Inflammation and emerging risk factors in diabetes mellitus and atherosclerosis

Type 2 diabetes mellitus and atherosclerosis are complex and progressive conditions that share several common antecedents. Recent data suggest that inflammation may play a central role in the origins and complications of cardiovascular disease and, possibly, type 2 diabetes mellitus. C-reactive protein and plasminogen activator inhibitor-1 are circulating markers of low-grade inflammation, thrombosis, and vascular injury. Together with homocysteine, they have been associated with the underlying inflammatory processes and are considered to be "nontraditional" risk factors of atherosclerosis. The role of their measurement in clinical practice remains unclear. In this article, we review the available evidence demonstrating a link between inflammation, cardiovascular disease, and diabetes. We discuss how therapeutic agents used for both cardiovascular disease and diabetes modulate the inflammatory responses and possibly attenuate the complications of these two chronic disorders that cause significant morbidity and mortality.     

Diabetes,Hypertension, and Cardiovascular Disease: Clinical Insights and Vascular Mechanisms

Hypertension and type 2 diabetes are common comorbidities. Hypertension is twice as frequent in patients with diabetes compared with those who do not have diabetes. Moreover, patients with hypertension often exhibit insulin resistance and are at greater risk of diabetes developing than are normotensive individuals. The major cause of morbidity and mortality in diabetes is cardiovascular disease, which is exacerbated by hypertension. Accordingly, diabetes and hypertension are closely interlinked because of similar risk factors, such as endothelial dysfunction, vascular inflammation, arterial remodelling, atherosclerosis, dyslipidemia, and obesity. There is also substantial overlap in the cardiovascular complications of diabetes and hypertension related primarily to microvascular and macrovascular disease. Common mechanisms, such as upregulation of the renin-angiotensin-aldosterone system, oxidative stress, inflammation, and activation of the immune system likely contribute to the close relationship between diabetes and hypertension. In this article we discuss diabetes and hypertension as comorbidities and discuss the pathophysiological features of vascular complications associated with these conditions. We also highlight some vascular mechanisms that predispose to both conditions, focusing on advanced glycation end products, oxidative stress, inflammation, the immune system, and microRNAs. Finally, we provide some insights into current therapies targeting diabetes and cardiovascular complications and introduce some new agents that may have vasoprotective therapeutic potential in diabetes.     

Insulin resistance in type 1 diabetes: what is ‘double diabetes’ and what are the risks?

In this review, we explore the concept of ‘double diabetes’, a combination of type 1 diabetes with features of insulin resistance and type 2 diabetes. After considering whether double diabetes is a useful concept, we discuss potential mechanisms of increased insulin resistance in type 1 diabetes before examining the extent to which double diabetes might increase the risk of cardiovascular disease (CVD). We then go on to consider the proposal that weight gain from intensive insulin regimens may be associated with increased CV risk factors in some patients with type 1 diabetes, and explore the complex relationships between weight gain, insulin resistance, glycaemic control and CV outcome. Important comparisons and contrasts between type 1 diabetes and type 2 diabetes are highlighted in terms of hepatic fat, fat partitioning and lipid profile, and how these may differ between type 1 diabetic patients with and without double diabetes. In so doing, we hope this work will stimulate much-needed research in this area and an improvement in clinical practice.     

Do glucose and lipids exert independent effects on atherosclerotic lesion initiation or progression to advanced plaques?

It is becoming increasingly clear that suboptimal blood glucose control results in adverse effects on large blood vessels, thereby accelerating atherosclerosis and cardiovascular disease, manifested as myocardial infarction, stroke, and peripheral vascular disease. Cardiovascular disease is accelerated by both type 1 and type 2 diabetes. In type 1 diabetes, hyperglycemia generally occurs in the absence of elevated blood lipid levels, whereas type 2 diabetes is frequently associated with dyslipidemia. In this review article, we discuss hyperglycemia versus hyperlipidemia as culprits in diabetes-accelerated atherosclerosis and cardiovascular disease, with emphasis on studies in mouse models and isolated vascular cells. Recent studies on LDL receptor-deficient mice that are hyperglycemic, but exhibit no marked dyslipidemia compared with nondiabetic controls, show that diabetes in the absence of diabetes-induced hyperlipidemia is associated with an accelerated formation of atherosclerotic lesions, similar to what is seen in fat-fed nondiabetic mice. These effects of diabetes are masked in severely dyslipidemic mice, suggesting that the effects of glucose and lipids on lesion initiation might be mediated by similar mechanisms. Recent evidence from isolated endothelial cells demonstrates that glucose and lipids can induce endothelial dysfunction through similar intracellular mechanisms. Analogous effects of glucose and lipids are also seen in macrophages. Furthermore, glucose exerts many of its cellular effects through lipid mediators. We propose that diabetes without associated dyslipidemia accelerates atherosclerosis by mechanisms that can also be activated by hyperlipidemia.     

Imaging Atherosclerosis in Diabetes: Current State

Cardiovascular events, including myocardial infarction and stroke, are the primary causes of mortality in both type 1 and type 2 diabetes. Affected patients frequently have asymptomatic coronary artery disease. Studies have shown heterogeneity in cardiovascular risk among patients with diabetes. Imaging can help categorize risk of future cardiovascular events by identifying those patients with atherosclerosis, rather than relying on risk prediction based on population-based studies. In this article, we will review the evidence regarding use of atherosclerosis imaging in patients with diabetes to predict risk of coronary heart disease and mortality.     

2型糖尿病和动脉粥样硬化性心血管病的关系

动脉粥样硬化性心血管病是2型糖尿病患者死亡和残疾的主要原因,2型糖尿病患者发生动脉粥样硬化病变的风险显著高于非糖尿病患者。虽然目前关于2型糖尿病与动脉粥样硬化发生和发展之间的关系尚未完全阐明,但大量基础与临床研究已证实二者之间存在密切的内在联系。现有研究提示,2型糖尿病患者发生动脉粥样硬化病变的机制可能涉及高血糖、胰岛素抵抗、血管钙化、氧化应激、内皮功能障碍和炎症反应等。结合近年来最新的研究结果,现总结分析2型糖尿病与动脉粥样硬化性心血管病之间的潜在联系与可能机制。     

Diabetes and Cardiovascular Disease: The Potential Benefit of Incretin-Based Therapies

The health burden of type 2 diabetes mellitus continues to increase worldwide. A substantial portion of this burden is due to the development of cardiovascular disease in patients with diabetes. Recent failures of clinical trials of intensive glucose control to reduce macrovascular events, coupled with reports of potential harm of certain diabetic therapy, have led to increased scrutiny as new diabetic therapies are developed. Incretin peptides are a group of gastrointestinal proteins that regulate glucose metabolism through multiple mechanisms, and incretin-based therapies have been developed to treat type 2 diabetes. These agents include glucagon-like peptide-1 (GLP-1) and dipeptidyl peptidase-IV (DPP-IV) inhibitors. In addition to effects on glucose homeostasis, growing evidence suggest that these peptides may also affect the cardiovascular system. In this review, we discuss recent findings concerning the potential, yet untested, benefits of incretin-based pharmacotherapy in the treatment of cardiovascular disease.     

Hypoglycemic pharmacological treatment of type 2 diabetes: Targeting the endothelium

Cardiovascular disease is by far the most common complication of type 2 diabetes and also the most serious one. Suffering from type 2 diabetes mellitus not only dramatically increases the risk of cardiovascular disease but is also associated with poor survival, both acutely and in the long term after a myocardial infarction. In fact, total mortality from coronary artery disease in subjects with type 2 diabetes mellitus, without a previous myocardial infarction, is as high as that of non-diabetic individuals with a previous infarction. Intense research efforts have thus been directed towards exploring the reasons for why particularly type 2 diabetic patients have such a poor prognosis suffering from cardiovascular disease. Obesity-related type 2 diabetes (“diabesity”), including the metabolic syndrome, is rapidly rising in prevalence. About 80% of all type 2 diabetes co-exists with insulin resistance. Endothelial dysfunction is a ubiquitous abnormality in insulin-resistant states that might contribute to premature atherosclerosis in a multifactorial and complex way. Low grade inflammation may play a role in development insulin resistance and type 2 diabetes and it has been proposed that atherosclerosis is basically an inflammatory disease. Thus, the pathophysiology of insulin resistance, the metabolic syndrome, and atherosclerosis may share inflammatory basis as a common denominator. Also, insulin resistance is not confined to skeletal muscle, adipose tissue and the liver, but also to the endothelium. Insulin resistance and endothelial dysfunction co-exist, where chronic inflammation may be a crucial factor. Accordingly, the possibility that physical activity or pharmacological agents that increase insulin sensitivity also improve endothelial function, or vice versa, has been investigated. Many different alterations in life style and drugs that improve endothelial function are known to lower the risk of contracting diabetes. In this review, the pharmacological treatment available against type 2 diabetes mellitus is discussed with particular emphasis on its impact on the endothelium.     

Phenomics, lipodystrophy, and the metabolic syndrome

The metabolic syndrome (MetS) is a common multiplex cluster of phenotypes strongly related to cardiovascular disease that includes central obesity with hypertension, dyslipidemia, and type 2 diabetes. The core molecular defect of the MetS is insulin resistance; indeed, the terms "MetS" and "insulin resistance syndrome" often are used interchangeably. The successful translation to clinical medicine of molecular genetic research on other rare monogenic metabolic disorders has stimulated the evaluation of such rare monogenic forms of insulin resistance as partial lipodystrophy resulting from mutations in either LMNA or PPARG genes. Careful phenotypic evaluation of carriers of monogenic insulin resistance using a range of diagnostic methods--an approach sometimes called "phenomics"--may help to find early presymptomatic biomarkers of cardiovascular disease, which, in turn, may uncover new pathways and targets for interventions for the common MetS, diabetes, and atherosclerosis.     

Factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients: association with atherosclerosis

Type 2 diabetes is a heterogeneous syndrome characterized by defective insulin secretion and/or insulin resistance. In distinct from Caucasian populations, Japanese type 2 diabetic patients are divided into two categories: one with insulin resistance and the other with normal insulin sensitivity. This unique feature allows us to explore the factors responsible for the evolution of insulin resistance in Japanese type 2 diabetic patients. In this article, we describe the factors responsible for insulin resistance in Japanese type 2 diabetic patients and discuss the relationships between these factors and atherosclerosis. Japanese type 2 diabetic patients with insulin resistance had significantly higher concentrations of triglyceride, remnant-like particle cholesterol, subcutaneous and visceral abdominal fat areas, leptin, high sensitive C-reactive protein (hs-CRP), and soluble E-selectin and lower concentration of adiponectin when compared to those with normal insulin sensitivity. There were, however, no significant difference in tumor necrosis factor (TNF)-alpha and soluble TNF receptors between the two groups. Serum triglyceride was positively correlated to visceral abdominal fat area, while serum leptin was positively correlated with subcutaneous abdominal fat area. In contrast, serum adiponectin was negatively correlated to visceral abdominal fat area. High sensitive CRP was positively correlated to BMI, triglyceride, and leptin, but was negatively correlated to adiponectin. Tumor necrosis factor-alpha and soluble TNF receptors, however, were not associated with any of these factors. Thus, it may be hypothesized that Japanese type 2 diabetic patients are divided into two categories: one with normal insulin sensitivity and the other with insulin resistance. The former group has a low cardiovascular risk factor, whereas the latter one has a markedly increased cardiovascular disease risk factor. Furthermore, abdominal fat related insulin resistance seems to be associated with insulin resistance in Japanese type 2 diabetic patients. In this section, we would like to focus on the factors contributing to insulin resistance and discuss the association of these factors with atherosclerosis in Japanese type 2 diabetic patients.     

New diagnostic criteria for diabetes and coronary artery disease: insights from an angiographic study

OBJECTIVES: The goal of this research was to study coronary atherosclerosis in patients with type 2 diabetes compared with patients without diabetes according to the new definition of diabetes advocated by the American Diabetes Association in 1997. BACKGROUND: Patients with diabetes (fasting plasma glucose above 7.0 mM/L) have a higher risk of cardiovascular death. The correlation with the pattern and severity of their coronary atherosclerosis, especially in the new patients with "mild" diabetes (7.0 mM/L < or = fasting plasma glucose < 7.8 mM/L), remains unclear. METHODS: A cohort of 466 patients undergoing coronary angiography but free of any previous infarction, coronary intervention and insulin therapy were prospectively recruited. Ninety-three had diabetes (fasting plasma glucose > 7.0 mM/L or hypoglycemic oral treatment). Five angiographic indexes were calculated to describe severity and extent of coronary atherosclerosis. RESULTS: Overall, patients with diabetes had more diffuse coronary atherosclerosis, a greater prevalence of mild, moderate and severe stenoses and a two-fold higher occlusion rate than patients without diabetes, even after adjustment for age, gender, body mass index, hypertension, lipid parameters, smoking, family history of cardiovascular events and ischemic symptoms. Patients with "mild diabetes" had a coronary atherosclerosis pattern more similar to patients with normal fasting plasma glucose than to patients formerly defined as diabetic according to the World Health Organization criteria, except that they had a higher prevalence of <50% stenoses. CONCLUSIONS: In patients with type 2 diabetes, those with 7.0 mM/L < or = fasting plasma glucose < 7.7 mM/L have a slightly greater prevalence of mildly severe lesions that may partly explain their higher cardiovascular event rate.     

Circulating microRNAs: novel biomarkers and extracellular communicators in cardiovascular disease?

In the past few years, the crucial role of different micro-RNAs (miRNAs) in the cardiovascular system has been widely recognized. Recently, it was discovered that extracellular miRNAs circulate in the bloodstream and that such circulating miRNAs are remarkably stable. This has raised the possibility that miRNAs may be probed in the circulation and can serve as novel diagnostic markers. Although the precise cellular release mechanisms of miRNAs remain largely unknown, the first studies revealed that these circulating miRNAs may be delivered to recipient cells, where they can regulate translation of target genes. In this review, we will discuss the nature of the stability of miRNAs that circulate in the bloodstream and discuss the available evidence regarding the possible function of these circulating miRNAs in distant cell-to-cell communication. Furthermore, we summarize and discuss the usefulness of circulating miRNAs as biomarkers for a wide range of cardiovascular diseases such as myocardial infarction, heart failure, atherosclerosis, hypertension, and type 2 diabetes mellitus.     

Impact of cardiovascular outcomes on the development and approval of medications for the treatment of diabetes mellitus

All medications currently approved by the Food and Drug Administration (FDA) for the treatment of type 2 diabetes mellitus are indicated to improve glycemic control. Since 1995, FDA has used HbA1c as the primary basis for approval of these therapies because a reduction in blood glucose lessens the symptoms of hyperglycemia and lowering of HbA1c has been shown to reduce the risk for some of the chronic complications of diabetes. Despite evidence of clinical benefit with therapies that reduce HbA1c, concerns have been raised that some diabetes medications may increase cardiovascular risk in a patient population that is already vulnerable to cardiovascular disease. Therefore, FDA convened a public advisory committee meeting to discuss the role of cardiovascular assessment in the pre-approval and post-approval settings for medications developed for the treatment of type 2 diabetes. After considering the advisory panel’s recommendations and other data, FDA published a guidance document requesting evidence showing that new treatments for type 2 diabetes do not result in an unacceptable increase in cardiovascular risk. This review article begins by summarizing the events leading up to publication of this guidance. Subsequent sections discuss the guidance itself as well as general considerations for implementing the new cardiovascular recommendations. The new approach to developing medications for the treatment of type 2 diabetes will lead to evaluation in patients more representative of those who will use these therapies, if approved, and will help healthcare providers make informed decisions when choosing a medication within the growing treatment armamentarium for type 2 diabetes.     

代谢重编程:单核/巨噬细胞训练免疫参与动脉粥样硬化的新机制

动脉粥样硬化是血管的慢性炎症性疾病,单核/巨噬细胞的异常活化与动脉粥样硬化的发生发展密切相关。近期研究发现单核/巨噬细胞可以通过训练免疫发生代谢重编程,促进炎症反应,加快动脉粥样硬化的进展,并可以导致心血管意外事件的发生。文章综述了单核/巨噬细胞代谢重编程在训练免疫发生中的作用和机制,可能为动脉粥样硬化的防治提供新的治疗靶点和方法。     

Coronary artery and abdominal aortic calcification are associated with cardiovascular disease in type 2 diabetes

Aims/hypothesis The goals of this study were to determine whether coronary calcium is associated with the presence of clinical cardiovascular disease in individuals with type 2 diabetes and if the measurement of abdominal aortic calcium may have an independent or added benefit as a surrogate marker for clinical vascular disease.Methods A cross-sectional study of subjects with type 2 diabetes enrolled in seven medical centres in the USA participating in a Veterans Affairs Cooperative Study of glycaemic control. Enrolled subjects included 309 veterans over 40 years of age with type 2 diabetes, with or without stable cardiovascular disease, who had inadequate glycaemic control (HbA₁c>7.5%) on oral agents and/or insulin. The study assessed lifestyle behaviours, standard cardiovascular risk factors and coronary artery and abdominal aorta calcification by electron beam computed tomography.Results Subjects with coronary artery or abdominal aorta calcification present had a strikingly higher prevalence of peripheral artery disease, coronary artery disease and all combined cardiovascular disease. Prevalence of each condition increased from 5- to 13-fold with increasing quintiles of coronary artery calcification and from 2- to 3-fold with increasing abdominal aorta calcification. These associations persisted after adjustment for lifestyle behaviours and standard cardiovascular risk factors.Conclusions/interpretation These results support the notion that vascular calcium in type 2 diabetes provides additional information beyond that of standard risk factors in identifying the presence of cardiovascular disease. Subclinical measures of atherosclerosis such as arterial calcification may help more precisely stratify these individuals and alert healthcare providers to those individuals who have particularly accelerated atherosclerosis.     

Fatty Acid Binding Proteins and Cardiovascular Risk

The role of fatty acid-binding proteins in cardiovascular disease has been the subject of several studies and viewpoints in recent years. These proteins are involved in the atherosclerotic plaque formation mainly in macrophages through a complex processing of lipids and inflammatory responses. In addition, they may signal the presence of obesity, insulin resistance, and type 2 diabetes mellitus, co-morbidities with a demonstrated impact in cardiovascular risk. The present review aims to summarize the most relevant findings over the past years to the function of fatty acid-binding proteins (FABPs) along the spectrum of metabolic disorders and cardiovascular disease. Finally, we will discuss the potential use of FABPs as cardiovascular risk markers and therapeutic targets to halt the progression of atherosclerosis.     

Glucose control in diabetes: which target level to aim for?

The most important goal in the treatment of patients with diabetes is to lower the risk of long-term diabetes complications. Hyperglycaemia is the most important risk factor for microvascular complications in diabetes, but, in addition to hyperglycaemia, several other risk factors, particularly dyslipidaemia, elevated blood pressure and smoking, also determine the risk of macrovascular complications. In this review, we present evidence from longitudinal population-based studies that hyperglycaemia is an important risk factor for long-term complications of diabetes and discuss the results from clinical trials of the effects of the treatment of hyperglycaemia on the prevention of long-term micro- and macrovascular complications in type 1 and type 2 diabetes. An HbA(1c) target of <7.0% for the treatment of diabetes is generally accepted on the basis of evidence from several trials, whereas a target of <6.5% may be reasonable for patients with a short duration of type 2 diabetes and without extensive atherosclerosis.     

The expanding scope of the metabolic syndrome and implications for the management of cardiovascular risk in type 2 diabetes with particular focus on the emerging role of the thiazolidinediones

Over the last decade, new factors including endothelial dysfunction, vascular inflammation, and abnormalities of blood coagulation have joined more established components of the metabolic syndrome, such as hyperglycemia, hypertension, dyslipidemia, and visceral obesity. Many of these factors are known to promote atherosclerosis and the clustering of metabolic abnormalities within the syndrome makes a major contribution to the increased risk of cardiovascular disease and death associated with type 2 diabetes. Given that most patients have multiple cardiovascular risk factors, good glycemic control does not, by itself, adequately reduce the burden of cardiovascular disease associated with diabetes and clinical management needs to address the full profile of cardiovascular risk. The thiazolidinediones have potentially beneficial effects on many components of the metabolic syndrome and so may help to improve cardiovascular outcomes in type 2 diabetes.     

Nova abordagem para o tratamento da diabetes: da glicemia à doença cardiovascular

Diabetes, a metabolic disease with vascular consequences due to accelerated atherosclerosis, is one of the 21st century's most prevalent chronic diseases. Characterized by inability to produce or use insulin, leading to hyperglycemia and insulin deficiency, diabetes causes a variety of microvascular (such as retinopathy and kidney disease) and macrovascular complications (including myocardial infarction and stroke) which reduce the quality of life and life expectancy of individuals with diabetes.We describe the close relationship between diabetes, cardiovascular risk factors, and cardiovascular disease, and examine multifactorial approaches to diabetes treatment, including reducing cardiovascular risk in individuals with type 2 diabetes. Finally, we analyze new prospects for the treatment of type 2 diabetes, resulting from the development of novel antidiabetic drugs.The aim of this review is that the clinician should assume the crucial role of guiding individuals with diabetes in the control of their disease, in order to improve their quality of life and prognosis. In view of the currently available evidence, the emergence of new glucose‐reducing therapies with proven cardiovascular benefit means that the best therapeutic strategy for diabetes must go beyond reducing hyperglycemia and aim to reduce cardiovascular risk.