自噬介导运动改善2型糖尿病骨代谢紊乱的作用机制

文题释义：骨代谢：骨作为生命活动的重要器官之一,其细胞在不断进行代谢,细胞之间还会产生相互作用,在此过程中还存在骨髓中的红细胞生成细胞和基质细胞的相互作用,进而完成骨的修复和重建。 骨自噬：在骨组织细胞内发生的一种分化和吸收的循环过程,是骨组织细胞代谢的重要组成部分和必要的环节,正常状态下的自噬维持着骨中细胞的吸收和分化,在受到内部或外部刺激后,骨自噬水平会加强,以完成对骨细胞代谢的调控和对病态的应激。 背景：研究发现,自噬可通过核因子κB受体活化因子配体、哺乳动物雷帕霉素靶蛋白、Wnt/β-连环蛋白途径和p38丝裂原活化蛋白激酶等信号通路来调控2型糖尿病骨代谢。 目的：分析总结近年来自噬在运动改善2型糖尿病骨代谢紊乱中的作用及可能分子机制。 方法：以“自噬;运动;2型糖尿病;骨代谢”“autophagy;exercise;type 2 diabetes mellitus;bone metabolism”作为关键词在PubMed、中国知网等文献资料库中查询有关自噬介导运动改善2型糖尿病骨紊乱的相关文献,并对其进行研究,然后按照一定逻辑进行分析和综述。 结果与结论：①研究发现自噬可以通过PPAR-γ、Hedgehog、MITF和过氧化物酶体增殖激活受体等信号通路作用,从而在运动改善2型糖尿病骨代谢紊乱中发挥调控作用;②自噬在2型糖尿病中能上调成骨细胞的分化能力以及下调破骨细胞吸收能力,并对成骨细胞形成骨组织细胞和骨钙素的矿化产生重要影响。 ORCID: 0000-0001-5058-0101(陆鹏程) 中国组织工程研究杂志出版内容重点：组织构建;骨细胞;软骨细胞;细胞培养;成纤维细胞;血管内皮细胞;骨质疏松;组织工程     

SIRT1在糖尿病肾病进展中的作用

SIRT1是一种高度保守的NAD~+依赖的Ⅲ类组蛋白去乙酰化酶,广泛存在于胚胎以及人类组织中,通过染色质的修饰促进染色质沉默,通过去乙酰化非组蛋白调节糖和脂代谢、应激反应、凋亡、炎性反应和自噬等。糖尿病肾病的发生发展与炎性反应、氧化应激、缺血缺氧和衰老密切相关,SIRT1可能是该病进展中的上游调控因子。     

基于肠道菌群探讨运动改善2型糖尿病的可能机制

2型糖尿病（T2DM）是常见的慢性代谢性紊乱疾病,其发病机制尚无一致结论。随着微生态研究技术的革新,认为肠道菌群失调可能是T2DM的诱发原因之一。运动是糖尿病管理的有效手段之一,但其调节糖代谢的作用机制仍存在许多待解决的问题。近年来,人们发现运动可以改善肠道内环境和肠道菌群,本文将基于肠道菌群探讨运动对T2DM的影响,并对其机制研究进行综述,旨在为今后探究运动改善T2DM提供新思路。     

2型糖尿病患者骨代谢生化指标的临床意义

目的 :探讨 2型糖尿病患者骨代谢生化指标的临床意义。方法 :对 4 0例 2型糖尿病患者及 31例正常人进行血骨钙素 (BGP)、钙 (Ca)、碱性磷酸酶 (ALP) ;尿脱氧吡啶啉 (DPD)、Ca、肌酐 (Cr)测定。结果 :糖尿病组血清BGP较正常对照组明显降低 (P <0 0 5 ) ;尿DPD/Cr比值 ,Ca/Cr比值显著高于正常对照组 (P <0 .0 5 ,P <0 .0 5 ) ;血清Ca、ALP两组无统计学差异。结论 :2型糖尿病患者骨代谢异常引发骨量减少、骨质疏松与骨形成减少和骨吸收增加有关 ;血BGP、尿DPD/Cr、Ca/Cr可作为早期诊断糖尿病骨量减少、骨质疏松敏感的骨代谢生化指标。     

骨形成蛋白-9于2型糖尿病时在肝组织中的表达

目的 研究2型糖尿病鼠肝组织骨形成蛋白-9(bone morphogenetic proteins-9,BMP-9)基因转录及蛋白表达的变化.方法 将大鼠随机分为2型糖尿病模型组与正常对照组,分别于造模后5、10、20 d处死,以RT-PCR及Western-blot对肝组织BMP-9基因转录及蛋白表达水平进行检测与分析.结果 2型糖尿病模型组BMP-9基因转录及蛋白表达水平与正常组相比均显著性降低(P＜0.05);并且2型糖尿病大鼠5、10、20 d处死组BMP-9基因转录及蛋白表达水平呈逐步下降趋势.结论 2型糖尿病大鼠肝组织BMP-9基因转录及蛋白表达水平较正常显著降低,这一变化可能与2型糖尿病的发生发展相关.     

能量限制条件下SIRT1和SIRT2的表达变化

目的研究不同程度的能量限制（CR）下,大鼠脑组织中SIRT1和SIRT2的表达变化。方法 60只大鼠随机分成四组：正常对照组、75%CR组（喂养食物为正常对照组的75%）,55%CR组（喂养食物为正常对照组的55%）和高脂组,喂养8周。免疫组织化学检测大鼠脑组织中SIRT1和SIRT2的表达与定位。RT-PCR及Western-blot检测各实验组中SIRT1、SIRT2的表达。结果在大鼠脑组织中发现SIRT1可于细胞浆和细胞核中表达,且主要于细胞核中表达;SIRT2主要在细胞核中表达。能量限制下,与对照组相比SIRT1表达升高;高脂食物条件下,SIRT1表达相对于对照组增高,但是比CR组减少。75%CR与55%CR相比,后者中的SIRT1的表达增加更多。与对照组相比,55%CR增加SIRT1的表达差异有统计学意义（P〈0.05）,而75%CR和HFa增加SIRT1的表达差异无统计学意义。SIRT2在CR和HFa下表达无明显变化。结论 CR能增加SIRT1而不增加SIRT2的表达,重度CR比中等程度CR对SIRT1表达的影响更大。     

SIRT1的调节及其在感染性疾病中的作用

沉默信息调节因子2相关酶1(sirtuin 1,SIRT1)是一种NAD+依赖的组蛋白去乙酰化酶,参与多种生物学进程,如细胞分化、衰老、凋亡和能量代谢等.SIRT1受到多种蛋白及miRNA的调节,对多种免疫性疾病、肿瘤性疾病及感染性疾病具有显著影响.本文主要对SIRT1的调控及其在感染性疾病中的作用机制进行综述.     

2型糖尿病男性患者骨代谢指标与骨密度的相关性研究

目的：探讨2型糖尿病男性患者骨密度与骨代谢生化指标间的关系。方法：选取我科2014年1月至2015年12月入院的2型糖尿病男性患者102例,采用双能X线骨密度仪,测定腰椎(L2~L4)、股骨上端[包括股骨颈(Neck)、华氏三角(Ward)及股骨粗隆(Troch)]和全身的骨密度(bone mineral density, BMD)值;根据T值将这些患者分为骨量正常组(44例)、骨量减少组(36例)和骨质疏松组(29例),采用酶联免疫法测定各组碱性磷酸酶(alkaline phosphatase,ALP)、N-端中段骨钙素(N-MID-OT)、总Ⅰ型胶原氨基端延长肽(type 1 amino-terminal propeptide,tP1NP)和β胶原特殊序列(β-CTX)的浓度,比较三组骨代谢指标的变化,并对BMD与各项骨代谢指标进行相关性分析。结果：随着骨密度的降低,骨代谢指标的水平逐渐增高,其中,N-MID-OT和β-CTX的水平在三组间的差异皆有统计学意义(P<0.05);tP1NP在骨质疏松组和其余两组有统计学差异(P<0.05);ALP在三组间无统计学差异(P>0.05)。骨量减少组中,N-MID-OT与Neck、Troch及全身的BMD呈负相关(r=?0.754,?0.663,?0.743;P<0.05),β-CTX与Ward的BMD呈负相关(r=?0.273;P<0.05);骨质疏松组中, N-MID-OT与所有部位的BMD呈负相关(r=?0.736,?0.562,?0.715,?0.521,?0.436;P<0.05),β-CTX与Neck、Ward及全身的BMD呈负相关(r=?0.532,?0.614,?0.764;P<0.05)。结论：2型糖尿病男性患者骨密度与骨代谢指标呈负相关,两者联合评估有助于早期预防骨质疏松。     

2型糖尿病患者骨代谢标志物变化的研究

目的 探讨2型糖尿病(type 2 diabetes mellitus,T2DM)患者骨代谢标志物的变化及其与血糖、血脂代谢的相关性.方法 选取203例T2DM患者作为研究对象,选取同期体检的210例健康人作为对照组,分别测定各组骨代谢指标包括25-羟维生素D[25-hydroxyvitamin D,25(OH)D]、...     

Low bone turnover and reduced angiogenesis in streptozotocin-induced osteoporotic mice

It is known that type 1 diabetes (T1D) reduces bone mass and increases the risk for fragility fractures, an effect that has been largely ascribed to decreased bone formation. However, the potential role of decreased angiogenesis as a factor in osteogenesis reduction has not been extensively studied. Furthermore, there is controversy surrounding the effect of T1D on bone resorption. This study characterized bone microstructure, bone strength, and bone turnover of streptozotocin (STZ)-induced diabetic mice (T1D mice) and explored the role of angiogenesis in the pathogenesis of T1D-induced osteoporosis. Results demonstrate that T1D deteriorated trabecular microarchitecture and led to reduced bone strength. Furthermore, T1D mice showed reduced osteoblast number/bone surface (N.Ob/BS), mineral apposition rate, mineral surface/BS, and bone formation rate/BS, suggesting attenuated bone formation. Decreased angiogenesis was shown by a reduced number of blood vessels in the femur and decreased expression of platelet endothelial cell adhesion molecule (CD31), nerve growth factor, hypoxia-inducible factor-1α, and vascular endothelial growth factor was observed. On the other hand, reduced bone resorption, an effect that could lead to impaired osteogenesis, was demonstrated by lower osteoclast number/BS and decreased tartrate-resistant acid phosphatase and cathepsin K mRNA levels. Reduced number of osteoblasts and decreased expression of receptor activator for nuclear factor-κB ligand could be responsible for compromised bone resorption in T1D mice. In conclusion, T1D mice display reduced bone formation and bone resorption, suggesting decreased bone turnover. Furthermore, this study points to impairments in angiogenesis as a pivotal cause of decreased bone formation.     

2型糖尿病骨质疏松大鼠骨重建研究

目的通过建立2型糖尿病骨质疏松大鼠模型,探讨其骨重建特点。方法 雌性Wistar大鼠分为假手术组(NS组);去卵巢组(NOVX组);2型糖尿病假手术组(DS组)和2型糖尿病去卵巢组(DOVX组)。糖尿病组大鼠造模成功后行双侧卵巢切除术,0、4、8和12周测血糖(FPG)、胰岛素(FINS)、雌激素(E2)及血清骨特异性碱性磷酸酶(B-ALP)和抗酒石酸酸性磷酸酶(TRACP5b),同期测定骨密度(BMD)并行成骨和破骨细胞培养。结果 0周时DOVX组的血糖(13.1±4.9)mmol/L明显高于NS组的(4.4±0.6)mmol/L(P<0.05)。4周时DOVX组的BMD为(0.073±0.012)g/cm2明显低于NS组的(0.098±0.016)g/cm2(P<0.05)。4、8和12周时DOVX组的B-ALP与NS组均无差异,而4和8周时DOVX组的TRACP5b明显高于NS组(P<0.05)。4、8和12周时DOVX组的成骨细胞活力与NS组均无差异,而DOVX组的破骨细胞计数明显高于NS组(P<0.05)。结论 2型糖尿病骨质疏松大鼠骨重建特点为骨吸收活跃而骨形成相对减慢。     

2型糖尿病并发视网膜病变的骨密度分析

目的：探讨2型糖尿病患者合并视网膜病变其骨密度的变化。方法：选择2型糖尿病患者111例,按糖尿病视网膜病变分为糖尿病视网膜病变组和糖尿病眼底正常对照组,采用全自动生化检测仪测定甘油三酯、总胆固醇、高密度脂蛋白胆固醇、低密度脂蛋白胆固醇、血尿酸,骨密度采由美国Norland公司XR-36型双能X线骨密度仪测定,分别测定腰椎正位(L2、L3、L4)、左侧股骨颈、大粗隆区、Ward’s三角区的骨密度。结果：1)糖尿病视网膜病变组股骨颈、大粗隆区、Ward’s三角区的骨密度低于对照组,差异有统计学意义(P<0.05);而在腰椎正位两者的差异无统计学意义(P>0.05);2)糖尿病患者的骨密度与体重指数、尿酸呈正相关,与年龄、糖尿病病程、甘油三脂、总胆固醇、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇呈负相关。结论：2型糖尿病合并视网膜病变其骨密度降低。     

SIRT1 is associated with a decrease in acute insulin secretion and a sex specific increase in risk for type 2 diabetes in Pima Indians

Genetic variation in SIRT1 affects obesity-related phenotypes in several populations. The purpose of this study was to determine whether variation in SIRT1 affects susceptibility to obesity or type 2 diabetes in Pima Indians, a population with very high prevalence and incidence rates of these diseases. Genotypic data from single nucleotide polymorphisms (SNPs) identified by sequencing regions of SIRT1 combined with SNPs in/near SIRT1 from a prior genome-wide association study determined that 4 tag SNPs (rs7895833, rs10509291, rs7896005, and rs4746720) could capture information across this gene and its adjacent 5′ region. The tag SNPs were genotyped in a population-based sample of 3501 Pima Indians (44% had diabetes, 58% female) for association with type 2 diabetes and BMI. Metabolic trait data and adipose biopsies were available on a subset of these subjects. Two tag SNPs, rs10509291 and rs7896005, were nominally associated with type 2 diabetes (P = 0.01, OR = 1.25 95%CI 1.05–1.48, and P = 0.02, OR = 1.17 95%CI 1.02–1.34, respectively; additive P values adjusted for age, sex, birth year, and family membership), but not BMI (adjusted P values 0.52 and 0.45, respectively). Among metabolically characterized subjects with normal glucose tolerance (N = 243), those carrying the diabetes risk allele (T) for rs10509291 and (G) for rs7896005 had a reduced acute insulin response (AIR) to an intravenous glucose bolus (adjusted P = 0.045 and 0.035, respectively). SIRT1 expression in adipose biopsies was negatively correlated with BMI (adjusted P = 0.00001). We conclude that variation in SIRT1 is nominally associated with reduced AIR and increased risk for type 2 diabetes. SIRT1 expression in adipose is correlated with BMI, but it remains unknown whether this is a cause or consequence of obesity.     

Insulin gene VNTR, CTLA-4 +49A/G and HLA-DQB1 alleles distinguish latent autoimmune diabetes in adults from type 1 diabetes and from type 2 diabetes group

Recent research has underlined the need to explore pathogenic, genetic and clinical spectrum of adult onset autoimmune diabetes, also known as latent autoimmune diabetes in adults (LADA). We aimed to investigate whether genetic factors that are associated with type 1 diabetes (T1D) susceptibility, namely HLA-DQB1 alleles, cytotoxic T-lymphocyte antigen 4 gene (CTLA-4) and insulin gene (INS) polymorphisms, are also associated with an atypical subset of patients diagnosed with type 2 diabetes (T2D). The case-control study included 70 T1D, 305 T2D and 252 nondiabetic controls. The T2D group was divided into atypical T2D (LADA, n = 61) or typical T2D (n = 244) subgroups based on the presence of at least one pancreas-specific antibody. Our data suggested that HLA-DQB1 alleles of all three risk classes, INS variable number of tandem repeat (VNTR) I/I and CTLA-4 +49 GG or AG genotypes, were independent risk factors for developing LADA and could be used as a diagnostic tool to discriminate between LADA and T2D. Additionally, there was an increased association between LADA and CTLA-4 diabetes-susceptibility genotypes and decreased association with INS VNTR and high-risk HLA-DQB1 alleles, compared with T1D. Our study suggested the need for further investigation into the genetic background and functional genomics of LADA in comparison with T1D and T2D.     

SIRT1影响间充质干细胞骨修复的研究进展

激活沉默信息调节因子2相关酶1(SIRT1)可延长细胞寿命,延缓衰老的发生.SIRT1在调节炎性反应过程中也发挥着重要作用.基于在间充质干细胞的组织修复过程中,细胞衰老及炎性反应严重影响其修复能力.因此,有望通过调节SIRT1活性改变间充质干细胞组织修复能力.     

2型糖尿病易感位点的功能性L1逆转录转座子的研究

目的通过一种新的策略寻找2型糖尿病的易感基因.方法应用美国生物技术信息中心提供的BLAST(basic local alignment search tool)检索工具,对已报道的2型糖尿病易感位点的核酸序列进行检索分析,发现功能性L1逆转录转座子可能是易感基因.然后应用逆转录-聚合酶链反应检测25例2型糖尿病患者和22名正常对照的L1逆转录转座子表达水平,用SPSS10.0软件包进行统计学分析,并对6例患者和4名正常人的L1逆转录转座子进行定位克隆、基因组序列测定.结果对人类基因组及GenBank数据库进行全面搜索分析发现L1逆转录转座子分布在除19号、21号和Y染色体外的其它染色体上.这种分布情况与已报道的易感位点在染色体上的分布情况有相似性.功能性L1逆转录转座子在2型糖尿病患者组的表达水平明显低于正常对照组(P＜0.001).L1逆转录转座子在2型糖尿病患者有不同程度的缺失和(或)无意义突变,而在正常对照无突变.结论功能性L1逆转录转座子可能是2型糖尿病的某一易感基因或者是其易感基因的重要调节因子之一.功能性L1逆转录转座子表达水平的高低可能可以作为筛选2型糖尿病的一个生物学指标.