Association between insulin resistance and the development of cardiovascular disease

Growing up in postwar Germany as I did taught me something that is hard to forget. When people had relatively little to eat, diseases such as NIDDM and atherosclerosis were almost unheard of. Today, these diseases occur in epidemic proportions. Furthermore, atherosclerosis is now the most common and deleterious complication of NIDDM. This issue of Circulation contains the first, long-awaited results of the Insulin Resistance Atherosclerosis Study, which examines the association between insulin sensitivity and IMT of the carotid artery as an index of atherosclerosis. The study is based on observations in three distinctly different ethnic groups of approximately equal size in four communities of the United States.1 The results show an inverse relation between insulin sensitivity and atherosclerosis in Hispanic and non-Hispanic white Americans but not among black Americans. When the investigators adjusted their results for the traditional risk factors of coronary artery disease, glucose tolerance, measures of adiposity, and fasting insulin levels, this inverse relation was reduced but not eliminated. The powerful analysis suggests therefore that insulin resistance per se is an independent cause of atherosclerosis in non-Hispanic and Hispanic whites. It also suggests that the inverse relation between insulin sensitivity and atherosclerosis is stronger than the relation between insulin and atherosclerosis. The ethnic differences are not so readily explained, although it is of interest that non-Hispanic and Hispanic whites share the same characteristics. The findings of the present study1 provide support for the clinical observation that diabetes and macrovascular disease not only coexist but may spring from common roots. On the one hand, the results suggest that it is possible to identify patients early who are at risk for the development of atherosclerotic vascular disease. On the other hand, they provide a challenge for the practicing physician to diagnose and treat subclinical forms of glucose …

Selective Insulin and Leptin Resistance in Metabolic Disorders

Cardiovascular disease in HIV-positive patients

Our friend and colleague Wayne Fenton asked to write this article for the Journal because of his desire to educate other psychiatrists about the treatment of schizophrenia, including what he recognized to be a growing problem with the metabolic syndrome. This lifelong passion, which he pursued from his psychiatry residency at Yale, through his directorship of Chestnut Lodge, to his position at NIMH as Director of the Division of Adult Translational Research and Associate Director for Clinical Affairs, ended tragically with his killing during an evaluation of a psychotic young man. Wayne had worked tirelessly to secure support for new drug discovery in the NIMH programs that he directed. The Journal will be initiating in 2007 a series of articles on the discovery of new mental illness treatments. We will dedicate this series to Wayne's memory and include with it a memorial of his life and contributions to the treatment of mental illness.

Molecular Mechanisms Involved in Inflammation and Insulin Resistance in Chronic Diseases and Possible Interventions

Implications of Elevated Serum Alanine Aminotransferase Levels: Think Outside the Liver

Diabetes mellitus (DM) is characterized by fasting hyperglycaemia and a high risk of atherothrombotic disorders affecting the coronary, cerebral and peripheral arterial trees. The risk of myocardial infarction (MI) is 3-5 fold higher in Type 2 DM and a DM subject with no history of MI has the same risk as a non-DM subject with a past history of MI. In total around 70% of deaths are vascular with poorer outcomes to both acute events and cardiological interventions. It was proposed that clustering of vascular risk factors (hyperinsulinaemia, dysglycaemia, dyslipidaemia and hypertension) around insulin resistance (IR) accounted for the increase in risk with Type 2 DM. The importance of this became apparent with the recognition that risk clustering occurs in normoglycaemic and impaired glucose tolerance (IGT) subjects with IR, in total around 25% of the population in addition to long-standing Type 1 subjects with renal disease. Evidence indicates that thrombotic risk clustering also occurs in association with IR, suppression of fibrinolysis due to elevated concentrations of the fibrinolytic inhibitor, plasminogen activator inhibitor-1 (PAI-1) is invariable with IR and there is evidence that this is regulated by the effects of triglyceride on the PAI-1 gene promoter. Other studies indicated that prothrombotic risk (coagulation factors VII, XII and fibrinogen) also associates with the IR syndrome. The development of endothelial cell dysfunction with suppression of nitric oxide and prostacyclin synthesis, combined with platelet resistance to the anti-aggregatory effects of these hormones leads to loss of control over platelet activation. In addition, hyperglycaemia and glycation have marked effects on fibrin structure function, generating a clot which has a denser structure, resistant to fibrinolysis. The combination of increased circulating coagulation zymogens, inhibition of fibrinolysis, changes in fibrin structure/function and alterations in platelet reactivity creates a thrombotic risk clustering which underpins the development of cardiovascular disease.

The metabolic syndrome, a combination of interrelated metabolic risk factors, is associated with insulin resistance and promotes the development of cardiovascular diseases and type 2 diabetes mellitus. There is a close link between inflammation and metabolic disease, but the responsible mechanisms remain elusive. The aim of this study was to identify differentially expressed genes in insulin-resistant skeletal muscle tissue of women with the metabolic syndrome compared with healthy control women. Women with the metabolic syndrome (n = 19) and healthy control women (n = 20) were extensively phenotyped, insulin sensitivity was measured using a hyperinsulinaemic euglycaemic clamp, and a skeletal muscle biopsy was obtained. Gene expression levels were compared between the two groups by microarrays. The upregulated genes in skeletal muscle of the women with the metabolic syndrome were primarily enriched for inflammatory response-associated genes. The three most significantly upregulated of this group, interleukin 6 receptor (IL6R), histone deacetylase 9 (HDAC9) and CD97 molecule (CD97), were significantly correlated with insulin resistance. Taken together, these findings suggest an important role for a number of inflammatory-related genes in the development of skeletal muscle insulin resistance.

See related article, pages 1589–1596 The prevalence of obesity, especially among adolescents, has increased considerably over the past 20 years because of increased caloric intake and reduced physical activity. It has been estimated that 20% of the world’s population is overweight and nearly 300 million are obese (BMI >30 kg/m2).1,2 Excess body weight and obesity are associated with the development of metabolic syndrome and type II diabetes, both of which are associated with insulin resistance and increased risk of cardiovascular complications.1,2 Atherothrombotic vascular disease, resulting from a complex interplay between dyslipidemia and vascular immunoinflammatory processes, is responsible for a majority of the excess morbidity and mortality that characterizes metabolic syndrome and type II diabetes.1,2 Several studies have shown that obesity is associated with activation of inflammatory pathways and that inflammatory responses are associated with impaired insulin signaling and insulin resistance.3–8 Considerable progress has been made in the last 2 decades in our understanding of molecular events that link obesity to inflammation, insulin resistance, type II diabetes, and enhanced vascular disease. Obesity-mediated skeletal muscle insulin resistance has been linked to defects in cellular signaling events triggered by insulin.3–8 In obesity, the skeletal muscle levels of several kinases such as protein kinase C isoforms (PKC), I Kappa B Kinase-β …

Chapter 10 - Summery and perspective for future research on insulin resistance and insulin resistance–linked visceral and neurological disorders

Patients with human immunodeficiency virus (HIV) infection have sustained alterations in metabolism (lipids and insulin/glucose homeostasis) and body composition (fat distribution) that are proatherogenic (the Figure). HIV infection itself and/or its therapies may contribute to these alterations (the Table); although most effects are reversible, there are some possibly irreversible consequences of treatment. With the relative restoration to health seen in the era of highly active antiretroviral therapy (HAART), many traditional risk factors and promoters of dyslipidemia and diabetes also are present; they interact with HIV-specific inducers to worsen dyslipidemia and to increase the prevalence of insulin resistance and diabetes. Figure. Overview of the effects of HIV and its therapies on CVD risk. The contribution of traditional risk factors must be kept in mind, and they may occur with increased prevalence in people with HIV infection (eg, smoking). HIV, likely through the inflammatory response, and antiretroviral therapies independently affect many of the mediators of CVD risk. The effects on lipids are a prominent but complex example; HIV infection lowers LDL levels, but antiretroviral therapy raises LDL back up to normal levels. The bidirectional arrows indicate associations, but there is not yet adequate proof of causality. The dotted arrow between body composition and CVD indicates that body fat is known to affect the mediators such as dyslipidemia and insulin resistance but may also have a direct effect. FFA indicates free fatty acids; ARV, antiretroviral. View this table: Table. Effects of HIV Treatment These disturbances in lipid and glucose metabolism and renal disease may contribute, at least in part, to the excess cardiovascular disease (CVD) morbidity and mortality observed in HIV-infected individuals (the Figure). However, the relative contribution to excess CVD risk of traditional CVD risk factors, especially smoking, compared with these infection- and treatment-specific complications requires clarification. More prospective data with multivariable modeling are needed. …

A Branched-Chain Amino Acid-Related Metabolic Signature that Differentiates Obese and Lean Humans and Contributes to Insulin Resistance

<i>Circulation Research</i> Thematic Synopsis Diabetes and Obesity

Diabetes is associated with increased atherosclerosis and other causes of myocardial dysfunction. The pathogenesis of cardiovascular disease (CVD) in diabetes is multifactorial and can be affected by metabolic and other factors. Under physiological conditions, the endothelial cell (EC) layer acts as a barrier to separate circulating factors and cells from the arterial intima and media. It also serves as an anticoagulant and fibrinolytic surface producing tissue plasminogen activator, which counters the effects of procoagulant factors such as fibrinogen and plasminogen activator inhibitor-1 (PAI-1). Endothelial cells produce nitric oxide (NO), which is a vasodilator and restrains smooth muscle cell (SMC) migration and proliferation. Circulating factors (hyperglycemia, increased free fatty acids, altered lipoproteins, and derivatives of glycation and oxidation) and hypertension, all of which are common in diabetes, can damage ECs, leading to their dysfunction. Plasma proteins, among them lipoproteins, cross the endothelial barrier, where they can be retained by subendothelial matrix molecules such as collagen and proteoglycans.1 These and other matrix molecules are produced by ECs and SMCs. Blood components can be modified, eg, by oxidation and glycation.2 Modified proteins and lipids can alter EC and SMC gene expression, leading to increased production of procoagulants, adhesion molecules, chemotactic factors, and cytokines. The net effect is the adhesion and penetration of circulating monocytes into the arterial intima, where they undergo differentiation and activation to macrophages. Lipids can accumulate intracellularly after uptake of modified lipoproteins (glycation, oxidation, and glycoxidation) by different scavenger receptors on macrophages and SMCs, as well as extracellularly by attaching to matrix molecules.3 The resulting lesion is termed the fatty streak. Both ECs and macrophages produce cytokines and growth factors that permit SMCs to migrate from the media to the intima. In the intima, SMCs proliferate in response to several growth factors. These SMCs and the matrix …

It is unclear whether the role of insulin resistance in the development of atherosclerotic cardiovascular disease is similar in populations in which the incidence of atherosclerotic diseases significantly differs from that in Western countries. The aim of this study was to determine the relationship between insulin resistance and the development of cardiovascular disease in the Japanese population. We conducted 75 g-oral glucose tolerance tests (OGTTs) on 1,928 inhabitants of two towns in Hokkaido, Japan. Subjects using antihypertensive agents and known diabetic patients were excluded from the study. Data from the remaining 1,227 subjects (540 males and 687 females; mean age 56.0 +/- 10.8 years) were used for the analysis, and 1,051 subjects were seen in a follow-up care setting for a period of 8 years. The presence of insulin resistance was defined according to the guidelines reported our previous study: insulin levels of 64.0 mU/l or higher 2 h after the 75 g-OGTT. The insulin-resistant (IR) group had several risk factors such as hypertension, diabetes, treated or untreated hypercholesterolemia, hypertriglyceridemia, low high-density-lipoprotein (HDL) cholesterol levels, and obesity. During the follow-up period of 8 years, the incidence of coronary artery disease, which was adjusted for age, body mass index, sex, systolic blood pressure, fasting plasma glucose, total cholesterol, triglyceride, and HDL cholesterol was significantly (3.2 times) higher in the IR group than in the insulin non-resistant group. The results suggested that insulin resistance is an independent risk factor for coronary artery disease in Japanese subjects, as has also been demonstrated in the case of individuals in Europe and USA.