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From a clinical perspective, the aspect of insulin resistance most studied is defective insulin-mediated glucose uptake and utilization (1,43,65,66). In patients, this defect is defined by a reduction in nonoxidative glucose disposal (gly-cogen synthesis) in muscle and liver. With the observation that the rate-limiting step in cellular glucose metabolism is the plasma membrane transport, Glut-4 defects have the potential to readily result in insulin resistance at the level of the glucose...

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The evidence suggests that the metabolic syndrome of PCOS is placing young women at risk for premature macrovascular disease. Accordingly, management S of PCOS in the future may shift from solely the control of symptoms to the primary prevention of chronic disease through management of cardiovascular risk factors. Women with PCOS should be carefully evaluated for the presence Ja of obesity, hypertension, dyslipidemia, insulin resistance, and glucose intoler- J ance. Some authorities advocate...

Prothrombotic Activity

An additional mechanism proposed to explain the accelerated atherosclerosis observed with insulin resistance and type 2 diabetes is a hypercoagulable state. The body's fibrinolytic system normally limits vascular thrombosis and appears responsible for dissolution of thrombi after vascular repair has occurred. However, a disturbance of the fibrinolytic system favors the development of vascular damage and the final occlusion event in the progress of coronary heart disease (108-113). t A balance...

Assessment of Diastolic Function

Diastolic dysfunction is the hallmark of diabetic cardiomyopathy and echocardi-ography is invariably the most commonly employed test at the present time to reliably assess diastolic functional abnormalities. Left ventricular diastolic filling abnormalities in patients with diabetes do not correlate with the duration of diabetes nor with the presence of other complications such as retinopathy, nephropathy, or peripheral neuropathy. In diabetic cardiomyopathy, the initial abnormality of diastolic...

General Principles

It is well recognized that diabetics even those without overt manifestations of CAD are at significantly increased risk for developing MI. Finnish investigators reported that the risk of developing a MI was similar in diabetic patients without prior infarction compared with the risk in nondiabetic patients with a history of prior MI. Such a propensity for developing MI among diabetics without a history of MI argues persuasively for an aggressive strategy of primary prevention in diabetics that...

Info

Hepatic Lipoproteins and Transport of Endogenous Lipids in Diabetes Mellitus VLDL are assembled in the endoplasmic reticulum of hepatocytes when the core lipids, triglycerides and cholesterol, are the core lipids associate with apo B-100 and phospholipids. Although some apo C-I, apo C-II, apo C-III, and apo E may be present on the nascent VLDL particles as they are secreted from the hepato-cyte, the majority of these molecules are probably added to VLDL after their entry into plasma. Recent...

Syndrome X And

Definition of risk factors for any clinical syndrome have historically relied upon the combination of results from population-based studies of the natural history of the condition being examined, as well as placebo-controlled intervention studies in which a specific risk factor is decreased, and the clinical impact assessed. This process works very well when the role of a single risk factor is being evaluated. For example, there is no longer any question that a high-LDL cholesterol...

Lifestyle Modifications Smoking Cessation And Exercise

Much of the work documenting the impact of smoking on health does not discuss results on subsets of subjects with diabetes, suggesting that the identified risks are at least equivalent to those found in the general population. Other studies of individuals with diabetes consistently report a heightened risk of morbidity and premature death associated with the development of macrovascular complications among smokers. Although smokers have repeatedly heard of the pulmonary effects of smoking, the...

Ivthrombosis Complicating Plaque Rupture

Diabetes increases the risk of thrombosis complicating plaque rupture. Accordingly, diabetic compared with nondiabetic subjects are more likely to be the victims of acute coronary syndromes including myocardial infarction and unstable angina and of sudden cardiac death secondary to thrombosis in response to plaque rupture. Exaggerated thrombosis can predispose to recurrent events and to accelerated progression of atherosclerosis. Accordingly, mechanisms of prothrombosis must be delineated and...

Impact On Cardiovascular Disease The Dcct And Ukpds Studies

Clinical atherosclerosis results largely from acute embolic or thrombotic events that arise from long-term changes in the arterial wall. The pathogenesis of the arterial wall changes in relation to the metabolic abnormalities that attend poorly controlled diabetes are not well known in humans. Epidemiological studies indicate that both hyperglycemia and hyperinsulinemia increase the risk of atherosclerosis and of the acute clinical complications of that condition. The high triglyceride and low...

Cardiovascular Disease In Type Diabetes

Type 2 diabetes is very different from type 1 diabetes in its underlying etiology and its natural history. Insulin resistance, which is defined as a less than normal effect of insulin on in vivo glucose uptake and metabolism, occurs in a high proportion of the population of societies embracing western culture (10,26). Factors responsible for the development of insulin resistance are only partially understood. Fetal malnutrition predisposes to insulin resistance in postnatal life (27). Excess...

Diabetic Cardiomyopathy Does It Exist

In addition to the epidemiological data mentioned above, there are a host of other observations, both clinical and experimental, that point toward cardiomyopathic manifestations specifically related to the presence of diabetes. (In reviewing clinical data for this purpose, it is important to search for evidence of cardiomyopathy in the absence of the confounding presence of coronary artery disease and hypertension, both of which can cause CHF by themselves.) The occurrence of dilated...

Measurement Of Insulin Resistance

Several methods have been used to assess insulin resistance, but most are not readily available or practical for use in clinical practice. The easiest approach is to measure fasting plasma glucose and insulin concentrations or the glucose and insulin responses during an OGTT or test meal. The higher the insulin concentration in relation to the glucose level, the more insulin resistant the subject. One can also obtain similar information by measuring the C-peptide concentration in the fasting...

Summary

The management of the diabetic patient with symptomatic CAD is both complex and challenging for the clinician. Advances in our understanding of the pathogenesis of vascular injury in diabetic patients, and the role of metabolic, biological, and hematological abnormalities in the genesis of accelerated atherosclerosis in both native vessels and following angioplasty, should continue to drive improvements in the care of diabetic patients. The evolution of catheter-based technologies including...

David J Schneider and Burton E Sobel

University of Vermont, Burlington, Vermont Optimal treatment of patients with diabetes requires an understanding of the mechanisms underlying the disease. Treatment must be designed not only to control hyperglycemia but also to prevent or retard complications that result from diverse processes underlying the development of diabetes. This chapter will focus on the therapeutic promise of elucidation of such processes and their cardiovascular consequences. All diabetic subjects exhibit...

Insulin Stimulated Glucose Transport

The generation of the second messengers following insulin receptor binding and activation promotes cellular glucose transport into the cell. The enhanced insulin-stimulated glucose transport is mediated by translocation of a large number of glucose transporters from an intracellular pool to the plasma membrane (42). The glucose transporters consist of at least five homologous transmembrane proteins (Glut-1, -2, -3, -4, and -5) encoded by distinct genes, and have distinct specificities, kinetic...

Use of Lipid Altering Therapy

While there have been no prospective, randomized, clinical trials to evaluate the effects of lipid-altering therapy in the subsequent development of CAD among -o diabetic patients, there is a consistent body of scientific evidence derived from subset analyses. These results indicate that lipid-altering therapy is beneficial in both primary and secondary prevention. A subset analysis of the Scandinavian g Simvastatin Survival Study (4S) showed that, in diabetic patients with elevated < j total...

Selected Metabolic Aspects Of Diabetesg

A lay person would describe diabetes as too much sugar in the blood. So would J most medical students and physicians. However, hyperglycemia is simply the tip of the iceberg, albeit one of profound pathogenetic impact. Type 2 diabetes is, in fact, a syndrome in which resistance to insulin in peripheral tissues is present for years, if not decades, before hyperglycemia becomes evident. As compensatory pancreatic secretory mechanisms in response to the insulin resistance begin to fail, relative...

Control of Hyperglycemia

Several studies demonstrate the importance of intensive glycemic control in preventing or reducing microvascular complications of DM. The effect of intensive glycemic control on macrovascular complications in type 1 and type 2 DM is not as convincing. The Diabetes Control and Complications Trial (DCCT) demonstrated compelling evidence in support of a major reduction in chronic micro-vascular complications among type 1 diabetics under tight glycemic control. In the same study, tight glycemic...

Use of Pharmacotherapy for CAD and MI in Diabetics

Numerous studies have demonstrated that DM is a major independent predictor of acute and long-term post-MI morbidity and mortality. This is particularly true in women and in non-insulin-requiring diabetics. Many factors, including a greater extent and magnitude of angiographically severe CAD, associated comor- bidity, metabolic disturbances, silent myocardial ischemia, and late or atypical clinical presentation (often without chest discomfort) may contribute to a lower utilization of...

Cardiovascular Complications In Diabetes

Diabetes plays a powerful role in the development of cardiovascular diseases (810). The incidence of cardiovascular disease is two times higher in men with diabetes and three times higher in women with diabetes than nondiabetic subjects (10). Haffner et al. (11) reported that the risk of developing a myocardial infarction in type 2 diabetic patients without a previous history of myocardial infarction is similar to that of nondiabetic patients who have had a prior myocardial infarction. Diabetic...

Procoagulant Activity

There is evidence that impaired fibrinolysis and a hypercoaguable state are associated with insulin resistance hyperinsulinemia. 1. Plasminogen Activator Inhibitor-1 (PAI-1) PAI concentrations are higher in patients with hypertriglyceridemia, hypertension, and CHD, suggesting that PAI-1 concentrations are related to insulin resistance and or compensatory hyperinsulinemia. Epidemiological evidence in sup- -o port of this view comes from the European Concerted Action on Thrombosis and...

Lipoprotein Metabolism

Intestinal Lipoproteins and Transport of Dietary Lipids in Diabetes Mellitus Chylomicrons are assembled in the enterocytes of the small intestine after ingestion of dietary fat (triglyceride) and cholesterol. In the lymph and the blood, chylomicrons acquire several apolipoproteins, including apo C-II, apo C-III, and apo E. In the capillary beds of adipose tissue and muscle, chylomicrons interact with the enzyme lipoprotein lipase (LPL), which is activated by apo C-II, and the chylomicron...

Platelet Function And Diabetes Mellitus

Patients with diabetes, particularly those with macrovascular disease, have an increased circulating platelet mass secondary to increased ploidy of megakaryocytes. In addition, platelets isolated from the blood of subjects with diabetes exhibit impaired capacity to mediate vasodilatation, apparently because of release of a short-acting platelet-derived substance(s) that interferes with the ADP-induced dilatory response seen in normal vessels with intact endothelium. Platelets from diabetic...

Identifying The Responsible Cellular Event

The cellular abnormality accounting for clinical insulin resistance could theoretically involve any one of the multiple steps of the insulin signaling cascade as described above. Alterations in insulin production, insulin binding, or intracellular signaling each have the potential to induce an insulin-resistant state. For example, an abnormal beta-cell product resulting from a mutation in the gene coding for the insulin molecule (i.e., mutant insulin syndromes) may be associated with impaired...

Obstructive Sleep Apnea

Obese women with PCOS are at increased risk for obstructive sleep apnea (OSA) (56). Based on the increased prevalence of OSA in men, and recent evidence that androgens may play a role in the male predominance, overnight polysomnog-raphy was performed in obese women with PCOS and age weight-matched con- -o trols (56). Women with PCOS had a significantly higher apnea-hypopnea index (AHI), and were more likely to suffer from symptomatic OSA syndrome. The AHI correlated with waist-hip ratio, as...

Fibrinolysis And Diabetes

Decreased fibrinolytic system capacity is observed consistently as judged from analysis of blood from patients with diabetes mellitus, particularly those with type 2 diabetes. We have found that impaired fibrinolysis in subjects with type 2 diabetes mellitus, not only under baseline conditions but also in response to physiological (transitory venous occlusion) challenge, is attributable to augmented concentrations in blood of circulating plasminogen activator inhibitor type-1 (PAI-1). Increased...

Impaired Glucose Tolerance And Type Diabetes

Obesity is a well-recognized risk-factor for development of type 2 diabetes, but alone is insufficient to cause glucose intolerance. Thus, while it is generally accepted that women with PCOS are predisposed to type 2 diabetes (13,14), the development of diabetes cannot be attributed solely to the obesity that typically accompanies PCOS. Initial studies placed the prevalence of diabetes in PCOS at approximately 20 (8). More recent data have established that the prevalence of impaired glu- -o...

Atherogenesis In The Prediabetic State

The 15 incidence of cardiac death in the first 10 years after the diagnosis of J diabetes emphasizes the profound acceleration of progression of atherosclerosis that occurs long before diabetes becomes overt. The prediabetic state provides particularly fertile ground for germination of vulnerable plaques. Thus, a focus on treatment in the prediabetic state is likely to be important in preventing cardiovascular events later in ultimately diabetic subjects. One example is women with the...

B Cabg Surgery in Patients with Symptomatic CAD and Diabetes Mellitus

It is well recognized that DM is a powerful risk factor for poor early and late outcome after CABG surgery. Further, DM is an important predictor of subsequent saphenous vein graft occlusion as well as progression of atherosclerosis in both bypassed and nonbypassed vessels. As described previously, the BARI trial has shown that patients with DM and angiographic multivessel CAD randomized to an initial strategy of CABG surgery have a striking reduction in mortality compared to diabetic patients...

Clinical Interventions In The Management Of The Insulin Resistance Syndrome

On the basis of convincing clinical studies, it is no longer questioned that the -o insulin resistance syndrome is associated with an increased morbidity and mortal- ity. A more relevant question is whether improvement of insulin resistance with effective clinical interventions will decrease mortality and morbidity associated with the syndrome. Addressing the question will be problematic, as a clinically practical and reliable test to assess insulin resistance, or a way to serially measure...

Assessment Of Clinical Insulin Resistance

A number of techniques that differ in sophistication, complexity, and sensitivity are currently available to assess the degree of insulin resistance in patients (67,68). The most widely accepted research ''gold standard'' for delineation of insu- -o lin resistance is the euglycemic hyperinsulinemic clamp technique (67,68). In this procedure, exogenous insulin is infused to maintain a constant plasma insulin level above fasting while glucose is infused at varying rates to keep the blood glucose...

Pathogenesis Of Hypertension In Diabetes

Several factors are involved in the pathogenesis of hypertension in patients with diabetes mellitus. These include genetic factors, sodium retention, and hyperin-sulinemia. Genetic predisposition plays an important role in the development of hypertension in both type 1 and type 2 diabetes. The higher prevalence of hypertension in certain ethnic groups, such as African Americans, suggests the role of genetic factors (5). Diabetic patients with hypertension are reported to have high frequencies...

Detection And Diagnosis Of Abnormal Glucose Metabolism In Insulin Resistance Syndrome

In 1997, the American Diabetes Association Expert Committee on the Diagnosis and Classification of Diabetes Mellitus established a new classification system and diagnostic criteria to define various states of abnormal glucose metabolism (43). Fasting plasma glucose was divided into three diagnostic categories (1) normal < 110 mg dL (6.1 mmol L) (2) impaired fasting glucose (IFG) 110 to 125 mg dL (6.1 to 6.9 mmol L) and (3) diabetes mellitus > 126 mg dL (7.0 -o mmol L). Likewise, the plasma...

Clinical Trials Relevant To Treatment Of Hypertension And Prevention Of Cardiovascular Complications In Diabetes

Treatment of hypertension is crucial for the reduction of cardiovascular complications. There have been a considerable number of prospective randomized trials showing the benefits of treating hypertension in diabetes. The SHEP (Systolic Hypertension in the Elderly Program) trial showed that treatment of isolated sys- -o tolic hypertension in elderly type 2 diabetic patients with a diuretic, chlorthali-done, was associated with a significant decrease in the 5-year rates of cardiovas- S cular...

Surgical And Interventional Management Of Cad In Diabetics

Several clinical trials have demonstrated that outcomes after myocardial revas-cularization are different in diabetic patients compared to nondiabetic patients. These differences should influence treatment decisions. Over the last decade, percutaneous coronary intervention (PCI) has gained increasing acceptance as an alternative to CABG surgery in selected patients. However, several reports demonstrating reduced long-term survival in diabetic patients treated with standard coronary balloon...

In Patients With Diabetes

Most diabetic patients with CHF have it in conjunction with some other known cause(s) of CHF, usually coronary artery disease and or hypertension. Thus, there are relatively few patients with CHF in whom the only predisposing factor is diabetes. Stated another way, although there is strong evidence that cardiomyopa-thy is caused by diabetes, it is unusual for it to account for overt CHF by itself. Moreover, in an individual patient, it is usually impossible to delineate the qualitative and...

Vcardiomyopathy And Diabetes

Induction of cardiomyopathic changes in hearts of animals rendered insulin deficient is a well-recognized phenomenon. Accordingly, the term ''diabetic cardio- a myopathy'' has been extant for decades. Implicated derangements include impaired function of the sarcoplasmic reticulum, an organelle responsible for the uptake and release of intracellular calcium and, therefore, pivotal in modulating cardiac contractility. However, cardiomyopathy changes may not be related exclusively to metabolic...

The Insulin Resistance Syndrome

Insulin resistance and hyperinsulinemia are frequently associated with a cluster of clinical and biochemical abnormalities that have been described with increasing detail and given a variety of names including deadly quartet, syndrome X, insulin resistance syndrome, metabolic syndrome, and cardiovascular dysmeta-bolic syndrome (9-13). Many prefer to call it insulin resistance syndrome because insulin resistance and the resulting hyperinsulinemia appear to be the underlying abnormalities from...

Insulin Resistance In The Natural History Of Type Diabetes

Reduced insulin-dependent glucose transport is frequently found in nondiabetic relatives and offspring of patients with type 2 diabetes (5). This observation, as demonstrated in families and populations with a high incidence of type 2 diabetes, suggests that insulin resistance may be a primary factor in the development of type 2 diabetes and the early development of accelerated atherosclerosis. As such, the natural history of type 2 diabetes suggests that patients may be euglycemic and have...

Treatment Of The Hormonal And Metabolic Abnormalities Of Diabetes

Control of hyperglycemia retards progression of microvascular disease in both type 1 and type 2 diabetes. Accordingly, stringent glycemic control is imperative. Yet glycemic control exerts only a modest impact in retarding progression of macrovascular disease. Clearly other steps are needed. The recently initiated BARI 2D trial has been designed to provide information useful in this regard. Patients are being assigned randomly to stringent and comparable glycemic control with regimens that are...

Cellular Events Defining Insulin Action

Understanding the cellular mechanism(s) of action in the insulin-sensitive tissues responsible for insulin resistance would be important in the goal of identifying its genetic basis. Further, an understanding of the cellular defect would allow both the development of effective therapies and optimal use of current therapies. As stated, the aspect of insulin resistance that has been the most well described is inefficient glucose uptake and utilization in peripheral tissues in response to -o...

Role Of Diabetes In The Genesis Of

There are several clinical, angiographic, and biological features particular to DM that increase the propensity for developing CAD in diabetic patients. In the aggregate, these risk factors increase the likelihood for sustaining a clinical event and have important prognostic implications. Endothelial dysfunction, platelet and coagulation abnormalities, and metabolic disorders associated with DM play a major role in accelerating the process of atherosclerosis and generating coronary thrombosis....

Heart Disease And Prediabetic States

The duration of diabetes influences the development of CAD in patients with type 1 diabetes, but such a relationship has not been demonstrated in those with type 2. Therefore, it is unclear whether the duration of asymptomatic hyperglyce-mia, or the state of impaired glucose tolerance, may have an important role on the development of CAD preceding the overt manifestations of type 2 diabetes (31,32). Several studies have shown that the mortality rate due to CAD was higher in patients with...

Chusny Syndrome

Microvascular and macrovascular reactivity is reduced in subjects at risk for type 2 diabetes. Diabetes 1999 48 1856-1862. 38. Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, Haring HU. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with type 2 diabetes in association with insulin resistance. Circulation 2000 101 1780-1784. 39. Festa A, D'Agostino Jr R, Howard G, Mykkanen, L,...

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Lawson ML, Gerstein HC, Tsui E, Zinman B. Effect of intensive therapy on early macrovascular disease in young individuals with type 1 diabetes A systematic review and meta-analysis. Diabetes Care 1999 22(suppl 2) B35-B39. 22. Lebovitz HE. The effect of the postprandial state on nontraditional risk factors. Am J Cardiol 2001 88(Suppl) 20H-25H. 23. Erbey JR, Kuller LH, Becker DJ, Orchard TJ. The association between a family history of type 2 diabetes and coronary artery disease in a type 1...

Huf

The characteristic abnormality of lipoprotein metabolism S in patients with syndrome X is hypertriglyceridemia, usually associated with a low-HDL cholesterol concentration, increased postprandial lipemia, and small, dense LDL particles. The use of fibric acid derivatives in patients with syndrome X will significantly lower plasma TG concentrations, as well as improve all of J the abnormalities associated with hypertriglyceridemia. In addition, there is now evidence that the use of...

Harold E Lebovitz

State University of New York Health Science Center at Brooklyn, Brooklyn, New York Diabetes mellitus is a syndrome in which blood glucose levels are inappropriately high for the individual's physiological state. In most populations both fasting and postprandial plasma glucose levels are continuous variables that are skewed toward the higher range. The differentiation between normal and abnormal is therefore arbitrary and must be defined by additional criteria. Diabetic retinopathy is the most...

Overcoming the Manifestations of Syndrome X

Although therapeutic efforts aimed at enhancing insulin sensitivity may be limited, there is no reason to adopt a nihilistic approach to attenuating the CHD risk lt j factors in patients with syndrome X. Indeed, there are both dietary and pharmacological interventions that can substantially reduce the manifestations of syndrome X. As indicated earlier, weight loss will significantly improve insulin sensitivity in overweight, insulin-resistant individuals. However, not all overweight patients...

The Coagulation System And Diabetes Mellitus

The final common pathway resulting from activation of the coagulation system is generation of thrombin and thrombin-mediated formation of fibrin from fibrin-ogen. Generation of thrombin depends on activation of procoagulant factors and is limited by antithrombotic factors and inhibitors. A marker of thrombin activity is fibrinopeptide A FPA , released when fibrinogen is cleaved by thrombin. This peptide has a very short half-life in the circulation because it is cleared promptly by the kidneys....

Metabolic Syndrome

The metabolic abnormalities associated with DM are well recognized and include insulin resistance or, more appropriately, dysinsulinemia , hyperglycemia, hypertension, and dyslipidemia. These factors are associated with a panoply of biological perturbations that result in endothelial dysfunction with impaired coronary flow reserve, increased platelet activity, increased thromboxane A2 secretion, higher fibrinogen and factor VII levels, lower antithrombin III and plasma fi- S brinolytic...