糖尿病大鼠肾组织中核因子-kB调控单核细胞趋化蛋白-1表达作用的研究

糖尿病肾病(DN)是糖尿病(DM)最常见的慢性并发症之一,发病机制十分复杂，至今仍未完全阐明。被多数学者认可的病因有：高糖一蛋白激酶C(PKC)途径、蛋白质的非酶糖化一晚期糖化终产物(AGEs)途径、醛糖还原酶(AR)-多元醇途径、氧化应激(oxidativestress，OS)途径一，以及局部肾素血管紧张素系统(RAS)等。     

糖化和脂氧化终末产物与羰基应激

机体代谢紊乱引起氧化应激 ,导致反应性羰基化合物 (RCO)大量增生 ,引起羰基应激。羰基应激促进体内糖基化终末产物 (AGEs)和脂氧化终末产物 (ALEs)的大量生成和蓄积。RCO可直接对细胞产生病理影响 ,也可通过促进AGEs或ALEs的蓄积而引起一系列病理损害。故采用抗氧化剂、羰基抑制剂和血液净化治疗可抑制AGEs和ALEs的生成 ,为糖尿病及其并发症的治疗提供了思路。     

氨基胍对糖尿病大鼠心脏保护作用的超声心动图研究

晚期糖基化终末产物(AGEs)是由还原糖和大分子物质发生非酶糖基化反应生成的大分子物质，在糖尿病(DM)高糖环境下这种反应加剧．生成的AGEs超过机体清除能力，造成大量AGEs在机体内堆积而致病。研究证明，AGEs在DM多种慢性并发症发展中起重要作用。2002年12月至2003年12月，我     

波动性高血糖、代谢记忆与糖尿病慢性并发症

糖尿病治疗的核心是防治糖尿病慢性并发症,波动性高血糖通过刺激氧化应激,会增加患者产生代谢记忆及诱发糖尿病并发症的机率.代谢记忆已逐渐成为糖尿病治疗中新的挑战.一、波动性高血糖和糖尿病并发症血糖紊乱分为持续性高血糖和血糖波动为特征的波动性高血糖[1].波动性高血糖是指间歇性或阵发性高血糖状态,亦称血糖飘移.早期的研究多关注于长期慢性高血糖与并发症的关系,随着血糖监测手段的发展,糖尿病患者血糖波动逐渐为人们所重视.近年来的研究表明,波动性高血糖相对于持续性高血糖更能增加糖尿病患者发生并发症的危险性.糖尿病慢性并发症的发生、发展不仅与整体血糖水平相关,而且与血糖的波动性密切相关[2].血糖波动通过活化氧化应激、炎症反应损失内皮细胞参与糖尿病并发症的进展,因此,对血糖波动的正确认识、评价和积极控制将有助于减缓糖尿病并发症的发生.波动性高血糖导致糖尿病慢性并发症,可能与血糖波动产生氧化应激产物激活血管损伤的4条途径有关[3].     

晚期糖基化终末产物与动脉粥样硬化的关系

糖尿病是冠状动脉疾病和外周动脉疾病等血管病变独立的危险因素,以动脉粥样硬化(AS)为基础的糖尿病血管并发症成为常见代谢病发病率和死亡率的首因.AS发生过程涉及动脉壁细胞、细胞外基质、血液成分、局部血流动力学、环境及遗传等诸多因素的相互作用,但其发病分生机制至今不明.虽高血糖可通过多种因素调节血管功能,但是糖尿病AS形成最重要的影响因素,是在长期高血糖状态下,蛋白质非酶糖基化形成的晚期糖基化终末产物(AGEs)[1].AGEs可氧化LDL及修饰胶原,也可与其主要配体RAGE(Receptor for AGEs)结合,从多条途径促进AS的发生发展.RAGE是一种信号传导受体,与AGEs结合后激活许多细胞传导通路,产生病理效应.以下内容将主要围绕AGEs如何在血管壁细胞内外沉积并通过一系列分生机制导致糖尿病AS形成展开.     

2型糖尿病患者糖代谢对骨代谢的影响

<正>加上老年患者骨代谢减弱,导致老年糖尿病患者容易合并骨质疏松症~([1])。泌的激素骨钙素(OC)。下面就2型糖尿病患者糖代谢对代谢的影响因素加以分析。1高血糖内长期的高糖环境,逐步导致大血管和微血管病变从而使骨质丢失是骨质疏松的主要原因。易发生非酶糖化反应,形成糖基化终末产物(AGEs),而AGEs阻碍成     

糖尿病血管内皮细胞代谢改变的研究进展

血管内皮细胞功能障碍是糖尿病（DM）血管并发症的始动环节。高血糖所致的氧化应激水平升高、异常糖代谢途径激活、晚期糖基化终产物（AGEs）累积和蛋白激酶C（PKC）通路活化等代谢改变均可介导内皮细胞损伤。如何抑制内皮细胞异常代谢并改善内皮细胞功能一直是DM血管并发症的研究重点。本文主要就DM患者血管内皮细胞的代谢改变作一综述。     

二甲双胍的抗炎作用及其糖尿病肾脏保护作用

炎性反应在糖尿病肾病(DN)的发生、发展中起重要作用.高糖作为始动因素,与晚期糖基化终末产物(AGEs)、氧化应激及肾内血流动力学的改变共同引起了糖尿病肾脏炎性反应的发生.而二甲双胍作为治疗糖尿病的一线药物,近年研究显示其除降糖作用以外,还可通过激活腺苷酸活化蛋白激酶(AMPK)、抗氧化应激和改善胰岛素抵抗等机制发挥抗炎作用,从而预防和延缓DN的发生和发展.     

高级糖基化终末产物的合成及其与疾病的关系

高级糖基化终末产物(advanced glycation end products,AGEs)是由蛋白或者脂质暴露于还原糖中而形成的一组复杂且具有异质性的物质.该物质可通过内源性或外源性途径形成,大体可分为6种.AGEs可在不同种类的细胞内累积,影响细胞内及细胞外的结构和功能,同时它还可以通过和细胞表面的受体作用,通过信号传导,引发一系列的病理生理过程.AGEs沉积在细胞内,影响细胞功能,导致糖尿病血管并发症的发生.AGEs还与各种肿瘤的生物学特性相关,它可以修饰热休克蛋白27或者与AGEs受体相结合来影响肿瘤细胞的生长和浸润.AGEs的抑制物,如OPB-9195,可抑制这一系列病理生理过程.     

糖化和脂氧化终末产物与羰基应激

机体代谢紊乱引起氧化应激，导致反应性羰基化合物（RCO）大量增生，引起羰基应激。羰基应激促进体内糖基化终末产物（AGEs)和脂氧化终末产物（ALEs)的大量生成和蓄积。RCO可直接对细胞产生病理影响，也可通过促进AGEs或ALEs的蓄积而引起一系列病理损害。故采用抗氧化剂、羰基抑制和血液净化治疗可抑制AGEs和ALEs的生成，为糖尿病及其并发症的治疗提供了思路。     

The role of oxidative stress in the pathogenesis of type 2 diabetes mellitus micro- and macrovascular complications: avenues for a mechanistic-based therapeutic approach

A growing body of evidence suggests that oxidative stress plays a key role in the pathogenesis of micro- and macrovascular diabetic complications. The increased oxidative stress in subjects with type 2 diabetes is a consequence of several abnormalities, including hyperglycemia, insulin resistance, hyperinsulinemia, and dyslipidemia, each of which contributes to mitochondrial superoxide overproduction in endothelial cells of large and small vessels as well as the myocardium. The unifying pathophysiological mechanism that underlies diabetic complications could be explained by increased production of reactive oxygen species (ROS) via: (1) the polyol pathway flux, (2) increased formation of advanced glycation end products (AGEs), (3) increased expression of the receptor for AGEs, (4) activation of protein kinase C isoforms, and (5) overactivity of the hexosamine pathway. Furthermore, the effects of oxidative stress in individuals with type 2 diabetes are compounded by the inactivation of two critical anti-atherosclerotic enzymes: endothelial nitric oxide synthase and prostacyclin synthase. Of interest, the results of clinical trials in patients with type 2 diabetes in whom intensive management of all the components of the metabolic syndrome (hyperglycemia, hypercholesterolemia, and essential hypertension) was attempted (with agents that exert a beneficial effect on serum glucose, serum lipid concentrations, and blood pressure, respectively) showed a decrease in adverse cardiovascular end points. The purpose of this review is (1) to examine the mechanisms that link oxidative stress to micro- and macrovascular complications in subjects with type 2 diabetes and (2) to consider the therapeutic opportunities that are presented by currently used therapeutic agents which possess antioxidant properties as well as new potential antioxidant substances.     

Osmotic stress induced oxidative damage: possible mechanism of cataract formation in diabetes

Chronic hyperglycemia causes increased level of reactive oxygen species which is thought to be involved in the pathogenesis of diabetes associated complications including cataract. In diabetic cataractous lens, over production of free radicals and decreased capacity of antioxidant defense system are the major contributors to oxidative damage by polyol pathway and advanced glycation end products. The current study focused on analysis of factors associated with osmotic imbalance and oxidative stress in aging and diabetic human cataractous lenses. We examined activities of polyol pathway enzymes, G6PD and glutathione system in lenses from subjects suffering from cataract due to aging and diabetes. We observed elevated activities of aldose reductase and sorbitol dehydrogenase while G6PD and glutathione system enzyme activities were found to be lower in cataractous subjects suffering from diabetes. The findings from the current study support the premise that osmotic imbalance, AGEs formation and oxidative stress contribute synergistically to the development of lens opacity in hyperglycemia.     

Metabolic memory: mechanisms and implications for diabetic retinopathy

Chronic hyperglycemia of diabetes leads to microvascular complications that severely impact quality of life. Diabetic retinopathy (DR) may be the most common of these and is a leading cause of visual impairment and blindness among working age adults in developed nations. Many large-scale type 1 and type 2 diabetes clinical trials have demonstrated that early intensive glycemic control can reduce the incidence and progression of micro and macrovascular complications. On the other hand, epidemiological and prospective data have revealed that the stressors of diabetic vasculature persist beyond the point when glycemic control has been achieved. These kinds of persistent adverse effects of hyperglycemia on the development and progression of complications has been defined as "metabolic memory", and oxidative stress, advanced glycation end products and epigenetic changes have been implicated in the process. Recent studies have indicated that such "hyperglycemic memory" may also influence DR, suggesting that manipulation of hyperglycemic memory may prove a beneficial approach to prevention and treatment. This review summarizes the evidence from DR-related clinical trials and mechanistic studies to investigate the significance of metabolic memory in DR and understand its potential as a target of molecular therapeutics aimed at reversing hyperglycemic memory.     

Glycation and cardiovascular disease in diabetes: A perspective on the concept of metabolic memory

Epidemiological studies have suggested that cumulative diabetic exposure, namely prolonged exposure to chronic hyperglycemia, contributes to the increased risk of cardiovascular disease (CVD) in diabetes. The formation and accumulation of advanced glycation end‐products (AGEs) have been known to progress under hyperglycemic conditions. Because AGEs‐modified collagens are hardly degraded and remain in diabetic vessels, kidneys and the heart for a long time, even after glycemic control has been achieved, AGEs could become a marker reflecting cumulative diabetic exposure. Furthermore, there is a growing body of evidence that an interaction between AGEs and the receptor for AGEs (RAGE) plays a role in the pathogenesis of CVD. In addition, AGEs induce the expression of RAGE, thus leading to sustained activation of the AGEs–RAGE axis in diabetes. Herein we review the pathological role of the AGEs–RAGE axis in CVD, focusing particularly on the phenomenon of metabolic memory, and discuss the potential clinical usefulness of measuring circulating and tissue levels of AGEs accumulation to evaluate diabetic macrovascular complications.     

Pathogenesis of diabetic nephropathy: the role of oxidative stress and protein kinase C

Hyperglycemia, a well recognized pathogenetic factor of long-term complications in diabetes mellitus, not only generates more reactive oxygen species but also attenuates antioxidative mechanisms through glycation of the scavenging enzymes. Therefore, oxidative stress has been considered to be a common pathogenetic factor of the diabetic complications including nephropathy. A causal relationship between oxidative stress and diabetic nephropathy has been established by observations that (1) lipid peroxides and 8-hydroxydeoxyguanosine, indices of oxidative tissue injury, were increased in the kidneys of diabetic rats with albuminuria; (2) high glucose directly increases oxidative stress in glomerular mesangial cells, a target cell of diabetic nephropathy; (3) oxidative stress induces mRNA expression of TGF-beta1 and fibronectin which are the genes implicated in diabetic glomerular injury, and (4) inhibition of oxidative stress ameliorates all the manifestations associated with diabetic nephropathy. Proposed mechanisms involved in oxidative stress associated with hyperglycemia are glucose autooxidation, the formation of advanced glycosylation end products, and metabolic stress resulting from hyperglycemia. Since the inhibition of protein kinase C (PKC) effectively blocks not only phorbol ester-induced but also high glucose- and H2O2-induced fibronectin production, the activation of PKC under diabetic conditions may also have a modulatory role in oxidative stress-induced renal injury in diabetes mellitus.     

Carbonyl stress in the pathogenesis of diabetic nephropathy.

Diabetic nephropathy is a major chronic complication of diabetes mellitus and an important cause of increased morbidity and mortality in diabetic patients. Although several lines of evidence have suggested that poor glycemic control undoubtedly plays a significant role, the metabolic events responsible for its development are not understood well. Possible mediators of untowards effects of hyperglycemia include the advanced glycation end products (AGEs). AGEs, carboxymethyllysine and pentosidine, whose formation is closely linked to oxidation, accumulate in the characteristic diabetic glomerular lesions, such as the expanded mesangial matrix and nodular lesions, in co-localization with other oxidation-specific protein adducts, such as malondialdehyde-lysine, 4-hydroxynonenal-protein adduct, and acrolein-protein adduct. These five biomarkers are formed under oxidative stress by carbonyl amine chemistry between protein amino group and carbonyl compounds derived from carbohydrates, lipids, and amino acids. This article focuses on new aspects of the pathology of diabetic nephropathy, implicating an increased oxidative stress and carbonyl modification of proteins by autoxidation products of carbohydrates, lipids, and amino acids in diabetic glomerular tissue damage ("carbonyl stress").     

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)     

Advanced glycation end products: role in pathology of diabetic cardiomyopathy

Increasing evidence demonstrates that advanced glycation end products (AGEs) play a pivotal role in the development and progression of diabetic heart failure, although there are numerous other factors that mediate the disease response. AGEs are generated intra- and extracellularly as a result of chronic hyperglycemia. Then, following the interaction with receptors for advanced glycation end products (RAGEs), a series of events leading to vascular and myocardial damage are elicited and sustained, which include oxidative stress, increased inflammation, and enhanced extracellular matrix accumulation resulting in diastolic and systolic dysfunction. Whereas targeting glycemic control and treating additional risk factors, such as obesity, dyslipidemia, and hypertension, are mandatory to reduce chronic complications and prolong life expectancy in diabetic patients, drug therapy tailored to reducing the deleterious effects of the AGE–RAGE interactions is being actively investigated and showing signs of promise in treating diabetic cardiomyopathy and associated heart failure. This review shall discuss the formation of AGEs in diabetic heart tissue, potential targets of glycation in the myocardium, and underlying mechanisms that lead to diabetic cardiomyopathy and heart failure along with the use of AGE inhibitors and breakers in mitigating myocardial injury.     

Oxidative stress and diabetic complications

Oxidative stress plays a pivotal role in the development of diabetes complications, both microvascular and cardiovascular. The metabolic abnormalities of diabetes cause mitochondrial superoxide overproduction in endothelial cells of both large and small vessels, as well as in the myocardium. This increased superoxide production causes the activation of 5 major pathways involved in the pathogenesis of complications: polyol pathway flux, increased formation of AGEs (advanced glycation end products), increased expression of the receptor for AGEs and its activating ligands, activation of protein kinase C isoforms, and overactivity of the hexosamine pathway. It also directly inactivates 2 critical antiatherosclerotic enzymes, endothelial nitric oxide synthase and prostacyclin synthase. Through these pathways, increased intracellular reactive oxygen species (ROS) cause defective angiogenesis in response to ischemia, activate a number of proinflammatory pathways, and cause long-lasting epigenetic changes that drive persistent expression of proinflammatory genes after glycemia is normalized ("hyperglycemic memory"). Atherosclerosis and cardiomyopathy in type 2 diabetes are caused in part by pathway-selective insulin resistance, which increases mitochondrial ROS production from free fatty acids and by inactivation of antiatherosclerosis enzymes by ROS. Overexpression of superoxide dismutase in transgenic diabetic mice prevents diabetic retinopathy, nephropathy, and cardiomyopathy. The aim of this review is to highlight advances in understanding the role of metabolite-generated ROS in the development of diabetic complications.