Lipids versus glucose in inflammation and the pathogenesis of macrovascular disease in diabetes

Type 1 and type 2 diabetes both accelerate cardiovascular disease, yet the triggers are likely different for the two types of diabetes. Results from large-scale clinical trials suggest that intense blood glucose control can reduce cardiovascular events many years later in patients with type 1 diabetes. In type 2 diabetes, mechanisms related to insulin resistance and obesity may be more prominent in promoting atherosclerosis. In this article, we discuss the potential effects of hyperglycemia and diabetes-induced lipid abnormalities on atherosclerosis, particularly focusing on advanced stages of atherosclerosis and evidence from mouse models. In addition, we discuss new research findings in monocyte/macrophage biology that may present intriguing new areas of research related to diabetes and atherosclerosis.     

Predictors of renal and cardiovascular mortality in patients with non-insulin-dependent diabetes: A brief overview of microalbuminuria and insulin resistance

Both microalbuminuria and insulin resistance are present at some stage in the natural history of non-insulin-dependent diabetes mellitus (NIDDM). Microalbuminuria predicts both progression to endstage renal disease and an increase in cardiovascular mortality compared to diabetic patients without microalbuminuria. Conversely, microalbuminuria is not a strong predictor of either renal or cardiovascular mortality in hypertensive nondiabetic subjects. This difference in risk may relate to the presence of glycated albumin in patients with diabetes. Glycation of albumin occurs because of persistent hyperglycemia. Glycated albumin is directly toxic to both renal and vascular tissue through stimulation of reactive oxygen species by both renal and immune protective cells. Blunting the rise in microalbuminuria with either aggressive blood glucose control or angiotensin-converting enzyme (ACE) inhibition, early in the course of the disease, markedly reduces renal mortality. In contrast to microalbuminuria, which is a reflection of renal injury, insulin resistance is a genetically determined problem that directly relates to peripheral glucose utilization. In most cases, insulin resistance is phenotypically expressed as diabetes as a result of environmental factors such as obesity. Insulin resistance is associated with an increased risk for development of both hypertension and NIDDM as well as atherosclerosis. Diabetic or hypertensive subjects with insulin resistance have an increased risk of cardiovascular but not renal mortality. Sustained weight loss is the best way to reduce insulin resistance and arterial pressure. Additionally, blockers, more than other antihypertensive agents reduce insulin resistance. This class of drugs, however, has not been shown to reduce either microalbuminuria or overall cardio-renal mortality.     

C肽与动脉粥样硬化的研究进展

以胰岛素抵抗为特征的代谢综合征及2型糖尿病患者倾向于更早期发生弥漫性动脉粥样硬化,甚至出现于高血糖之前,动脉粥样硬化是糖尿病死亡的首要原因。除了传统危险因素外,近年发现一直被认为无生物活性的C肽可能参与了动脉粥样硬化的关键发展步骤,其参与了炎症反应、促进单核巨噬细胞迁移趋化及向泡沫细胞转化、促进血管平滑肌细胞的增殖,几项队列研究提示血清C肽水平升高与全因死亡、心血管疾病、恶性肿瘤死亡相关。文章就C肽的生物学作用从基础研究到临床研究进展做一综述。     

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 - the Role of Metabolomics in the Discovery of New Mechanisms and Novel Biomarkers

Diabetes is a noncommunicable disease associated with ineffective production or utilization of insulin, which causes hyperglycemia and both short- and long-term effects on health including diabetic complications (nephropathy, neuropathy, and retinopathy) and an increased risk of developing cardiovascular diseases. Globally, there were 346 million people diagnosed with diabetes in 2011. The majority of deaths due to diabetes are observed in the developing world and an estimated 12 % of all healthcare costs are attributed to its treatment. Diabetes is a metabolic disorder and in recent decades it has been shown that metabolites other than glucose play important roles in insulin resistance and development of diabetes. To this end the holistic study of metabolites (termed metabolomics) is an important research tool to apply in diabetes research. Here, the importance of metabolomics in discovering novel mechanisms and biomarkers is highlighted through studies published in the period January 2011 to August 2012. Particular focus is placed on the study of branched chain amino acid metabolism, insulin secretion from ß-cells, diabetes complications and interventions, as well as showing how studies in cell and animal models can complement or validate observations in the human population.     

Atherosclerosis in type 2 diabetes mellitus and insulin resistance: mechanistic links and therapeutic targets

The ongoing heavy burden of cardiovascular disease associated with diabetes mellitus highlights the failure of current treatment strategies to address effectively the cardiovascular risk profile in such patients. Insulin resistance is not only an underlying feature in most cases of type 2 diabetes, but is also associated, through the Insulin Resistance Syndrome, with cardiovascular risk factors that promote atherothrombosis through diverse mechanisms. Growing evidence suggests that treatment with anti-diabetic agents that improve insulin sensitivity, such as the thiazolidinediones, improve multiple components of the Insulin Resistance Syndrome, have beneficial effects on various atherothrombotic mechanisms, and reduce atherosclerosis in animal models and perhaps humans as well. Given data implicating chronic inflammation as a central feature of atherosclerosis, the anti-inflammatory activity of the thiazolidinediones may contribute to their potential anti-atherosclerotic effects. An improved understanding of the mechanisms linking diabetes, atherosclerosis, and cardiovascular disease is needed in order to understand how these and other current and emerging therapies might reduce diabetes-associated cardiovascular disease.     

Clinical thiazolidinediones as PPARgamma ligands with the potential for the prevention of cardiovascular disease in diabetes

Thiazolidinediones (TZDs) are PPARgamma ligands and the newest class of agents in routine clinical practice for the treatment of hyperglycemia in type 2 diabetes. The prime reason for treating hyperglycemia and related aspects of the metabolic syndrome is to prevent accelerated cardiovascular disease (CVD) in diabetes. The formation and subsequent rupture of atherosclerotic "plaques", establishes CVD as the major cause of premature mortality in diabetes. Metabolically, TZDs act as insulin sensitizers resulting in improved glucose uptake, lower blood glucose and reduced hyperinsulinemia, however, they also appear to have beneficial direct vascular actions. TZDs have a range of actions directly on vascular cells and the predominance of the reported actions is potentially beneficial. TZDs inhibit vascular smooth muscle cell proliferation, inhibit the expression of adhesion molecules and modify the structure of vascular proteoglycans in a manner that results in reduced lipid binding. These actions manifest as reduced lipid deposition in the vessels of animals with experimental diabetes and atherosclerosis. Early clinical data indicates that TZDs may prevent or delay CVD including atherosclerosis and restenosis following coronary angiography. TZDs may be the first class of oral hypoglycemic agents with significant anti atherogenic effects to combat one of the major complications of diabetes.     

高糖条件下高胰岛素水平对细胞内脂质平衡的影响

糖尿病是一种因体内胰岛素绝对不足(Ⅰ型糖尿病)或者相对不足(Ⅱ型糖尿病)而导致的代谢综合征,高血糖是其主要特征之一.现阶段糖尿病的最佳治疗方案仍是胰岛素治疗,但考虑到糖尿病常常并发动脉粥样硬化,且高胰岛素水平对动脉粥样硬化的作用仍然存在着争议,因此阐明高糖条件下,高胰岛素水平对细胞内脂质平衡的影响对糖尿病动脉粥样硬化的治疗有着重要的意义.     

Chronic hepatitis C,atherosclerosis and cardiovascular disease: What impact of direct-acting antiviral treatments?

Hepatitis C virus (HCV) infection is associated with extrahepatic manifestations, among these there is an increased risk of atherosclerosis and cardiovascular disease as well as an increased cardiovascular mortality. Several direct and indirect HCV pro-atherogenic mechanisms have been proposed. HCV lives and replicates within carotid plaques, promoting a local environment of pro-atherogenic factors. In addition, it causes conditions such as insulin resistance, diabetes, hepatic steatosis, cryoglobulinemia and endotoxinemia that are associated with the development of atherosclerosis and cardiovascular disease. Therapeutic regimens based on direct-acting antiviral agents (DAA) are currently available with high efficacy in HCV clearance and improvement of liver disease, but does HCV eradication also improve atherosclerosis and the risk of cardiovascular disease? Recently, a multi-center study has shown that elimination of HCV improves carotid atherosclerosis. Two studies have shown that DAA treatments significantly reduce the risk of cardiovascular events. Several studies have assessed the impact of HCV clearance on pro-atherosclerosis metabolic conditions showing improvement in cardiovascular risk biomarkers, disappearance or improvement of insulin resistance, reduction of risk of developing diabetes and improvement of glycemic control. There are also evidences that HCV clearance promotes the recovery of cytokines and inflammatory markers associated with atherosclerosis and the disappearance of cryoglobulinemia. Available data show that clearance of HCV by DAAs is associated with an improvement in atherosclerosis and metabolic and immunological conditions that promote the development of cardiovascular disease. However, the data are not sufficient to allow definitive conclusions and further studies will be needed to definitively clarify the impact of HCV clearance on atherosclerosis and cardiovascular disease.     

Effects of macronutrient excess and composition on oxidative stress: Relevance to diabetes and cardiovascular disease

Type 2 diabetes is a disease that is increasing in prevalence worldwide. In genetically predisposed patients, the combination of excess caloric intake and reduced physical activity induces a state of insulin resistance. When β-cells are not able to compensate for insulin resistance by adequately increasing insulin production, impaired glucose tolerance occurs, which is characterized by excessive postprandial hyperglycemia. Impaired glucose tolerance may evolve into overt diabetes. These three conditions (ie, insulin resistance, impaired glucose tolerance, and overt diabetes) are associated with an increased risk of cardiovascular disease. Intervention trials have demonstrated that diabetes can be prevented by means of lifestyle modifications, antidiabetic drugs directed against insulin resistance or simply postprandial hyperglycemia, and cardiovascular drugs devoid of effects on blood glucose levels. All of these have intracellular antioxidant effects. Evidence on the efficacy of antioxidant interventions is accumulating, and oxidative stress may be a therapeutic target to prevent diabetes as well as cardiovascular complications.     

Adiponectin: An adipokine linking adipocytes and type 2 diabetes in humans

Adipocyte-derived adiponectin is an insulin-sensitizing and antiatherosclerotic hormone, and replenishment of adiponectin in animal models ameliorated insulin resistance and atherosclerosis. In humans, recent studies have demonstrated that adiponectin level is a good predictor of developing type 2 diabetes and coronary artery disease. Decreasing level of adiponectin is caused by the interaction between genetic factors, such as single nucleotide polymorphisms in the adiponectin gene, and environmental factors, such as high-fat diet. Agents that increase blood level of adiponectin or enhance the actions of adiponectin can be an ideal medicine for ameliorating insulin resistance and type 2 diabetes.     

Lipid management reduces cardiovascular complications in individuals with diabetes and prediabetes

Patients with type 2 diabetes are known to have an elevated risk of cardiovascular morbidity and mortality. Prior to the development of hyperglycemia and type 2 diabetes, individuals undergo a prolonged prediabetic phase involving hyperglycemia and insulin resistance. This has been associated with increased cardiovascular risk and is considered a cardiovascular risk equivalent. It is well known that dyslipidemia is an important contributor to the development of coronary artery disease. Treating diabetes with lipid-lowering agents reduces patients' cardiovascular risk. Preliminary studies have shown that similar benefits are seen even in persons with prediabetes. Hence, lipid-lowering agents should be considered not only in patients with type 2 diabetes, but also in individuals with prediabetes and with elevated lipid levels.     

Coronary microvascular dysfunction in diabetes mellitus: A review

The exploration of coronary microcirculatory dysfunction in diabetes has accelerated in recent years. Cardiac function is compromised in diabetes. Diabetic patients manifest accelerated atherosclerosis in coronary arteries. These data are confirmed in diabetic animal models, where lesions of small coronary arteries have been described. These concepts are epitomized in the classic microvascular complications of diabetes, i.e. blindness, kidney failure and distal dry gangrene. Most importantly, accumulating data indicate that insights gained from the link between inflammation and diabetes can yield predictive and prognostic information of considerable clinical utility. This review summarizes the evidence for the predisposing factors and the mechanisms involved in diabetes, and assesses the current state of knowledge regarding the triggers for inflammation in this disease. We evaluate the roles of hyperglycemia, oxidative stress, polyol pathway, protein kinase C, advanced glycation end products, insulin resistance, peroxisome proliferator-activated receptor-γ, inflammation, and diabetic cardiomyopathy as a "stem cell disease". Furthermore, we discuss the mechanisms responsible for impaired coronary arteriole function. Finally, we consider how new insights in diabetes may provide innovative therapeutic strategies.     

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.     

Insulin resistance is a cardiovascular risk factor in humans

Diabetes is a common metabolic disorder associated to elevated cardiovascular morbidity and mortality that is not explained by hyperglycemia or traditional cardiovascular risk factors such as smoking or hypercholesterolemia. Intensive glycemic control with insulin that achieves near-normal glycemia does not reduce significantly macrovascular complications compared with conventional glycemic control. Cardiovascular disease continues to develop in patients with diabetes despite adequate glycemic control. In contrast, intensive control with metformin (leading to insulin resistance improvement) reduces diabetes complications, including cardiovascular events, suggesting that enhancement of insulin sensitivity rather than plasma glucose level has a major role improving diabetes outcomes. Accordingly, insulin resistance estimated by glucose tolerance tests is better predictor of future cardiovascular events than fasting glucose level in nondiabetic individuals. Insulin resistance precedes for decades the clinical onset of type 2 diabetes and deteriorates metabolic control of type 1 diabetes. Numerous investigations including cross-sectional and prospective studies, meta-analyses, and systematic reviews provide compelling evidence that insulin resistance by itself is a cardiovascular risk factor in a variety of population groups, including the general population and patients with diabetes. Several estimations of insulin resistance have been consistently associated with elevated rate of cardiovascular events independently of other cardiovascular risk factors and diabetes status. The clinical expression of insulin resistance (the metabolic syndrome or any of its components including obesity, hyperinsulinemia, hypertension, and dyslipemia) has been related to cardiovascular disease as well. An estimation conducted by the Archimedes model confirms that insulin resistance is the most important single cause of coronary artery disease.     

Coronary heart disease and insulin concentration in type II diabetic patients--results of a diabetes intervention study]

There is experimental, clinical and epidemiological evidence that elevated insulin levels are associated with development of atherosclerosis. Early results came from studies in non-diabetics, but the situation with respect to diabetes is more complex and not so clear. The Diabetes Intervention Study is a population-based follow-up study in newly detected type II diabetics (30- to 55-yr-old). After 5 years 431 men and 320 women received a complex check up with oral glucose tolerance tests and measurements of plasma insulin and glucose levels, fasting and 2h post-load. Regarding the metabolic parameters, the fasting and postprandial insulin levels were higher among the patients having coronary heart disease (15% of men, 36% of women), as compared to patients without this disease. In multivariate analysis sex, age, antihypertensive treatment, blood pressure, body mass index, and fasting insulin levels were independently associated with the prevalence of coronary heart disease in patients with non-insulin dependent diabetes mellitus (NIDDM) treated with diet and/or oral antidiabetics. Body mass index and triglycerides were the only variables that independently correlated to insulin: fasting insulin = 0.4 (body mass index) + 0.1 (triglycerides) - 4,2. In future prospective studies of diabetics relating insulin concentrations to the development of vascular disease are of particular interest and necessity. Because hyperinsulinemia may contribute to accelerated atherosclerosis in NIDDM-patients, the aim of the treatment of type II-diabetes should be to correct hyperglycemia without aggravating insulin levels and other cardiovascular risk factors.     

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.     

The Incretin System and Cardiovascular Risk: Effects of Incretin-Targeted Therapies

Incretins, such as glucagon-like peptide-1 (GLP-1), are gut peptides that stimulate insulin secretion. Incretin-targeted therapeutics for type 2 diabetes include both direct GLP-1 receptor (GLP-1R) agonists and indirect dipeptidyl peptidase-4 (DPP-4) inhibitors, which inhibit the degradation of native GLP-1. Evidence from basic mechanistic studies in animal models of cardiovascular disease and emerging evidence from pooled analyses of clinical trials suggest beneficial cardiovascular effects of these drugs in addition to their ability to reduce hyperglycemia. This article reviews the actions of incretin-based drugs on blood pressure, vasomotor function, myocardial ischemia, and other cardiovascular risk factors and proposes additional avenues of research.