Potential utility of statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in diabetic retinopathy

Diabetic retinopathy is a common and potentially devastating microvascular complication in diabetes and is a leading cause of acquired blindness among the people of occupational age. However, therapeutic options for the treatment of proliferative diabetic retinopathy, photocoagulation and vitrectomy, are limited by considerable side effects. Therefore, to develop novel therapeutic strategies that specifically target diabetic retinopathy is desired for patients with diabetes. In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development and progression of diabetic retinopathy. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, have been recently shown to reduce the risk for cardiovascular events in diabetic patients with or without coronary artery disease. However, the efficacy of statin therapy for diabetic retinopathy is not fully investigated. We have recently found that protein prenylation is crucial for the AGE-RAGE signaling in microvascular endothelial cells. By blocking the protein prenylation, cerivastatin completely prevented the AGE-RAGE-elicited angiogenesis via suppression of vascular endothelial growth factor (VEGF). These observations let us to speculate that statins might be a promising remedy for treating patients with diabetic retinopathy by acting as a potential inhibitor of the AGE-RAGE signaling pathway in microvascular endothelial cells. In this paper, we would like to propose the possible ways of testing our hypotheses. (1) Does treatment with statins decrease the risk for the development and progression of diabetic retinopathy in patients with normocholesterolemia? (2) If the answer is yes, is this beneficial effect of statins superior to that of other cholesterol-lowering agents with equihypolipidemic properties? (3) Does statin treatment suppress retinal VEGF expression in diabetic patients? (4) Does treatment with pyridoxamine, a post-Amadori inhibitor of AGE formation, attenuate the beneficial effects of statins on diabetic retinopathy? These clinical studies could clarify whether the use of statins is of benefit in patients with AGE-RAGE-related disorders such as diabetic retinopathy, even in the absence of hypercholesterolemia.     

糖尿病性NA-AION的图形视觉诱发电位的研究

目的 研究糖尿病非动脉炎性前段缺血性视神经病变(NA-AION)的图形视觉诱发电位(P-VEP)P100波潜伏期和振幅的变化。方法 将有糖尿病且无糖尿病性视网膜病变的NA-AION患者17例纳入A组,将非增生期糖尿病视网膜病变的NA-AION患者21例纳入B组,将增生期糖尿病视网膜病变的NA-AION患者20例纳入C组,将无糖尿病的NA-AION患者25例纳入D组,行PVEP检查。结果 A、B、C、D组P100波0.25度方格平均潜伏期分别为127.27 ms、132.37 ms、139.58 ms、125.46 ms,振幅分别为119.13 μv、124.61μv、135.62 μv、116.08 μv,A、B、C组与D组P100波潜伏期、振幅分别比较,差异有统计学意义（P＜0.05）,1度方格结果同0.25度方格。结论 糖尿病性NA-AION患者视神经功能较非糖尿病性NA-AION患者下降更为明显,控制糖尿病可能会有效的减少NA-AION的发生。     

Inhibition of protein kinase C might be harmful to diabetic retinopathy

Selective loss of retinal pericytes is the earliest histopathological hallmark in diabetic retinopathy. Various structural and functional abnormalities in diabetic retinas are the consequent of the loss of pericytes. Therefore, elucidating the molecular mechanisms for pericyte loss and targeting this characteristics change in early diabetic retinopathy may help to slow the development and progression of sight-threatening retinopathy in diabetes. Protein kinase C (PKC) inhibition has been used in therapeutic trials intended to reduce the incidence of proliferative diabetic retinopathy. However, we speculate that it is likely to do more harm than good in diabetic retinopathy because PKC inhibition augments pro-apoptotic effects of high glucose on cultured retinal pericytes. In the DCCT-Epidemiology of Diabetes Interventions and Complications Research, the reduction in the risk of progressive retinopathy resulting from intensive therapy in patients with type 1 diabetes persisted for at least four years, despite increasing hyperglycemia. These clinical studies strongly suggest that so-called "hyperglycemic memory" causes vascular damage in diabetic retinopathy. Glucose react non-enzymatically with the amino groups of proteins to initiate a complex series of rearrangement and dehydration reactions to produce a class of irreversibly cross-linked, fluorescent moieties, termed advanced glycation end products (AGEs). The formation and accumulation of AGEs progress at an extremely accelerated rate in diabetic retinas, and these products have been implicated in the pathogenesis of loss of pericytes in diabetic retinopathy. The nature of AGEs is most compatible with the theory of 'hyperglycemic memory' as well. We hypothesize here that PKC inhibition is likely to do harm in diabetic retinopathy, while inhibition of AGE formation might be a promising therapeutic strategy for treatment of this devastating complication.     

Leukocyte-mediated endothelial cell injury and death in the diabetic retina

Endothelial cell death is a hallmark of diabetic retinopathy. Its occurrence is required for the formation of acellular (devitalized) capillaries, lesions that produce irreversible retinal ischemia through their inability to support blood flow. The mechanisms underlying diabetic retinal endothelial cell injury and death remain largely unknown. The current study demonstrates that adherent leukocytes are temporally and spatially associated with retinal endothelial cell injury and death within 1 week of streptozotocin-induced experimental diabetes in rats. Moreover, the antibody-based neutralization of intercellular adhesion molecule-1 and CD18 is shown to prevent both leukocyte adhesion and retinal endothelial cell injury and death. These data highlight the central and causal role of adherent leukocytes in the pathogenesis of diabetic retinopathy. They also underscore the potential utility of anti-intercellular adhesion molecule1- and anti-CD18-based therapies in the treatment of diabetic retinopathy, a newly recognized inflammatory disease.     

Blood antioxidant parameters in patients with diabetic retinopathy

It has been postulated that enhanced generation of reactive oxygen species (ROS) may take part in a pathogenesis of diabetic microvascular complication - retinopathy. There are two types of diabetic retinopathy, non-proliferative (simplex) and proliferative. ROS are anihilated by an intracelluar enzymatic system composed mainly of glutathione peroxidase (GPx), superoxide dismutase (SOD) and catalase (CAT). Beta-carotene, tocopherols and ascorbic acid are major components of serum antioxidants. All serum antioxidants are usually measured together as total antioxidant status (TAS). Erythrocyte activities of GPx, SOD, CAT and TAS were measured in diabetic patients without retinopathy, with non-proliferative and proliferative retinopathy. Obtained results were correlated with a period of diabetic history and a period of insulin treatment. SOD was significantly elevated in diabetics with non-proliferative retinopathy compared to patients without retinopathy. TAS was significantly lower in patients with proliferative retinopathy than in diabetics not developing retinopathy. Only CAT was significantly negatively correlated with the period of insulin treatment. This significant negative correlation was also observed in a subgroup of patients with proliferative retinopathy.     

2型糖尿病视网膜病变患者血清sVCAM-1水平的变化和意义

研究糖尿病视网膜病变不同时期血清可溶性血管内皮细胞粘附分子-1(sVCAM-1)与视网膜病变严重程度、诊断病程、血清胰岛素和血糖的相关性.采用ELISA法检测85例2型糖尿病视网膜病变患者血清sVCAM-1含量, 由同一眼科医师通过眼底镜或荧光造影检查, 将患者分为无视网膜病变组(NDR)、背景期视网膜病变组(BDR)和增殖期视网膜病变组(PDR).结果显示, 三组糖尿病患者血清sVCAM-1水平均高于对照组, 其中PDR组、BDR组血清sVCAM-1水平与对照组和NDR组比较, 均有显著性差异(P＜0.01), NDR组与对照组比较也存在显著性差异(P＜0.01).糖尿病患者血清sVCAM-1水平与血糖、血清胰岛素、诊断病程均无相关性(P＞0.05).研究表明, 糖尿病视网膜病变不同时期血清sVCAM-1水平的变化可作为判断视网膜病变发展和严重程度的指标, 为临床早期发现和治疗糖尿病视网膜病变提供较好的依据.     

Increased protein carbonylation of red blood cell membrane in diabetic retinopathy

We investigated the protein carbonylation of red blood cell (RBC) membrane in type 2 diabetic patients and the potential implication of carbonyl/oxidative stress in reflecting disease severity. Sixty-four diabetic patients with or without retinopathy of variable clinical severity (Groups DR and DM, respectively) and 20 healthy controls were included in the study. Protein carbonyls were determined in RBC membranes by immunoblotting. Compared to healthy volunteers, the RBC membranes of diabetic patients were characterized by significantly increased levels of carbonylated proteins. The carbonylation of Group DR was higher compared to that of Group DM. The subgroup of patients with proliferative retinopathy exhibited a trend towards a significant increase in protein carbonyls, compared to both free-of-retinopathy diabetic cases and non-proliferative diabetic retinopathy cases. The correlation between the chemical modifications of the erythrocyte membrane proteins and the clinical severity of diabetic retinopathy suggests a potential utility of membrane carbonylation as a marker and risk factor in the development of retinopathy.     

白内障术后糖尿病视网膜病变的综合治疗

目的观察激光光凝联合复方樟柳碱综合治疗白内障术后糖尿病视网膜病变（DR）的疗效。方法对50例（76眼）白内障术后DR患者施行激光光凝同时予复方樟柳碱注射液颞浅动脉旁皮下注射，以视力和眼底改变为疗效判断指标。结果白内障术后糖尿病视网膜病变稳定，黄斑水肿减轻或消退，视力稳定。结论白内障术后DR患者具有光凝指征应尽早综合治疗，对于控制糖尿病视网膜病变进展，提高白内障远期复明效果有重要意义。     

Minodronate, a nitrogen-containing bisphosphonate, is a promising remedy for treating patients with diabetic retinopathy

In diabetes mellitus, the formation and accumulation of advanced glycation end products (AGEs) progress. There is a growing body of evidence to show that AGEs-their receptor (RAGE) interactions are involved in the development and progression of diabetic retinopathy. Bisphosphonates are potent inhibitors of bone resorption and are widely used drugs for the treatment of osteoporosis and osteolytic bone metastasis. Recently, farnesyl pyrophosphate synthase has been shown as a molecular target of nitrogen-containing bisphosphonates, and inhibition of post-translational prenylation of small molecular weight G proteins is likely involved in their anti-resorptive activity on osteoclasts. NADPH oxidase-derived reactive oxygen species (ROS) generation is required for the AGE-RAGE signaling in vascular wall cells, and small G protein Rac is a critical component of vascular NADPH oxidase complex. These observations let us to speculate that minodronate, a newly developed nitrogen-containing bisphosphonate, might be a promising remedy for treating patients with diabetic retinopathy by inhibiting the AGE-RAGE signaling pathways through suppression of ROS generation via inhibition of Rac prenylation. In this paper, we like to propose the possible ways of testing our hypotheses: (1) Does treatment with minodronate decrease the risk for the development and progression of diabetic retinopathy in osteoporotic patients? (2) If the answer is yes, is this beneficial effect of minodronate superior to that of other nitrogen-noncontaining bisphosphonates with equihypolipidemic properties? (3) Does minodronate treatment suppress NADPH oxidase-mediated ROS generation in retinas of diabetic animals? (4) Does treatment with pyridoxamine, a post-Amadori inhibitor of AGE formation, attenuate these beneficial effects of minodronate on diabetic retinopathy? These clinical and animal studies could clarify whether the use of minodronate is of benefit in patients with AGE-RAGE-related disorders such as diabetic retinopathy, even in the absence of osteoporosis.     

Therapeutic implications of peptide interactions with G‐protein‐coupled receptors in diabetic vasculopathy

The dramatic worldwide increase in the prevalence of diabetes has generated an attempt by the scientific community to identify strategies for its treatment and prevention. Vascular dysfunction is a hallmark of diabetes and frequently leads to the development of atherosclerosis, coronary disease‐derived myocardial infarction, stroke, peripheral arterial disease and diabetic ‘triopathy’ (retinopathy, nephropathy and neuropathy). These vascular complications, developing in an increasingly younger cohort of patients with diabetes, contribute to morbidity and mortality. Despite the development of new anti‐diabetic or anti‐hyperglycaemic drugs, vascular complications remain to be a problem. This warrants a need for new therapeutic strategies to tackle diabetic vasculopathy. There is a growing body of evidence showing that peptide‐binding G‐protein‐coupled receptors (peptide‐binding GPCRs) play an important role in the pathophysiology of vascular dysfunction during diabetes. Thus, in this review, we discuss some of the peptide‐binding GPCRs involved in the regulation of vascular function that have potential to be a therapeutic target in the treatment of diabetic vasculopathy.     

Layer-specific anatomical, physiological and functional MRI of the retina

Most retinal imaging has been performed using optical techniques. This paper reviews alternative retinal imaging methods based on MRI performed with spatial resolution sufficient to resolve multiple well-defined retinal layers. The development of these MRI technologies to study retinal anatomy, physiology (blood flow, blood volume, and oxygenation) and function, and their applications to the study of normal retinas, retinal degeneration and diabetic retinopathy in animal models are discussed. Although the spatiotemporal resolution of MRI is poorer than that of optical imaging techniques, it is unhampered by media opacity and can thus image all retinal and pararetinal structures, and has the potential to provide multiple unique clinically relevant data in a single setting and could thus complement existing retinal imaging techniques. In turn, the highly structured retina with well-defined layers is an excellent model for advancing emerging high-resolution anatomical, physiological and functional MRI technologies.     

Bioinformatics analysis of diabetic retinopathy using functional protein sequences

Diabetic retinopathy is the leading cause of blindness among patients with diabetes mellitus. We evaluated the role of several proteins that are likely to be involved in diabetic retinopathy by employing multiple sequence alignment using ClustalW tool and constructed a phylogram tree using functional protein sequences extracted from NCBI. Phylogram was constructed using Neighbor-Joining Algorithm in bioinformatics approach. It was observed that aldose reductase and nitric oxide synthase are closely associated with diabetic retinopathy. It is likely that vascular endothelial growth factor, pro-inflammatory cytokines, advanced glycation end products, and adhesion molecules that also play a role in diabetic retinopathy may do so by modulating the activities of aldose reductase and nitric oxide synthase. These results imply that methods designed to normalize aldose reductase and nitric oxide synthase activities could be of significant benefit in the prevention and treatment of diabetic retinopathy.     

Basic and clinical aspects of gene therapy for retinopathy induced by diabetes

Diabetes mellitus invariably induces retinopathy which causes a loss of vision that is the major cause of blindness in people of working age across most ethnic groups. Although there have been major advances in gene therapy technologies, there is still no effective cure-all gene therapy for diabetes mellitus. This may be due to (i) involvement of multiple genes that may have different influences on diabetes across different ethnic groups, (ii) immune response to viral vectors, (iii) local, specific transfection only and not into systemic circulation, (iv) lack of stable long-term expression, and (v) lack of control of gene expression. Hence, a separate approach to gene therapy of diabetic retinopathy is necessary due to the difficulties in treating the underlying diabetes. Diabetic retinopathy is the inevitable microvascular complication in the retina from diabetes mellitus. There are possible genetic bases in several pathophysiological pathways for diabetic retinopathy, including oxidation of retinal cells, polyol accumulation pathways, increased non-enzymatic glycation in retinal cells and the release of growth factors by endothelial cells. We review the candidate genes in these putative pathways for diabetic retinopathy and discuss the challenges for gene therapy. The eye is an isolated system with a strong blood-retinal barrier and therefore provides a challenge for delivery of drugs and vectors from the systemic circulation using traditional approaches. Newer delivery approaches include the use of nanoparticles, liposomes, and iontophoresis. We also consider the social and health economic dimension of diabetic retinopathy gene therapy. Diabetic retinopathy is the most common cause of blindness for people of working age. The loss of visual acuity caused by diabetic retinopathy creates a detrimental impact on the patient's quality of life. This results in quality-of-life costs to the individual, the health care system and to society. Significant progress has been made in gene therapy approaches for diabetic retinopathy, and it appears that this is an important area for continued research in order to improve visual outcomes and reduce the healthcare costs of diabetic retinopathy in our communities.     

The role of advanced glycation in the pathogenesis of diabetic retinopathy

Retinopathy is one of the commonest microvascular complications of diabetes and is still the prevailing cause of registerable blindness in the working population of developed countries. The clinicopathology of microvascular lesions and the dysregulation of an array of biochemical pathways in the diabetic retina have been extensively studied, although the relative contribution of various biochemical sequelae of hyperglycaemia remains ill- defined. There is little doubt that the pathogenesis of this diabetic complication is highly complex and there is a pressing need to establish new therapeutic regimens that can effectively prevent or retard the initiation and progression of retinal microvascular cell dysfunction and death which is characteristic of the vasodegenerative stages of diabetic retinopathy. Among the several pathogenic mechanisms that may contribute to diabetic retinopathy are the formation and accumulation of advanced glycation endproducts (AGEs). AGEs can form on the amino groups of proteins, lipids, and DNA through a number of complex pathways, including nonenzymatic glycation by glucose and reaction with metabolic intermediates and reactive dicarbonyl intermediates. These reactions not only modify the structure and function of proteins, but also cause intramolecular and intermolecular cross-link formation. AGEs are known to accumulate in the diabetic retina where they may have important effects on retinal vascular cell function in vitro and in vivo. Evidence now points toward a pathogenic role for advanced glycation in the initiation and progression of diabetic retinopathy. This review will examine the basis of AGE-related pathology in the diabetic retina at cellular and molecular levels. It will also outline how recent strategies to inhibit AGE formation or limit their pathogenic influence during chronic diabetes may have an important role to play in the treatment of retinopathy.     

The role of clinical and metabolic factors in the genesis and development of diabetic retinopathy

AIM: Diabetes is a complex polygenic, auto-aggressive disease caused by many different factors. Diabetic retinopathy is the leading cause of new cases of blindness in people aged between 25 and 65 years (working population) in industrialized countries. The aim was to determine whether disease duration, diabetes type and blood concentrations of some metabolites may be risk factors for the genesis and development of diabetic retinopathy. METHODS: This retrospective study included 402 diabetic patients from the Split-Dalmatia County. Laboratory testing included blood glucose, glycosylated hemoglobin A1c, total cholesterol, HDL and LDL cholesterol fractions, and apolipoprotein A and B concentrations. DISCUSSION: The incidence of diabetic retinopathy is increasing in our region, with nonproliferative form as the most common type. Women suffer more frequently from diabetic retinopathy, those aged 60 being at the highest risk. The genesis of diabetic retinopathy is directly correlated with the type and duration of diabetes. Changes in total cholesterol concentration, especially LDL fraction, and apolipoproteins A and B (especially B) indicate an increased relative risk of developing diabetic retinopathy. CONCLUSION: In our opinion, testing of glycosylated hemoglobin, HDL and LDL cholesterol fractions, and apolipoproteins A and B in the standard follow-up protocol for diabetic patients would significantly contribute to the prevention and reduction of diabetic retinopathy as the most common and most difficult diabetic eye complication.     

Manganese superoxide dismutase gene polymorphism (V16A) is associated with diabetic retinopathy in Slovene (Caucasians) type 2 diabetes patients

Substantial data indicate that oxidative stress is involved in the development of diabetic retinopathy. Two candidate genes that affect the oxidative stress are manganese mitochondrial superoxide dismutase (Mn-SOD) and endothelial nitric oxide synthase (eNOS). The aim of the present study was to examine the role of the V16A polymorphism of the Mn-SOD gene and the 4a/b polymorphism of the eNOS gene in the development of diabetic retinopathy in Caucasians with type 2 diabetes. In this cross sectional case-control study 426 unrelated Slovene subjects (Caucasians) with type 2 diabetes mellitus were enrolled: 283 patients with diabetic retinopathy and the control group of 143 subjects with type 2 diabetes of duration of more than 10 years who had no clinical signs of diabetic retinopathy. A significantly higher frequency of the VV genotype of the V16A polymorphism of the Mn-SOD was found in patients with diabetic retinopathy compared to those without diabetic retinopathy (OR=2.1, 95% whereas the 4a/b polymorphism of the eNOS gene failed to yield an association with diabetic retinopathy. We may conclude that the VV genotype of the V16A polymorphism of the Mn-SOD gene was associated with diabetic retinopathy in Caucasians with type 2 diabetes, therefore it might be used as a genetic marker of diabetic retinopathy in Caucasians.     

Severe proliferative retinopathy in a young man with diabetes of very short duration

A 22-year-old man developed typical insulin-dependent diabetes mellitus. At the time of diagnosis no signs of diabetic retinopathy were found by an experienced ophthalmologist, but florid proliferative diabetic retinopathy was observed only seven months later. Despite treatment with laser and vitrectomy the eye lesions progressed to total blindness within 30 months after the diagnosis of diabetes.     

The -106CC genotype of the aldose reductase gene is associated with an increased risk of proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes

Diabetic retinopathy is a sight-threatening chronic complication of diabetes mellitus and is the leading cause of acquired blindness in adults. The -106C>T polymorphism in the promoter region of the aldose reductase (AR) gene has been shown to be associated with the susceptibility to diabetic nephropathy in type 2 diabetes, but the findings regarding the occurrence of diabetic retinopathy are conflicting. In this case-control study, we investigated whether the -106C>T polymorphism in the AR gene is involved in the development and progression of diabetic retinopathy in 579 Brazilians with type 2 diabetes (424 Caucasian- and 155 African-Brazilians). Patients underwent a clinical and laboratory evaluation consisting of a questionnaire, physical examination, assessment of diabetic complications and laboratory tests. Genotype analysis was performed using the polymerase chain reaction followed by digestion with restriction enzyme. Logistic regression analysis was used to control for independent risk factors associated with diabetic retinopathy. There were no differences in either genotype or allele frequencies for the -106C>T polymorphism between type 2 diabetic patients with or without diabetic retinopathy, in both ethnic groups. However, the CC genotype was associated with an increased risk of having proliferative diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes (odds ratio (OR)=2.04; 95% confidence interval (CI)=1.21-3.45; P=0.007), independently of other risk factors associated with this complication. Thus, our results show that the -106CC genotype (-106C>T polymorphism) in the AR gene is related to the progression of diabetic retinopathy in Caucasian-Brazilians with type 2 diabetes.     

Concise review: Mesenchymal stem cell treatment of the complications of diabetes mellitus

Mesenchymal stem cells (MSCs) are multipotent, self-renewing cells that can be found in almost all postnatal organs and tissues. The main functional characteristics of MSCs are their immunomodulatory ability, capacity for self-renewal, and differentiation into mesodermal tissues. The ability of MSCs to differentiate into several cell types, including muscle, brain, vascular, skin, cartilage, and bone cells, makes them attractive as therapeutic agents for a number of diseases including complications of diabetes mellitus. We review here the potential of MSCs as new therapeutic agents in the treatment of diabetic cardiomyopathy, diabetic nephropathy, diabetic polyneuropathy, diabetic retinopathy, and diabetic wounds. Also, in this review we discuss the current limitations for MSCs therapy in humans.     

mTOR 在糖尿病血管病变中的研究进展

糖尿病血管病变是糖尿病致残、 致死的主要原因, 然而目前多种治疗策略对糖尿病血管病变的 防治仍未取得理想的结果。 哺乳动物雷帕霉素靶蛋白 (mechanistic target of rapamycin kinase, mTOR) 是一 种存在于真核生物中的丝氨酸/ 苏氨酸蛋白激酶, 在多种生物过程中发挥着重要作用。 研究发现 mTOR 可 通过调节细胞增殖、 凋亡、 自噬、 氧化应激及炎性反应等路径参与糖尿病血管病变的发生发展。 文章就 mTOR 对糖尿病相关动脉粥样硬化、 糖尿病肾病及糖尿病视网膜病变中的影响及相关机制进行综述, 为糖 尿病血管病变的防治提供新策略。