Importantly, an elevated hs-CRP is specific for cardiovascular events but not for other diseases such as cancer (95, 102).
Recently, Ridker et al. (95) demonstrated that hs-CRP measurements add to the predicted value of total cholesterol in determining the risk of a first myocardial infraction. More importantly, subjects who have hs-CRP greater than the 75th percentile and a total cholesterol less than 75th percentile had a significantly increased risk of events.
The impact of hs-CRP interaction with lipids on cardiovascular risk has been reviewed recently (103). It appears that the predicted value of hs-CRP is independent of the total cholesterol and is additive to the risk determined by total cholesterol. It is particularly important to compare the value of measuring plasma CRP protein and LDL cholesterol levels in predicting cardiovascular risk. Ridker et al. (104) measured both at baseline in 27,939 apparently healthy American women, who were then followed for a mean of 8 yr. Although CRP and LDL cholesterol were minimally correlated (r = 0.08), baseline levels of each had a strong linear relation with the incidence of cardiovascular events. After adjustment for other factors, the relative risks of first cardiovascular events according to increasing quintiles of CRP, as compared with the women in the lowest quintile, were 1.4, 1.6, 2.0, and 2.3 (P < 0.001), whereas the corresponding relative risks in increasing quintiles of LDL cholesterol, as compared with the lowest, were 0.9, 1.1, 1.3, and 1.5 (P < 0.001) (104). A significant proportion of events occurred among women with normal LDL cholesterol. By contrast, because CRP and LDL cholesterol measurements tended to identify different high-risk groups, screening for both biological markers provided better prognostic information than screening for either alone. Independent effects were also observed for CRP in analyses adjusted for all components of the Framingham risk score (104). These data suggest that the CRP level is a stronger predictor of cardiovascular events than the LDL cholesterol level and that it adds prognostic information to that conveyed by the Framingham risk score.
Because many of the features of the metabolic syndrome are associated with increased levels of CRP, it is important to evaluate the relationship between the two (105). Among 14,719 apparently healthy women who were followed up for an 8-yr period, 24% had the metabolic syndrome at study entry. At baseline, median CRP levels for those with zero, one, two, three, four, or five characteristics of the metabolic syndrome were 0.68, 1.09, 1.93, 3.01, 3.88, and 5.75 mg/liter, respectively [P(trend) <0.0001] (106). Over the 8-yr follow-up, cardiovascular event-free survival rates based on CRP levels above or below 3.0 mg/liter were similar to survival rates based on having three or more characteristics of the metabolic syndrome. At all levels of severity of the metabolic syndrome, however, CRP added prognostic information on subsequent risk (106).
Recently, recommendations have been made on standardization of the hs-CRP assay methodology and simplification of ranges of plasma hs-CRP as risk indicators. Using widely available high-sensitivity assays, CRP levels of less than 1, 1–3, and more than 3 mg/liter correspond to low-, moderate-, and high-risk groups for future cardiovascular events (107). Individuals with LDL cholesterol below 130 mg/dl who have CRP levels more than 3 mg/liter represent a high-risk group often missed in clinical practice. The addition of CRP to standard cholesterol evaluation may thus provide a simple and inexpensive method by which to improve global risk prediction and compliance with preventive approaches (107).
In summary, hs-CRP measurement has shown to be an important risk marker of CVD, as well as the risk of developing diabetes, and thereby has several potential clinical applications. Plasma hs-CRP measurements could serve as an adjunct to lipid screening in the protection of individuals at high risk for both conditions, e.g., the metabolic syndrome. It may provide us with a method to better target statin therapy, particularly in the setting of primary prevention. It may have potential prognostic value in acute coronary syndrome. Finally, inflammation is likely to represent a new target for treatment and prevention of cardiovascular events and possibly even diabetes.
B. Proposed mechanisms linking inflammation with CVD in diabetes
The mechanism linking inflammation with CVD in diabetes is not clear. It has been proposed that the markers of inflammation may be somewhat nonspecific. Nevertheless, a recent paper by Burke et al. (108) reported that CRP is present in the lipid core of atherothrombotic lesions in subjects who die suddenly. The CRP is present adjacent to cholesterol and clots. In this context, a recent in vivo study has demonstrated that CRP, at concentrations known to predict adverse vascular events, directly quenches the production of the NO, in part, through posttranscriptional effects on eNOS mRNA stability (95, 96, 97, 101, 109). CRP promotes monocyte chemotaxis, cytokine release, and tissue factor secretion. In endothelial cells, CRP inhibits eNOS and stimulates adhesion molecules (VCAM and ICAM) and adhesion of monocytes to the endothelial cells (110).
Of particular importance to the subject of CVD in diabetes is the fact that hs-CRP clusters with other risk factors associated with diabetes (95, 96), including other features of the metabolic syndrome (34). Much of the link between CRP with the metabolic syndrome could relate to obesity and increased CRP production in response to a signal from adipose tissue through a variety of cytokines. An elevated CRP is common in patients with obesity: 60% in women with a body mass index greater than 30 kg/m2 in one study (111). Plasma levels of TNF, an important mediator of inflammation, are elevated in people with obesity and fall with weight loss (112). Although obesity itself may explain a link between diabetes and inflammation, other factors, including a diet containing foods with a high glycemic load, may also play a role (113). Glucose intake also results in an increase in production of reactive oxygen species (114).
Recent data have suggested that an elevated hs-CRP in high-risk subjects may predict the subsequent development of type 2 diabetes. In at least one study, the predictive value of hs-CRP for the development of diabetes appeared to be independent of obesity (115). Other studies that have demonstrated the relationship between elevated CRP and the risk of conversion to diabetes include the Cardiovascular Health Study (116) and the Insulin Resistance Atherosclerosis Study (117). In the West of Scotland Coronary Prevention Study (118, 119), the baseline plasma samples for CRP measurement were available for 5245 men, of whom 127 were classified as having a transition from normal glucose control to overt diabetes during the study. Baseline CRP was an important predictor of the development of diabetes in univariate analysis (hazard ratio for an increase of 1 SD = 1.55). In multivariate analysis, CRP remained a predictor of diabetes development independent of other clinically employed predictors, including baseline body mass index and fasting triglyceride and glucose concentrations. Moreover, there was a graded increase in risk across CRP quintiles throughout the study, evident at even 1 yr of follow-up. The highest quintile (CRP > 4.18 mg/liter) was associated with a greater than 3-fold risk of developing diabetes in a multivariate analysis at 5 yr. Thus, CRP predicts the development of type 2 diabetes independently of established risk factors.
Although definitive proof of a causal role of infection contributing to atherogenesis is lacking, multiple investigations have demonstrated that infectious agents evoke cellular and molecular changes supportive of such a role (120, 121). Moreover, both Chlamydia pneumoniae and cytomegalovirus exacerbate lesion development in animal models of atherosclerosis and restenosis. Additional human studies are necessary to further test the validity of the infection/atherosclerosis link and to provide more insight into the mechanisms by which infection may contribute to atherosclerosis, information critical for devising strategies to reduce or eliminate any contribution to atherosclerosis caused by infection.
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VI. Microalbuminuria |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Several studies have demonstrated that microalbuminuria is a risk factor for cardiovascular events (122, 123, 124, 125, 126, 127). Recent data suggest that it may occur even in nondiabetics and be a precursor of CVD and may be related to IR (128, 129, 130, 131). Microalbuminuria may precede and predict the development of type 2 diabetes (132), and the progression of microalbuminuria is associated with a worsening prognosis for CVD risk (127).
B. Proposed mechanisms linking microalbuminuria with CVD in diabetes
In population-based studies, an increased urinary albumin excretion rate has been shown to cluster with other CVD risk factors and is included in the criteria used by the WHO to define the IRS. Indeed, microalbuminuria has been correlated with insulin levels (after an oral glucose load), salt sensitivity, resistance to insulin-stimulated glucose uptake, central obesity, dyslipidemia, left ventricular hypertrophy, and the absence of nocturnal drops in both systolic and diastolic blood pressures. Elevated systolic blood pressure is a significant determining factor in the development of microalbuminuria and the progression of albuminuria in type 2 diabetes. This is very important, because insulin-resistant patients, like those with clinical diabetes, have a predilection toward elevated blood pressures.
In insulin-resistant individuals, microalbuminuria may be a manifestation of endothelial dysfunction (133) indicating endothelial permeability and is also related to increased carotid intima-media thickness (IMT) (134). Data also suggest that microalbuminuria reflects increased leakage of albumin across the endothelial barrier and is therefore a clinically easily measurable indicator of endothelial integrity. Indeed, patients with microalbuminuria are likely to have several biochemical and functional abnormalities of endothelial function.
In summary, microalbuminuria is a strong, clinically useful, and easily treatable predictor of CVD in diabetes. Furthermore, the onset of microalbuminuria is associated with the development of abnormalities in most of the other nontraditional risk factors, which are discussed in this review.
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VII. Hyperhomocysteinemia |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Elevated plasma tHcy concentrations, both fasting and postmethionine load, are associated with higher prevalence of CVD in patients with diabetes (135, 140). In a study of more than 300 type 2 diabetes patients, plasma tHcy concentration was noted to be strongly and independently associated with the presence of CHD. Each micromole per liter of increment of fasting plasma tHcy concentration was associated to an odds ratio of 1.45 for the presence of CHD (59). In another population-based study, the odds ratio per 5 µmol/liter increments in plasma tHcy concentration for any CVD was 1.38 in normal glucose tolerance, 1.55 in IGT, and 2.33 in non-insulin-dependent diabetes mellitus (138). Thus, the magnitude of association is stronger (1.6-fold) for type 2 diabetes patients than in nondiabetic subjects. These findings may relate to an interaction of age, IR, and diabetes on both homocysteine metabolism and CVD.
B. Proposed mechanisms linking homocysteine with CVD in diabetes
Putative mechanisms of atherothrombosis in hyperhomocysteinemia include endothelial cell injury, endothelial dysfunction, increased vascular smooth muscle cell growth, increased platelet adhesiveness, enhanced LDL oxidation and deposition in the arterial wall, and direct activation of the coagulation cascade. The vascular changes in hyperhomocysteinemia are likely to be multifactorial and have been reviewed previously (135).
Evidence exists that directly relates hyperhomocysteinemia to endothelial dysfunction. Vascular reactivity is significantly impaired in elderly patients with hyperhomocysteinemia compared with control subjects (141). In contrast, vasodilation after administration of sublingual nitroglycerin (endothelium independent) is normal. Endothelium-dependent and -independent vasodilation is significantly impaired in elderly subjects with hyperhomocysteinemia compared with control subjects in the absence of diabetes (142).
Hyperhomocysteinemia has also been associated with albuminuria and renal failure (143, 144). Urinary albumin excretion rates correlate with the fasting and postmethionine load plasma tHcy concentrations (145, 146). Patients with diabetes and microalbuminuria have higher fasting tHcy concentrations than those with normal albumin excretion.
Finally, the potential regulation of homocysteine metabolism by insulin, through regulation of the enzyme cystathionine ß-synthase, provides a mechanistic link between hyperhomocysteinemia and diabetes (135, 143, 148, 149, 150).
In summary, hyperhomocysteinemia appears to be a risk factor for cardiovascular events in patients with diabetes, although it may be a marker of established vascular damage rather than a primary risk factor. Specific treatment of hyperhomocysteinemia appears attractive and may be an inexpensive therapy for reducing risk and improving prognosis of patients with established CVD, although further clinical trials in patients with diabetes are needed.
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VIII. Vascular Wall Abnormalities—Carotid IMT and Arterial Stiffness |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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Recent advances in technology have resulted in the development of techniques to detect early structural and functional changes that occur in the vessel wall. These changes include measurement of carotid IMT and aortic pulse wave velocity and arterial stiffness (152). IMT represents a structural abnormality in the arterial wall and is a particularly good predictor of subsequent cardiovascular risk (153).
IMT is a safe noninvasive and validated method that uses high-resolution B-mode ultrasound images and permits quantitative measurements of the vessel wall, most often the carotid artery. Methods of IMT measurement can be categorized by two approaches: 1) measurement at multiple extracranial carotid sites in near and far walls; and 2) computerized measurement restricted to the far wall of the distal common carotid artery. IMT values correlate well with cardiovascular outcomes, other cardiovascular risk factors, and change in risk during disease management. IMT measurement thus has become an important component of epidemiological studies of cardiovascular risk as well as studies of the effect of interventions on surrogate markers for cardiovascular outcomes.
Several studies have demonstrated abnormal carotid IMT in patients with diabetes (151, 152, 153, 154, 155). Many of these studies have suggested a link between increased carotid IMT and IR (156). This finding is compatible with the possible effect of hyperinsulinemia on growth of vascular smooth muscle cells and extracellular matrix (157). Carotid IMT is increased in newly diagnosed patients with type 2 diabetes without overt CVD (158). Thus, carotid IMT represents a structural abnormality in the arterial wall and is a good predictor of subsequent cardiovascular risk (159).
Increased arterial stiffness is another indicator of early atherosclerosis that has been found with increased frequency in patients with diabetes (160). Arterial stiffness can be assessed noninvasively by either direct or indirect methods (160). Whereas a simple measure of pulse pressure may be an indicator of arterial stiffness, a more robust method is measurement of aortic pulse wave velocity. These measurements of arterial stiffness have been shown in several studies to be predictive of cardiovascular events in diabetics as well as nondiabetics (160, 161, 162, 163, 164). Interestingly, arterial stiffness is associated with IR (165, 166) and also correlates with carotid IMT (167) and endothelial dysfunction (168, 169).
Another vascular abnormality used in clinical practice is calcification of the arterial wall, which has been applied using electron beam-computed tomography (EBCT) as a simple noninvasive marker of established CVD (170). Abnormal calcium scores on EBCT are remarkably common in patients with diabetes, although the significance of such abnormalities in predicting cardiovascular events in these patients is unclear in testing therapeutic interventions (151, 171, 172, 173). Nevertheless, carotid IMT and EBCT provide valid measures of subclinical atherosclerosis.
B. Proposed mechanisms linking vascular wall abnormalities with CVD in diabetes
The Insulin Resistance Atherosclerosis Study (156) evaluated SI by the frequently sampled iv glucose tolerance test with analysis by the minimal model of Bergman and measured IMT of the carotid artery. There was a significant negative association between SI and the IMT of the carotid artery both in Hispanics and in non-Hispanic whites. This effect was not totally explained by adjustment for traditional CVD risk factors, including glucose tolerance, measures of adiposity, and fasting insulin levels. There was no association, however, between SI and the IMT of the carotid artery in blacks.
Increased arterial stiffness in diabetes may be related to glycation of arterial collagen and elastin and accumulation of advanced glycation end products (174). However, nondiabetic young relatives of patients with diabetes also have arterial stiffness (175, 176), suggesting some genetic influence or perhaps early metabolic abnormality such as IR.
In summary, patients with diabetes have several abnormalities in the vessel wall that are related to both IR and hyperglycemia and may predict future events.
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IX. Postprandial Hyperglycemia |
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TopAbstractI. IntroductionII. Hyperinsulinemia/IRIII. Endothelial DysfunctionIV. Impaired Fibrinolysis and...V. Inflammation and CVD...VI. MicroalbuminuriaVII. HyperhomocysteinemiaVIII. Vascular Wall...IX. Postprandial HyperglycemiaX. Impact of Various...XI. Summary and Clinical...References |
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The oral glucose tolerance test, although not physiological, has commonly been used as the model of the postprandial state. Epidemiological studies have shown that IGT is associated with an increased risk of CVD, with the blood glucose concentration 2 h after the glucose challenge being a direct and independent risk factor (178, 179, 180, 181, 182, 183, 184, 185, 186, 187). These studies have demonstrated that subjects with mild to moderate hyperglycemia, after an oral glucose load (but not necessarily in the fasting state), have an increased cardiovascular risk. Furthermore, the postchallenge, as well as postprandial, glucose concentrations of subjects with type 2 diabetes were found to be directly associated with incident CVD, independent not only of fasting glucose, but also other risk factors (187).
The DECODE study assessed mortality associated with the American Diabetes Association fasting-glucose criteria compared with the WHO 2 h postchallenge glucose criteria (179). Baseline data were analyzed on glucose concentrations at fasting and 2 h after the 75-g oral glucose tolerance test from 13 prospective European cohort studies, which included 18,048 men and 7,316 women aged 30 yr or older. Mean follow-up was 7.3 yr. The risk of death according to the different diagnostic glucose categories was computed. Compared with subjects who had normal fasting glucose, patients with newly diagnosed diabetes mellitus by the American Diabetes Association fasting criteria had a significantly increased hazard ratio for death. In contrast, for impaired fasting glucose, the hazard ratios were increased for men but not for women. For the WHO criteria (using an oral glucose tolerance test), the ratios were significantly increased in both men and women for newly diagnosed diabetes as well as for IGT. Within each fasting-glucose classification, mortality increased with increasing 2-h glucose. However, for 2-h glucose classifications of IGT and diabetes, there was no trend for increasing fasting glucose concentrations. Thus, fasting-glucose concentrations alone do not identify individuals at increased risk of hyperglycemia-associated death. The oral glucose tolerance test provides additional prognostic information and enables detection of individuals with IGT, who have the greatest attributable risk of death. These data strongly support the notion that postchallenge hyperglycemia is an important determinant of CVD. </
