Molecular signaling mechanisms of renal gluconeogenesis in nondiabetic and diabetic conditions

The kidneys are as involved as the liver in gluconeogenesis which can significantly contribute to hyperglycemia in the diabetic condition. Substantial evidence has demonstrated the overexpression of rate-limiting gluconeogenic enzymes, especially phosphoenolpyruvate carboxykinase and glucose 6 phosphatase, and the accelerated glucose release both in the isolated proximal tubular cells and in the kidneys of diabetic animal models and diabetic patients. The aim of this review is to provide an insight into the mechanisms that accelerate renal gluconeogenesis in the diabetic conditions and the therapeutic approaches that could affect this process in the kidney. Increase in gluconeogenic substrates, reduced insulin concentration or insulin resistance, downregulation of insulin receptors and insulin signaling, oxidative stress, and inappropriate activation of the renin–angiotensin system are likely to participate in enhancing renal gluconeogenesis in the diabetic milieu. Several studies have suggested that controlling glucose metabolism at the renal level favors effective overall glycemic control in both type 1 and type 2 diabetes. Therefore, renal gluconeogenesis may be a promising target for effective glycemic control as a therapeutic strategy in diabetes.     

长链非编码RNA与糖尿病及其并发症

长链非编码RNA起初被认定是基因转录"噪音",随着DNA元件百科全书的研究进展发现,lnc RNA能以RNA的形式在表观遗传、转录以及转录后水平调控基因的表达,参与多种重要的生命调控过程,与人类疾病的发生发展和预防都有着紧密联系。文章介绍lnc RNA的功能和特点,结合对lnc RNA的研究思路,并在已有研究的基础上综述lnc RNA与糖尿病及其并发症的关系,这些研究进展将为进一步理解糖尿病及其发生发展的分子医学基础提供依据。     

COX-2与糖尿病并发症关系研究进展

糖尿病是一种慢性、低度炎症性疾病。多种因素刺激下,环氧化酶COX-2在胰岛及多种组织中高水平表达。它通过与炎症因子和炎症介质,如一氧化氮、核因子-κB、前列腺素E等相互作用,对相应组织产生作用,从而促进了糖尿病并发症的发生和发展。对COX-2的研究可进一步揭示糖尿病并发症发生的分子机制,为预防和治疗糖尿病并发症提供新的思路。     

Rapamycin/metformin co‐treatment normalizes insulin sensitivity and reduces complications of metabolic syndrome in type 2 diabetic mice

Rapamycin treatment has positive and negative effects on progression of type 2 diabetes (T2D) in a recombinant inbred polygenic mouse model, male NONcNZO10/LtJ (NcZ10). Here, we show that combination treatment with metformin ameliorates negative effects of rapamycin while maintaining its benefits. From 12 to 30 weeks of age, NcZ10 males were fed a control diet or diets supplemented with rapamycin, metformin, or a combination of both. Rapamycin alone reduced weight gain, adiposity, HOMA‐IR, and inflammation, and prevented hyperinsulinemia and pre‐steatotic hepatic lipidosis, but exacerbated hyperglycemia, hypertriglyceridemia, and pancreatic islet degranulation. Metformin alone reduced hyperinsulinemia and circulating c‐reactive protein, but exacerbated nephropathy. Combination treatment retained the benefits of both while preventing many of the deleterious effects. Importantly, the combination treatment reversed effects of rapamycin on markers of hepatic insulin resistance and normalized systemic insulin sensitivity in this inherently insulin‐resistant model. In adipose tissue, rapamycin attenuated the expression of genes associated with adipose tissue expansion (Mest, Gpam), inflammation (Itgam, Itgax, Hmox1, Lbp), and cell senescence (Serpine1). In liver, the addition of metformin counteracted rapamycin‐induced alterations of G6pc, Ppara, and Ldlr expressions that promote hyperglycemia and hypertriglyceridemia. Both rapamycin and metformin treatment reduced hepatic Fasn expression, potentially preventing lipidosis. These results delineate a state of “insulin signaling restriction” that withdraws endocrine support for further adipogenesis, progression of the metabolic syndrome, and the development of its comorbidities. Our results are relevant for the treatment of T2D, the optimization of current rapamycin‐based treatments for posttransplant rejection and various cancers, and for the development of treatments for healthy aging.     

Differential expression of proteins in kidney, eye, aorta, and serum of diabetic and non-diabetic rats

Diabetes mellitus (DM) is a chronic progressive disease that often results in microvascular and macrovascular complications, yet its pathogenesis is not clear. Automated proteomic technology, coupled with powerful bioinformatics and statistical tools, can provide new insights into the molecular alterations implicated in DM. Following our previous findings of redox changes in the eye and aorta of diabetic rats, as well as the activities of different antioxidant enzymes during the development of DM, this study is further launched to find potential biomarkers by comparing the serum and tissue samples of 26 diabetic rats (8 weeks after streptozotocin [STZ] administration) with 29 normal controls using surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) technology. Eight potential biomarkers were found in the serum, one potential biomarker was found in the kidney and eye, respectively, whereas three potential biomarkers were discovered in the aorta. One of the serum biomarker candidates was found to match the C-reactive protein (CRP) in the Swiss-Prot knowledgebase. Further validation has been conducted by ELISA kit to confirm the role of CRP during the development of DM. To conclude, the increased level of CRP in diabetic serum demonstrated in this study indicates that the development of DM is associated with inflammation. This is also the first report demonstrating that some potential lysate biomarkers in the kidney, eye, and aorta may be involved in the development of diabetes and its complications. Further identification and evaluation of these potential biomarkers will help unravel the underlying mechanisms of the disease.     

Protein O-GlcNAcylation and Cardiovascular (Patho)physiology

Our understanding of the role of protein O-GlcNAcylation in the regulation of the cardiovascular system has increased rapidly in recent years. Studies have linked increased O-GlcNAc levels to glucose toxicity and diabetic complications; conversely, acute activation of O-GlcNAcylation has been shown to be cardioprotective. However, it is also increasingly evident that O-GlcNAc turnover plays a central role in the delicate regulation of the cardiovascular system. Therefore, the goals of this minireview are to summarize our current understanding of how changes in O-GlcNAcylation influence cardiovascular pathophysiology and to highlight the evidence that O-GlcNAc cycling is critical for normal function of the cardiovascular system.     

New potentials for 3-hydroxy-3-methyl-glutaryl-coenzymeA reductase inhibitors: Possible applications in retarding diabetic complications

The prevalence of diabetes mellitus is increasing all over the world and it is apparent that treatment of diabetic complications has the same importance as primary diabetes treatment and glycemic control. Diabetic complications occur as a result of prolonged hyperglycemia and its consequences, such as advanced glycation end products and reactive oxygen species. Impairment of lipid profile is also contributed to worsening diabetic complications. Therefore, it seems that the application of lipid-lowering agents may have positive effects on reversing diabetic complications besides glycemic control. Statins, a group of lipid-lowering compounds, have been shown to exert antioxidant, immunomodulatory, anti-inflammatory, and antiproliferative properties beyond their lipid-lowering effects. Furthermore, they have been reported to improve diabetic complications with different pathways. In this review, we will discuss the clinical importance, molecular biology of the most important microvascular/macrovascular diabetic complications, possible application of statins and their mechanism of action in retarding these complications.     

Proteomic analysis of adipose tissue: informing diabetes research

Diabetes, one of the most common endocrine diseases worldwide, results from complex pathophysiological mechanisms that are not fully understood. Adipose tissue is considered a major endocrine organ and plays a central role in the development of diabetes. The identification of the adipose tissue-derived factors that contribute to the onset and progression of diabetes will hopefully lead to the development of preventive and therapeutic interventions. Proteomic techniques may be useful tools for this purpose. In the present review, we have summarized the studies conducting adipose tissue proteomics in subjects with diabetes and insulin resistance, and discussed the proteins identified in these studies as candidates to exert important roles in these disorders.     

A novel truncated form of apolipoprotein A-I transported by dense LDL is increased in diabetic patients

Diabetic (DM) patients have exacerbated atherosclerosis and high CVD burden. Changes in lipid metabolism, lipoprotein structure, and dysfunctional HDL are characteristics of diabetes. Our aim was to investigate whether serum ApoA-I, the main protein in HDL, was biochemically modified in DM patients. By using proteomic technologies, we have identified a 26 kDa ApoA-I form in serum. MS analysis revealed this 26 kDa form as a novel truncated variant lacking amino acids 1-38, ApoA-IΔ(1-38). DM patients show a 2-fold increase in ApoA-IΔ(1-38) over nondiabetic individuals. ApoA-IΔ(1-38) is found in LDL, but not in VLDL or HDL, with an increase in LDL3 and LDL4 subfractions. To identify candidate mechanisms of ApoA-I truncation, we investigated potentially involved enzymes by in silico data mining, and tested the most probable molecule in an established animal model of diabetes. We have found increased hepatic cathepsin D activity as one of the potential proteases involved in ApoA-I truncation. Cathepsin D-cleaved ApoA-I exhibited increased LDL binding affinity and decreased antioxidant activity against LDL oxidation. In conclusion, we show for the first time: a) presence of a novel truncated ApoA-I form, ApoA-IΔ(1-38), in human serum; b) ApoA-IΔ(1-38) is transported by LDL; c) ApoA-IΔ(1-38) is increased in dense LDL fractions of DM patients; and d) cathepsin D-ApoA-I truncation may lead to ApoA-IΔ(1-38) binding to LDLs, increasing their susceptibility to oxidation and contributing to the high cardiovascular risk of DM patients.     

综述: 植物蛋白O-GlcNAc糖基化及生物学功能

蛋白质的O-GlcNAc糖基化现象发现迄今已有30多年历史．动物中,O-GlcNAc糖基化在调控细胞信号转导、基因转录、表观遗传和新陈代谢等方面发挥重要作用．而植物中,O-GlcNAc糖基化在近几年才得到关注并进行初步研究．本文对植物中O-GlcNAc修饰的糖供体合成途径、O-GlcNAc修饰关键酶、O-GlcNAc修饰蛋白的检测及功能等方面的研究工作进行归纳总结,发现O-GlcNAc糖基化在植物的生长发育、激素网络调控、信号转导、植物病毒侵染等过程均发挥重要作用,为进一步研究植物中O-GlcNAc糖基化的生物学功能提供参考．     

糖尿病及糖尿病心血管并发症患者肠道菌群的特征

【目的】比较2型糖尿病患者、糖尿病心血管并发症患者与健康人肠道菌群差异,分析肠道菌群与血糖、血脂等临床指标的关联,探讨肠道细菌在2型糖尿病、糖尿病心血管并发症发生、发展中的作用。【方法】招募健康人251例、糖尿病心血管并发症患者160例及糖尿病患者295例,三组各随机选取30例、30例和40例,进行血液生化指标分析和肠道菌群的宏基因组检测。【结果】与健康对照组比较,糖尿病心血管并发症组和2型糖尿病组血清丙氨酸氨基转移酶、碱性磷酸酶、甘油三酯、空腹血糖、胰岛素、糖化血红蛋白指标显著升高(P0.05);糖尿病患者组、糖尿病心血管并发症患者组的肠道菌群α-多样性明显降低,菌群发生改变。健康对照组中大部分优势菌属来自拟杆菌门和厚壁菌门,而糖尿病心血管并发症患者组和糖尿病患者组中大部分优势菌属则来自拟杆菌门、变形菌门和放线菌门。与健康对照组相比,糖尿病心血管并发症患者组和糖尿病患者组中,厚壁菌门比例明显下降,放线菌门和变形菌门比例明显上升。种水平上,空腹血糖与黏膜乳杆菌(Lactobacillus mucosae)、大肠埃希氏菌(Escherichia coli)、脆弱拟杆菌(Bacteroides fragilis)呈正相关,与细枝真杆菌(Eubacterium ramulus)、Roseburia inulinivorans、Roseburia hominis、挑剔真杆菌(Eubacterium eligens)、伶俐瘤胃球菌(Ruminococcus callidus)呈负相关;低密度脂蛋白胆固醇与嵴链球菌(Streptococcus cristatus)呈正相关,与Lachnospiraceae bacterium_6_1_63FAA和淀粉乳杆菌(Lactobacillus amylovorus)呈负相关;总胆固醇与血链球菌(Streptococcus sanguinis)呈正相关。【结论】2型糖尿病和糖尿病心血管并发症患者存在明显的糖脂代谢异常和肠道菌群失调,肠道菌群紊乱可能在糖尿病发病、进展过程中发挥重要作用。     

The role of ncRNAs-mediated pyroptosis in diabetes and its vascular complications

Over the past decade, the prevalence of diabetes has increased significantly worldwide, leading to an increase in vascular complications of diabetes (VCD), such as diabetic cardiomyopathy (DCM), diabetic nephropathy (DN), and diabetic retinopathy (DR). Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs), long Noncoding RNAs (lncRNAs), and circular RNAs (circRNAs), play a key role in cellular processes, including the pathophysiology of diabetes and VCD via pyroptosis. ncRNAs (e.g., miR-17, lnc-MEG3, and lnc-KCNQ1OT1) can regulate pyroptosis in pancreatic β cells. Some ncRNAs are involved in VCD progression. For example, miR-21, lnc-KCNQ1OT1, lnc-GAS5, and lnc-MALAT1 were reported in DN and DCM, and lnc-MIAT was identified in DCM and DR. Herein, this review aimed to summarize recent research findings related to ncRNAs-mediated pyroptosis at the onset and progression of diabetes and VCD.     

糖尿病心肌病发病机制的研究进展

糖尿病心肌病（diabetic cardiomyopathy, DCM）是一种特殊类型的心脏疾病,在一定程度上增加了糖尿病患者发生心力衰竭的风险,也是糖尿病患者死亡的主要原因之一。DCM的发病机制涉及多个方面,心肌细胞代谢紊乱（如高血糖和胰岛素抵抗）、心肌炎症和纤维化是DCM发病的基础,这些因素单独或联合作用于DCM的发生和发展。目前临床上尚无根治DCM的有效药物,研究疾病的发病机制在开发靶向治疗药物中具有重要意义。主要对当前DCM发病机制的研究进展展开综述,以期为DCM的早期预防和治疗提供理论基础。     

O-乙酰氨基葡萄糖(O-GlcNAc)修饰及其生物学功能研究进展

O-GlcNAc修饰系发生在蛋白质丝氨酸、苏氨酸羟基末端连接的乙酰氨基葡萄糖上的单糖基修饰。自1984年以来,针对O-GlcNAc糖基化修饰的研究日益升温。O-GlcNAc修饰是动态变化、可调控的,满足蛋白质翻译后修饰参与信号通路的必要条件。在多数情况下,O-GlcNAc修饰与磷酸化修饰发生在蛋白质的相同氨基酸残基上,故两种修饰之间常存在竞争性抑制,亦被称之为"阴阳"制衡。O-GlcNAc修饰参与细胞内多种信号通路的调控,调节着生长、增殖、激素响应等过程,在糖尿病、神经退行性疾病和肿瘤等代谢性疾病中扮演重要角色。探究O-GlcNAc修饰及其在生理、病理状态中的作用具有极为重要的意义。     

Association of vaspin rs2236242 gene polymorphism with serum vaspin level,insulin resistance and diabetes in an Iranian diabetic/pre-diabetic population

BackgroundIn recent years, the role of vaspin as an insulin-sensitizer has been studied widely. This is the investigation that examined the association of vaspin polymorphism rs2236242 on the vaspin level and the risk of type 2 diabetes and insulin-resistant Iranian pre-diabetic/diabetic population.MethodsA case-control study was conducted on 160 participants includes 80 participants holding (FBG) fasting blood glucose 3.88-5.55 (mmol/L) in the normal group, and 80 participants holding FBG≥5.55 (mmol/L) in a diabetic/pre-diabetic group. The serum vaspin and insulin were determined with ELISA (enzyme-linked assay) and biochemical variables by standard method. Tetra arms amplification system for the vaspin gene was performed. Statistical analysis was done using SPSS software version 20.ResultsThe means of age, body mass index (BMI), waist circumference (WC), hip circumference (HC), FBG, and vaspin were significantly different between normal and type 2 diabetic/impaired fasting blood group (P-value<0.05). rs2236242 showed association with Hip circumference (P-value<0.05). A significant association between allele A of rs2236242 with type 2 diabetes was seen (P-value<0.001). The vaspin levels showed a negative correlation with FBG (r =-0.296, P=0.001).ConclusionsAllele A of rs2236242 is a protective risk for type 2 diabetes, but no association of rs2236242 with insulin resistance was seen. The lower level of vaspin is a predictor for the progression of type 2 diabetes.     

A review of the anti-inflammatory properties of antidiabetic agents providing protective effects against vascular complications in diabetes

The global prevalence of Type 2 diabetes mellitus and its associated complications are growing rapidly. Although the role of hyperglycemia is well recognized in the pathophysiology of diabetic complications, its exact underlying mechanisms are not fully understood. In this regard, accumulating evidence suggests that the role of inflammation appears pivotal, with studies showing that most diabetic complications are associated with an inflammatory response. Several classes of antidiabetic agents have been introduced for controlling glycemia, with evidence that these pharmacological agents may have modulatory effects on inflammation beyond their glucose-lowering activity. Here we review the latest evidence on the anti-inflammatory effects of commonly used antidiabetic medications and discuss the relevance of these effects on preventing diabetic complications.