Panvascular risk factor – Diabetes

Diabetes mellitus is the metabolic bed rock on which macrovascular and microvascular complications develop, hence diabetes is often regarded as a panvascular risk factor. Diabetes, a major risk factor of coronary artery disease (CAD), is also a maker for systemic atherosclerosis. Macrovascular complications include CAD, cerebrovascular disease and peripheral arterial disease (PAD), while microvascular complications include retinopathy, nephropathy and neuropathy. The underlying pathophysiological mechanism of diabetic vasculopathy is complex and multi-factorial, which requires an active research for potential therapeutic targets. The Achilles heel of diabetes related morbidity and mortality is diabetic vasculopathy and its related complications. Hence the management of diabetes per se is often translated into managing its vascular complications. A comprehensive understanding of diabetes as a panvascular risk factor is important. This review has briefly addressed the pathophysiology of diabetic vasculopathy and its complications.     

Nitric oxide and vascular responses in Type I diabetes

Vascular complications are major causes of morbidity and mortality in patients with diabetes mellitus. The mechanisms underlying the development of microvascular and macrovascular angiopathy in Type I (insulin-dependent) diabetes mellitus are complex and incompletely understood. The discovery of endothelium-derived nitric oxide has greatly improved our understanding of vascular biology. Nitric oxide has an important role in the regulation of vascular tone and impaired nitric oxide activity could be implicated in the development of diabetic vasculopathy. Vascular studies of endothelial function in Type I diabetes have produced conflicting results. The role of nitric oxide in diabetic vasculopathy is still not clear. [Diabetologia (2000) 43: 137–147]     

脂肪酸结合蛋白与糖尿病血管病变的研究进展

糖尿病在全球的患病率日益增加,糖尿病血管并发症是目前老龄人群中致死和致残的首要原因。脂肪酸结合蛋白(FABP)是一类脂质伴侣家族,是联结肥胖、糖尿病与血管疾病的关键炎症分子,在糖尿病血管病变中发挥重要作用。本文对FABP家族成员在糖尿病及其血管病变发生发展中的分子机制、作为干预靶点的治疗价值以及成为生物标志物的临床意义进行综述,以期为以FABP为代表的抗糖尿病血管病变的药物研发提供证据与思路。     

Early manifestation of macrovasculopathy in newly diagnosed never treated type II diabetic patients with no traditional CVD risk factors

Type II diabetes patients have increased risk of macrovascular complications compared with the general population. Arterial stiffness is considered as an independent predictor of macrovascular events. This study investigated arterial stiffness in newly diagnosed never treated diabetes and impaired glucose tolerance (IGT) patients without any traditional cardiovascular diseases (CVD) risk factors. After preliminary screening of 1620 individuals, 30 diabetic and 30 IGT patients were recruited and compared with age- and sex-matched 30 normoglycaemic subjects. The subjects were newly diagnosed, never treated, normotensive, non-obese, non-hyperlipidaemic and non-smoker. Haemodynamic variables, pulse wave velocity (PWV) and augmentation index (AI) were measured. The PWV was significantly higher in diabetic patients (10.37+/-2.64m/s vs. 8.70+/-1.29m/s; p=0.035) and was of borderline significant in IGT subjects (9.54+/-1.56m/s vs.8.70+/-1.29m/s, p=0.078) compared to normoglycaemic individuals. Augmentation index was higher of borderline significant in diabetic (134.53+/-17.32% vs. 129.17+/-11.18%, p=0.055) and IGT patients (132.02+/-16.11% vs. 129.17+/-11.18%, p=0.059) compared to normoglycaemic individuals. The study demonstrated that newly diagnosed never treated diabetic patients without any CV complications had early manifestation of macrovascular diseases as evident by increased arterial stiffness. The findings also revealed early manifestations of preclinical vasculopathy and potentially increased risk for development of macrovascular diseases at an early age in diabetic patients.     

Macro‐ and microvascular endothelial dysfunction in diabetes

Endothelial cells, as well as their major products nitric oxide (NO) and prostacyclin, play a key role in the regulation of vascular homeostasis. Diabetes mellitus is an important risk factor for cardiovascular disease. Diabetes‐induced endothelial dysfunction is a critical and initiating factor in the genesis of diabetic vascular complications. The present review focuses on both large blood vessels and the microvasculature. The endothelial dysfunction in diabetic macrovascular complications is characterized by reduced NO bioavailability, poorly compensated for by increased production of prostacyclin and/or endothelium‐dependent hyperpolarizations, and increased production or action of endothelium‐derived vasoconstrictors. The endothelial dysfunction of microvascular complications is primarily characterized by decreased release of NO, enhanced oxidative stress, increased production of inflammatory factors, abnormal angiogenesis, and impaired endothelial repair. In addition, non‐coding RNAs (microRNAs) have emerged as participating in numerous cellular processes. Thus, this reviews pays special attention to microRNAs and their modulatory role in diabetes‐induced vascular dysfunction. Some therapeutic strategies for preventing and restoring diabetic endothelial dysfunction are also highlighted.     

Molecular complexities underlying the vascular complications of diabetes mellitus – A comprehensive review

Diabetes is a chronic disease, characterized by hyperglycemia, which refers to the elevated levels of glucose in the blood, due to the inability of the body to produce or use insulin effectively. Chronic hyperglycemia levels lead to macrovascular and microvascular complications. The macrovascular complications consist of peripheral artery disease (PAD), cardiovascular diseases (CVD) and cerebrovascular diseases, while the microvascular complications comprise of diabetic microangiopathy, diabetic nephropathy, diabetic retinopathy and diabetic neuropathy. Vascular endothelial dysfunction plays a crucial role in mediating both macrovascular and microvascular complications under hyperglycemic conditions. In diabetic microvasculature, the intracellular hyperglycemia causes damage to the vascular endothelium through – (i) activation of four biochemical pathways, namely the Polyol pathway, protein kinase C (PKC) pathway, advanced glycation end products (AGE) pathway and hexosamine pathway, all of which commutes glucose and its intermediates leading to overproduction of reactive oxygen species, (ii) dysregulation of growth factors and cytokines, (iii) epigenetic changes which concern the changes in DNA as a response to intracellular changes, and (iv) abnormalities in non-coding RNAs, specifically microRNAs. This review will focus on gaining an understanding of the molecular complexities underlying the vascular complications in diabetes mellitus, to increase our understanding towards the development of new mechanistic therapeutic strategies to prevent or treat diabetes-induced vascular complications.     

Non-insulin-dependent diabetes in older patients. Complications and risk factors

Non-insulin-dependent diabetes mellitus is predominantly a disease of aging, with more than 70 percent of non-insulin-dependent (type II) diabetic patients older than 55 years of age. The prevalence of macrovascular, microvascular, and neurologic complications in outpatients with type II diabetes between the ages of 55 and 74 was compared with that in a similarly aged nondiabetic group of patients. The association between duration of diabetes, hypertension, age, and other putative risk factors that are prevalent in this elderly diabetic population and the occurrence of complications was explored. This cross-sectional survey confirmed a significant increase in retinopathy, neuropathy, impotence, and macrovascular complications in patients with type II diabetes. Within the diabetic population, duration of disease was associated with the occurrence of retinopathy and neuropathy, but not associated with such macrovascular complications as coronary artery disease. Gender, type of therapy, and previously identified risk factors for vascular disease such as hypertension had little impact on the prevalence of complications in this population. The notion that type II diabetes in the elderly represents "mild" diabetes with regard to complications must be discarded. Further identification of risk factors within this diabetic population may suggest therapeutic approaches that will prevent or ameliorate the development of complications.     

红景天对糖尿病血管并发症的防治作用及机制概述

由于生活方式的改变，糖尿病（DM）已经成为威胁国人健康的高发病。DM自身症状并不显著，但其引起的并发症，尤其是血管并发症具有较高的致残、致死率。糖尿病血管并发症（DVC）根据血管类型不同分为大血管病变（冠状动脉疾病和外周血管疾病）和微小血管病变（糖尿病肾病、糖尿病视网膜病变、糖尿病神经病变及糖尿病心肌病）。然而，目前临床上仍缺少治疗糖尿病血管病变的特效药物。红景天是一种临床应用较广的传统药物，可用于治疗动脉粥样硬化（AS）、DM、肾病、缺血/再灌注损伤等多种疾病。红景天具有降血糖、抗氧化应激、抑制血管平滑肌增殖、保护血管内皮细胞、抗AS、促进NO释放等多种作用机制，对DVC具有较好的防治作用。本文回顾了近十年来国内外关于红景天治疗DVC的研究，希望能为当前DVC的研究和治疗提供更多的思路。     

Molecular mechanisms of diabetic vascular complications

Diabetic complications are the major causes of morbidity and mortality in patients with diabetes. Microvascular complications include retinopathy, nephropathy and neuropathy, which are leading causes of blindness, end‐stage renal disease and various painful neuropathies; whereas macrovascular complications involve atherosclerosis related diseases, such as coronary artery disease, peripheral vascular disease and stroke. Diabetic complications are the result of interactions among systemic metabolic changes, such as hyperglycemia, local tissue responses to toxic metabolites from glucose metabolism, and genetic and epigenetic modulators. Chronic hyperglycemia is recognized as a major initiator of diabetic complications. Multiple molecular mechanisms have been proposed to mediate hyperglycemia’s adverse effects on vascular tissues. These include increased polyol pathway, activation of the diacylglycerol/protein kinase C pathway, increased oxidative stress, overproduction and action of advanced glycation end products, and increased hexosamine pathway. In addition, the alterations of signal transduction pathways induced by hyperglycemia or toxic metabolites can also lead to cellular dysfunctions and damage vascular tissues by altering gene expression and protein function. Less studied than the toxic mechanisms, hyperglycemia might also inhibit the endogenous vascular protective factors such as insulin, vascular endothelial growth factor, platelet‐derived growth factor and activated protein C, which play important roles in maintaining vascular homeostasis. Thus, effective therapies for diabetic complications need to inhibit mechanisms induced by hyperglycemia’s toxic effects and also enhance the endogenous protective factors. The present review summarizes these multiple biochemical pathways activated by hyperglycemia and the potential therapeutic interventions that might prevent diabetic complications. (J Diabetes Invest, doi: 10.1111/j.2040‐1124.2010.00018.x, 2010)