Elevated catalase and heme oxygenase-1 may contribute to improved postischaemic cardiac function in long-term type 1 diabetes

1. Although increased oxidative stress has been shown repeatedly to be implicated in diabetes, the cardiovascular anti-oxidant state and heart response to ischaemia in long-term Type 1 diabetes remain largely unknown. The present study was designed to observe heart tolerance to ischaemia-reperfusion and endogenous anti-oxidants in the cardiovascular system in long-term hyperglycaemic rats. 2. Hearts from Sprague-Dawley rats surviving up to 6 months with streptozocin-induced severe hyperglycaemia (blood glucose > 20 mmol/L) were isolated and subjected to global ischaemia and reperfusion. Cardiac function, electrocardiogram and anti-oxidants in the myocardium and aorta were examined. In addition, the morphology of the myocardial mitochondria and the in vitro function of aortic vessels were assessed. 3. Hearts from diabetic rats demonstrated lower baseline heart function but had higher postischaemic coronary flow and left ventricular developed pressure compared with their respective controls (P < 0.05). In addition, hearts from diabetic animals had fewer arrhythmias (P < 0.01) and lower left ventricular end-diastolic pressure during reperfusion (P < 0.05). Higher catalase and heme oxygenase-1 content was found in the aorta and myocardium from diabetic rats (P < 0.01). In aortas from diabetic animals, acetylcholine-induced vasodilatation was enhanced and was approximately 15% after inhibition of nitric oxide synthase, compared with 0% in controls. The 15% relaxation was abrogated by heme oxygenase blockade. Mitochondria from the myocardium of diabetic rats showed significant increases in both size and number (P < 0.05). 4. Hearts of long-term Type 1 diabetic rats demonstrated improved recovery of postischaemic cardiac function and reduced reperfusion arrhythmia. Hyperglycaemia may enhance cardiovascular anti-oxidant capacity and mitochondrial neogenesis, which renders the heart resistant to ischaemia and oxidative injury.     

暴发性1型糖尿病与经典1型糖尿病临床特征比较

目的：分析暴发性1型糖尿病（fulminant type 1 diabetes,FT1 DM）与经典1型糖尿病（T1 DM）的临床特征,以指导临床治疗。方法回顾性分析该院内分泌科2008年12月—2014年8月间以酮症酸中毒起病的暴发型1型糖尿病患者9例（FT1DM组）和初诊经典1型糖尿病患者23例（T1 DM组）的临床特征,包括起病时间、年龄、性别、体重指数、流感样症状、妊娠人数、腹痛、入院时随机血糖、糖化血红蛋白、C肽、肌酐、血钾、动脉血pH、白细胞计数等,并用t检验和χ2检验分别对计量资料和计数资料进行统计分析。结果与经典1型糖尿病相比,暴发性1型糖尿病的年龄较大,起病时间明显缩短,入院时血糖更高,糖化血红蛋白较低,胰岛功能更差,血糖达标时间延长,妊娠期女性更多（P＜0．05）;暴发性1型糖尿病组患者较经典1型糖尿病组患者入院时肌酐及谷草转氨酶显著升高,血钠水平降低,酸中毒明显（均P＜0．05或P＜0．01）。结论暴发性1型糖尿病患者起病更急,代谢紊乱更严重,熟悉其临床特征有利于早期临床治疗,改善预后。     

PTP-1B及其抑制剂与2型糖尿病的研究现状

蛋白酪氨酸磷酸酶-1B (PTP-1B)是蛋白酪氨酸磷酸酶(PTP)家族中的一员,在胰岛素信号转导途径中发挥重要作用.经研究发现,PTP-1B与2型糖尿病的发生、发展有密切关系. 本文按PTP-1B 小分子抑制剂的结构类别对近年来文献报道的代表性小分子PTP-1B 抑制剂进行综述.表明深入研究PTP-1B及其有效的抑制剂对于2型糖尿病治疗具有良好的发展前景.     

鼻粘膜免疫融合蛋白Hsp65-6×p277预防NOD小鼠1型糖尿病的发生

目的提高多肽p277的免疫原性,从而提高其对自身免疫性糖尿病的预防作用.方法将p277 6次重复与Hsp 65融合置于pET28a中构建重组Hsp 65-6×p277表达质粒.该重组质粒在大肠杆菌BL21中以高效可溶形式表达.依次通过细胞裂解、硫酸铵沉淀、双蒸水透析、DEAE纤维素52柱层析纯化获得目的蛋白.用纯化后的融合蛋白Hsp 65-6×p277通过鼻腔给药方式,在不添加任何佐剂的情况下3次免疫4周龄雌性NOD小鼠.每月眼角取血,检测抗体和血糖浓度.结果初步药效学实验表明融合蛋白Hsp 65-6×p277可抑制NOD小鼠中1型糖尿病的发生.结论融合蛋白Hsp 65-6×p277有可能发展成为一种具有防治胰岛素依赖性糖尿病作用的疫苗.     

脂微球前列腺素E1对2型糖尿病C-反应蛋白的影响

目的:研究脂微球前列腺素E1(LipoPGE1)对2型糖尿病(T2DM)C-反应蛋白(CRP)的影响。方法:66例T2DM随机分为两组。用免疫比浊法,分别测定治疗前后血清CRP含量。结果:(1)两组患者的临床基本特征差异均无显著性。(2)两组患者血清CRP含量显著高于正常人(P<0.01)。(3)两组患者用药前及治疗两周后空腹及餐后2小时血糖差异无显著性,但治疗后比用降糖药前明显下降(P<0.01)。治疗前两组血清CRP未见差异,应用LipoPGE1两周后,CRP含量则明显降低(P<0.5)。结论:T2DM患者存在着血管内膜的慢性炎症反应。LipoPGE1不仅能直接扩张血管,还能间接减轻血管内膜的炎症反应,且这种改变不依赖于血糖的降低。     

Advances in pharmacological treatment of type 1 diabetes during pregnancy

Introduction: In women with type 1 diabetes mellitus (T1DM), pregnancy is associated with a potential risk of maternal, foetal and neonatal outcomes. Stringent metabolic control is required to improve these outcomes.

Areas covered: In this review, the authors summarise the current evidence from studies on the pharmacological therapy and on monitoring of T1DM during pregnancy. The authors also discuss the use of new technologies to improve therapeutic management and patient compliance.

Expert opinion: Pre-conception counselling is essential in T1DM to minimise pregnancy risks. Pregnancy in T1DM is always considered a high-risk pregnancy. During pregnancy, the target haemoglobin A1C (HbA_1c) is near-normal at <6%, without excessive hypoglycaemia. Strict control of pre- and post-prandial glucose is also required. Human soluble insulin, neutral protamine Hagedorn and the quick-acting insulin analogues aspart and lispro are widely used. Insulin is administered either as a basal-bolus regimen or by continuous subcutaneous insulin infusion. Careful and strict glucose monitoring is also needed during labour and delivery, including caesarean section. Moreover, the control of retinopathy, hypertension, nephropathy, hyper- and hypothyroidism is required. Post-partum, insulin requirements decrease, and less stringent glycaemic control is pursued, to avoid hypoglycaemias. Finally, breastfeeding is recommended and should be encouraged.     

Glutamine enhances the heat shock protein 70 expression as a cardioprotective mechanism in left heart tissues in the presence of diabetes mellitus

Objective: Effects of diabetes mellitus on myocardium were investigated, by assessing levels of heat shock protein (HSP) 70, and efficacy of glutamine was tested.

Materials and Methods: Thirty male rats were divided into three groups: control group (Group 1), diabetic group (Group 2) and glutamine-induced diabetic group (Group 3). Diabetes was created by intravenous streptozocin injection. Rats were examined one month later for cardiac complications of diabetes. Serum and tissue samples were obtained to measure HSP 70 levels.

Results: Following streptozocin administration, glucose levels increased markedly. This resulted in a significant increase in HSP 70 in serum and tissues. When Group 3 was compared with other groups, HSP 70 was more increased in serum and tissues. When Groups 2 and 3 were compared, more increased HSP 70 values were observed in Group 3, statistical significance was obtained for left atrial and left ventricular HSP 70 levels. Elevated blood glucose was correlated with elevated HSP 70 levels. Increased serum HSP 70 levels were correlated with tissue HSP 70 values.

Conclusions: HSP 70 levels increase in the myocardium of rats in diabetes mellitus as a protective mechanism. Levels of HSP 70 may further be increased with parenteral administration of glutamine. Efficacy of glutamine is more pronounced in left heart structures.     

Evaluation of linagliptin and insulin combined therapy on unfolded protein response in type 1 diabetic mouse heart

The aim of this study is to reveal the effects of the use of linagliptin, a DPP-4 inhibitor due to its beneficial cardiovascular effects, on endoplasmic reticulum stress (ERS) signaling, which is involved in the pathogenesis of cardiovascular complications related to type 1 diabetes. BALB/c female mice (n = 72) were divided into six groups: control, diabetes+insulin, diabetes+linagliptin, diabetes+linagliptin+insulin, diabetes+TUDCA, and diabetes+TUDCA+insulin. Immunohistochemistry and western blot method, qRT-PCR, ELISA method, and malondialdehyde (MDA) measurements were performed. Linagliptin administered to the type 1 diabetic mouse heart significantly reduced the expression levels of the total and cleaved forms of ATF6, ATF4, and p-JNK, caspase 3. Immunohistochemical and western blot analyses revealed that cleaved caspase 3 protein expression was significantly increased in the diabetes+insulin group compared to the other groups. According to ELISA findings, TUDCA was more effective in reducing NOX 1 and MDA levels than linagliptin. While linagliptin decreased the Chop mRNA level, no change was observed in the Grp78 mRNA level. Our findings showed that there was not much difference between the administration of linagliptin alone or in combination with insulin. Our study reveals that linagliptin is an effective therapeutic agent on ERS and apoptotic UPR in type 1 diabetic hearts.     

SGLT抑制剂联合胰岛素在1型糖尿病中的应用

钠-葡萄糖共转运蛋白抑制剂(SGLTi)通过抑制肾脏葡萄糖重吸收/延缓肠道葡萄糖吸收发挥降糖作用。SGLTi辅助胰岛素治疗1型糖尿病,不仅可降低糖化血红蛋白、改善血糖变异性和增加葡萄糖目标范围内时间,而且不增加低血糖、心肾事件和骨折的风险,还具有减少胰岛素用量和改善代谢的作用。SGLTi的不良反应主要有酮症酸中毒和生殖系统感染,其作为1型糖尿病患者胰岛素的补充治疗显示出一定的应用前景,但要根据患者的个体情况,平衡获益与风险,为患者选择最佳的治疗决策。     

1型糖尿病外周血Th1/Th2细胞因子表达水平的研究

目的检测1型糖尿病患者外周血CD_4~+T细胞分泌细胞因子的水平变化,探讨患者Th1/Th2细胞因子的平衡状态及其在1型糖尿病中的作用。方法对49例1型糖尿病患者和30例健康时照组外周血用刺激物刺激细胞,增加细胞内细胞因子的表达,再加入荧光标记的特异性抗细胞因子单克隆抗体,特异性抗原抗体结合,以流式细胞仪分析特异性细胞因子表达水平。结果1型糖尿病患者Th1型细胞因子干扰素-γ(IFN-γ)、白细胞介素-2(IL-2)表达水平较正常对照组升高,差异有统计学意义(P<0.01)。Th2型细胞因子白细胞介素-4(IL-4)、白细胞介素-10(IL-10)表达水平较正常时照组显著降低,差异有统计学意义(P<0.01)。结论1型糖尿病患者Th1/Th2平衡失调,Th1型反应模式处于优势状态,Th2型反应模式处于弱势状态。Th1/ Th2平衡向Th1方向漂移。     

Biphasic insulin aspart 30 for the treatment of type 1 diabetes mellitus

Background: Type 1 diabetes mellitus is associated with acute and long-term complications, to which pre- and postprandial hyperglycemia are independent contributors. The objective of this review was to evaluate evidence-based information using biphasic insulin aspart 30 in the treatment of type 1 diabetes mellitus. Methods: The study reviewed the Cochrane Database and scientific literature (PubMed) published until January 2008 using the words biphasic insulin aspart 30 insulin or premixed aspart insulin. Conclusions: Biphasic insulin aspart 30 is similar in efficacy to biphasic human insulin in improving hemoglobin A_1c levels, with the advantage of a better postprandial glucose profile. Expert opinion. There is evidence supporting the efficacy and safety of biphasic insulin aspart 30 insulin. However, the need for well-designed clinical trials aimed at understanding the potential differences in safety and efficacy between patients with type 1 and type 2 diabetes is crucial.     

2型糖尿病糖化血红蛋白与全天7点血糖水平的关系

目的探讨2型糖尿病患者糖化血红蛋白（HbA1c）与全天7点血糖水平的关系。方法 162例2型糖尿病患者检测三餐前、三餐后2 h及睡前共7次血糖值,并计算平均血糖水平（MBG）,同时测定HbA1c。按HbA1c水平不同将患者分为两组：血糖控制尚可组（HbA1c≤7.5%,A组）和控制差组（HbA1c〉7.5%,B组）。直线回归相关分析总体及各组HbA1c与MBG、全天7点血糖的相关性。结果 162例患者中,MBG与HbA1c显著正相关（r=0.849,P〈0.01）,MBG=-0.72＋1.31×HbA1c;HbA1c与全天7点血糖水平均呈正相关,逐步多元线性回归分析显示HbA1c与空腹、晚餐后、中餐后及早餐后血糖相关。A组的HbA1c与晚餐后、中餐后及中餐前血糖相关,而B组HbA1c与空腹、晚餐后、中餐后及早餐后血糖相关。结论 HbA1c受全天平均血糖水平的影响,血糖控制尚可组晚餐后、中餐后及中餐前的血糖对HbA1c影响明显,而血糖控制差组空腹、晚餐后、中餐后及早餐后的血糖对HbA1c影响明显。     

Aspirin relieves the calcification of aortic smooth muscle cells by enhancing the heat shock response

ContextVascular calcification is a major complication of chronic renal failure, which has been identified as an active process partly driven by osteogenic transition of vascular smooth muscle cells (VSMCs). Aspirin could prevent cardiomyocyte damage by inducing heat shock response.ObjectiveThis study investigates the effect of aspirin on alleviating VSMC calcification.Materials and methodsAn in vitro VSMC calcification model was established by 10-day calcification induction in osteogenic medium. VSMCs were grouped as following: control group (normal medium), calcified group (osteogenic medium) and treated group (osteogenic medium with 1 or 4 mmol/L aspirin). VSMC calcification was evaluated by calcified nodules formation, intracellular calcium concentration and osteoblastic marker (OPN and Runx2) expression.ResultsAfter 10-day culture, the intracellular calcium concentration in calcified group was significantly higher than that in control group (1.16 ± 0.04 vs. 0.14 ± 0.01 μg/mg, p < 0.01), but significantly reduced in 1 mmol/L aspirin treated group (0.74 ± 0.05 μg/mg, p < 0.01), and 4 mmol/L aspirin treated group (0.93 ± 0.03 μg/mg, p < 0.01). The elevated expression of OPN and Runx2 induced by osteogenic medium was significantly relieved after 1 or 4 mmol/L aspirin treatment. The expression of HSF1, HSP70 and HSP90 was decreased in calcification-induced VSMCs, but significantly increased after treatment of aspirin. Furthermore, inhibition of HSP70 (or HSP90) by small-molecule inhibitor or small interfering RNA could partially abolish the anti-calcification effect of aspirin, proved by the changes of intracellular calcium concentration and osteoblastic marker expression.Discussion and conclusionsAspirin could relieve the calcification of VSMCs partially through HSP70- or HSP90-mediated heat shock response. These findings expanded the understanding of aspirin pharmacology, and imply that local induction expression of HSPs might be a potential therapeutic strategy for the prevention and therapy of vascular calcification.     

Increased availability of angiotensin AT 1 receptors leads to sustained arterial constriction to angiotensin II in diabetes - role for Rho-kinase activation

BACKGROUND AND PURPOSE

Antagonists of angiotensin AT₁ receptors elicit beneficial vascular effects in diabetes mellitus. We hypothesized that diabetes induces sustained availability of AT₁ receptors, causing enhanced arterial constriction to angiotensin II.

EXPERIMENTAL APPROACH

To assess functional availability of AT₁ receptors, constrictions to successive applications of angiotensin II were measured in isolated skeletal muscle resistance arteries (∼150 µm) of Zucker diabetic fatty (ZDF) rats and of their controls (+/Fa), exposed acutely to high glucose concentrations (HG, 25 mM, 1 h). AT₁ receptors on cell membrane surface were measured by immunofluorescence.

KEY RESULTS

Angiotensin II-induced constrictions to first applications were greater in arteries of ZDF rats (maximum: 82 ± 3% original diameter) than in those from +/Fa rats (61 ± 5%). Constrictions to repeated angiotensin II administration were decreased in +/Fa arteries (20 ± 6%), but were maintained in ZDF arteries (67 ± 4%) and in +/Fa arteries vessels exposed to HG (65 ± 6%). In ZDF arteries and in HG-exposed +/Fa arteries, Rho-kinase activities were enhanced. The Rho-kinase inhibitor, Y27632 inhibited sustained constrictions to angiotensin II in ZDF arteries and in +/Fa arteries exposed to HG. Levels of surface AT₁ receptors on cultured vascular smooth muscle cells (VSMCs) were decreased by angiotensin II but were maintained in VSMCs exposed to HG. In VSMCs exposed to HG and treated with Y27632, angiotensin II decreased surface AT₁ receptors.

CONCLUSIONS AND IMPLICATIONS

In diabetes, elevated glucose concentrations activate Rho-kinase which inhibits internalization or facilitates recycling of AT₁ receptors, leading to increased functional availability of AT₁ receptors and sustained angiotensin II-induced arterial constriction.     

1型糖尿病干细胞治疗的研究进展

1型糖尿病是T细胞介导的以胰岛13细胞破坏为主的自身免疫性疾病,需应用外源性胰岛素控制血糖,目前没有根治办法。干细胞是一类具有自我复制能力的多潜能细胞,能诱导分化成胰岛素分泌细胞,已经成为人们寻找诱导β细胞替代物的新资源。本文综述干细胞在1型糖尿病治疗方面的研究现状。     

2型糖尿病血清可溶性血管细胞黏附分子-1水平与心率变异性关系

目的研究2型糖尿病患者血清可溶性血管细胞黏附分子-1与心率变异性的关系。方法随机选择2型糖尿病人60例、健康对照者59例,所有的研究者进行24 h动态心电图监测及空腹血清VCAM-1检测,并进行分析。结果DM组患者平均心率、最慢心率与对照组比较显著增加,P<0.01,糖尿病组心率变异指数与对照组比较显著降低,P<0.01;最快心率两组比较无明显差异;DM组的血清SCVAM-1水平比对照组明显升高,P<0.01;HRVI低于25的患者其血清SCVAM-1水平明显高于HRVI高于25的患者,P<0.01。结论血清SCVAM-1与2型糖尿病心脏自主神经病变关系密切,参与2型糖尿病自主神经病变的发生与发展。     

国内外1型糖尿病临床实践指南质量评价

目的：评价国内外1型糖尿病临床指南现状,为规范我国糖尿病循证临床指南制订和现有指南的更新提供参考。方法检索中国知网、万方、PubMed、EMBase等数据库、中国临床指南文库、美国国家指南交换所、指南国际网的网站及各相关协会官方网站,入选2009－01－01—2014－07－31发表的有关1型糖尿病临床实践指南,由2位评价员用指南研究与评价工具Ⅱ（ AGREE Ⅱ）对纳入的指南从6个领域及质量进行评价。结果共纳入16篇包含1型糖尿病相关内容的指南,其中1篇中文,15篇英文。指南质量经AGREE Ⅱ评分显示,全部指南各领域平均得分：范围和目的72％、指南制定参与人员53％、制定严谨性51％、明晰陈述与表达72％、适用性53％、编撰的独立性49％。5篇指南（分别为NICE、BOHTA、CDA、SIGN、NKF）在6个领域的评分均高于50％,质量较高。结论纳入的1型糖尿病指南整体质量较高。中国1型糖尿病指南在指南制定参与人员、制定严谨性、适用性和编撰独立性等领域亟待提高。     

Exenatide once weekly in type 2 diabetes mellitus

Introduction: Exenatide once weekly (EQW) is an injectable glucagon-like peptide-1 receptor agonist that is pending approval at present by regulatory authorities for treatment of type 2 diabetes mellitus. Its glucose-reducing and weight-loss properties, together with minimal hypoglycemia and a once-weekly dosing schedule, make it a potentially attractive treatment option for overweight type 2 diabetics.

Areas covered: A literature search using PubMed resulted in a search for all published clinical trials with EQW, entitled the DURATION trials, which are reviewed in this paper. Efficacy and safety data are compared with other available antidiabetes agents. Molecular structure, pharmacokinetics, pharmacodynamics and mechanism of action are also reviewed.

Expert opinion: EQW is a potentially attractive medication for overweight type 2 diabetics with efficacy in both glycemic control and weight loss, as well as minimal hypoglycemia. Owing to its route of administration and expected cost compared with generic metformin, it will probably have a role as add-on therapy rather than monotherapy. Additional studies are ongoing to compare its efficacy against liraglutide.