Alteration in Oxidative Stress

Increases of oxidative stress by metabolic derangement has long been reported in diabetic states and proposed to cause vascular complications (44,59,63,64). In diabetic states, induction of oxidative stress could be as a result of the increased production of superoxide anion via the induction of NADPH oxidase and mitochondrial pathway decreases of superoxide clearance lipid and protein modification and the reduction of endogenous antioxidants such as ascorbic acid, vitamin E, and glutathione....

Nitric oxide and the development of atherosclerosis

All the major cardiovascular risk factors (including hypertension, high levels of low-density lipoprotein LDL cholesterol, tobacco use, and hyperhomocysteinemia) are associated with decreased endothelium-dependent vasodilation prior to the development of clinically apparent vascular disease. This would suggest that the endothelial damage is implicated in the development of atherosclerosis (35). After endothelial injury, platelets aggregate in those areas of cell damage, releasing growth factors...

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 AT1 antagonism has been reported to improve muscle sympathetic nerve activity and...

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...

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...

Lipoprotein Oxidation and Glyco Oxidation

Glycation of LDL under hyperglycemic conditions is likely to result in increased formation of oxidized LDL (154). Several mechanisms have been proposed to explain the increased oxidation of lipoproteins in diabetes. One of them involves the auto-oxidation of simple monosaccharides (155,156), such as glucose, and of fructose-lysine (155,156,157), the first Amadori rearrangement product, under physiological conditions and in the presence of trace amounts of metal ions. Auto-oxidation of these...

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...

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...

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...

Modified LDL Antibodies and LDLContaining Immunocomplexes

In addition to the interactions described above, modification of proteins, such as oxidation and AGE modification, may alter their structure sufficiently to render them immunogenic. The presence of antibodies to oxidized LDL and AGE-LDL has been described in the sera of several groups of patients and controls. The levels of oxidized LDL (oxLDL) antibodies have been repeatedly reported to correlate with different endpoints considered as evidence of atherosclerotic vascular disease, progression...

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...

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...

Polycystic Ovary Syndrome Diabetes and Cardivascular Disease

PCOS is the most common endocrinopathy that affects women of reproductive age (177). Data on the exact prevalence are variable mostly because of the lack of well-accepted diagnostic criteria. At present, the diagnosis of PCOS is based on the presence of ovulatory dysfunction and clinical or biochemical evidence of hyperandrogenism. The diagnosis requires a complete evaluation for exclusion of other causes of hyperandrogenism such as nonclassic adrenal 21-hydroxylase deficiency and androgen...

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...

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...

Sources of Estrogens in Women

The estrogen compounds to which target tissues in women, including the vascular system, may be exposed are multiple and they arise from endogenous and exogenous sources. The naturally occuring estrogens 17 -estradiol (E2), estrose (E1), and estriol (E2) are C18 steroids and are derived from cholesterol in steroidogenic cells. In the premenopausal women, the primary source of estrogens are the ovaries. E1 and E3 are primarily formed in the liver from E2 (10). After menarche, when circulating E2...

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...

Advance Glycation End Products

Extended exposure of proteins to hyperglycemia can result in nonenzymatic reactions, in which the condensation of glucose with primary amines forms Schiff bases. These products can rearrange to form Amadori products and advanced glycation end-products (AGE). The glycation process occurs both intracellularly and extracellularly. It has been reported that the glycation modification target to intracellular signaling molecules and extracellular structure proteins alike, and furthermore, alter...

Info

The insulin receptor is a member of the tyrosine kinase family, and the activation of the receptor by insulin-binding results in autophosphorylation of receptor and activation of tyrosine kinase (Fig. 1). As in other cells, insulin receptors in vascular cells can activate at least two different signal transduction pathways one is PI 3-kinase (PI3K) cascades and the other is Ras-mitogen-activated protein (MAP) kinase cascades. These signaling processes mediate...

Platelet function in subjects with diabetes mellitus

The activation of platelets and their participation in a thrombotic response to rupture of an atherosclerotic plaque are critical determinants of the extent of thrombosis, incremental plaque growth, and the development of occlusive thrombi. Increased adherence of platelets to vessel walls manifesting early atherosclerotic changes and the release of growth factors from a-granules can exacerbate the evolution of atherosclerosis. Patients with diabetes, particularly those with macrovascular...

Conclusion

Over the last 15 years, it has become established that insulin is a vascular hormone. Insulin's vascular actions extend beyond its effect to increase skeletal muscle blood flow and glucose uptake. Current data suggest that insulin modulates vascular tone, and vascular smooth muscle cell proliferation and migration via the release of NO and other yet unidentified mechanisms. Thus, insulin's effects on the vascular system may be important to prevent or delay the progression of CVD. The metabolic...

Jorge Plutzky md

The Basic Science of Peroxisome Proliferator-Activated Receptor For many years, advances in understanding steroid hormone action typically proceeded through sequential stages that involved first identifying the role of a putative hormone, then isolating it, often from large quantities of body fluid, and ultimately identifying the nuclear receptor through which the cellular effects were being achieved 1 . More recently, this stepwise progression has been reversed by modern molecular biology...

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...

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...

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 AT1 receptor antagonist Irbesartan 72 . Both ACE and AT1 receptor expression are increased in aortic lesions...

Cell Adhesion Molecules

Endothelial cells elaborate leukocyte-specific adhesion molecules, both constitutively and in response to cytokines and other mediators 78,79 . Circulating monocytes display receptors for these cell adhesion molecules. Vascular cell adhesion molecule VCAM - 1 80,81 , intercellular adhesion molecule ICAM -1 81,82 , E-selectin 81 , and platelet endothelial cell adhesion molecule CD31 81 , are expressed in atherosclerotic lesions. Recent investigations have documented that soluble forms of these...

Mechanisms responsible for the overexpression of pai 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 105,107-109 ....

Effects of HRT on Carbohydrate Metabolism in Women With Diabetes

There is a degree of reluctance among health care professionals to prescribe HRT to women with diabetes. A community-based survey in London found that diabetic postmenopausal women were less than half as likely as the general population to be prescribed HRT 137 . Doctors and health care professionals perceive HRT as detrimental for diabetic women because of fear about glycemic control as is also the case with the oral contraceptive pill 138 . Yet there is no evidence that HRT results in...

Effects of the Renin Angiotensin System on Insulin Signaling

Angiotensin Ati Signalization

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 mimicked...

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...

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...

And Receptors

Aminopeptidase Angiotensin Cathepsin

The actions of the RAS are regulated both by angiotensinases in the extracellular milieu and by angiotensin receptor-coupled signaling networks. The precursor for angio- From Contemporary Cardiology Diabetes and Cardiovascular Disease, Second Edition Edited by M. T. Johnstone and A. Veves Humana Press Inc., Totowa, NJ Fig. 1. Overview of the renin-angiotensin system. Angiotensinogen and angiotensin I-derived peptides are cleaved via a number of extracellular proteases resulting in at least four...

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...

Fibrinolysis and arterial mural proteolysis

Results of recent work have highlighted the potential role of plasminogen activators and PAI-1 in the evolution of macroangiography in two compartments, blood in the arterial lumen as described above and in the arterial wall itself 125 . Intramural plasminogen activators and PAI-1 influence proteolytic activity of matrix metalloproteinases MMPs that are activated from zymogens by plasmin. Cell surface plasmin-dependent proteolytic activation of MMPs promotes migration of SMCs and macrophages...

Second Edition

Diabetes and Cardiovascular Disease, Second Edition, edited by Michael T. Johnstone, md, cm, frcp c and Aristidis Veves, md, dsc, 2005 Cardiovascular Disease in the Elderly, edited by Gary Gerstenblith, md, 2005 Platelet Function Assessment, Diagnosis, and Treatment, edited by Martin Quinn, mb bch bao, phd and Desmond Fitzgerald, md, frcpi, 2005 Angiogenesis and Direct Myocardial Revascularization, edited by Roger J. Laham, md and Donald S. Baim, md, 2005 Interventional Cardiology percutaneous...

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

Activation of the Dagpkc Pathway

Pkc Insulin Resistance

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 ,...

Dyslipidemia

In more than half of all diabetic patients, especially those with type 2 diabetes and insulin resistance, decreases in high-density lipoprotein HDL cholesterol and hypertriglycemia have been reported 102 . Increases in low-density lipoprotein LDL cholesterol levels are also frequently observed in diabetic patients, but such increases are more frequently in those with poor glycemic control or in parallel with hypertriglycemia. Additionally, LDLs can be modified in diabetes, as in the formation...

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...

Michael T Johnstone md and Eli V Gelfand md

Endothelium-Derived Relaxing Factor Physiologic Effects of Nitric Oxide on the Vascular System Nitric Oxide and the Development of Atherosclerosis Endothelial Dysfunction and Diabetes Mellitus Possible Mechanisms of Impaired Endothelium-Dependent Vasodilation Other Risk Factors in Diabetic Endothelial Dysfunction Potential Preventive and Therapeutic Options Conclusions References Diabetes mellitus DM is a major source of morbidity in the United States, affecting between 10 and 15 million people...

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...

Activation of the Polyol Pathway

Increased activity of the polyol pathway has been documented in culture studies using vascular cells exposed to diabetic level of D-glucose and in animals with diabetes 58,59 . In these studies, hyperglycemia has been shown to increase the activity of aldose reduc-tase and enhances the reduction of glucose to sorbitol, then further oxidized to fructose by sorbitol dehydrogenase. Abnormality in the polyol pathway has been suggested to cause vascular damage in the following ways a osmotic damage...

PPARa

PPAR-a is a transcription factor that enhances insulin sensitivity in adipose and other tissues 36 . In a randomized, double blind, placebo-controlled trial, patients with type 2 diabetes given 6 months of rosiglitazone, a PPAR-a agonist, had increased levels of adiponectin 37 , with a similar change being seen even in humans without insulin resistance 38 . PPAR-a agonists may mediate their effect by directly promoting adiponectin transcription or by inhibiting the actions of TNF-a 34,39 ....

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 proliferator-activated...

Maria F Lopes Virella md phd and Gabriel Virella md phd

Introduction Endothelial Dysfunction Quantitative Qualitative Abnormalities of Lipoproteins Abnormalities in Platelet Function Abnormalities in Coagulation Abnormalities in the Fibrinolytic System References Macrovascular disease is the leading cause of mortality and morbidity in diabetes. The study of factors that may uniquely contribute to the accelerated development of atherosclerosis in diabetes has been an ongoing process for several years. However, the concepts behind both the pathogenic...

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...

Exogenous Sources of Advanced Glycoxidation End Products

AGEs can also be introduced in biological systems from exogenous sources. Methods of food processing heating in particular have a significant accelerating effect in the generation of diverse highly reactive a- -dicarbonyl derivatives of glyco- and lipoxidation reactions that occur in complex mixtures of nutrients 20-23 . About 10 of a single AGE-rich meal is absorbed into the body 24,25 . Food-derived AGEs, rich in MG, CML, and other derivatives, are potent inducers of oxidative stress and...