开裂的七重奏一糖尿病发病与肾脏组织及其临床处理

糖尿病。肾病（DN）是糖尿病主要的微血管并发症之一,也是成人慢性肾功能衰竭的首要病因。1型糖尿病（T1DM）患者的糖尿病肾病的发生率较高,为30％．40％。在2型糖尿病（T2DM）患者中约有20％发生糖尿病肾病。目前认为糖尿病肾病发病可能与遗传易感性、糖脂代谢紊乱及肾小球血流动力学改变等因素有关。     

开裂的七重奏—糖尿病发病与肾脏组织及其临床处理

糖尿病肾病（DN）是糖尿病主要的微血管并发症之一,也是成人慢性肾功能衰竭的首要病因。Ⅰ型糖尿病（T₁DM）患者的糖尿病肾病的发生率较高,为30%～40%。在2型糖尿病（T₂DM）患者中约有20%发生糖尿病肾病。目前认为糖尿病肾病发病可能与遗传易感性、糖脂代谢紊乱及肾小球血流动力学改变等因素有关。     

葡萄糖转运蛋白及其在糖尿病肾病中的作用

糖尿病肾病是糖尿病的主要慢性并发症。糖代谢紊乱在其发病机制中起着重要的作用 ,葡萄糖转运蛋白是调节葡萄糖进入系膜细胞的主要载体 ,其可能通过糖代谢途径 ,蛋白激酶C(PKC)途径 ,转化生长因子 (TGF) β1等细胞因子及基因背景等多因素途径参与糖尿病肾病的发生发展。     

葡萄糖转运蛋白及其在糖尿病肾病中的作用

糖尿病肾病是糖尿病的主要慢性并发症。糖代谢紊乱在其发病机制中起着重要的作用，葡萄糖转运蛋白是调节葡萄糖进入系膜细胞的主要载体，其可能通过糖代谢途径，蛋白激酶C（PKC）途径，转化生长因子（TGF）β1等细胞因子及基因背景等多因素途径参与糖尿病肾病的发生发展。     

非酒精性脂肪性肝病的药物治疗

非酒精性脂肪性肝病(NAFLD)是以肝脏脂质过度沉积为基础发生单纯性非酒精性脂肪肝、非酒精性脂肪性肝炎(NASH)、肝硬化和肝细胞癌的系列疾病,常伴发肥胖、2型糖尿病、高脂血症等代谢紊乱,心血管疾病为其主要致死因素,其治疗措施主要针对NAFLD的致病因素、发病与进展关键环节和相关代谢紊乱,推荐药物包括吡格列酮、二甲双胍、利拉鲁肽、卡格列净等改善胰岛素抵抗,他汀类降脂药物、ω-3长链脂肪酸,以及过氧化物酶体增殖物激活受体(PPAR)α和PPARγ激动剂等调节糖脂代谢、减少肝脏脂质沉积,维生素E、奥贝胆酸和复方中药等抗氧化、抗炎、抗纤维化,肠道微生态调节制剂调节肠道菌群。多种正在研究中的新型靶向脂代谢调节、抗炎和抗纤维化的药物有待临床验证。     

糖尿病肾病与脂肪细胞因子表达的相关性

糖尿病肾病（DN）是糖尿病（DM）最主要的微血管并发症之一,也是导致慢性肾功能衰竭的主要原因之一。DN的发生、发展是多因素综合作用的结果,糖脂代谢紊乱、血流动力学改变、多种细胞因子紊乱、胰岛素抵抗（IR）、炎症细胞浸润及遗传因素、氧化自由基、血管活性物质参与等。     

糖尿病肾病炎性反应发生机制及抗炎治疗的研究进展

糖尿病肾病（DN）是糖尿病最常见和最严重的慢性并发症之一。既往研究主要集中在血糖、血脂代谢紊乱和血流动力学异常等方面,近来越来越多的研究表明DN是一种慢性低水平炎性反应性疾病,本文阐述DN炎性反应发生机制及抗炎治疗的研究进展,为进一步延缓或逆转DN的进程提供新的方法。     

糖尿病肾病诊断与治疗新进展

糖尿病是一组由环境与遗传等多种病因共同引起的以糖代谢紊乱为特征的代谢性疾病。糖尿病肾病(DN)是糖尿病患者最常见、最严重的慢性合并症。目前,糖尿病肾病约占糖尿病患者的40%,是全世界慢性肾病的主要原因。中国已是世界第一糖尿病大国,也是糖尿病肾病大国。本文就糖尿病肾病诊断与治疗方面的新研究进展进行综述,旨在提供有关DN诊断和治疗的最新信息。     

线粒体自噬在糖尿病心肌病中的研究进展

糖尿病心肌病是与糖脂代谢紊乱相关的心肌并发症, 增加了糖尿病患者死亡和心力衰竭的风险。线粒体功能障碍参与了糖尿病心肌病的发生发展。近期研究显示, 通过线粒体自噬清除心肌细胞内受损线粒体, 可恢复线粒体稳态、减轻氧化应激及改善糖尿病心肌病。因此, 本文就线粒体自噬在糖尿病心肌病中的调控机制、作用特点进行综述, 以期为糖尿病心肌病防治提供新思路和理论依据。     

Krüppel样转录因子9在糖尿病肾脏病中的研究进展

糖尿病肾脏病(DKD)是糖尿病的重要并发症, 可发展为终末期肾病, 其发生发展与高血糖、氧化应激、炎症等导致的肾脏纤维化相关, 早期诊断及干预可延缓DKD进展, 但目前仍有诸多局限。近年来, 寻找DKD特异性的生物标志物协助早期诊断、探索新的治疗靶点已成为研究热点。Krüppel样转录因子(KLF)家族是一类与真核细胞的转录调控密切相关的转录家族, 参与细胞增殖、分化和凋亡等多个生命过程的调控, 其家族成员KLF9是一种能调控机体多种途径、发挥不同生物学作用的转录因子, 参与多种系统疾病的发生发展。越来越多的研究表明, KLF9可以调节与糖尿病/肥胖诱导的肾脏疾病及其细胞凋亡、炎症、氧化应激等相关的多种途径, 在糖尿病及其并发症中起到关键的调节作用, 但目前KLF9在DKD中的相关研究尚未见系统综述报道。该文重点从机体糖脂代谢紊乱、氧化应激、免疫炎症等病理生理过程为切入点, 系统综述KLF9在DKD中的研究进展, 以提高临床对KLF9与DKD发生发展相关性的认识。     

Physiological mechanisms of TLR4 in glucolipid metabolism regulation: Potential use in metabolic syndrome prevention

Over-nourishment or an unbalanced diet has been linked to an increase in the prevalence of metabolic syndrome. An imbalance in glucolipid metabolism is a major cause of metabolic syndrome, which has consequences for human health. Toll-like receptor 4 (TLR4), a member of the innate immune pattern recognition receptor family, is involved in inflammation-related disorders, autoimmune diseases, and tumors. Recent research has shown that TLR4 plays a key role in glucolipid metabolism, which is linked to insulin resistance, intestinal flora, and the development of chronic inflammation. TLR4 activation regulates glucolipid metabolism and contributes to the dynamic relationship between innate immunity and nutrition-related disorders. Further, TLR4 regulates glucolipid metabolism by controlling glycolysis and pyruvate oxidative decarboxylation, interfering with insulin signaling, regulating adipogenic gene expression levels, influencing preadipocyte differentiation and lipid accumulation, and altering the intestinal microbiota and permeability. TLR4 functions may provide new therapeutic applications for the prevention and treatment of metabolic syndrome. The purpose of this review is to enrich mechanistic research of diabetes, atherosclerosis, and other nutrition-related disorders by summarizing the role of TLR4 in the regulation of glucolipid metabolism as well as its physiological mechanisms.     

膳食营养干预对老年糖尿病患者糖脂代谢和抗氧化能力影响研究

目的研究膳食营养干预对老年糖尿病患者糖脂代谢和体内抗氧化能力的影响。方法43名超重或肥胖的老年2型糖尿病患者,采用随机交叉试验（cross-over study）随机分配至以低血糖指数为特征的膳食营养干预组（试验组）和普通膳食营养干预组（对照组）,每种膳食分别连续使用4周,间隔洗脱期4周,测定试验前后糖脂代谢谱和抗氧化指标的变化。结果试验组和对照组的血清胰岛素分别降低20.3%、5.5%,HOMA胰岛素抵抗指数分别下降33.3%、17.5%,两组间下降幅度差异有统计学意义（P〈0.05）,试验组和对照组的空腹静脉血糖分别下降16.8%、13.9%,果糖胺分别下降6.3%、4.3%,两组间下降幅度差异无统计学意义（P〉0.05）;试验组和对照组的甘油三酯分别下降28.6%、18.3%,两组间差异无统计学意义（P〉0.05）;试验组低密度脂蛋白下降17.2%,对照组低密度脂蛋白上升4.4%,两组间下降幅度差异有统计学意义（P〈0.01）;试验组和对照组的SOD分别升高了15.68%、21.33%,MDA分别下降23.94%、21.55%,GSH-PX分别升高了15.74%、17.09%,两组间的MDA差异有统计学意义（P〈0.05）,而SOD和GSH-PX两组间差异无统计学意义（P〉0.05）。结论在控制总能量基础上,采用低GI的营养治疗策略更有助于改善病人糖脂代谢和氧化应激水平。     

Renal Lipid Metabolism and Lipotoxicity in Diabetes

The pathogenesis of diabetic kidney disease is a complex process caused by both glucotoxicity and lipotoxicity due to lipid accumulation. In cases of diabetic animals, lipid deposition is found in both tubular and glomerular portions of the kidneys, which are the major sites of diabetic nephropathy lesions. The aim of this review was to provide insights into the mechanisms that lead to the development of renal lipid accumulation and the effects of renal lipotoxicity in the diabetic condition. An increased number of lipogenic genes and a decreased number of lipid oxidation genes are also detected in diabetic kidneys, both of which lead to lipid accumulation. The induction of oxidative stress, inflammation, fibrosis and apoptosis caused by lipid accumulation and lipid metabolites is called lipotoxicity. Renal lipotoxicity due to derangement in lipid metabolism may be a pathogenic mechanism leading to diabetic nephropathy and renal dysfunction.     

Oxidative stress in early diabetic nephropathy: fueling the fire

Diabetic nephropathy is a major microvascular complication of diabetes mellitus and the most common cause of end-stage renal disease worldwide. The treatment costs of diabetes mellitus and its complications represent a huge burden on health-care expenditures, creating a major need to identify modifiable factors concerned in the pathogenesis and progression of diabetic nephropathy. Chronic hyperglycemia remains the primary cause of the metabolic, biochemical and vascular abnormalities in diabetic nephropathy. Promotion of excessive oxidative stress in the vascular and cellular milieu results in endothelial cell dysfunction, which is one of the earliest and most pivotal metabolic consequences of chronic hyperglycemia. These derangements are caused by excessive production of advanced glycation end products and free radicals and by the subjugation of antioxidants and antioxidant mechanisms. An increased understanding of the role of oxidative stress in diabetic nephropathy has lead to the exploration of a number of therapeutic strategies, the success of which has so far been limited. However, judicious and timely use of current therapies to maintain good glycemic control, adequate blood pressure and lipid levels, along with lifestyle measures such as regular exercise, optimization of diet and smoking cessation, may help to reduce oxidative stress and endothelial cell dysfunction and retard the progression of diabetic nephropathy until more definitive therapies become available.     

Research progress in signalling pathway in diabetic nephropathy

Diabetic nephropathy, a lethal diabetic complication, is a leading cause of end‐stage renal disease, which is pathologically characterized by thickened tubular basal and glomerular membranes, accumulated extracellular matrix, and progressive mesangial hypertrophy. Growing evidence indicates that diabetic nephropathy is induced by multiple conditions, such as glucose metabolism disorder, oxidative stress, numerous inflammatory factors and cytokines, and haemodynamic changes that lead to the occurrence and development of diabetic nephropathy based on genetic susceptibility. A variety of abnormalities in the signalling pathway may interact to produce these pathologic processes. Research has aimed to highlight the signalling pathway mechanisms that lead to diabetic nephropathy so that preventative strategies and effective therapies might be developed. In this review, important pathways that appear to be involved in driving these processes are discussed. Copyright © 2014 John Wiley & Sons, Ltd.     

Urinary excretion of 8-oxo-7, 8-dihydro-2′-deoxyguanosine as a predictor of the development of diabetic nephropathy

AIMS/HYPOTHESIS: The increased oxidative stress in diabetes is known to contribute to the progression of diabetes and its complications. We have reported a significant relation between the content of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG), a product of oxidative DNA damage in urine or leukocytes and the severity of diabetic nephropathy and retinopathy [1]. We investigated whether 8-oxodG in urine or leukocytes is associated with the progression of diabetic nephropathy. METHODS:We measured urinary 8-oxodG contents at entry and carried out a prospective longitudinal study to assess the progression of nephropathy over 5 years. RESULTS: There was a significant progression of diabetic nephropathy in the patients with higher excretion of 8-oxodG in urine compared with the patients with moderate or lower excretion of 8-oxodG. There was no significant association between the leukocyte 8-oxodG contents and the development of nephropathy. The multivariate logistic regression analysis suggests that the urinary 8-oxodG was the strongest predictor of nephropathy among several known risk factors. CONCLUSION/INTERPRETATION: This study provides evidence that increased oxidative stress has a primary role in the pathogenesis of diabetic nephropathy. A local enhancement of oxidative stress in diabetic kidney might explain the possible linkage between the increased urinary excretion of 8-oxodG and the development of nephropathy. 8-oxodG in urine is a useful clinical marker to predict the development of diabetic nephropathy in diabetic patients.     

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.     

Relationship between Oxidative Stress and Inflammatory Cytokines in Diabetic Nephropathy

The prevalence of diabetes has dramatically increased worldwide due to the vast increase in the obesity rate. Diabetic nephropathy is one of the major complications of type 1 and type 2 diabetes and it is currently the leading cause of end‐stage renal disease. Hyperglycemia is the driving force for the development of diabetic nephropathy. It is well known that hyperglycemia increases the production of free radicals resulting in oxidative stress. While increases in oxidative stress have been shown to contribute to the development and progression of diabetic nephropathy, the mechanisms by which this occurs are still being investigated. Historically, diabetes was not thought to be an immune disease; however, there is increasing evidence supporting a role for inflammation in type 1 and type 2 diabetes. Inflammatory cells, cytokines, and profibrotic growth factors including transforming growth factor‐β (TGF‐β), monocyte chemoattractant protein‐1 (MCP‐1), connective tissue growth factor (CTGF), tumor necrosis factor‐α (TNF‐α), interleukin‐1 (IL‐1), interleukin‐6 (IL‐6), interleukin‐18 (IL‐18), and cell adhesion molecules (CAMs) have all been implicated in the pathogenesis of diabetic nephropathy via increased vascular inflammation and fibrosis. The stimulus for the increase in inflammation in diabetes is still under investigation; however, reactive oxygen species are a primary candidate. Thus, targeting oxidative stress‐inflammatory cytokine signaling could improve therapeutic options for diabetic nephropathy. The current review will focus on understanding the relationship between oxidative stress and inflammatory cytokines in diabetic nephropathy to help elucidate the question of which comes first in the progression of diabetic nephropathy, oxidative stress, or inflammation.     

Oxidative Stress, Nitric Oxide, and Diabetes

In the recent decades, oxidative stress has become focus of interest in most biomedical disciplines and many types of clinical research. Increasing evidence from research on several diseases show that oxidative stress is associated with the pathogenesis of diabetes, obesity, cancer, ageing, inflammation, neurodegenerative disorders, hypertension, apoptosis, cardiovascular diseases, and heart failure. Based on this research, the emerging concept is that oxidative stress is the “final common pathway”, through which risk factors of several diseases exert their deleterious effects. Oxidative stress causes a complex dysregulation of cell metabolism and cell-cell homeostasis. In this review, we discuss the role of oxidative stress in the pathogenesis of insulin resistance and beta-cell dysfunction. These are the two most relevant mechanisms in the pathophysiology of type 2 diabetes, and in the pathogenesis of diabetic vascular complications, the leading cause of death in diabetic patients.     

Impact of high glucose and transforming growth factor-β on bioenergetic profiles in podocytes

Diabetic nephropathy is the most common cause of chronic renal failure in industrialized countries. Depletion of podocytes plays an important role in the progression of diabetic glomerulopathy. Various factors in the diabetic milieu lead to serious podocyte stress driving the cells toward cell cycle arrest (p27(Kip1)), hypertrophy, detachment, and apoptosis. Mitochondria are responsible for oxidative phosphorylation and energy supply in podocytes. Recent studies indicated that mitochondrial dysfunction is a key factor in diabetic nephropathy. In the present study, we investigated metabolic profiles of podocytes under diabetic conditions. We examined oxygen consumption rates (OCRs) and oxidative phosphorylation complex activities in murine podocytes. Cells were exposed to high glucose for 48 hours, cultured for 10 passages under high-glucose conditions (30 mmol/L), or incubated with transforming growth factor-β (5 ng/mL) for 24 hours. After prolonged exposure to high glucose, podocytes showed a significantly increased OCR at baseline and also a higher OCR after addition of oligomycin, indicating significant changes in mitochondrial energy metabolism. Higher OCRs after inhibition of respiration by rotenone also indicated changes in nonmitochondrial respiration. Podocytes stimulated with a proapoptotic concentration of transforming growth factor-β displayed similar bioenergetic profiles, even with decreased citrate synthase activity. In all tested conditions, we found a higher cellular nicotinamide adenine dinucleotide content and changes in activities of respiratory chain complexes. In summary, we provide for the first time evidence that key factors of the diabetic milieu induce changes in glucose metabolism and mitochondrial function in podocytes.