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☆☆欢迎参加内分泌期刊文摘翻译第8期☆☆

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26.Liver X receptor agonists ameliorate TNFa-induced insulin resistance in murine brown adipocytes by downregulating protein tyrosine phosphatase-1B gene expression
Authors S. Fernández-Veledo, I. Nieto-Vazquez, C. M. Rondinone and M. Lorenzo
DOI 10.1007/s00125-006-0472-4
Aims/hypothesis The nuclear receptors, including nuclear receptor subfamily 1, group H, member 3 (NR1HR, also known as liver X receptor [LXR]), are sensors of cholesterol metabolism and lipid biosynthesis that have recently been proposed as insulin sensitisers. TNFα has been described as a link between obesity and the development of insulin resistance, an important contributor to the pathogenesis of type 2 diabetes. Therefore, we decided to investigate the ability of NR1HR agonists to ameliorate TNFα-induced insulin resistance in brown adipocytes.
Methods Primary brown adipocytes from rat fetuses, and from wild-type neonate mice and neonate mice deficient in the gene encoding protein tyrosine phosphatase-1B (Ptpn1, also known as Ptp1b) were cultured in the absence or presence of TNFα and different nuclear receptor agonists. Among them, the unrelated NR1HR ligands T0901317, GW3965 and (22R)-hydroxycholesterol were tested. After insulin stimulation, glucose uptake and solute carrier family 2 (facilitated glucose transporter), member 4 (SLC2A4, formerly known as GLUT4) translocation were measured. Next the insulin signalling cascade was determined by submitting cells to lysis, immunoprecipitation and immunoblotting.
Results NR1HR agonists ameliorate TNFα-induced insulin resistance restoring completely insulin-stimulated glucose uptake and SLC2A4 translocation to plasma membrane. This effect is parallel to the recovery of the insulin cascade insulin receptor/IRS-2/phosphatidylinositol 3-kinase/protein kinase B, and could be due to the fact that T0901317 prevents the increase of PTPN1 production and phosphatase activity produced by TNFα. In this regard, Ptpn1-deficient brown adipocytes showed protection against insulin resistance by TNFα. Moreover, we observed that T0901317 produced in itself a significant increase over basal glucose uptake consistent with an increase of SLC2A4 protein content in plasma membrane, attributable to the activation of protein kinase ζ and/or the increase of Slc2a4 expression.
Conclusions/interpretation Nuclear receptors NR1HR are interesting potential targets for drug treatment of insulin resistance.

肝X受体激动剂在小鼠棕色脂肪细胞中通过下调蛋白酪氨酸磷酸酶-1B基因表达改善TNF-α诱导的胰岛素抵抗
目的/假设：核受体，包括核受体亚家族1，群H，3号成员（NR1HR，也被称作肝X受体LXR），是胆固醇代谢和脂质合成的感受器，最近被认为是胰岛素增敏剂。TNFα被认为是联系肥胖和胰岛素抵抗发展的桥梁，也是2型糖尿病的重要致病因素。因此，我们决定研究在棕色脂肪细胞中NR1HR激动剂改善TNFα诱导的胰岛素抵抗的能力。
方法：原代棕色脂肪细胞自大鼠胚胎、野生型新生小鼠和蛋白酪氨酸磷酸酶-1B基因基因(Ptpn1, 也被称作 Ptp1b)缺陷新生小鼠，在加或者不加TNFα和不同浓度核受体激动剂中培养。其中，各种不相关的NR1HR 配体T0901317，GW3965 和 (22R)-氢氧胆固醇被应用。在胰岛素刺激后，葡萄糖摄取和转运蛋白家族2（葡萄糖转运体），成员4 (SLC2A4, 以前被称作 GLUT4)的转位被测量。在胰岛素信号传导级联反应下的过程通过细胞融解后免疫沉淀。免疫印迹检测。
结果：NR1HR 激动剂改善TNFα诱导的胰岛素抵抗，并可完全恢复胰岛素刺激后的葡萄糖摄入和SLC2A4在膜的转位。这种作用平行于胰岛素级联反应的恢复：胰岛素受体/IRS-2/磷脂酰肌醇3-激酶/蛋白激酶B，并且可能还由于T0901317阻止TNFα诱导的PTPN1生成的增加和磷酸酶活性增强。因此，Ptpn1缺乏的棕色脂肪细胞表现出对TNFα诱导的胰岛素抵抗的缓解作用。此外，我们观察到了T0901317导致了显著的高于基础水平的葡萄糖摄入，与此相应的是SLC2A4蛋白在胞浆膜的增加，有助于蛋白激酶ζ的激活和/或Slc2a4 表达增加。
结论/解释：核受体NR1HR 是令人感兴趣的潜在的胰岛素抵抗药物治疗靶点。

2007-02-07 10:51

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• 其他医生用我的工号出报告

coffeenight

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37.The DREAM trial – Authors' reply
The main aim of the DREAM trial was to determine whether the interventions prevent diabetes, and not to determine their effect on cardiovascular outcomes. Indeed the very low rate of cardiovascular outcomes seen means that there was low power to detect any difference between groups, and that the observed differences in the cardiovascular composite outcome probably occurred by chance. We agree with Steven Nissen that only a large trial involving high-risk patients can reliably answer this question.
Christian Herder and colleagues point out that both lifestyle and rosiglitazone can dampen inflammation. Of note, both interventions can also increase the action of insulin, and because insulin has an anti-inflammatory effect, an increase in “insulin effect” might also be anti-inflammatory. The possible mechanisms through which the drug is mediating its effect will be explored in ongoing analyses of stored blood in subsets of participants.
Diseases are categories of health defined by prespecified criteria, and if these criteria are not met, the disease is regarded as not having occurred. Whether or not an intervention prevents the criteria for a disease from being met provides no information about its mechanism of action. Thus rosiglitazone prevented diabetes in the people who would otherwise have met the criteria for diabetes, whether or not it did so by pharmacologically keeping glucose concentrations from rising while it is being taken, or by partly or completely reversing the underlying abnormalities contributing to the dysglycaemic state. A washout phase that is now being analysed will provide insights into which of these two possible mechanisms best explains the observed effect on diabetes prevention. We certainly agree with John Yudkin that it is important to determine whether preventing diabetes also prevents the consequences of diabetes. In this regard, the effect of rosiglitazone on the renal consequences of diabetes in DREAM are currently being analysed and will be reported in the near future.
Finally, as pointed out by Jacobus Lubsen and Philip Poole-Wilson, two separate publications reported the answers to the two questions posed by the DREAM trial: (a) does rosiglitazone prevent diabetes; and (b) does ramipril prevent diabetes. Each question was answered with two treatment groups comprising half of all participants: the active drug group and the placebo group. Because there was no evidence of a statistical interaction (p>0•11) between the two interventions, the hazard ratio for the effect of rosiglitazone on the subgroup of participants on ramipril was the same as the effect on the subgroups of participants on placebo. Thus it was clearly appropriate to report the results independently.
In response to Lubsen and Poole-Wilson's query about annual death rates, the overall rates listed in table 2 are equivalent to 0•39 and 0•36 per 100 person-years of follow-up for the placebo and rosiglitazone groups, respectively.

DREAM 试验 – 作者的回答
DREAM 的主要目的是观察已知干预是否能阻止糖尿病，而不是观察干预对心血管终点的作用。事实上心血管事件发生率非常低，这意味着无法区别组间差别，已经观察到的心血管复合终点事件的差别可能是偶然。我们同意Steven Nissen的意见：只有一个入选了高危病人的大型试验才能可信的回答这个问题。
Christian Herder和其同事指出生活方式和罗格列酮都能减轻炎症。众所周知，这两种干预都可以增加胰岛素的作用，并由于胰岛素有抗炎作用，一种加强胰岛素作用可能也具有抗炎作用。药物发生作用的可能的机制会在对入选者的血样进行分析后得出。
疾病通过已确定的标准进行分类，如果还没有适合的标准，那么这种疾病就被认为还没有遇到过。一种药物是否能阻止病程进展到适合诊断的程度不能说明其发生作用的机制。因此罗格列酮延缓发生糖尿病的患者会以其他方式发生糖尿病，不管服用罗格列酮是否在药理上有助于控制升高的血糖，或者部分或全部的逆转血糖异常状态。对洗脱期的分析可能有助于更好的对这两种机制预防糖尿病的作用进行解释。我们当然同意John Yudkin的看法：判断预防糖尿病是否能预防糖尿病并发症是重要的。因此，DREAM试验中罗格列酮对糖尿病肾病的作用正在分析中并且会在近期公布。
最后，正如Jacobus Lubsen和Philip Poole-Wilson指出的，两种不同的出版物会报道DREAM试验中的两个问题：a罗格列酮是否能预防糖尿病 b雷米普利是否能预防糖尿病。每个问题会由2个治疗组的数据回答，每组包括半数入选者，包括药物组和安慰剂组。由于两种干预没有统计学差别(p>0•11)，罗格列酮相对于雷米普利及相对于安慰剂的危害比相同。因此，单独报告这个结果是合适的。
对于Lubsen and Poole-Wilson's 的关于每年死亡率的回答，总死亡率在表2中，随访的安慰剂和罗格列酮组分别为0.39/100人和0.36/100人。

2007-02-07 11:39

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2ndrainbow

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27.Sustained activation of the mammalian target of rapamycin nutrient sensing pathway is associated with hepatic insulin resistance, but not with steatosis, in mice
Authors E. Korsheninnikova, G. C. M. van der Zon, P. J. Voshol, G. M. Janssen, L. M. Havekes, A. Grefhorst, F. Kuipers, D.-J. Reijngoud, J. A. Romijn, D. M. Ouwens and J. A. Maassen
DOI 10.1007/s00125-006-0439-5
Aims/hypothesis Activation of nutrient sensing through mammalian target of rapamycin (mTOR) has been linked to the pathogenesis of insulin resistance. We examined activation of mTOR-signalling in relation to insulin resistance and hepatic steatosis in mice.
Materials and methods Chronic hepatic steatosis and hepatic insulin resistance were induced by high-fat feeding of male C57BL/6Jico mice for 6 weeks. In addition, acute hepatic steatosis in the absence of insulin resistance was induced by pharmacological blockade of β-oxidation using tetradecylglycidic acid (TDGA). mTOR signalling was examined in liver homogenates.
Results High-fat feeding caused obesity (p<0.001), hepatic steatosis (p<0.05) and hepatic insulin resistance (p<0.05). The phosphorylation of mTOR and its downstream targets p70S6 kinase and S6 ribosomal protein was two-fold higher in mice on a high-fat diet than in mice fed standard chow (all p<0.05) and associated with enhanced rates of protein synthesis. Acute induction of hepatic steatosis with TDGA had no effect on mTOR activity. The increased activity of the mTOR pathway in livers from mice on a high-fat diet could not be ascribed to diet-induced alterations in known modulators of mTOR activity such as circulating plasma leucine levels, phosphorylation of protein kinase B and AMP-activated protein kinase, and changes in mitochondrial function.
Conclusions/interpretation High-fat diet induces increase of the mTOR nutrient sensing pathway in association with hepatic insulin resistance, but not with hepatic lipid accumulation as such.
哺乳动物雷帕霉素营养感受通路靶点的持续激活在小鼠与肝脏胰岛素抵抗有关，但与脂肪变性无关
目的/假设哺乳动物雷帕霉素营养感受通路靶点的激活已经与胰岛素抵抗的发病机制相关。我们在小鼠检验了mTOR信号传导的激活与胰岛素抵抗和肝脏脂肪变性。
材料和方法：慢性肝脏脂肪变性和肝胰岛素抵抗通过对雄性C57BL/6Jico大鼠6周的高脂饮食诱导产生。此外，急性肝脂肪变性不伴胰岛素抵抗通过药物TDGA阻断β-氧化诱导产生。mTOR信号通过检查肝组织匀浆获得。
结果：高脂饮食产生肥胖（p<0.001）、肝脂肪变性（p<0.05）和肝胰岛素抵抗（p<0.05）。磷酸化的mTOR和它的下游目标p70S6激酶和S6核蛋白体蛋白在高脂饮食喂养的小鼠比正常饮食小鼠增高2倍(p<0.05)并且蛋白合成增强。TDGA的急性肝脂肪变性对mTOR活性没有影响。高脂饮食小鼠肝mTOR传导路径活性增强不能规因于饮食诱导改变了已知的mTOR调节因子如血浆亮氨酸浓度、磷酸化蛋白激酶B和AMP激活的蛋白激酶和线粒体功能的改变。
结论/解释：高脂饮食诱导了mTOR营养感受通路的增强，这与肝胰岛素抵抗有关，但与肝脂肪堆积无关。

2007-02-08 20:56

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• 上海市2021年2月CPC病例讨论（已揭秘）

2ndrainbow

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28.The PEA15 gene is overexpressed and related to insulin resistance in healthy first-degree relatives of patients with type 2 diabetes
Authors R. Valentino, G. A. Lupoli, G. A. Raciti, F. Oriente, E. Farinaro, E. Della Valle, M. Salomone, G. Riccardi, O. Vaccaro, G. Donnarumma, G. Sesti, M. L. Hribal, M. Cardellini, C. Miele, P. Formisano and F. Beguinot
DOI 10.1007/s00125-006-0455-5
Aims/hypothesis Overexpression of the gene encoding phosphoprotein enriched in astrocytes 15 (PEA15), also known as phosphoprotein enriched in diabetes (PED), causes insulin resistance and diabetes in transgenic mice and has been observed in type 2 diabetic individuals. The aim of this study was to investigate whether PEA15 overexpression occurs in individuals at high risk of diabetes and whether it is associated with specific type 2 diabetes subphenotypes.
Subjects and methods We analysed PEA15 expression in euglycaemic first-degree relatives (FDR) of type 2 diabetic subjects.
Results The expression of PEA15 in peripheral blood leucocytes (PBLs) paralleled that in fat and skeletal muscle tissues. In PBLs from the FDR, PEA15 expression was two-fold higher than in euglycaemic individuals with no family history of diabetes (control subjects), both at the protein and the mRNA level (p < 0.001). The expression of PEA15 was comparable in FDR and type 2 diabetic subjects and in each group close to one-third of the subjects expressed PEA15 levels more than 2 SD higher than the mean of control subjects. Subjects with IFG with at least one type 2 diabetes-affected FDR also overexpressed PEA15 (p < 0.05). In all the groups analysed, PEA15 expression was independent of sex and unrelated to age, BMI, waist circumference, systolic and diastolic BP, and fasting cholesterol, triacylglycerol and glucose levels. However, in euglycaemic FDR of type 2 diabetic subjects, PEA15 expression was inversely correlated with insulin sensitivity (r = −557, p = 0.01).
Conclusions/interpretation We conclude that PEA15 overexpression represents a common defect in FDR of patients with type 2 diabetes and is correlated with reduced insulin sensitivity in these individuals.

PEA15基因在2型糖尿病患者健康的一级亲属中过度表达并和胰岛素抵抗相关
目的/假设：编码磷蛋白得基因过度表达使其在星形胶质细胞15（PEA15）含量增加，并且已知磷蛋白在糖尿病中表达的增加在转基因小鼠中引起了胰岛素抵抗和糖尿病，在人类2型糖尿病患者已经观察到这种情况。这个研究得目的是为了调查PEA15在高危糖尿病患者中是否过度表达，以及是否与特殊的2型糖尿病亚型表型相关。
对象和方法：我们分析了糖尿病患者血糖正常得一级亲属（FDR）PEA15表达情况。
结果：PEA15表达在外周血细胞和脂肪、骨骼肌中平行。FDR外周血细胞PEA15表达相对于非糖尿病患者的正常血糖亲属（对照）高2倍，无论在蛋白还是mRNA水平。 (p< 0.001). FDR与糖尿病组得PEA15表达是可比较的，并且每组中有1/3的对象比对照的评价水平表达高2个标准差。有IFG和最少一个2型糖尿病亲属的FDR也过度表达PEA15(p<0.05)。在分析所有组别时，PEA15的表达独立于性别、年龄、BMI、腰围、收缩压、舒张压、空腹胆固醇水平、空腹甘油三酯、空腹血糖水平。但是，在正常血糖FDR，PEA15表达与胰岛素敏感性呈负相关 (r=−557, p=0.01) 。
结论/解释：我们认为PEA15过度表达代表了FDR的一种普遍的缺陷，并且与这些人的胰岛素敏感性减低有关。

2007-02-09 15:26

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