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Suppression of the nuclear factor Eny2 increases insulin secretion in poorly functioning INS-1E insulinoma cells. 抑制核因子Eny2可增加功能不良的INS-1E胰岛素瘤细胞的胰岛素分泌。
Pub Date : 2012-01-01 Epub Date: 2012-05-10 DOI: 10.1155/2012/460869
P Dames, M Weise, R Puff, B Göke, K G Parhofer, J Seissler, A Lechner

Eny2, the mammalian ortholog of yeast Sus1 and drosophila E(y)2, is a nuclear factor that participates in several steps of gene transcription and in mRNA export. We had previously found that Eny2 expression changes in mouse pancreatic islets during the metabolic adaptation to pregnancy. We therefore hypothesized that the protein contributes to the regulation of islet endocrine cell function and tested this hypothesis in rat INS-1E insulinoma cells. Overexpression of Eny2 had no effect but siRNA-mediated knockdown of Eny2 resulted in markedly increased glucose and exendin-4-induced insulin secretion from otherwise poorly glucose-responsive INS-1E cells. Insulin content, cellular viability, and the expression levels of several key components of glucose sensing remained unchanged; however glucose-dependent cellular metabolism was higher after Eny2 knockdown. Suppression of Eny2 enhanced the intracellular incretin signal downstream of cAMP. The use of specific cAMP analogues and pathway inhibitors primarily implicated the PKA and to a lesser extent the EPAC pathway. In summary, we identified a potential link between the nuclear protein Eny2 and insulin secretion. Suppression of Eny2 resulted in increased glucose and incretin-induced insulin release from a poorly glucose-responsive INS-1E subline. Whether these findings extend to other experimental conditions or to in vivo physiology needs to be determined in further studies.

Eny2是酵母Sus1和果蝇E(y)2的哺乳动物同源基因,是参与基因转录和mRNA输出的几个步骤的核因子。我们之前已经发现小鼠胰岛在妊娠代谢适应过程中Eny2的表达发生了变化。因此,我们假设该蛋白参与了胰岛内分泌细胞功能的调节,并在大鼠INS-1E胰岛素瘤细胞中验证了这一假设。Eny2的过表达没有影响,但sirna介导的Eny2敲低导致葡萄糖和exendin-4诱导的胰岛素分泌明显增加,否则葡萄糖反应较差的INS-1E细胞。胰岛素含量、细胞活力和葡萄糖感知的几个关键成分的表达水平保持不变;然而,敲除Eny2后,葡萄糖依赖型细胞代谢更高。Eny2的抑制增强了cAMP下游的细胞内肠促胰岛素信号。特异性cAMP类似物和途径抑制剂的使用主要涉及PKA和较小程度的EPAC途径。总之,我们发现了核蛋白Eny2和胰岛素分泌之间的潜在联系。抑制Eny2导致葡萄糖增加和肠促胰岛素诱导的胰岛素从葡萄糖反应不良的INS-1E亚群中释放。这些发现是否适用于其他实验条件或体内生理需要在进一步的研究中确定。
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引用次数: 5
Bone: incretin hormones perceiver or receiver? 骨:肠促胰岛素激素的感知者还是接受者?
Pub Date : 2012-01-01 Epub Date: 2012-06-17 DOI: 10.1155/2012/519784
Ilaria Dicembrini, Edoardo Mannucci, Carlo Maria Rotella
Novel incretin-based drugs, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i), have been last introduced in the pharmacological treatment of type 2 diabetes. In the last few years, the interest on the relationship of gut hormones with bone metabolism in diabetes has been increasing. The aim of present paper is to examine in vitro and in vivo evidence on the connections between incretin hormones and bone metabolism. We also discuss results of clinical trials and metaanalysis, explore the effects of incretin drugs in vitro on osteogenic cells and osteoclasts, and speculate on the possibility of different effects of GLP-1 RA and DPP-4i on the risk of bone fractures risk in humans. Although existing preliminary evidence suggests a protective effect on the bone, at least for DPP-4i, further controlled, long-term studies with measurement of bone markers, bone density, and clinical fractures rates are needed to substantiate and confirm those findings.
新型肠促胰岛素类药物,如胰高血糖素样肽-1受体激动剂(GLP-1 RA)和二肽基肽酶-4抑制剂(DPP-4i),最近被引入到2型糖尿病的药物治疗中。近年来,人们对肠道激素与糖尿病患者骨代谢关系的研究日益关注。本文旨在探讨肠促胰岛素激素与骨代谢之间的联系的体外和体内证据。我们还讨论了临床试验和荟萃分析的结果,探讨了体外肠促胰岛素药物对成骨细胞和破骨细胞的影响,并推测了GLP-1 RA和DPP-4i对人类骨折风险的不同影响的可能性。尽管现有的初步证据表明DPP-4i对骨骼有保护作用,至少对DPP-4i有保护作用,但需要进一步的对照、长期研究,测量骨骼标志物、骨密度和临床骨折率,以证实和确认这些发现。
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引用次数: 25
Topical application of Sadat-Habdan mesenchymal stimulating peptide (SHMSP) accelerates wound healing in diabetic rabbits. 局部应用Sadat-Habdan间充质刺激肽(SHMSP)促进糖尿病家兔伤口愈合。
Pub Date : 2012-01-01 Epub Date: 2012-06-19 DOI: 10.1155/2012/531961
Abdulmohsen H Al-Elq, Mir Sadat-Ali, Mohamed Elsharawy, Ibrahim Al-Habdan, Fatin Othman Al-Aqeel, Magda M Naim

Objective: Diminished wound healing is a common problem in diabetic patients due to diminished angiogenesis. SHMSP was found to promote angiogenesis. The present study was carried out to examine the effect of this peptide in healing of wounds in diabetic rabbits.

Materials and methods: Twenty male New Zealand rabbits were used in this study. Diabetes mellitus was induced and the rabbits were randomly divided into two equal groups: control group and peptide group. A-full thickness punch biopsy was made to create a wound of about 10 mm on the right ears of all rabbits. Every day, the wound was cleaned with saline in control groups. In the peptide group, 15 mg of SHMSP was applied after cleaning. On day 15th, all animals were sacrificed, and the wounds were excised with a rim of 5 mm of normal surrounding tissue. Histo-pathological assessment of wound healing, inflammatory cell infiltration, blood vessel proliferation, and collagen deposition was performed.

Results: There were no deaths among the groups. There was significant increase in wound healing, blood vessel proliferation and collagen deposition, and significant decrease in inflammatory cell infiltration in the peptide group compared to the control group.

Conclusion: Topical application of SHMSP improves wound healing in diabetic rabbits.

目的:血管生成减少是糖尿病患者创面愈合减少的常见问题。发现SHMSP促进血管生成。本研究旨在探讨该肽在糖尿病家兔伤口愈合中的作用。材料与方法:选用雄性新西兰兔20只。将诱导糖尿病的家兔随机分为对照组和多肽组。在所有兔的右耳上进行全层穿刺活检,创面约10 mm。对照组每天用生理盐水清洗创面。肽组清洗后给予15 mg SHMSP。第15天处死所有动物,切除创面,周围留下5 mm的正常组织。进行伤口愈合、炎症细胞浸润、血管增生和胶原沉积的组织病理学评估。结果:各组无死亡病例。与对照组相比,肽组伤口愈合、血管增生和胶原沉积明显增加,炎症细胞浸润明显减少。结论:局部应用SHMSP可促进糖尿病家兔创面愈合。
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引用次数: 7
Transcriptional mechanisms controlling miR-375 gene expression in the pancreas. 胰腺中调控miR-375基因表达的转录机制
Pub Date : 2012-01-01 Epub Date: 2012-06-20 DOI: 10.1155/2012/891216
Tali Avnit-Sagi, Tal Vana, Michael D Walker

MicroRNAs (miRNAs) are a class of small non-coding RNAs that play an important role in mediating a broad and expanding range of biological activities. miR-375 is expressed selectively in the pancreas. We have previously shown that selective expression of miR-375 in pancreatic beta cells is controlled by transcriptional mechanisms operating through a TATA box-containing promoter. Expression of miR-375 has been reported in non-beta cells within the endocrine pancreas, and indeed inactivation of miR-375 leads to perturbation in cell mass and number of both alpha and beta cells. Consistent with its expression throughout the endocrine pancreas, we now show that the promoter of the miR-375 gene shows selective activity in pancreatic endocrine alpha cells, comparable to that observed in beta cells. We previously identified a novel negative regulatory element located downstream of the miR-375 gene transcription start site. By generating luciferase reporter genes, we now show that the sequence is functional also when positioned upstream of a heterologous promoter, thus proving that the repressor effect is mediated at least in part at the level of transcription. Further characterization of the transcriptional control mechanism regulating expression of miR-375 and other pancreatic miRNAs will contribute to a better understanding of pancreas development and function.

MicroRNAs (miRNAs)是一类小的非编码rna,在介导广泛且不断扩大的生物活性方面发挥着重要作用。miR-375在胰腺中选择性表达。我们之前已经表明,miR-375在胰腺β细胞中的选择性表达是由转录机制控制的,该机制通过一个TATA盒启动子运作。据报道,miR-375在内分泌胰腺的非β细胞中表达,miR-375的失活确实会导致细胞质量和α细胞和β细胞数量的扰动。与其在整个内分泌胰腺中的表达一致,我们现在发现miR-375基因的启动子在胰腺内分泌α细胞中表现出选择性活性,与在β细胞中观察到的活性相当。我们之前发现了位于miR-375基因转录起始位点下游的一个新的负调控元件。通过生成荧光素酶报告基因,我们现在表明该序列在位于异源启动子上游时也具有功能,从而证明抑制因子的作用至少部分是在转录水平上介导的。进一步表征调节miR-375和其他胰腺mirna表达的转录控制机制将有助于更好地了解胰腺的发育和功能。
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引用次数: 17
Hyperglycemia induces the variations of 11β-hydroxysteroid dehydrogenase type 1 and peroxisome proliferator-activated receptor-γ expression in hippocampus and hypothalamus of diabetic rats. 高血糖可引起糖尿病大鼠海马和下丘脑11β-羟基类固醇脱氢酶1型和过氧化物酶体增殖物激活受体-γ表达的变化。
Pub Date : 2012-01-01 Epub Date: 2012-06-26 DOI: 10.1155/2012/107130
Wen-wen Qi, Li-yong Zhong, Xiao-rong Li, Guang Li, Zhao-xia Liu, Jin-feng Hu, Nai-hong Chen

In this paper, we first observed that there were differences in expressions of 11β-HSD1 and PPAR-γ, in hippocampi and hypothalami, among constant hyperglycemia group, control group and the fluctuant glycemia group, using Immunohistochemical analysis. However, whether in expression o f 11β-HSD1 or PPAR-γ, there were no statistic differences between the control group or the fluctuant glycemia group. So, we removed the fluctuant glycemia group, retaining only constant hyperglycemia group and control group, being fed for 8 weeks. After 8 weeks of induction, 11β-HSD1 expression increased and PPAR-γ expression decreased in the constant hyperglycemia group compared with control group, both in hippocampi and hypothalami, by Western Blot. The constant hyperglycemia group also showed impaired cognition in MORRIS watermaze, lower serum corticosterone level, and higher Serum ACTH concentration after 8 weeks. We inferred that the cognition impairment may be related to the abnormal expression of 11β-HSD1 and PPAR-γ in central nerves system. As for 11β-HSD1 is a regulating enzyme, converting the inactive 11-dehydrocorticosterone into the active glucocorticoid corticosterone, thus amplifying GC action in local tissues. It is also well known that high local GC levels can affect the cognitive function. In addition, PPAR-a protective receptor, which is related to cognition.

本文首先采用免疫组化方法观察恒定高血糖组、对照组和波动血糖组海马和下丘脑11β-HSD1和PPAR-γ的表达差异。然而,无论是11β-HSD1还是PPAR-γ的表达,在对照组和波动血糖组之间均无统计学差异。因此,我们去掉波动血糖组,只保留恒定高血糖组和对照组,饲喂8周。诱导8周后,Western Blot结果显示,与对照组相比,持续高血糖组海马和下丘脑11β-HSD1表达升高,PPAR-γ表达降低。持续高血糖组8周后MORRIS水迷宫认知功能受损,血清皮质酮水平降低,血清ACTH浓度升高。我们推测认知功能障碍可能与中枢神经系统11β-HSD1和PPAR-γ的异常表达有关。11β-HSD1是一种调节酶,将失活的11-脱氢皮质酮转化为活性的糖皮质激素皮质酮,从而放大局部组织的GC作用。众所周知,局部GC水平高会影响认知功能。此外,ppar是一种与认知有关的保护性受体。
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引用次数: 18
Effects of rosiglitazone with insulin combination therapy on oxidative stress and lipid profile in left ventricular muscles of diabetic rats. 罗格列酮与胰岛素联合治疗对糖尿病大鼠左心室肌氧化应激及血脂的影响。
Pub Date : 2012-01-01 Epub Date: 2012-07-05 DOI: 10.1155/2012/905683
Servet Kavak, Lokman Ayaz, Mustafa Emre

Purpose: In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation.

Methods and materials: Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mg kg(-1)), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3-nitrotyrosine levels in left ventricular muscle were measured.

Result: Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3-nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3-nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05).

Conclusion: Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective.

目的:在本研究中,我们验证了罗格列酮(RSG)和胰岛素能够通过预防NAD(P)H氧化酶激活来抑制高糖引起的氧化应激的假设。方法和材料:雄性白化Wistar大鼠随机分为未经治疗的对照组(C)、单次腹腔注射链脲佐菌素(45mg kg(-1))的糖尿病组(D)和每天两次灌胃RSG和每天一次皮下注射胰岛素的罗格列酮组(B组)。测定循环中HbA1c和血糖水平以及左心室肌中丙二醛和3-硝基酪氨酸水平。结果:用B组治疗D大鼠可使血糖呈时间依赖性下降。我们发现,B组大鼠的脂质状况和HbA1c水平在治疗期结束时达到了对照组D大鼠的值。与C组相比,D组的3-硝基酪氨酸水平升高。与D组相比,B组的丙二醛和3-硝基酪氨酸含量降低(P<0.05)。因此,在糖尿病相关的血管疾病中,B组治疗可能具有心脏保护作用。
{"title":"Effects of rosiglitazone with insulin combination therapy on oxidative stress and lipid profile in left ventricular muscles of diabetic rats.","authors":"Servet Kavak,&nbsp;Lokman Ayaz,&nbsp;Mustafa Emre","doi":"10.1155/2012/905683","DOIUrl":"10.1155/2012/905683","url":null,"abstract":"<p><strong>Purpose: </strong>In this study, we tested the hypothesis that rosiglitazone (RSG) with insulin is able to quench oxidative stress initiated by high glucose through prevention of NAD(P)H oxidase activation.</p><p><strong>Methods and materials: </strong>Male albino Wistar rats were randomly divided into an untreated control group (C), a diabetic group (D) that was treated with a single intraperitoneal injection of streptozotocin (45 mg kg(-1)), and rosiglitazone group that was treated with RSG twice daily by gavage and insulin once daily by subcutaneous injection (group B). HbA1c and blood glucose levels in the circulation and malondialdehyde and 3-nitrotyrosine levels in left ventricular muscle were measured.</p><p><strong>Result: </strong>Treatment of D rats with group B resulted in a time-dependent decrease in blood glucose. We found that the lipid profile and HbA1c levels in group B reached the control group D rat values at the end of the treatment period. There was an increase in 3-nitrotyrosine levels in group D compared to group C. Malondialdehyde and 3-nitrotyrosine levels were found to be decreased in group B compared to group D (P < 0.05).</p><p><strong>Conclusion: </strong>Our data suggests that the treatment of diabetic rats with group B for 8 weeks may decrease the oxidative/nitrosative stress in left ventricular tissue of rats. Thus, in diabetes-related vascular diseases, group B treatment may be cardioprotective.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"905683"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/905683","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30788562","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 7
The synergistic effect of valsartan and LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] on vascular oxidative stress and inflammation in type 2 diabetic mice. 缬沙坦与LAF237 [(S)-1-[(3-羟基-1-金刚烷基)弹药]乙酰-2-氰吡啶]对2型糖尿病小鼠血管氧化应激和炎症的协同作用。
Pub Date : 2012-01-01 Epub Date: 2012-03-15 DOI: 10.1155/2012/146194
Min Shen, Dongdong Sun, Weijie Li, Bing Liu, Shenxu Wang, Zheng Zhang, Feng Cao

Aim: To investigate the combination effects and mechanisms of valsartan (angiotensin II type 1 receptor blocker) and LAF237 (DPP-IV inhibitor) on prevention against oxidative stress and inflammation injury in db/db mice aorta.

Methods: Db/db mice (n = 40) were randomized to receive valsartan, LAF237, valsartan plus LAF237, or saline. Oxidative stress and inflammatory reaction in diabetic mice aorta were examined.

Results: Valsartan or LAF237 pretreatment significantly increased plasma GLP-1 expression, reduced apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NAD(P)H oxidase subunits also significantly decreased resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5 ± 0.7, P < 0.05; LAF237: 10.2 ± 1.7, P < 0.05), VCAM-1 (fold change: valsartan : 5.2 ± 1.2, P < 0.05; LAF237: 4.8 ± 0.6, P < 0.05), and MCP-1 (fold change: valsartan: 3.2 ± 0.6, LAF237: 4.7 ± 0.8; P < 0.05) expression. Moreover, the combination treatment with valsartan and LAF237 resulted in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction was also higher than monotherapy with valsartan or LAF237.

Conclusion: These data indicated that combination treatment with LAF237 and valsartan acts in a synergistic manner on vascular oxidative stress and inflammation in type 2 diabetic mice.

目的:探讨缬沙坦(血管紧张素II型1受体阻断剂)与LAF237 (DPP-IV抑制剂)联合应用对db/db小鼠主动脉氧化应激和炎症损伤的预防作用及机制。方法:40只Db/ Db小鼠随机接受缬沙坦、LAF237、缬沙坦+ LAF237或生理盐水治疗。观察糖尿病小鼠主动脉氧化应激和炎症反应。结果:缬沙坦或LAF237预处理可显著提高糖尿病小鼠主动脉内皮细胞GLP-1的表达,减少其凋亡。NAD(P)H氧化酶亚基的表达也显著降低,导致超氧化物生成和ICAM-1减少(倍数变化:缬沙坦:7.5±0.7,P < 0.05;LAF237: 10.2±1.7,P < 0.05), VCAM-1(折叠变化:缬沙坦:5.2±1.2,P < 0.05;LAF237: 4.8±0.6,P < 0.05), MCP-1(折叠变化:缬沙坦:3.2±0.6,LAF237: 4.7±0.8;P < 0.05)表达。缬沙坦与LAF237联合治疗GLP-1表达升高更为显著。血管氧化应激和炎症反应的降低也高于缬沙坦或LAF237单药治疗。结论:LAF237联合缬沙坦对2型糖尿病小鼠血管氧化应激和炎症有协同作用。
{"title":"The synergistic effect of valsartan and LAF237 [(S)-1-[(3-hydroxy-1-adamantyl)ammo]acetyl-2-cyanopyrrolidine] on vascular oxidative stress and inflammation in type 2 diabetic mice.","authors":"Min Shen,&nbsp;Dongdong Sun,&nbsp;Weijie Li,&nbsp;Bing Liu,&nbsp;Shenxu Wang,&nbsp;Zheng Zhang,&nbsp;Feng Cao","doi":"10.1155/2012/146194","DOIUrl":"https://doi.org/10.1155/2012/146194","url":null,"abstract":"<p><strong>Aim: </strong>To investigate the combination effects and mechanisms of valsartan (angiotensin II type 1 receptor blocker) and LAF237 (DPP-IV inhibitor) on prevention against oxidative stress and inflammation injury in db/db mice aorta.</p><p><strong>Methods: </strong>Db/db mice (n = 40) were randomized to receive valsartan, LAF237, valsartan plus LAF237, or saline. Oxidative stress and inflammatory reaction in diabetic mice aorta were examined.</p><p><strong>Results: </strong>Valsartan or LAF237 pretreatment significantly increased plasma GLP-1 expression, reduced apoptosis of endothelial cells isolated from diabetic mice aorta. The expression of NAD(P)H oxidase subunits also significantly decreased resulting in decreased superoxide production and ICAM-1 (fold change: valsartan : 7.5 ± 0.7, P < 0.05; LAF237: 10.2 ± 1.7, P < 0.05), VCAM-1 (fold change: valsartan : 5.2 ± 1.2, P < 0.05; LAF237: 4.8 ± 0.6, P < 0.05), and MCP-1 (fold change: valsartan: 3.2 ± 0.6, LAF237: 4.7 ± 0.8; P < 0.05) expression. Moreover, the combination treatment with valsartan and LAF237 resulted in a more significant increase of GLP-1 expression. The decrease of the vascular oxidative stress and inflammation reaction was also higher than monotherapy with valsartan or LAF237.</p><p><strong>Conclusion: </strong>These data indicated that combination treatment with LAF237 and valsartan acts in a synergistic manner on vascular oxidative stress and inflammation in type 2 diabetic mice.</p>","PeriodicalId":12109,"journal":{"name":"Experimental Diabetes Research","volume":"2012 ","pages":"146194"},"PeriodicalIF":0.0,"publicationDate":"2012-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1155/2012/146194","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30549909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 11
L(+) and D(-) lactate are increased in plasma and urine samples of type 2 diabetes as measured by a simultaneous quantification of L(+) and D(-) lactate by reversed-phase liquid chromatography tandem mass spectrometry. 通过反相液相色谱串联质谱同时定量L(+)和D(-)乳酸测定,2型糖尿病患者血浆和尿液样品中的L(+)和D(-)乳酸增加。
Pub Date : 2012-01-01 Epub Date: 2012-03-08 DOI: 10.1155/2012/234812
Jean L J M Scheijen, Nordin M J Hanssen, Marjo P H van de Waarenburg, Daisy M A E Jonkers, Coen D A Stehouwer, Casper G Schalkwijk

Background: Plasma and urinary levels of D-lactate have been linked to the presence of diabetes. Previously developed techniques have shown several limitations to further evaluate D-lactate as a biomarker for this condition.

Methods: D- and L-lactate were quantified using ultraperformance liquid chromatography tandem mass spectrometry with labelled internal standard. Samples were derivatized with diacetyl-L-tartaric anhydride and separated on a C(18)-reversed phase column. D- and L-lactate were analysed in plasma and urine of controls, patients with inflammatory bowel disease (IBD), and patients with type 2 diabetes (T2DM).

Results: Quantitative analysis of D- and L-lactate was achieved successfully. Calibration curves were linear (r(2) > 0.99) over the physiological and pathophysiological ranges. Recoveries for urine and plasma were between 96% and 113%. Inter- and intra-assay variations were between 2% and 9%. The limits of detection of D-lactate and L-lactate in plasma were 0.7 μmol/L and 0.2 μmol/L, respectively. The limits of detection of D-lactate and L-lactate in urine were 8.1 nmol/mmol creatinine and 4.4 nmol/mmol creatinine, respectively. Plasma and urinary levels of D- and L-lactate were increased in patients with IBD and T2DM as compared with controls.

Conclusion: The presented method proved to be suitable for the quantification of D- and L-lactate and opens the possibility to explore the use of D-lactate as a biomarker.

背景:血浆和尿中d -乳酸水平与糖尿病有关。先前开发的技术在进一步评估d -乳酸作为这种疾病的生物标志物方面显示出一些局限性。方法:采用内标超高效液相色谱串联质谱法定量测定D-乳酸和l -乳酸。样品用二乙酰- l-酒石酸酐衍生,在C(18)反相柱上分离。分析了对照组、炎症性肠病(IBD)患者和2型糖尿病(T2DM)患者血浆和尿液中的D-和l -乳酸。结果:D-和l -乳酸的定量分析成功。校正曲线在生理和病理生理范围内呈线性关系(r(2) > 0.99)。尿液和血浆的回收率在96% ~ 113%之间。测定间和测定内的变异在2%到9%之间。血浆中d -乳酸和L-乳酸的检出限分别为0.7 μmol/L和0.2 μmol/L。尿中d -乳酸和l -乳酸的检出限分别为8.1 nmol/mmol肌酐和4.4 nmol/mmol肌酐。与对照组相比,IBD和T2DM患者血浆和尿中D-和l -乳酸水平升高。结论:该方法适用于D-乳酸和l -乳酸的定量测定,为D-乳酸作为生物标志物的应用开辟了可能性。
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引用次数: 71
The effects of green tea consumption on cardiometabolic alterations induced by experimental diabetes. 绿茶对实验性糖尿病引起的心脏代谢改变的影响。
Pub Date : 2012-01-01 Epub Date: 2012-02-29 DOI: 10.1155/2012/309231
Patricia Fiorino, Fabiana Sant'Anna Evangelista, Fernando Santos, Fátima Maria Motter Magri, Jan Carlo Morais O B Delorenzi, Milton Ginoza, Vera Farah

We evaluated cardiac autonomic modulation by heart rate (HRV), and arterial pressure variability (APV), and metabolic response in streptozotocin diabetic rats treated with green tea. Male Wistar rats were separated in groups: control, drinking tap water (C), green tea-treated (GT) group, diabetic, drinking tap water (D), and diabetic, treated with green tea (DGT). Kidney mass was greater in D and DGT than in C and GT, but reduced in DGT compared to D. Green tea prevented the increase in creatinine clearance and reduced hyperglycemia in DGT compared to D. Arterial pressure was increased in GT and decreased in D compared to C. HRV was reduced in D compared with all groups. APV was decreased in D compared to C and recovery in DGT. Sympathetic modulation of APV was decreased in D compared with all groups. Green tea reduced hyperglycemia, prevented renal injury and autonomic dysfunction, suggesting reduced cardiovascular risk and target organ damage in diabetes.

我们通过心率(HRV)、动脉压变异性(APV)和绿茶治疗链脲佐菌素糖尿病大鼠的代谢反应来评估心脏自主调节。雄性Wistar大鼠分为对照组,饮用自来水组(C),绿茶处理组(GT),糖尿病组,饮用自来水组(D),糖尿病组,绿茶处理(DGT)。与C组和GT组相比,D组和DGT组的肾体积更大,但与D组相比,DGT组的肾体积更小。绿茶阻止了DGT组肌酐清除率的增加,并降低了DGT组的高血糖。与D组相比,GT组的动脉压升高,D组的血压降低。与C相比,D组APV降低,DGT组APV恢复。与各组比较,D组APV交感调节减弱。绿茶可以降低高血糖,预防肾损伤和自主神经功能障碍,表明可以降低糖尿病患者的心血管风险和靶器官损伤。
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引用次数: 18
TXNIP links innate host defense mechanisms to oxidative stress and inflammation in retinal Muller glia under chronic hyperglycemia: implications for diabetic retinopathy. TXNIP将先天宿主防御机制与慢性高血糖下视网膜Muller胶质细胞的氧化应激和炎症联系起来:对糖尿病视网膜病变的影响。
Pub Date : 2012-01-01 Epub Date: 2012-03-18 DOI: 10.1155/2012/438238
Takhellambam S Devi, Icksoo Lee, Maik Hüttemann, Ashok Kumar, Kwaku D Nantwi, Lalit P Singh

Thioredoxin Interacting Protein (TXNIP) mediates retinal inflammation, gliosis, and apoptosis in experimental diabetes. Here, we investigate the temporal response of Muller glia to high glucose (HG) and TXNIP expression using a rat Muller cell line (rMC1) in culture. We examined if HG-induced TXNIP expression evokes host defense mechanisms in rMC1 in response to metabolic abnormalities. HG causes sustained up-regulation of TXNIP (2 h to 5 days), ROS generation, ATP depletion, ER stress, and inflammation. Various cellular defense mechanisms are activated by HG: (i) NLRP3 inflammasome, (ii) ER stress response (sXBP1), (iii) hypoxic-like HIF-1α induction, (iv) autophagy/mitophagy, and (v) apoptosis. We also found in vivo that streptozocin-induced diabetic rats have higher retinal TXNIP and innate immune response gene expression than normal rats. Knock down of TXNIP by intravitreal siRNA reduces inflammation (IL-1β) and gliosis (GFAP) in the diabetic retina. TXNIP ablation in vitro prevents ROS generation, restores ATP level and autophagic LC3B induction in rMC1. Thus, our results show that HG sustains TXNIP up-regulation in Muller glia and evokes a program of cellular defense/survival mechanisms that ultimately lead to oxidative stress, ER stress/inflammation, autophagy and apoptosis. TXNIP is a potential target to ameliorate blinding ocular complications of diabetic retinopathy.

硫氧还蛋白相互作用蛋白(TXNIP)介导实验性糖尿病视网膜炎症、胶质瘤和细胞凋亡。在这里,我们利用培养的大鼠Muller细胞系(rMC1)研究Muller胶质细胞对高糖(HG)和TXNIP表达的时间反应。我们研究了hg诱导的TXNIP表达是否在rMC1中引起宿主防御机制,以应对代谢异常。HG引起TXNIP持续上调(2小时至5天)、ROS生成、ATP消耗、内质网应激和炎症。HG可激活多种细胞防御机制:(i) NLRP3炎性体,(ii)内质网应激反应(sXBP1), (iii)缺氧样HIF-1α诱导,(iv)自噬/有丝自噬,(v)细胞凋亡。我们在体内也发现链脲佐菌素诱导的糖尿病大鼠视网膜TXNIP和先天免疫反应基因表达高于正常大鼠。通过玻璃体内siRNA敲低TXNIP可减少糖尿病视网膜的炎症(IL-1β)和胶质细胞增生(GFAP)。体外TXNIP消融可抑制ROS生成,恢复rMC1的ATP水平和自噬LC3B诱导。因此,我们的研究结果表明,HG维持Muller神经胶质中TXNIP的上调,并引发细胞防御/生存机制程序,最终导致氧化应激、内质网应激/炎症、自噬和凋亡。TXNIP是改善糖尿病视网膜病变致盲性眼部并发症的潜在靶点。
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引用次数: 181
期刊
Experimental Diabetes Research
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