Polycystic Ovary Syndrome and Cardiovascular Risk

PCOS is associated with an increase in cardiovascular risk factors (189). In addition to obesity that is commonly present and independently associated with increased cardiovascular risk, women with PCOS have dyslipedemia, hypertension and elevated PAI-1 levels. Obesity is a prominent feature in women with PCOS as about half of the patients are obese. Also, obesity appears to confer an additive and synergistic effect on the mani festations of the syndrome and additionally, it is one of the...

Possible mechanisms of impaired endotheliumdependent vasodilation

Although the data are conflicting, overwhelming evidence presently suggests that DM is associated with an impairment of endothelial vasodilation. The mechanism(s) for this impairment is even less well understood. The most likely initial insult is hyperglycemia. Tesfamarian and colleagues took normal rabbit aortic rings and exposed them to high concentrations of glucose (up to 800 mg dL for 3 hours), resulting in a decrease in endothelium-dependent relaxation, in response to acetylcholine and...

Vascular Effects of Estrogens

Blood vessels are complex structures with walls containing smooth muscle cells (SMCs) and an endothelial lining. Far from being only an anatomic barrier, the endothe-lium is a metabolically active organ system that maintains vascular homeostasis by modulating vascular tone, regulating local cellular growth and extracellular matrix deposition and also regulating the hemostatic, inflammatory, and reparative responses to local injury (24). Vasoregulation occurs as a balance between the release of...

Obesity and Nutritional Intake

Obesity, in general, is associated with decreased adiponectin expression in adipose tissue and plasma levels (7,13). In both men and women, overall obesity, assessed by parameters such as body mass index (BMI) and fat mass, is negatively correlated to adiponectin, although prolonged weight reduction leads to increased adiponectin levels (7,14-17). Nutritional intake does not seem to explain this relationship. Although fasting decreases adiponectin messenger ribonucleic acid (mRNA) levels in...

Effects of HRT on Endothelial Function in Postmenopausal Women With Diabetes

Endothelial dysfunction is the hallmark of diabetes and is regarded as an early manifestation of atherogenesis. In postmenopausal women with diabetes, multiple pathophysiological processes may contribute to endothelial dysfunction. These are diabetes- related, as a result of hyperglycemia and obesity insulin resistance and menopause-related as a result of loss of the protective effect of estrogen, as discussed earlier. Despite the importance of the endothelium, there is limited data on the...

Insulin Resistance and Nitric Oxide

Although hyperglycemia plays an essential role in the pathophysiology of DM, elevated serum insulin levels may also play an important role in atherogenesis, specifically in noninsulin DM. Furthermore, insulin resistance is a known cardiac risk factor. Insulin mediates NO production through specific pathway, which includes insulin receptor tyrosine, phosphatidyl inositol 3-kinase and its downstream effector, akt (118,119). This increase in NO release, in turn, results in vasodilation (120). This...

Endothelium Dependent Vasodilatation

Endothelial dysfunction associated with impaired production and or stability of NO occurs in both type 1 and type 2 diabetics (79,80), and in obese insulin-resistant subjects (119). Multiple mechanisms contribute to the impairment in endothelium-dependent vasorelaxation in diabetes, including the oxidative inactivation of NO, reduced eNOS expression, reduced eNOS activity, vascular insulin resistance, elevation of circulating levels of asymmetric dimethylarginine (an endogenous NOS inhibitor),...

HMG CoA Reductase Inhibitors

Large clinical trials have determined that hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) significantly reduce cardiovascular morbidity and mortality. Furthermore, lipid-lowering therapy has been shown to improve endothelial function in several studies (204,205). Attempts to ameliorate the impaired endothelium-dependent vascular relaxation that occurs in diabetic patients with dyslipidemia are few and the results mixed. Impaired endothelium-dependent vasodilation in patients...

Human Studies of Endothelium Dependent Vasodilation

Human studies evaluating the effects of DM on endothelium-dependent vasodilation have yielded some conflicting results, although they generally corroborate those found in animal studies. Saenz de Tejada et al. (60) studied penile tissue excised from men with erectile dysfunction and found that endothelium-dependent relaxation is reduced in the corpus cavernosa of impotent men with diabetes relative to those who are nondiabetic. However, in vivo studies involving human subjects with...

Peroxisome Proliferator Activated Receptora Key Regulator of Fatty Acid Oxidation

PPAR-a is expressed in heart, liver, kidney, and skeletal muscle in which it plays a central role in the regulation of lipid, and especially fatty acid, metabolism (16). PPAR-a target genes participate in the conversion of fatty acids to acyl-coenzyme A derivatives, peroxisome P-oxidation, and apolipoprotein expression (A1, AII, and CIII) (10,17). Reminiscent of the story of PPAR-y, fibrates in clinical use for lowering triglycerides and raising high-density lipoprotein (HDL), namely...

Macrophage Activation

Release of Cytokines and Growth Factors by Modified Lipoproteins and LDL-Immune Complexes AGE product-receptor interactions in macrophages may induce release of cytokines, TNF and IL-1 (204) and these cytokines may mediate growth and remodeling and accelerate the atherosclerotic process. Vlassara and associates (205) identified a specific receptor for AGE products on monocyte macrophages. Macrophages expressing this receptor may phagocytose proteins and even entire cells expressing...

Endogenous Peroxisome Proliferator Activated Receptor Activation New Connections Between Fatty Acids Lipid Metabolism

The metabolic benefits seen with synthetic PPAR agonists frame a key biological question what does the body make to activate these receptors Presumably, such molecules might replicate the effects of synthetic PPAR drugs, possibly protecting individuals from diabetes mellitus, dyslipidemia, and or atherosclerosis. Early studies into endogenous PPAR agonists focused mainly on specific candidate molecules. Oxidized linoleic acid in the form of 9 or 13 hydroxyoctadecanoic acid (HODE) appears to...

Expression of the Renin Angiotensin System in Diabetes

The production and action of Ang II is regulated at multiple levels, including the availability of angiotensinogen, levels and activities of angiotensin-processing enzymes, angiotensin receptor isotype expression, and postreceptor signaling (Fig. 1). Although quantitation of Ang II levels would provide a direct measure of extracellular RAS activation, these measurements are complicated by the rapid degradation of this peptide (46,47) and its tissue-specific production (26,27,48). Reports on the...

Alternative Therapies to Hormone Replacement Therapy

SERMs are nonsteroidal estrogenic compounds with both estrogenic agonist (on bone and lipoproteins) and estrogenic-antagonist (on breast and endometrium) effects in use for the treatment of osteoporosis. Although SERMs have shown beneficial effects on some surrogate markers of CVD it is not known whether this will translate into clinical benefit. The recent secondary analysis of the osteoporosis prevention study, the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, suggested that there...

Intravascular Actions of the Renin Angiotensin System

In addition to its potent effects on vasoconstriction and BP control, Ang II also exerts a variety of effects on vascular biology, which are independent of vascular tone and pressure. AT1 receptors are expressed in most vascular cell types, including endothelial and VSMCs, cardiomyocytes, and cardiac fibroblasts (23). Activation of these receptors affects a diverse array of vascular cell functions including growth, migration, oxidant production, and gene expression (100). Overproduction of Ang...

Endothelin1

Endothelin-1 (ET-1) was first described in 1988 and since then a considerable amount of research has been performed to study this potent vasoconstrictor. Early studies suggested that ET-1 concentrations in the plasma of type 1 and type 2 diabetic patients were significantly elevated (approx 3.5-fold) compared to levels in nondiabetic patients (63) but no significant correlations between endothelin levels and complications were observed. In contrast, subsequent studies found a significant...

Mechanisms responsible for hyperreactivity of platelets in people with diabetes

Increased expression of the surface GPs Ib and IIb IIIa has been observed in platelets from subjects with both type 1 and type 2 diabetes (43). GP Ib-IX binds to von Willebrand factor in the subendothelium and is responsible for adherence of platelets at sites of vascular injury. Interaction between GP Ib-IX and von Willebrand factor leads to activation of platelets. Activation of GP IIb IIIa leads to the binding of fibrinogen and aggregation of platelets. Thus, increased expression of either...

Biology and Atherosclerosis

Early reports established not only that PPAR-y was expressed in monocytes, macrophages, and human atherosclerosis, but also that PPAR-y agonists could repress key proteins such as inflammatory cytokines and matrix metalloproteinases (MMPs) implicated in atherosclerosis and or its complications (30,31). These observations were countered by the finding that PPAR-y agonists could also increase expression of CD36, a receptor mediating uptake of oxidized LDL (32). Increased CD36 might be expected to...

Suketu Shah md Alina Gavrila md and Christos S Mantzoros md

Introduction Structure of Adiponectin Regulation of Adiponectin Adiponectin and Cardiovascular Disease Risk Factors Adiponectin's Direct Vascular Effects Adiponectin, a recently discovered protein produced exclusively by adipocytes, is thought to be a possible mediator between obesity, insulin resistance, and cardiovascular disease (CVD). Although its function is not entirely known, body fat distribution, insulin, sex hormones, tumor necrosis factor (TNF)-a, and peroxisome...

And Insulin Sensitivity

There is growing evidence that inhibition of the RAS system by either ACE inhibition or AT1 receptor antagonism can increase insulin sensitivity and glucose utilization. Studies using euglycemic hyperinsulinemic clamps have shown that ACE inhibitor treatment improves insulin sensitivity in most (136-140), but not all (141,142) individuals with hypertension, obesity, and or type 2 diabetes. Similarly, although ATI antagonism has been reported to improve muscle sympathetic nerve activity and...

Dyslipidemia

Besides diabetes and insulin resistance, adiponectin is also related to dyslipidemia, another risk factor for CVD. Adiponectin is a strong independent positive predictor of high-density lipoprotein levels and is negatively associated with serum triglycerides (14,59,60). In contrast, low-density lipoprotein and total cholesterol do not have significant independent relationships to adiponectin levels (19). Adiponectin may lead to favorable lipid profiles by stimulating fatty acid oxidation. The...

Outcomes in Diabetic Patients

Meta-analyses of ACE inhibitor trials provide compelling evidence that ACE inhibitors reduce cardiovascular events and mortality related to acute myocardial infarction (MI) and heart failure (90,91). Because diabetes is an independent risk factor for CVD (92) and the RAS and diabetes appear to interact at multiple levels, it is possible that diabetes may affect the efficacy of ACE inhibition on CVD. Several recent reports have provided retrospective analyses of data from diabetic subgroups,...

Diabetes and Insulin Resistance

Adiponectin's involvement in CVD is likely multifactorial, but one of its main roles is likely in affecting traditional risk factors associated with coronary artery disease (CAD), particularly diabetes. As one of the diabetes susceptibility genes and the adiponectin gene both localize to 3q27, mutation at this locus has been associated with both type 2 diabetes and decreased adiponectin (41). The majority of data for animal studies thus far suggest that adiponectin acts as an...

Angiotensin Converting Enzyme Inhibitors

Angiotensin-converting enzyme (ACE) inhibitors have been shown both to improve endothelial function and to reduce the development of atherosclerosis in various animal models of hypercholesterolemia (192,193), independent of its BP-lowering effect. Similarly, the Heart Outcomes Prevention Evaluation (HOPE) study has demonstrated the utility of the ACE inhibitor ramipril in preventing cardiovascular events in diabetics (194) although the mechanism of this effect remains obscure. Clinical trials...

Diabetes and fibrinolysis

Decreased fibrinolytic system capacity is observed consistently in blood from patients with DM, particularly those with type 2 diabetes (93,94). It has been known for many years that obesity is associated with impaired fibrinolysis (95) that elevated blood triglycerides and other hallmarks of hyperinsulinemia are associated with increased activity of PAI-1 (96) and that elevated PAI-1 is a marker of increased risk of acute MI as judged from its presence in survivors compared with age-matched...

Summary

Subjects with DM have a high prevalence and rapid progression of coronary artery, peripheral vascular, and cerebral vascular disease secondary in part to (a) increased platelet reactivity (b) increased thrombotic activity reflecting increased concentrations and activity of coagulation factors and decreased activity of anti-thrombotic factors and (c) decreased fibrinolytic system capacity resulting from overexpression of PAI-1 by hepatic, arterial, and adipose tissue in response to...

HRT and Genetic Factors

Genetic variants that modify the effect of estrogens on various domains of estrogen action may account for the clinical heterogeneity in response to HRT. Thus the estrogen associated risk for thrombosis may be increased in the presence of the prothrombin 20210 G A variant, the factor V Leiden mutation or platelet antigen-2 polymorphisms (95-97). A common sequence variation of the ER gene is associated with the magnitude of the response of HDL cholesterol levels to HRT in women with coronary...

Antihypertensive Agents

Recently, losartan and olmesartan, antihypertensive drugs known to act through angiotensin receptor inhibition, have been shown to decrease AGE formation (191). Hydralazine, another antihypertensive agent whose effect does not involve the renin-angiotensin system, has AGE-inhibitory effects similar to those of low-dose olmesartan (192). The renoprotective effects shown by these drugs suggest that they derive not only from the drugs effect on lowering blood pressure and blocking angiotensin but...

Effects of HRT on Lipids in Women With Diabetes

Serum lipid parameters show an overall beneficial change on HRT in postmenopausal diabetic women. Unopposed oral estradiol increases HDL-C and reduces LDL-C, whereas the addition of norethisterone may not alter this beneficial effect (132,148). Oral CEE 0.625 mg daily has been shown to reduce total and LDL-Cin women with diabetes, although increasing HDL-C (149). In one study, the increase in HDL-C was less than among nondiabetic women (150). Not all studies have shown an increase in...

Estrogen

The incidence of CAD in premenopausal women is less than in age-matched males (181). One possible explanation is the effect of estrogen. Estrogen may have important effects on vascular function that are not totally explained on the basis of an improved lipoprotein profile (182). Diabetic women have the same cardiovascular risk as nondia-betic men, suggesting that they are denied the cardiovascular protection of estrogen enjoyed by other premenopausal women (182). Estrogen's possible beneficial...

Renin Angiotensin System Inhibition and New Onset Diabetes

Several large clinical studies have reported that ACE inhibitor treatment is associated with a reduction in the incidence of new-onset diabetes. The MICRO-HOPE study reported that the relative risk for new diagnosis of diabetes in the ramipril ACE inhibitor-treated group was 0.66 (p < 0.001) compared with the placebo-treated controls (96). The Captopril Prevention Project trial reported that the relative risk of developing diabetes in the ACE inhibitor treated group was 0.86 (p 0.039)...

Ppar8

Major tissues Ligands Biologic roles Adipogenesis Insulin sensitivity Lipid metabolsim Although peroxisome proliferator-activated receptor (PPAR) isoforms have a number of common attributes, they can also be distinguished by a number of unique characteristics. Perhaps most central to their different roles in metabolism, each PPAR is activated by different ligands, leading to regulation of specific target genes. A general overview utilizing illustrative examples for each PPAR isoform is listed...

Relationship to Insulin Resistance and Diabetes

Although the exact mechanisms that lead to the development of PCOS are not clear it has been shown that insulin resistance and compensatory hyperinsulinemia possess the central role in the pathophysiology of the syndrome. Women with PCOS have both basal and glucose-stimulated hyperinsulinemia compared with weight-matched women and the high levels of insulin are thought to mediate the development of hyperandrogenemia, anovulation, and infertility. At the same time, insulin resistance and...

Endothelial dysfunction and diabetes mellitus

Although the link between diabetes and cardiovascular disease is not well understood, endothelial dysfunction may be implicated in the pathogenesis of diabetic vascular disease. The evidence of endothelial dysfunction in diabetes comes largely from studies measuring the endothelial substances that mediate fibrinolysis and coagulation. Chapters 2 and 6 give detailed descriptions of these studies. For example, plasminogen activator inhibitor-1 levels are increased, whereas fibrinolytic activity...

Advanced Glycoxidation End Product Crosslink Breakers

Recently, a promising therapeutic strategy has been to attack the irreversible intermolecular AGE crosslinks formed in biological systems providing prevention or reversal of various diabetes- and aging-related complications. This approach aims to break preaccumulated AGE and help renal elimination of resulting smaller peptides. PTB was originally studied (187) and more recently ALT-711 (8,13,188). Long-term studies are in progress to establish the safety of this new category of anti-AGE agents

Abnormalities in the fibrinolytic system

The fibrinolytic system controls the patency of the vascular tree and is likely a critical regulator of thrombosis. One hypothesis is that small amounts of fibrin are constantly deposited on the endothelium and that these fibrin deposits are continually dissolved, resulting in a dynamic balance between coagulation and fibrinolysis. The generation and activity of plasmin, the enzyme responsible for the degradation of fibrin deposits and thrombi, are regulated mainly by the production of two...

Role of the reninangiotensin system in cardiovascular disease in diabetes

As reviewed elsewhere in this book, multiple factors, including hyperglycemia, insulin resistance, dyslipidemia, hypercoagulability, and inflammation contribute to the pathogenesis of atherosclerosis in DM. Although there is considerable evidence for a role of the RAS in vascular remodeling, inflammation, thrombosis, and atherogeneis (81-83), the role of this system in atherosclerosis in the context of the other diabetes-associated cardiovascular risk factors is not fully understood. There is a...

Thrombosis

The abnormalities in coagulation and platelet biology in type 2 diabetes patients are well documented (157). The development of thrombosis within the vasculature depends on the balance between procoagulant and anti-thrombotic factors, which are shifted toward thrombosis in type 2 diabetes patients (158). Plasminogen activator inhibitor(PAI-1) is produced by liver and endothelial cells and binds to the active site of both tissue plasminogen activator and urokinase plasminogen activator and...

Effect of Angiotensin Converting Enzyme Inhibition Following Acute Myocardial Infarction on Cardiovascular Outcomes in

The GISSI-3 study examined the short-term effects of ACE inhibition when administered within 24 hours following an acute MI in a population of more than 18,000 patients, including 2790 patients who reported a history of diabetes (10). Retrospective analysis of results from this study revealed that ACE inhibitor treatment provided greater protective effects against 6-week mortality in diabetic patients compared with nondiabetics. The overall risk reduction by ACE inhibitor treatment for the...

Effects of Estrogen on Risk Factors for Diabetes

The changes in lipid metabolism that occur with the menopause, including increased total and LDLC, triglycerides and Lp(a), and decreased HDL-C, resemble those of type 2 diabetes and the metabolic syndrome (12). Adverse changes in carbohydrate metabolism also emerge with the menopause including decreased insulin sensitivity and insulin secretion (128). These together with increased central adiposity contribute to the increased risk of CVD in postmenopausal women. The effects of estrogen on...

Endogenous Advanced Glycoxidation End Products Formation

It is now appreciated that normal living is associated with spontaneous chemical transformation of amine-containing molecules by reducing sugars in a process described since 1912 as the Maillard reaction. This process occurs constantly within the body and at an accelerated rate in diabetes (5,6). Reducing sugars react in a nonenzymatic way with free amino groups of proteins, lipids, and guanyl nucleotides in DNA and form Schiff base adducts. These further rearrange to form Amadori products,...

Hyperglycemia

Hyperglycemia has been shown to be the main cause of microvascular complications in the DCCT (11) and UKPDS study (12). For cardiovascular complications, the contribution of hyperglycemia is probably also significant. Several biochemical mechanisms appear to explain the adverse effects of hyperglycemia on vascular cells (Table 3). This is not surprising because the metabolism of glucose and its metabolites can affect multiple cellular pathways. Glucose is transported into the vascular cells...

HRT and Risk of Cardiovascular Disease in Women With Diabetes

CVD is the most common cause of death in type 2 diabetes. This increased risk is particularly apparent in women with diabetes in which the relative protection afforded by the female sex is lost (107). For women without diabetes, prospective cohort surveys such as the Nurse's Health Cohort Study, suggest that estrogen therapy decreases the risk of CHD in postmenopausal women who were initially healthy at the time of enrollment (5). However, data from the HERS and WHI clinical trials have...

Mechanisms responsible for a prothrombotic state associated with diabetes

Patients with DM have increased concentrations in blood of the prothrombotic factors fibrinogen, von Willebrand factor, and factor VII coagulant activity (77-79). Among the three coagulation factors, fibrinogen has been most strongly associated with the risk of development of CVD (80). Although the mechanisms responsible for increased concentrations of fibrinogen and von Willebrand factor have not yet been fully elucidated, elevated concentrations in blood of insulin and proinsulin may be...

Microangiopathy

Diabetic microangiopathy is a broad term that describes changes in microvascular beds in which endothelium and associated mural cells function are progressively disrupted, resulting in occlusion, ischemia, and organ damage. Although kidney and retina are most commonly affected, diabetic microangiopathy can occur in a wide range of tissues such as peripheral nerves and skin (4). A large number of studies have supported the pathogenic role of AGE in diabetic microangiopathy (4-6,41), even as...

NaKATPase

Na+-K+-ATPase, an integral component of the sodium pump, is involved in the maintenance of cellular integrity and functions such as contractility, growth and differentiation (147). It is well established that Na+ K+-ATPase activity is generally decreased in the vascular and neuronal tissues of diabetic patients and experimental animals (41,43,147149). However, the mechanism by which hyperglycemia inhibits Na+ K+-ATPase activity have provided some conflicting results regarding the role of PKC....

Peroxisome Proliferator Activated Receptory Key Regulator of Adipogenesis and Insulin Sensitivity

PPAR-y was first identified as a part of a transcriptional complex essential for the differentiation of adipocytes, a cell type in which PPAR-y is highly expressed and critically involved (6). Homozygous PPAR-y-deficient animals die at about day 10 in utero as a result of various abnormalities including cardiac malformations and absent white fat (7-9). PPAR-y is also involved in lipid metabolism, with target genes such as human menopausal gonadotropin coenzyme A synthetase and apolipoprotein...

Protein Kinase C Inhibitors

Hyperglycemia can activate PKC, which in turn increases oxidative stress. Inhibitors of PKC can restore vascular function and also increase mRNA expression of eNOS in aortic endothelial cells (143). Recently, an inhibitor of PKC, LY333531, has been developed it normalizes retinal blood flow and glomerular filtration rate in parallel with inhibition of PKC activity (169). LY333531 is discussed in detail in Chapter 2. Beckman and colleagues (170) found that this inhibitor of PKCP attenuated the...

Vascular Contractility and Blood Flow

Hemodynamic abnormalities such as blood flow and vascular contractility have been reported in many organs of diabetic animals or patients, including the kidney, retina, peripheral arteries, and microvessels of peripheral nerves. In the retina of diabetic patients and animals with a short duration and without clinical retinopathy, blood flow has been shown to be decreased (119-123). One possible explanation for the decreased retinal blood flow in early stage of diabetes is as a result of an...

Increased Nitric Oxide Inactivation Decreased Bioavailability andor Breakdown of Nitric Oxide

Interposed between the endothelium and the smooth muscle cells of the media is a layer of subendothelial collagen. The auto-oxidation of glucose results in a nonenzy-matic glycosylation reaction between glucose and the amino groups of protein, termed advanced glycosylation end-products (AGEs). AGE-modified proteins interact with specific binding proteins, and trigger oxidation-enhancing reactions (see Chapter 3). Recent studies demonstrated an important role for AGEs in pathogenesis of diabetic...

Diabetic Neuropathy

About half of all people with diabetes experience some degree of diabetic neuropathy, which can present either as polyneuropathy or mononeuropathy (109). Diabetic neuropathy can also affect the central and the autonomic nervous systems. Level of hyperglycemia seems to determine the onset and progression of diabetic neuropathy (110,111). In vitro studies have shown that glycation of cytoskeletal proteins such as tubulin, actin, and neurofilament results in slow axonal transport, atrophy, and...

Endothelium Dependent Vasodilation in Animal Models

Studies using different animal models of diabetes in several different vascular beds (46-49) suggest that there is a decrease in endothelium-dependent vasodilation in the diabetic state. In two such animal models of type 1 diabetes, rats are made diabetic with streptozocin or rabbits made diabetic with alloxan, pancreatic P-cells are destroyed, with a corresponding decrease in insulin secretion. Studies evaluating endothelium-depen-dent vasodilation in these animal models have demonstrated a...

The Kallikrein Kinin Pathway

Bradykinin is generated by kallikreins from their precursor kininogens and it is a potent vasodilator that increases vascular permeability and plays a primary role in inflammation. In noninjured vessels, bradykinin causes relaxation of the VSMC through the synthesis and release of NO from the endothelium (42). In contrast, when the integrity of the endothelium is compromised, bradykinin will act directly in VSMCs promoting their vasoconstriction (43) and fibrosis. The direct action of...

Effects of Estrogen on Endothelial Function

Endothelial function is most commonly assessed as a vasodilatory response to pharmacological or mechanical stimuli. Increased blood-flow shear (flow-mediated) is a mechanical means to stimulate vasodilation through NO release (29). The most com monly used clinical measure is high-frequency ultrasound assessed branchial artery diameter changes after blood pressure (BP) cuff-induced hyperemia (30). An assessment of nonendothelium-dependent vasodilation by use of nitroglycerin or nitroprusside is...

Endotheliumderived relaxing factor

In 1980, Furchgott discovered that the endothelium is responsible for the vasodilator action of acetylcholine (10). This finding has fostered a great number of investigations on the role of the endothelium on the initiation and development of vascular disease and its subsequent clinical sequelae. Further research indicated that acetylcholine released a soluble factor from the endothelium termed EDRF and that this substance was released by other agents including bradykinin, substance P,...

Contributors

Lloyd Paul Aiello, md, PhD, Beetham Eye Institute, Joslin Diabetes Center, Harvard Medical School, Boston, MA Aresh J. Anwar, md, mrcp, Division of Clinical Sciences, Warwick Medical School, University of Warwick and University Hospital of Coventry and Warwickshire, Coventry, UK Bernadette Aulivola, md, Division of Vascular Surgery, Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA Edward J. Boyko, md, mph, Department of Medicine, University of...

With Diabetes

In addition to beneficial effects on lipids, HRT has also been shown to improve other risk factors for atherothrombosis in diabetic women. CRP, a cardiovascular risk marker, is known to be increased in patients with type 2 diabetes. Sattar and associates (159) in a 6-month, double-blind, placebo-controlled study reported that transdermal estradiol in conjunction with continuous oral norethisterone significantly reduced CRP concentrations in postmenopausal women with type 2 diabetes. This is in...

Effects of the Renin Angiotensin System on Insulin Signaling

Renin Angiotensin Signaling

The effects of RAS inhibition on insulin action have been attributed to changes in both the inhibition of Ang II ATI receptor signaling and enhancement of bradykinin B2 receptor action. ACE, also called kininase II, degrades bradykinin 1-9 and thereby reduces bradykinin B2 receptor activation (Fig. 2). Several reports have shown that bradykinin B2-receptor antagonism blocks the decreases in insulin resistance and enhanced glucose uptake associated with ACE inhibition (148,149,157) and is...

Quantitativequalitative abnormalities of lipoproteins

In poorly controlled diabetic patients, plasma LDL, intermediate density lipoproteins and very low-density lipoprotein (VLDL) levels are elevated (106-110). The increase in VLDL levels has been attributed to increased hepatic production or decreased clearance of VLDL (111) and may be very significant in the development of arteriosclerosis in diabetes and in women (112). HDL levels in diabetes vary with the type of diabetes and, in some groups, with glycemic control. In type 2 diabetic patients,...

Inhibitors of AGE Production

The production of AGE, as a result of prolonged exposure of proteins to chronic hyperglycemia, can result in direct quenching of NO and increasing the oxidative stress. Fig. 6. Forearm blood flow (FBF) dose-response curves to intra-arterial methacholine chloride infusion before and during coinfusion of vitamin C in noninsulin-dependent diabetic subjects. The concomitant infusion of methacholine and vitamin C resulted in an improved endothelium-depen-dent vasodilation compared with methacholine...

Effect of Insulin Resistance Treatment on Polycystic Ovary Syndrome Weight Loss

Weight reduction is of paramount importance and cornerstone of every therapeutic strategy in PCOS. Although obesity does not seem to be the primary insult in PCOS, many studies have demonstrated the beneficial impact of weight reduction on the manifestations of the syndrome and especially insulin sensitivity, risk for diabetes and adverse cardiovascular risk profile (199). The effect of weight reduction by a hypocaloric low-fat diet on the metabolic and endocrine variables was studied in obese...

Therapeutic implications

Consideration of the derangements in platelet function, the coagulation system, and the fibrinolytic system and their contributions to exacerbation of macrovascular disease in type 2 diabetes gives rise to several therapeutic approaches. Empirical use of aspirin (160-325 mg per day in a single dose) seems appropriate in view of the high likelihood that covert CAD is present even in asymptomatic people with type 2 diabetes and the compelling evidence that prophylactic aspirin reduces the risk of...

Potential preventive and therapeutic options Oral Hypoglycemic Agents

The cornerstone of DM therapy is optimal glycemic control, because hyperglycemia is the basis of all the metabolic disturbances that occurs in the disease. As shown previously, both in vivo and in vitro elevated glucose levels have been shown to cause abnormal endothelium-dependent relaxation. Lower glucose levels also result in a decrease in insulin levels, which consequently may also improve endothelial function. Therefore, therapy should be directed toward lowering glucose levels and...

Activation of the Dagpkc Pathway

One major advance in the understanding of diabetic vascular disease is the unraveling of changes in signal transduction pathways in diabetic states. One of the best-characterized signaling changes is the activation of DAG-PKC pathway. Such activation appears to be related to elevation of DAG, a physiological activator of PKC. Increases in total DAG contents have been demonstrated in a variety of tissues associated with diabetic vascular complications, including retina (78), aorta, heart (79),...

Melpomeni Peppa md Jaime Uribarri md and Helen Vlassara md

Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Advanced Glycoxidation End-Products Microangiopathy Advanced Glycoxidation End-Products and Diabetic Macroangiopathy Antiadvanced Glycoxidation End-Product Strategies Conclusions References The incidence of diabetes, especially type 2 diabetes, is increasing at an alarming rate assuming epidemic proportions (1). Worldwide, 124 million people had diabetes by 1997, although an estimated 221...

Animal Models

STZ-induced diabetes increases atherosclerotic plaque area by four- to fivefold in the aorta of apo-E deficient mice (72,84,85). Treatment of diabetic apo-E - - mice with the ACE inhibitor perindopril reduces lesion area, macrophage infiltration, and collagen content (85). A similar reduction in aortic plaque area was observed in STZ-induced diabetic apo-E-deficient mice treated with the ATI receptor antagonist Irbesartan (72). Both ACE and ATI receptor expression are increased in aortic...

The coagulation system and diabetes mellitus

Activation of the coagulation system leads to the generation of thrombin and thrombin-mediated formation of fibrin from fibrinogen. The generation of thrombin depends on activation of procoagulant factors. It is limited by antithrombotic factors and inhibitors. Fibrinopeptide A (FPA) is released when fibrinogen is cleaved by thrombin. FPA has a very short half-life in the circulation and is cleared promptly by the kidneys. Elevated concentrations in blood are indicative of thrombin activity in...

Mechanisms

The mechanisms by which diabetes abolishes the cardiovascular protective effects of female sex hormones in premenopausal women are not well understood. In fact, the loss of the natural sex advantage in women with diabetes is independent of other diabetes-associated conventional risk factors. After adjusting for differences in hypertension, dyslipidemia, and obesity, the cardiovascular risk still remains higher in diabetic women than in men or women without diabetes (8,107). This suggests that...

Oxidative and Nitrosative Stress in Diabetes Induced Vascular Dysfunction

Various neurohumoral mediators and mechanical forces acting on the innermost layer of blood vessels, the endothelium, are involved in the regulation of the vascular tone. The main pathway of vasoregulation involves the activation of the constitutive, endothelial isoform of NO synthase (eNOS) resulting in NO production (53). Endothelium-depen-dent vasodilatation is frequently used as a reproducible and accessible parameter to probe endothelial function in various pathophysiological conditions....

Mechanisms responsible for the overexpression of pai1 in diabetes

Increased expression of PAI-1 in diabetes is undoubtedly multifactorial. A direct effect of insulin on the expression of PAI-1 has been suggested by a positive correlation between the concentration of insulin and PAI-1 in vivo (93,94,96,100-103,106). Triglycerides and their constituents (fatty acids) appear to contribute to the overexpression of PAI-1 in view of the fact that both insulin and triglycerides independently increase expression of PAI-1 by human hepatoma cells in vitro...

Conclusions and Future Directions

There are several plausible explanations for the divergent findings from the clinical trials and the observational studies regarding the effect of HRT on CVD in postmeno-pausal women. Some discrepancies may be methodological in nature and others may have a biological basis related to the pleiotropic effects of estrogens and the characteristics of the study population. The later may be related to age, time since menopause, state of the arterial endothelium and stage of atherogenesis. Genetic...

Clinical

13 The Metabolic Syndrome and Vascular S. J. Creely, Aresh J. Anwar, and Sudhesh Kumar 14 Diabetes and Samy I. McFarlane, Amal F. Farag, David Gardner, 15 Diabetes and Asha Thomas-Geevarghese, Catherine Tuck, 16 Diabetic Lloyd Paul Aiello and Jerry Cavallerano 17 Diabetic 18 Diabetic 19 Microcirculation of the Diabetic C. Cardiovascular System Peripheral Vascular System 20 Epidemiology of Peripheral Vascular Stephanie G. Wheeler, Nicholas L. Smith, and Edward J. Boyko 21 Noninvasive Methods to...