胰高血糖素样肽-1及其类似物的心血管保护作用研究进展

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)是一种主要由肠L细胞分泌的肠促胰素,在调节葡萄糖稳态中发挥重要作用,能够通过多种途径降低血糖,胰高血糖素样肽-1及其类似物已用于2型糖尿病治疗。研究发现GLP-1不仅具有降糖作用,还可以通过减轻体重、改善血脂等心血管危险因素和针对心脏及血管的直接作用起到心血管保护效应。目前GLP-1对心血管的保护效应愈来愈受到关注,本文就近年来有关GLP-1及其类似物的心血管保护作用及机制的研究进展做一综述。     

胰高血糖素样肽-1的研究进展

胰高血糖素样肽-1(GLP-1)是由远端回肠、直肠和结肠内分泌L细胞分泌的一种十分重要的肠促胰岛素,在调节体内葡萄糖稳态中起重要作用。其在胰腺内的主要生理学作用包括进食后刺激胰岛素的分泌和生物合成、促进胰腺β细胞的增殖、抑制其凋亡及抑制胰高血糖素的分泌。大量研究表明,在胰岛素作用的靶器官肝脏、骨骼肌和脂肪组织上亦存在高亲和力的GLP-1结合位点,GLP-1可促进肝脏、骨骼肌和脂肪组织的糖原合成和脂肪生成。此外,GLP-1受体还分布于神经、心血管、胃肠、肺脏组织等,其分布的广泛性也决定其作用的广泛性,具有多种生物学作用,这使得它成为一种治疗糖尿病的新型药物,具有很好的临床应用前景。近年来,人们对GLP-1在胰腺内、外的作用进行了广泛研究,现将其进展综述如下。     

胰高血糖素样肽-1在抑郁症中的作用及机制北大核心CSCD

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)是一种肠促胰岛素激素和肠脑轴的主要激素,与能量稳态的控制和肥胖的发生有关。除了抑制食欲外,GLP-1还作用于大脑中与压力反应和情绪调节有关的区域,具有神经保护作用。抑郁症是常见的精神类疾病,GLP-1与抑郁症关系密切。该文将对GLP-1在抑郁症中的作用及机制进行综述。     

胰高血糖素样肽-1的心血管益处及机制

心血管疾病是2型糖尿病患者的主要死亡原因之一。新近研究发现胰高血糖素样肽-1(GLP-1)不仅通过葡萄糖依赖的方式刺激胰岛素分泌和抑制糖原的不适当分泌,延缓胃排空,增加饱食感等方式调节血糖;还能通过GLP-1R和受体以外的方式发挥心血管保护作用,包括心肌、内皮细胞和血管等。越来越多的动物和临床研究显示,GLP-1和GLP-1R激动剂都能改善内皮细胞功能、促进钠的排泄、改善缺血损伤的心肌和心功能的恢复,减少心血管风险的危险因素和标志物。文中综述有关动物和人类研究中GLP-1对心血管系统的作用以及可能机制。     

胰高血糖素样肽1与糖尿病的治疗

胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)是由肠道L细胞分泌的一种重要的肠促胰岛素激素,其在体内的主要生理作用有刺激胰岛素的分泌和释放、抑制胰高血糖素的分泌、促进胰腺β细胞的增殖并抑制其凋亡、抑制胃的排空、促进饱食感的产生等。GLP-1对糖尿病和肥胖具有很好的治疗前景。由于GLP-1在体内很快被二肽酰基肽酶Ⅳ降解,血浆半衰期很短,因而限制了其临床应用。现已发现了促进GLP-1分泌的物质,开发了多种GLP-1的衍生物和二肽酰基肽酶Ⅳ抑制剂,为开发新型糖尿病治疗药物开辟了新的天地。     

胰高血糖素样肽-1与胃肠动力研究进展

胰高血糖素样肽-1(GLP-1)为一种重要的肠促胰岛素,可通过多种机制发挥重要的降血糖作用,因而在2型糖尿病(T2DM)的治疗中备受重视。另外,GLP-1亦发挥重要的心血管保护、肾脏保护、调节脂代谢,及改善胰岛素敏感性等功能。值得注意的是,GLP-1对胃排空及胃肠动力亦具有一定的抑制作用。因此,本文就GLP-1与胃肠动力关系的研究进展做一综述,旨在为GLP-1在胃肠动力障碍性疾病的发病机制及治疗中的潜在价值开辟新的视角。     

胰高血糖素样肽-1对糖尿病周围神经病变的影响

胰高血糖素样肽-1（Glucagon-like peptide-1,GLP-1）是肠道因进食而分泌的一类促胰岛素分泌肽,主要通过作用于GLP-1受体,激活多种信号通路而对神经系统发挥影响,主要包括加快神经传导速度,增加神经轴突的数量,为神经细胞直接提供营养因子,抑制神经细胞凋亡,拮抗氧化应激等作用。GLP-1及其受体激动剂可通过多种不同的途径改善糖尿病周围神经病变的症状,为糖尿病周围神经病变的治疗提供新的方法。     

胰高血糖素样肽1类似物的研究进展

主要介绍了胰高血糖素样肽-1(Glucagon—Like Peptide-1，GLP-1)类似物的研究进展以及临床应用情况，并指出了今后发展方向。     

利拉鲁肽对膝骨关节炎大鼠炎症反应的影响

目的 探讨胰高血糖素样肽-1(GLP-1)类似物利拉鲁肽对膝骨关节炎大鼠模型炎症反应的改善作用.方法 选取成年雄性SD大鼠60只,分为模型组、假手术组和利拉鲁肽组,每组20只.模型组和利拉鲁肽组大鼠通过关节腔内注射单碘乙酸盐(MIA,4 mg)诱导大鼠膝骨关节炎模型.假手术组大鼠关节腔内注射相同体积的生理盐水.拉鲁肽组大鼠皮下注射利拉鲁肽(50μg·kg-1·d-1)用于上调GLP-1受体(GLP-1R)的表达,共处理4周.蛋白质印迹法(Western blotting)检测GLP-1R、蛋白激酶A(PKA)、环状单磷酸腺苷反应元件结合蛋白(CREB)、聚集蛋白聚糖(aggrecan)、Ⅱ型胶原(collagenⅡ)、肿瘤坏死因子-α(TNF-α)、白细胞介素-1β(IL-1β)、白细胞介素-6(IL-6)、基质金属蛋白酶-13(MMP-13)和含Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶4(ADAMTS-4)的表达.免疫沉淀技术检测GLP-1R与PKA/CREB信号通路之间的相互作用.结果 与假手术组相比,模型组大鼠膝关节软骨组织中GLP-1R的蛋白相对表达量明显下调[(1.12±0.11)比(0.34±0.04)],而利拉鲁肽组(0.87±0.07)明显高于模型组(P<0.05).与假手术组相比,模型组大鼠膝关节软骨组织中PKA和CREB的磷酸化情况均被显著抑制(P<0.05),利拉鲁肽处理可显著提高PKA和CREB的磷酸化水平(P<0.05).模型组大鼠膝关节软骨组织中的aggrecan和collagenⅡ蛋白水平显著降低,利拉鲁肽组的两种蛋白的表达均显著升高(P<0.05).与假手术组相比,模型组大鼠的TNF-α、IL-1β、IL-6、MMP-13和ADAMTS-4蛋白表达水平均显著上调,利拉鲁肽处理可显著抑制膝骨关节炎大鼠膝关节软骨组织中上述因子的上调(P<0.05).结论 利拉鲁肽在膝骨关节炎大鼠模型中具有较好抗炎活性,可显著改善膝关节软骨组织.     

胰高血糖素样肽-1受体激动剂的研究进展

在健康人中,肠降血糖素胰高血糖素样肽-1(GLP-1)是在进食后分泌,并通过增加胰岛素分泌和抑制胰高血糖素释放而降低葡萄糖浓度。天然GLP-1在体内降解时间约为2~3 min,因此需要开发各种GLP-1受体激动剂以延长其体内作用时间。已开发出的GLP-1受体激动剂分为短期受体激活的化合物(例如艾塞那肽)和GLP-1受体的长效化合物(例如阿必鲁肽和利拉鲁肽等),以及小分子非肽类药物。这些GLP-1受体激动剂的个体性质可能使基于肠降血糖素的2型糖尿病治疗满足每个患者的需要。本文对当前GLP-1激动剂类药物的研究进行了综述。     

胰高血糖素样肽-1——阿尔采末病治疗新策略

胰高血糖素样肽-1(GLP-1)是一种由30个氨基酸组成的肠肽,结合于GLP-1R,并与cAMP第二信使途径相偶联。神经系统GLP-1 R的激活在神经可塑性及神经细胞的存活中起着重要作用。GLP-1可以诱导神经元轴突的生长,抵御体外培养神经细胞的兴奋性死亡和氧化损伤。GLP-1及其天然类似物exend in-4均可以降低小鼠脑中内源性Aβ的水平及神经元β前体蛋白(βAPP)的水平。因此,以GLP-1或其相关肽来实施治疗可以影响到AD相关的多个治疗靶点。该文对GLP-1治疗阿尔采末病(AD)的潜力进行探讨。     

胰高血糖素样肽-1及相关降糖药物的研究进展

胰高血糖素样肽-1（glucagon-like peptide-1,GLP-1）是近几年糖尿病治疗药物研究的热点之一,具备多重降血糖作用。它的两大类药物：GLP-1类似物和二肽基肽酶-Ⅳ抑制剂作为新的降糖药物相继完成临床研究,并在糖尿病治疗中发挥越来越重要的作用。本文就GLP-1的结构、药理作用以及两类相关降糖药物的临床应用作一概述。     

胰高血糖素样肽-1对骨质疏松症骨代谢影响的研究进展

目的:综述胰高血糖素样肽-1(GLP-1)对骨质疏松症骨代谢影响研究进展。方法:通过查阅相关文献及临床实践经验进行总结。结果:骨质疏松症与骨代谢密切相关,GLP-1能通过多种途径降低血糖,促进骨形成和抑制骨吸收,但它对成骨细胞及破骨细胞的具体作用仍不明确。结论:GLP-1受体已被用于治疗糖尿病,GLP-1通过调节体内血糖来间接影响骨代谢,从而为治疗骨质疏松症带来了新的希望。     

Emerging cardiovascular actions of the incretin hormone glucagon-like peptide-1: potential therapeutic benefits beyond glycaemic control?

Glucagon-like peptide-1 (GLP-1) is an incretin hormone secreted by the small intestine in response to nutrient ingestion. It has wide-ranging effects on glucose metabolism, including stimulation of insulin release, inhibition of glucagon secretion, reduction of gastric emptying and augmentation of satiety. Importantly, the insulinotropic actions of GLP-1 are uniquely dependent on ambient glucose concentrations, and it is this particular characteristic which has led to its recent emergence as a treatment for type 2 diabetes. Although the major physiological function of GLP-1 appears to be in relation to glycaemic control, there is growing evidence to suggest that it may also play an important role in the cardiovascular system. GLP-1 receptors (GLP-1Rs) are expressed in the heart and vasculature of both rodents and humans, and recent studies have demonstrated that GLP-1R agonists have wide-ranging cardiovascular actions, such as modulation of heart rate, blood pressure, vascular tone and myocardial contractility. Importantly, it appears that these agents may also have beneficial effects in the setting of cardiovascular disease (CVD). For example, GLP-1 has been found to exert cardioprotective actions in experimental models of dilated cardiomyopathy, hypertensive heart failure and myocardial infarction (MI). Preliminary clinical studies also indicate that GLP-1 infusion may improve cardiac contractile function in chronic heart failure patients with and without diabetes, and in MI patients after successful angioplasty. This review will discuss the current understanding of GLP-1 biology, examine its emerging cardiovascular actions in both health and disease and explore the potential use of GLP-1 as a novel treatment for CVD.     

The potential role of vildagliptin in the management and prevention of type 2 diabetes mellitus

Proper control of blood sugar in type 2 diabetes mellitus (T2DM) is not adequate till now in spite of use of well-planned dosage regimens containing oral hypoglycemic agents/insulin or both. Recently, the role of 'incretins,' particularly that of glucagon-like peptide-1 (GLP-1) in glucose homeostasis has been firmly established. The peptide (GLP-1) increases insulin secretion while decreasing that of glucagon in response to rise in plasma glucose in addition to delay of gastric emptying time, reduction of appetite, preservation of beta-cell function, and increase in beta-cell mass all of which will contribute toward lowering of blood sugar in T2DM. But the peptide hormone cannot be used orally as such because of its very short plasma half-life (2 min) and chemical nature, which needs continuous i.v. infusion or repeated s.c. or i.v. injections at short intervals. Hence, to prolong the duration of action of endogenous GLP-1, compounds have been synthesized which inhibit the enzyme dipeptidyl peptidase-4 (DPP-4), the enzyme responsible for metabolic degradation of GLP-1. One such compound is vildagliptin. In this article, an attempt has been made to compile some of the established recent advances in the therapeutic utility of vildagliptin along with a discussion about the physiological role of endogenous GLP-1 and its metabolism by DPP-4.     

Possible involvement of GLP-1(9�C36) in the regional haemodynamic effects of GLP-1(7�C36) in conscious rats

BACKGROUND AND PURPOSE

The incretin hormone, glucagon-like peptide (GLP)-1(7–36), is rapidly cleaved by dipeptidyl peptidase 4 (DPP-4) into GLP-1(9–36), and although it is agreed that most, if not all, of the metabolic effects are attributable to the intact peptide, the degree to which the cardiovascular effects are due to the cleavage product is unclear. The purpose of this study was to measure the regional haemodynamic effects of GLP-1(7–36), and determine the extent to which the cardiovascular effects of GLP-1(7–36) were influenced by DPP-4 inhibition and reproduced by GLP-1(9–36). Additional experiments investigated the involvement of autonomic mechanisms in the cardiovascular effects of GLP-1(7–36).

EXPERIMENTAL APPROACH

Regional haemodynamic effects of bolus doses and 4 h infusions of GLP-1(7–36) amide and GLP-1(9–36) amide were measured in conscious, chronically instrumented rats; the influence of DPP-4 inhibition and autonomic blockade on responses to GLP-1(7–36) were also assessed.

KEY RESULTS

Glucagon-like peptide-1(7–36) had clear regional haemodynamic effects comprising tachycardia, a rise in blood pressure, renal and mesenteric vasoconstriction and hindquarters vasodilatation, whereas GLP-1(9–36) was devoid of any cardiovascular actions. The effects of GLP-1(7–36) were enhanced by DPP-4 inhibition, and the tachycardia and hindquarters vasodilatation were β-adrenoceptor-mediated.

CONCLUSIONS AND IMPLICATIONS

In conscious rats, the cardiovascular effects of GLP-1(7–36) resemble those of the GLP analogue, exendin-4, and are attributable to the intact peptide rather than the cleavage product, GLP-1(9–36).     

Control of Blood Glucose by Novel GLP-1 Delivery Using Biodegradable Triblock Copolymer of PLGA-PEG-PLGA in Type 2 Diabetic Rats

PURPOSE: The incretin hormone glucagon-like peptide-1 (GLP-1) is a promising candidate for treatment of type 2 diabetes mellitus. However, plasma half-life of GLP-1 is extremely short, thus multiple injections or continuous infusion is required for therapeutic use of GLP-1. Therefore, we investigated a new delivery system as a feasible approach to achieve sustained GLP-1 release for a 2-week period. METHODS: A water-soluble, biodegradable triblock copolymer of poly [(DL-lactide-co-glycolide)-b-ethylene glycol-b-(DL-lactide-coglycolide)] (ReGel) was used in this study as an injectable formulation for controlled release of GLP-1. GLP-1 was formulated into ReGel as insoluble zinc complex to stabilize GLP-1 against aggregation and slow down release. The GLP-1 release profile was monitored in vitro and in vivo. Zucker Diabetic Fatty rats were administered subcutaneously with the GLP-1 formulation. The concentration of GLP-1, insulin, and glucose was monitored every day after the GLP-1 administration. RESULTS: The GLP-1 release from ReGel formulation in vitro and in vivo showed no initial burst and constant release for 2 weeks. Animal study demonstrated that the plasma insulin level was increased, and the blood glucose level was controlled for 2 weeks by one injection of ReGel/ ZnGLP-1 formulation. CONCLUSIONS: It is concluded that one injection of zinc-complexed GLP-1 loaded ReGel can be used for delivery of bioactive GLP-1 during a 2-week period. Because this new delivery system is biocompatible and requires twice-a-month injection, it can improve patient compliance and cost-effectiveness.