International journal of experimental diabetes research最新文献

英文中文

Markers for Risk of Type 1 Diabetes in Relatives of Alsacian Patients With Type 1 Diabetes 阿尔萨斯1型糖尿病患者亲属中1型糖尿病风险的标志物

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212527

J. Ongagna, R. Sapin, M. Pinget, A. Belcourt

Background: The cytotoxic T lymphocyteassociated antigen 4 gene (CTLA-4) encode the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. The receptor protein is a specific T lymphocyte surface antigen that is detected on cells only after antigen presentation. Thus, CTLA-4 is directly involved in both immune and autoimmune responses and may be involved in the pathogenesis of multiple T cell-mediated autoimmune disorders. There is polymorphism at position 49 in exon 1 of the CTLA-4 gene, providing an A-G exchange. Moreover, we assessed the CTLA-4 49 (Thr/Ala) polymorphism in diabetic patients and first-degree relatives as compared to control subjects. Research design and methods: Three loci (HLA-DQB1, DQA1 and CTLA-4) were analysed in 62 type 1 diabetic patients, 72 firstdegree relatives and 84 nondiabetic control subjects by means of PCR-RFLP. Results: A significant enrichment in DQB1 alleles encoding for an amino acid different from Asp in position 57 (NA) and DQA1 alleles encoding for Arg in position 52 was observed in diabetic subjects and first-degree relatives as compared to controls. The genotype and allele frequencies of these polymorphisms in type 1 diabetic patients and firstdegree relatives differed significantly from those of controls (p< 0.001 and 0.05 respectively). CTLA-49 Ala alleles frequencies were 75.8% in type 1 diabetic patients and 68.1% in first-degree relatives in comparison to 35.7% in control subjects. The Ala/Ala genotype conferred a relative risk of 18.8 (p < 0.001). Conclusion: The CTLA-4 49 Ala allele confers an increased risk of type 1 diabetes, independent of age and HLA-DQ genetic markers.

背景:细胞毒性T淋巴细胞相关抗原4基因(CTLA-4)编码T细胞受体，参与控制T细胞增殖和介导T细胞凋亡。受体蛋白是一种特异性的T淋巴细胞表面抗原，只有在抗原呈递后才能在细胞上检测到。因此，CTLA-4直接参与免疫和自身免疫反应，并可能参与多种T细胞介导的自身免疫性疾病的发病机制。CTLA-4基因外显子1第49位存在多态性，提供A-G交换。此外，与对照组相比，我们评估了糖尿病患者和一级亲属的ctla - 449 (Thr/Ala)多态性。研究设计与方法:采用PCR-RFLP方法对62例1型糖尿病患者、72例一级亲属和84例非糖尿病对照者的HLA-DQB1、DQA1和CTLA-4 3个基因座进行分析。结果:与对照组相比，糖尿病患者及其一级亲属的DQB1等位基因在57位(NA)上编码与Asp不同的氨基酸，DQA1等位基因在52位(NA)上编码精氨酸。1型糖尿病患者及其一级亲属的基因型和等位基因频率与对照组差异有统计学意义(p< 0.001和0.05)。CTLA-49等位基因频率在1型糖尿病患者中为75.8%，在一级亲属中为68.1%，而对照组为35.7%。Ala/Ala基因型的相对危险度为18.8 (p < 0.001)。结论:ctla - 449ala等位基因增加了1型糖尿病的风险，与年龄和HLA-DQ遗传标记无关。

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引用次数: 13

D-Chiro-Inositol – Its Functional Role in Insulin Action and its Deficit in Insulin Resistance d -氨基肌醇在胰岛素作用中的功能作用及其在胰岛素抵抗中的缺陷

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212528

J. Larner,

In this review we discuss the biological significance of D-chiro-inositol, originally discovered as a component of a putative mediator of intracellular insulin action, where as a putative mediator, it accelerates the dephosphorylation of glycogen synthase and pyruvate dehydrogenase, rate limiting enzymes of non-oxidative and oxidative glucose disposal. Early studies demonstrated a linear relationship between its decreased urinary excretion and the degree of insulin resistance present. When tissue contents, including muscle, of type 2 diabetic subjects were assayed, they demonstrated a more general body deficiency. Administration of D-chiro-inositol to diabetic rats, Rhesus monkeys and now to humans accelerated glucose disposal and sensitized insulin action. A defect in vivo in the epimerization of myoinositol to chiro-inositol in insulin sensitive tissues of the GK type 2 diabetic rat has been elucidated. Thus, administered D-chiro-inositol may act to bypass a defective normal epimerization of myo-inositol to D-chiro-inositol associated with insulin resistance and act to at least partially restore insulin sensitivity and glucose disposal.

在这篇综述中，我们讨论了d -氨基肌醇的生物学意义，它最初被认为是细胞内胰岛素作用的一种介质，作为一种假定的介质，它加速了糖原合成酶和丙酮酸脱氢酶的去磷酸化，这些酶是非氧化性和氧化性葡萄糖处理的限速酶。早期研究表明，尿量减少与胰岛素抵抗程度呈线性关系。当对2型糖尿病患者的组织内容物(包括肌肉)进行分析时，他们表现出更普遍的身体缺陷。给糖尿病大鼠、恒河猴和现在给人注射d -氨基肌醇加速了葡萄糖的处理，并使胰岛素的作用变得敏感。GK型2型糖尿病大鼠胰岛素敏感组织肌肌醇向手性肌醇的外显体化在体内存在缺陷。因此，给药的d -手性肌醇可以绕过与胰岛素抵抗相关的肌醇向d -手性肌醇的正常外显异构化缺陷，并至少部分恢复胰岛素敏感性和葡萄糖处理。

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引用次数: 252

Growth Factor-Dependent Proliferation of the Pancreatic β-cell Line βTC-tet: An Assay for β-cell Mitogenic Factors 胰腺β-细胞系βTC-tet生长因子依赖性增殖:β-细胞有丝分裂因子测定

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212526

D. Milo-Landesman, S. Efrat

The ability to expand normal pancreatic islet β cells in culture would significantly advance the prospects of cell therapy for diabetes. A number of growth factors can stimulate limited islet cell replication, however other factors may exist which are more effective β-cell-specific mitogens. The search for novel β-cell growth factors has been hampered by the lack of a β-cell-specific proliferation assay. We developed a simple and sensitive assay for β-cell growth factors based on a conditionally-transformed mouse β-cell line (βTC-tet). These cells express the SV40 T antigen (Tag) oncoprotein under control of the tetracycline (Tc) operon regulatory system. In the presence of Tc, Tag expression is tightly shut off and the cells undergo complete growth arrest. Here we show that the growth-arrested cells can proliferate in response to growth factors in the absence of Tag. Using this assay, a number of growth factors previously shown to be mitogenic to a mixed islet cell population were found to induce proliferation of pure β cells. We conclude that growth-arrested βTC-tet cells can be employed in a survey of factors from various sources for identifying novel factors with β-cell mitogenic activity.

在培养中扩增正常胰岛β细胞的能力将显著推进糖尿病细胞治疗的前景。许多生长因子可以刺激有限的胰岛细胞复制，但可能存在其他更有效的β细胞特异性丝裂原。由于缺乏β细胞特异性增殖试验，寻找新的β细胞生长因子一直受到阻碍。我们基于条件转化小鼠β细胞系(βTC-tet)开发了一种简单、灵敏的β细胞生长因子检测方法。这些细胞在四环素(Tc)操纵子调控系统的控制下表达SV40 T抗原(Tag)癌蛋白。在Tc的存在下，Tag的表达被紧密关闭，细胞完全停止生长。在这里，我们表明生长受阻的细胞可以在缺乏Tag的情况下对生长因子作出反应。使用该试验，许多生长因子先前被证明是有丝分裂的混合胰岛细胞群被发现可以诱导纯β细胞的增殖。我们得出的结论是，生长受阻的βTC-tet细胞可以用于各种来源的因子调查，以确定具有β细胞有丝分裂活性的新因子。

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引用次数: 11

Effect of Treating Streptozotocin-Induced Diabetic Rats With Sorbinil, Myo-Inositol or Aminoguanidine on Endoneurial Blood Flow, Motor Nerve Conduction Velocity and Vascular Function of Epineurial Arterioles of the Sciatic Nerve 山梨比尼、肌醇和氨基胍治疗链脲佐菌素诱导的糖尿病大鼠对坐骨神经神经外动脉血流、运动神经传导速度和血管功能的影响

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212525

L. Coppey, J. S. Gellett, E. Davidson, J. Dunlap, M. Yorek

Previously we have demonstrated that diabetes causes impairment in vascular function of epineurial vessels, which precedes the slowing of motor nerve conduction velocity. Treatment of diabetic rats with aldose reductase inhibitors, aminoguanidine or myo-inositol supplementation have been shown to improve motor nerve conduction velocity and/or decreased endoneurial blood flow. However, the effect these treatments have on vascular reactivity of epineurial vessels of the sciatic nerve is unknown. In these studies we examined the effect of treating streptozotocininduced rats with sorbinil, aminoguanidine or myo-inositol on motor nerve conduction velocity, endoneurial blood flow and endothelium dependent vascular relaxation of arterioles that provide circulation to the region of the sciatic nerve. Treating diabetic rats with sorbinil, aminoguanidine or myo-inositol improved the reduction of endoneurial blood flow and motor nerve conduction velocity. However, only sorbinil treatment significantly improved the diabetes-induced impairment of acetylcholinemediated vasodilation of epineurial vessels of the sciatic nerve. All three treatments were efficacious in preventing the appropriate metabolic derangements associated with either activation of the polyol pathway or increased nonenzymatic glycation. In addition, sorbinil was shown to prevent the diabetes-induced decrease in lens glutathione level. However, other markers of oxidative stress were not vividly improved by these treatments. These studies suggest that sorbinil treatment may be more effective in preventing neural dysfunction in diabetes than either aminoguanidine or myoinositol.

先前我们已经证明糖尿病会导致神经外膜血管功能的损害，这先于运动神经传导速度的减慢。用醛糖还原酶抑制剂、氨基胍或肌醇补充剂治疗糖尿病大鼠已被证明可以改善运动神经传导速度和/或减少神经内膜血流量。然而，这些治疗对坐骨神经神经外血管反应性的影响尚不清楚。在这些研究中，我们检测了用山梨比尼、氨基胍或肌醇治疗链脲毒素诱导的大鼠对运动神经传导速度、神经内膜血流量和为坐骨神经区域提供循环的小动脉内皮依赖性血管松弛的影响。山梨醇、氨基胍或肌醇治疗糖尿病大鼠，可改善神经内膜血流量和运动神经传导速度的减少。然而，只有山梨醇治疗能显著改善糖尿病引起的乙酰胆碱介导的坐骨神经神经外膜血管舒张损伤。所有三种治疗方法都有效地预防了与多元醇途径激活或非酶糖基化增加相关的适当代谢紊乱。此外，山梨醇可预防糖尿病引起的晶状体谷胱甘肽水平下降。然而，这些处理并没有明显改善氧化应激的其他指标。这些研究表明，山梨醇治疗在预防糖尿病神经功能障碍方面可能比氨基胍或肌醇更有效。

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引用次数: 79

A Note of Thanks to Our Reviewers 感谢我们的审稿人

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280214486

thanks to the reviewers of papers published in the first two volumes of the Journal. Critical but fair reviews by experts in the various fields of diabetes research has and will be pivotal to the quality and success of the journal. It is a time consuming exercise in colleague’s often busy routine that they volunteer. We are therefore thankful for their time and expertise that have, in no small measures, contributed to two successful initial years of the Journal.

引用次数: 0

Effect of Aldose Reductase Inhibition on Interleukin-1β-Induced Nitric Oxide (NO) Synthesis in Vascular Tissue 醛糖还原酶抑制对白细胞介素-1β诱导的血管组织一氧化氮合成的影响

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212523

J. Morales, J. Dunbar, J. Ram

Glucose metabolism via sorbitol pathway has been implicated as a possible contributor to the diabetes-related vascular changes. Nitric oxide plays a major regulatory role in the vascular dilatatory and constricted response. Also it has been observed that diabetes causes vascular changes leading to a decrease in nitric oxide production. Additionally the accumulation of sorbitol is also related to decreased nitric oxide production. In the present study we investigated the effect of normal and high glucose in the presence or absence of both interleukin-1β or an aldose reductase inhibitor on nitric oxide production in rat aortic rings in vitro. Aortic rings from normal male Wistar rats were dissected and incubated for 24 to 48 hrs in the presence of glucose (5.0 mM or 20 mM) or with or without interleukin (20 ng/ml). Other rings were incubated in the above media with the addition of the aldose reductase inhibitor (WAY 121509). Interleukin-1β stimulated the 24 hr nitric oxide production and WAY 121509 decreased it under both low and high glucose culture conditions. The interleukin-1β stimulation was continued for 72 hrs. Nitric oxide production in response to interleukin-1β was greater at all time points when compared to the incubation in media without interleukin-1β. In media containing WAY 121509 the nitric oxide production was decreased. Interleukin-1β stimulated a greater increase in nitric oxide production from aortic rings when incubated in high glucose when compared to normal glucose. The inhibitory effect of aldose reductase inhibition was reversible after 24 hr inhibition under both normal and high glucose conditions. We conclude that high glucose enhances the interleukin- 1β-induced nitric oxide synthesis and the cytokine-induced nitric oxide production was inhibited by aldose reductase inhibition. Nitric oxide production may be linked to redox influences caused by the polyol pathway.

通过山梨醇途径的葡萄糖代谢被认为是糖尿病相关血管改变的可能因素。一氧化氮在血管扩张和收缩反应中起着重要的调节作用。此外，据观察，糖尿病引起血管变化，导致一氧化氮的产生减少。此外，山梨糖醇的积累也与一氧化氮产生的减少有关。在本研究中，我们研究了在存在或不存在白细胞介素-1β或醛糖还原酶抑制剂的情况下，正常和高葡萄糖对体外大鼠主动脉环一氧化氮生成的影响。解剖正常雄性Wistar大鼠主动脉环，在葡萄糖(5.0 mM或20 mM)、白介素(20 ng/ml)和不含白介素的条件下孵育24 ~ 48小时。其他环在加入醛糖还原酶抑制剂(WAY 121509)的培养基中孵育。白细胞介素-1β刺激了24小时一氧化氮的产生，而WAY 121509在低糖和高糖培养条件下均降低了一氧化氮的产生。白细胞介素-1β刺激持续72小时。与不含白细胞介素-1β的培养基孵育相比，白细胞介素-1β对一氧化氮产生的反应在所有时间点都更大。在含有WAY 121509的培养基中，一氧化氮的产量降低。与正常葡萄糖相比，白细胞介素-1β在高葡萄糖条件下刺激主动脉环产生的一氧化氮增加更多。在正常和高糖条件下，醛糖还原酶抑制24小时后的抑制作用是可逆的。我们得出结论，高糖增强了白细胞介素- 1β诱导的一氧化氮合成，而醛糖还原酶抑制了细胞因子诱导的一氧化氮生成。一氧化氮的产生可能与多元醇途径引起的氧化还原影响有关。

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引用次数: 5

The Non-Immune RIP-kb Mouse is a Useful Host for Islet Transplantation, as the Diabetes is Spontaneous, Mild and Predictable 非免疫RIP-kb小鼠是胰岛移植的有效宿主，因为糖尿病是自发性的、轻度的和可预测的

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280212530

R. Sutherland, Joanne N. Mountford, J. Allison, L. Harrison, A. Lew

Chemically-induced diabetic mice and spontaneously diabetic NOD mice have been valuable as recipients for experimental islet transplantation. However, their maintenance often requires parenteral insulin. Diabetogenic chemicals can be cytotoxic to the host’s immune system and to other organs some of which are often used as the transplant site. Procurement of diabetic cohorts in the NOD mouse is problematic due to variability in the age of disease onset. We show that RIP-Kb mice, which spontaneously develop non-immune diabetes due to over-expression of the H-2Kb heavy chain in beta cells, offer many advantages as islet transplant recipients. Diabetes is predictable with a relatively narrow range of onset (4 wk) and blood glucose levels (23.0± 4.0 mmol/l for 39 males at 6 weeks of age). The diabetes is mild enough so that most diabetic mice can be maintained to 40 weeks of age without parenteral insulin. This consistency of diabetes avails that outcomes of intervention can be interpreted with confidence.

化学诱导的糖尿病小鼠和自发性糖尿病NOD小鼠作为实验性胰岛移植的受体是有价值的。然而，它们的维持通常需要注射胰岛素。致糖尿病化学物质可能对宿主的免疫系统和其他器官具有细胞毒性，其中一些器官经常被用作移植部位。由于疾病发病年龄的差异，在NOD小鼠中获取糖尿病队列是有问题的。我们发现，由于β细胞中H-2Kb重链的过度表达而自发发展为非免疫性糖尿病的RIP-Kb小鼠作为胰岛移植受体具有许多优势。糖尿病可预测，发病范围相对较窄(4周)，血糖水平(39例6周龄男性23.0±4.0 mmol/l)。糖尿病很轻微，因此大多数糖尿病小鼠可以在不注射胰岛素的情况下维持到40周龄。糖尿病的这种一致性使得干预的结果可以有信心地解释。

引用次数: 10

Renal AT1 Receptor Protein Expression During the Early Stage of Diabetes Mellitus 糖尿病早期肾脏AT1受体蛋白的表达

International journal of experimental diabetes research

Pub Date : 2002-01-01 DOI: 10.1080/15604280214483

L. Harrison-Bernard, J. Imig, P. Carmines

Experiments were performed to evaluate the hypothesis that the early stage of Type 1 diabetes mellitus (DM) increases renal angiotensin II (AngII) concentration and angiotensin type 1 (AT1) receptor protein levels. Nineteen or twenty days after vehicle (Sham rats) or streptozotocin (STZ rats) treatment, plasma [AngII] was higher in STZ rats (152±23 fmol/ml) than in Sham rats (101±7 fmol/ml); however, kidney [AngII] did not differ between groups. AT1 receptor protein expression was greater in STZ kidneys than in Sham kidneys. This increase was restricted to the cortex, where AT1 protein levels were elevated by 77±26% (42 kDa) and 101±16% (58 kDa) in STZ kidneys. Immunohistochemistry revealed this effect to be most evident in distal nephron segments including the connecting tubule/cortical collecting duct. Increased renal cortical AT1 receptor protein and circulating AngII levels are consistent with an exaggerated AngII-dependent influence on renal function during the early stage of DM in the rat.

我们通过实验验证了1型糖尿病(DM)早期升高肾血管紧张素II (AngII)浓度和血管紧张素1型(AT1)受体蛋白水平的假设。给药19、20 d后，STZ大鼠血浆[AngII]含量(152±23 fmol/ml)高于Sham大鼠(101±7 fmol/ml);然而，肾脏[AngII]在两组之间没有差异。AT1受体蛋白在STZ肾中的表达高于Sham肾。这种增加仅限于皮质，在STZ肾脏中，AT1蛋白水平升高了77±26% (42 kDa)和101±16% (58 kDa)。免疫组织化学显示，这种影响在包括连接小管/皮质集管在内的远端肾元段最为明显。肾皮质AT1受体蛋白和循环AngII水平的升高与大鼠DM早期血管依赖性对肾功能的过度影响一致。

引用次数: 42

Streptozocin diabetes elevates all isoforms of TGF-beta in the rat kidney. 链脲佐菌素糖尿病会升高大鼠肾脏中tgf - β的所有亚型。

International journal of experimental diabetes research

Pub Date : 2001-01-01 DOI: 10.1155/edr.2001.55

P H Lane, D M Snelling, W J Langer

Transforming growth factor beta (TGF-beta) is a major promoter of diabetic nephropathy. While TGF-beta1 is the most abundant renal isoform, types 2 and 3 are present as well and have identical in vitro effects. Whole kidney extracts were studied 2 weeks after induction of streptozocin diabetes and in control rats. Mean glomerular area was 25% greater in the diabetic animals. TGF-beta1 showed a 2-fold increase in message with a 3-fold increase in protein. TGF-beta2 mRNA increased approximately 6% while its protein doubled. TGF-beta-message increased by 25%, producing a 35% increase in its protein. TGF-beta-inducible gene H3 mRNA was increased 35% in the diabetic animals, consistent with increased activity of this growth factor. All isoforms of TGF-beta are increased in the diabetic rat kidney. Future studies need to address the specific role that each isoform plays in diabetic nephropathy as well as the impact of therapies on each isoform.

转化生长因子β (tgf - β)是糖尿病肾病的主要促进因子。虽然tgf - β是最丰富的肾脏亚型，但2型和3型也存在，并且在体外具有相同的作用。全肾提取物在链脲佐菌素诱导糖尿病2周后和对照大鼠进行研究。糖尿病动物的平均肾小球面积增加了25%。tgf - β 1的信息增加了2倍，蛋白质增加了3倍。tgf - β 2 mRNA增加约6%，其蛋白增加一倍。tgf - β信息增加了25%，使其蛋白质增加了35%。tgf - β诱导基因H3 mRNA在糖尿病动物中升高35%，与该生长因子活性升高一致。所有tgf - β亚型在糖尿病大鼠肾脏中均升高。未来的研究需要解决每种异构体在糖尿病肾病中的具体作用，以及治疗对每种异构体的影响。

引用次数: 16

Islet cell antibodies represent autoimmune response against several antigens. 胰岛细胞抗体代表针对几种抗原的自身免疫反应。

International journal of experimental diabetes research

Pub Date : 2001-01-01 DOI: 10.1155/edr.2001.85

L Månsson, C Törn, M Landin-Olsson

To study the antigens involved in the islet cell antibody (ICA) reaction we selected 30 patient serum samples (ten in each group) positive for ICA and one other additional autoantibody, such as glutamic acid decarboxylase antibodies (GADA), thyrosine phosphatase antibodies (IA-2A) or insulin autoantibodies (IAA). The serum samples were incubated with the specific antigen (GAD65, IA-2 or insulin) and the ICA analysis and the corresponding immunoprecipitation assay were performed before and after the absorption. We could then demonstrate that specific autoantibodies against GAD65 and IA-2 could be absorbed with the corresponding antigen, since ten GADA positive and six IA-2A samples turned completely negative. However, the ICA reaction after absorption with GADA, IA-2A and insulin was still present, although at significantly lower levels. The results strongly indicate that the ICA reaction represents simultaneous autoimmunity against several other antigens beside GAD65, IA-2 and insulin.

为了研究胰岛细胞抗体(ICA)反应所涉及的抗原，我们选择了30例(每组10例)ICA阳性的患者血清样本和另外一种自身抗体，如谷氨酸脱羧酶抗体(GADA)、甲状腺氨酸磷酸酶抗体(IA-2A)或胰岛素自身抗体(IAA)。将血清样品与特异性抗原(GAD65、IA-2或胰岛素)孵育，吸收前后分别进行ICA分析和相应的免疫沉淀试验。然后我们可以证明针对GAD65和IA-2的特异性自身抗体可以被相应的抗原吸收，因为10个GADA阳性和6个IA-2A完全阴性。然而，与GADA、IA-2A和胰岛素吸收后的ICA反应仍然存在，尽管水平明显降低。结果强烈表明，除了GAD65、IA-2和胰岛素外，ICA反应同时代表了对其他几种抗原的自身免疫。

引用次数: 19

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