血清炎症因子在OLETF鼠2型糖尿病发病过程中的动态变化

目的探讨自发性T2DM大鼠模型OLETF鼠发病过程中炎症因子与IR的关系。方法 20只雄性OLETF鼠(OLETF组)和10只雄性LETO鼠(LETO组)在8、32和40周龄被分批处死。检测血糖和血浆胰岛素水平。免疫散射比浊法检测各组血清高敏C反应蛋白(hsC-RP),ELISA检测血清TNF-α、IL-6、单核细胞趋化蛋白1(MCP-1)水平,并计算ISI。结果 8周龄时,OLETF组血清hsC-RP和MCP-1均高于LETO组;随周龄增加,OLETF组血清hsC-RP、TNF-α、IL-6、MCP-1水平逐渐升高,且40周龄时,均高于LETO组,仅ISI低于LETO组(P0.01)。32周龄和40周龄时,ISI与hsC-RP、IL-6呈负相关(P0.01),血清各炎症因子之间互为正相关(P0.05)。结论 OLETF鼠血清炎症因子在糖尿病发生前即升高,并随病情进展持续升高,与IR密切相关,参与T2DM的发生发展。     

自发的2型糖尿病动物模型——OLETF大鼠

ＯＬＥＴＦ（Ｏｔｓｕｋａ Ｌｏｎｇ－Ｅｖａｎｓ Ｔｏｋｕｓｈｉｍａ Ｆａｔｔｙ）大鼠是１９８４年由日本大冢制药公司开发的自发性２型糖尿病鼠中。该鼠胆囊收缩素（ＣＣＫ）－Ａ受体ｍＲＮＡ是表达完全缺失,其携带ＯＤＢ１和ＯＤＢ２基因与糖尿病的发病有关。睾酮是糖尿病的促发因素之一。该鼠贪食,不好运动,体形肥胖,逐渐出现糖尿病的临床表现。早期以胰岛素抵抗、糖脂代谢紊乱为主,以后逐渐出现胰腺功能减退,晚期合并     

炎症与2型糖尿病

炎症是机体消除损害因素和对局部组织损伤进行修复的过程,由非特异性(固有性)和特异性(适应性)免疫介导。越来越多的证据证明炎症在胰岛素抵抗和胰岛B细胞损伤的发生过程中起至关重要的作用。2型糖尿病是一种自然免疫和低度炎症性疾病。这种由细胞因子介导的急性相反应属先天性免疫反应,是一种慢性亚临床非特异性免疫介导     

脂肪炎症因子在2型糖尿病发病中的重要性

胰岛素抵抗和胰岛β细胞功能减退是2型糖尿病发病的两个关键因素，但2型糖尿病的病因和发病机制尚未完全阐明。近年来炎症病因学理论倍受关注。该理论认为，2型糖尿病是一种自然免疫和低度炎症性疾病。由细胞因子介导的急性相反应属于先天性免疫反应，在正常个体该反应能促进遭受破坏的内环境恢复稳态；而在对急性反应高度敏感的个体，这种反应将导致疾病的发生，而非修复。这些细胞因子是导致代谢综合征的主要原因，从而认为炎症是胰岛素抵抗的触发因素。目前炎症因子与2型糖尿病发病密切相关的证据主要来源于临床流行病学研究。美国的一项研究发现，血清C反应蛋白（CRP）升高者2型糖尿病发病率增加2．3倍。另一项前瞻性研究显示，     

自发的2型糖尿病动物模型——OLETF大鼠

ＯＬＥＴＦ（ＯｔｓｕｋａＬｏｎｇ－ＥｖａｎｓＴｏｋｕｓｈｉｍａＦａｔｙ）大鼠是１９８４年由日本大制药公司开发的自发性２型糖尿病鼠种。该鼠胆囊收缩素（ＣＣＫ）－Ａ受体ｍＲＮＡ的表达完全缺失,其携带的ＯＤＢ１和ＯＤＢ２基因与糖尿病的发病有关。睾酮是糖尿病的促发因素之一。该鼠贪食,不好运动,体形肥胖,逐渐出现糖尿病的临床表现。早期以胰岛素抵抗、糖脂代谢紊乱为主,以后逐渐出现胰腺功能减退,晚期合并糖尿病肾脏病变,与人类２型糖尿病极为相似。     

生脉散对2型糖尿病大鼠炎症因子及胰岛素抵抗的影响

目的探讨生脉散对2型糖尿病(T2DM)大鼠炎症因子及胰岛素抵抗的影响。方法采用小剂量链脲佐菌素(STZ)加高脂饮食饲养方法建立2型糖尿病大鼠模型,设立正常对照组、模型对照组、阿司匹林阳性对照组、生脉散低、中、高剂量治疗组,生脉散低、中、高剂量治疗组分别灌服生脉散汤剂[4.7 g/(kg·d)、9.4 g/(kg·d)、18.8 g/(kg·d)],阿司匹林阳性对照组灌服阿司匹林[200 mg/(kg·d)],模型对照组和正常对照组灌服等量生理盐水,治疗4周。采用尾静脉取血,用血糖仪检测治疗前后各组大鼠空腹血糖(FBG)、放射免疫法检测空腹胰岛素(FINS)水平,计算胰岛素敏感性指数(ISI)、胰岛素抵抗指数(HOMA-IR);酶联免疫吸附法(ELISA)检测血清肿瘤坏死因子α(TNF-α)、纤溶酶原激活物抑制剂1(PAI-1)、白细胞介素6 (IL-6)、C反应蛋白(CRP)的含量。结果治疗4周后,与模型对照组比较,阿司匹林阳性对照组及生脉散中、高剂量治疗组大鼠FBG、FINS、HOMA-IR水平显著降低,ISI水平显著升高(P0.05);与阿司匹林阳性对照组比较,生脉散低剂量治疗组大鼠FBG、FINS、HOMA-IR水平升高,ISI水平降低,生脉散中、高剂量治疗组大鼠FBG、FINS、HOMA-IR水平显著降低,ISI水平显著升高,差异均有统计学意义(P0.05)。与模型对照组比较,阿司匹林阳性对照组和生脉散低、中、高剂量治疗组血清TNF-α、PAI-1、IL-6、CRP的含量显著降低(P0.05)。结论生脉散可改善2型糖尿病大鼠胰岛素抵抗,可能与抑制炎症因子释放有关。     

2型糖尿病患者血浆炎症因子水平与糖代谢及胰岛素抵抗的关系

目的 探讨2型糖尿病(T2DM)患者血浆炎症因子(IL-1β、IL-6、 TNF-α、C-RP)水平与糖代谢及胰岛素抵抗(IR)的关系.方法 分别检测60名健康者、60例T2DM患者血浆中的炎症因子水平及其他相关指标,并进行统计分析.结果 T2DM组各炎症因子、FPG水平均高于正常对照组;TNF-α与C-RP的水平与HbA1c及IR指数呈正相关(P＜0.05).结论 血浆IL-1β、IL-6、 TNF-α、C-RP与T2DM的发生发展相关,TNF-α、C-RP是T2DM糖代谢紊乱和IR的重要指标.     

炎症与2型糖尿病

胰岛素抵抗（IR）和胰岛素分泌不足是2型糖尿病（T2DM）发病的两个关键因素，但其机制尚未阐明。近年来炎症学说备受关注，认为T2DM为一先天性免疫和低度慢性炎症性疾病。在T2DM的易感个体，随着老龄化和营养过剩等环境因素的作用，先天性免疫系统被激活，巨噬细胞、脂肪细胞等前哨细胞分泌TNF-α、IL-6等多种炎症因子，进而引起IR、胰岛素分泌功能障碍和代谢综合征的发生。先天性免疫系统的激活可能是TEDM和动脉粥样硬化发生的共同机制之一。近年来大量研究支持该学说。     

炎症因子与2型糖尿病及其并发症

2型糖尿病(T2DM)的发病主要与胰岛素敏感性降低和胰岛素分泌障碍有关,已达成共识。近年研究表明,炎性反应在T2DM及其并发症的发生发展中占有重要地位。本文就国内外研究比较集中的几个亚临床炎症标志物与T2DM及其并发症的发生、发展及预后的关系综述如下。     

慢性炎症与2型糖尿病

2型糖尿病的发病机制主要是胰岛素抵抗（IR）和胰岛素分泌不足。但近年来的研究显示2型糖尿病是一种慢性炎症疾病，许多炎症因子，如TNF-α、IL-6、CRP、PAI-1不但直接参与胰岛素抵抗，而且与糖尿病大血管并发症的危险性联系紧密，在2型糖尿病的发生发展进程中起着重要作用。     

自发2型糖尿病模型OLETF大鼠脂肪组织水通道蛋白7表达水平的研究

目的观察水通道蛋白7在自发糖尿病模型OLETF大鼠不同糖尿病病程的皮下和附睾脂肪组织中的表达,探讨AQP7与肥胖糖尿病的关系。方法OLETF大鼠组分为未治疗组（OLETF组）及盐酸二甲双胍治疗组（0I。ETF／M组）。观察不同周龄时大鼠的体重、血清甘油三酯、胆固醇、甘油、葡萄糖耐量实验血糖与胰岛素以及皮下和附睾脂肪组织AQP7mRNA和AQP7蛋白含量的变化。Real—timePCR测定AQP7mRNA水平,Westernblotting测定AQP7蛋白含量。结果随周龄增加,肥胖、血脂紊乱加重,胰岛素抵抗明显,血糖增高。OLETF组皮下脂肪AQP7mRNA及蛋白表达为逐渐上调趋势,附睾脂肪AQP7mRNA及蛋白表达先上调后下调,皮下脂肪AQP7mRNA及蛋白表达上调幅度大于附睾脂肪AQP7。盐酸二甲双胍改善了OLETF／M组大鼠的脂代谢和糖代谢紊乱,且OLETF／M组皮下及附睾脂肪组织AQP7mRNA及蛋白表达上调幅度均低于OLETF组。结论皮下及附睾脂肪组织的AQP7在肥胖和糖尿病的发生发展中起一定作用。     

The different mechanisms of insulin sensitizers to prevent type 2 diabetes in OLETF rats

OBJECTIVE: To investigate the effects of pioglitazone and metformin treatment during pre-diabetic period for the prevention of diabetes in a rat model. METHODS: OLETF rats aged 18-weeks, were treated with pioglitazone (10 mg/kg/day) and metformin (300 mg/kg/day) for 10 weeks from their pre-diabetic period. We measured weight, lipid profiles, fat distribution, glucose tolerance, and pancreatic insulin content. RESULTS: Prominent weight gain (mostly subcutaneous fat area) was observed in the pioglitazone-treated OLETF (O-P) rats versus significant weight loss was observed in the metformin-treated OLETF (O-M) rats. Pioglitazone reversed the serum triglyceride (TG) and FFAs levels to normal (TG 0.46 +/- 0.04 vs 0.88 +/- 0.05 mmol/l in LETO). At the age of 28 weeks, the O-P rats showed completely normal glucose tolerance, and the glucose disposal rate (GDR) was markedly improved (25.6 +/- 0.4 vs 20.6 +/- 0.5 mg/min/kg in O-C, p < 0.05). The O-M rats also showed an improved fasting glucose and GDR level, but not as much as those with O-P rats. The pancreas insulin contents were much improved in the O-P rats (22.9 +/- 1.2 vs 18.8 +/- 1.3 nmol/pancreas in O-M rats, p < 0.05) with histological improvement. CONCLUSION: The pre-diabetic treatment with pioglitazone, despite significant weight gain, completely prevents to develop diabetes and enhances beta cell function with preservation of islet cell changes. Metformin treatment was also effective, but mainly by ameliorating the insulin resistance with marked reduction in body weight. The reversal of dyslipidaemia and the fat redistribution might contribute to the greater improvement of pioglitazone treatment compared to metformin in OLETF rats.     

血脂变化对OLETF糖尿病大鼠肾小球细胞外基质成分含量的影响

目的：采用OLETF大鼠来观察血脂变化对2型糖尿病鼠肾小球细胞外基质含量的影响。方法：实验动物分为三组即正常对照组,糖尿病和非诺贝特治疗的糖尿病组,非诺贝特20mg.kg^-1.d^-1灌胃22周,用免疫组化的方法检测肾小球细胞外基质成分含量的变化,结果：糖尿病组血清总胆固醇,甘油三酯,极低密度脂蛋白和高密度脂蛋白水平明显高于正常对照（P＜0．05）,同时细胞外基质成分（Ⅳ型胶原,层粘连蛋白,纤维连接蛋白）含量亦较正常对照组增加（三者P＜0．01）,降脂治疗后肾脏细胞外基质积聚明显减少（与糖尿病未治疗组比P＜0．05）,结论：高脂血症可能与糖尿病肾小球硬化的发生有关,降脂治疗能够减缓肾脏的损害从而起到保护肾脏的作用。     

利拉鲁肽对糖耐量异常大鼠血清炎症指标的影响

目的观察利拉鲁肽对糖耐量异常(IGT)OLETF大鼠血清炎症指标的影响。方法将29只IGT的OLETF大鼠随机分成4组,其中生理盐水(NS)干预8只(NS组),利鲁拉肽50、100、200μg/kg干预分别为8、6、7只(50、100、200μg/kg组);均行腹腔注射,2次/d,共12周。另选8只OLETF或LETO大鼠作为正常组,腹腔注射NS,2次/d,共12周。干预12周后,检测各组血糖、胰岛细胞功能及胰岛素敏感性指标(包括空腹血糖、胰岛素、胰岛素敏感性指数、胰岛素抵抗指数、胰岛β细胞功能指数),以及血清炎症指标(包括IL-6、超敏C反应蛋白、纤溶酶原激活物抑制剂-1、纤维蛋白原)。结果与NS组比较,利拉鲁肽干预组的血糖、胰岛细胞功能及胰岛素敏感性明显改善,血清炎症指标水平明显降低(P均<0.05)。结论利拉鲁肽对IGT的OLETF大鼠具有抗炎作用,能改善其胰岛细胞功能及胰岛素敏感性,降低其血清炎症指标水平,具有潜在的预防糖尿病及心血管疾病发生的作用。     

二甲双胍对OLETF自发性糖尿病大鼠G蛋白信号调节因子表达的影响

目的 研究OLETF大鼠G蛋白信号调节因子(RGS)的表达及二甲双胍对其表达的影响.方法设LETO大鼠为对照组(Con组,n=6),OLETF大鼠随机分为糖尿病组(DM组,n=6)和二甲双胍治疗组(Met组,n=5).Con组和DM组予无菌蒸馏水灌胃;Met组予二甲双胍.提取28周大鼠组织总RNA,逆转录后用实时定量PCR方法 检测胸主动脉和左心室RGS2、RGS3和RGS4 mRNA的表达.结果 DM组胸主动脉和左心室RGS2、RGS3和RGS4 mRNA水平显著高于Con组(P<0.01).Met组胸主动脉和左心室RGS2、RGS3和RGS4 mRNA水平显著低于DM组和Con组(P<0.01). 结论 OLETF大鼠胸主动脉和左心室RGS2、RGS3和RGS4 mRNA的升高与糖尿病心血管病变相关;降低则与二甲双胍的作用相关.     

Early second trimester maternal serum markers in the prediction of gestational diabetes mellitus

Aims/Introduction

To determine whether maternal serum markers in the early second trimester are useful for prediction of gestational diabetes mellitus (GDM).

Materials and methods

A total of 876 singleton pregnancies were recruited in the present study. Blood samples were collected during 16–20 gestational weeks. GDM women were diagnosed by an oral glucose tolerance test during 24–28 gestational weeks. A total of 56 women with GDM and 73 healthy pregnant women were selected. Maternal serum concentrations of placental protein 13 (PP13), pentraxin 3 (PTX3), soluble fms‐like tyrosine kinase‐1 (sFlt‐1), myostatin and follistatin (FST) were detected at 16–20 weeks’ gestation. All of these markers concentrations were expressed as multiples of the medians. The Mann–Whitney U‐test was used for comparison of the multiples of the medians of different concentrations of these five serum markers between the GDM group and the control group. Receiver operating characteristic curve analysis was applied to assess the sensitivity and specificity of significant serum markers from a Mann–Whitney U‐test comparison.

Results

Compared with healthy pregnancies, the serum levels of PP13, PTX3, sFlt‐1, myostatin and FST in the early second trimester were significantly increased in patients who had developed GDM late. In screening for GDM by PP13, PTX3, sFlt‐1, myostatin and FST, the detection rates were 92.3, 94.9, 94.9, 92.5 and 92.3%, respectively at 80% specificity. PTX3 and sFlt‐1 were the most sensitive markers.

Conclusions

Maternal serum markers including PP13, PTX3, sFlt‐1, myostatin and FST increase in the early second trimester of women with GDM. These five markers, especially PTX3 and sFlt‐1, could have the value of prediction for those patients who would develop GDM in the late second trimester.     

不同脂肪酸组分饮食对OLETF雄性大鼠胰岛素抵抗的影响

本研究观察不同脂肪酸组分的饮食对雄性OLETF大鼠胰岛素抵抗的影响。结果显示,进食富含ω-3多不饱和脂肪酸饮食有助于改善大鼠的胰岛素敏感性。     

炎症因子在正常个体向2型糖尿病转化中的作用

炎症因子对正常个体向2型糖尿病（T2DM）的转化中可能起重要作用,是T2DM发生的重要预测因子。炎症因子可能通过干扰胰岛素信号转导,引起胰岛素抵抗（IR）和β细胞的功能缺陷,导致T2DM发生。炎症因子与T2DM关联的证据来自大量临床流行病学的研究。主要涉及到的炎症因子有TNF-α、IL-6、CRP、PAI-1等。     

OLETF大鼠脂肪组织chemerin及其受体1的基因表达

用实时定量PCR检测OLETF大鼠脂肪组织中chemerin及其受体1 mRNA的表达,结果两者表达水平较对照组明显升高(P<0.05或P<0.01),且网膜脂肪组织高于皮下脂肪组织(P<0.05或P<0.01),说明脂肪因子chemerin及其受体1基因表达的变化可能是肥胖、胰岛素抵抗和2型糖尿病发病的机制之一.     

Alteration in haemodynamics and pathological changes in the cardiovascular system during the development of Type 2 diabetes mellitus in OLETF rats

Aims/hypothesis The process of cardiovascular complications in Type 2 diabetes mellitus (DM) is unclear. We investigated pathophysiological changes of the heart and vessels in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat Type 2 DM model during a long time period.Methods Echocardiography was carried out at 22 and 62 weeks of age of OLETF (n=10, each) and age-matched Long-Evans Tokushima Otsuka (LETO) rats (n=10, each) as a reference. Haemodynamic measurements and histological examinations of the heart and the coronary and aortic vascular walls were done.Results The left ventricular (LV) maximal -dP/dt was reduced in OLETF rats at 62 weeks (–1085±35 mmHg/s) less than that at 22 weeks (–1892±396 mmHg/sec, p<0.05) and in LETO rats at 62 weeks (–1306±200 mmHg/sec, p<0.05). Wall thickening of intramyocardial coronary arteries, capillary tortuosity and thickening of basement membrane were evident in OLETF rats at 62 weeks. Intimal and medial wall thickening of the aorta were prominent in OLETF rats at 62 weeks (15±2.2 and 90±6.6 µm, in LETO rats at 62 weeks, 2±0.4 and 65±5.2 µm, p <0.05, and in OLETF rats at 22 weeks, 7±4.6 and 71±6.0 µm, p<0.05, respectively).Conclusions/interpretation In the Type 2 DM model, angiopathy, especially in coronary arteries including small vessels, as well as a LV relaxation abnormality, are induced in a late stage of DM. These are considered to be important complications in Type 2 DM.Abbreviations OLETF Otsuka Long-Evans Tokushima Fatty - DM diabetes mellitus - LETO Long-Evans Tokushima Otsuka - STZ streptozotocin - 2-DE two-dimensional echocardiography - LVDd left ventricular end-diastolic diameter - LVDs left ventricular end-systolic diameter - IVST diastolic intraventricular septal wall thickness - LVPWT left ventricular posterior wall thickness - LVEF left ventricular ejection fraction - LV left ventricle - dP/dt first derivative of LV pressure