长效胰高血糖素样肽-1受体激动剂研究进展

新型2型糖尿病治疗药物胰高血糖素样肽-1(GLP-1)受体激动剂与传统降糖药物相比,具有促β细胞增生、稳定患者血糖水平和减轻体重等特点.通过对GLP-1及其类似物exendin-4进行结构修饰已获得一系列长效GLP-1受体激动剂.本文基于对GLP-1受体及其受体结构和功能的认识,对长效GLP-1受体激动剂的研究进展进行综述.     

人GLP-1类似物利拉鲁肽LEAD系列研究荟萃分析

利拉鲁肽是将人胰高糖素样肽-1（GLP-1）第34位赖氨酸替换为精氨酸、并在26位增加一个16碳棕榈酰脂肪酸侧链而形成的长效GLP-1类似物,与天然GLP-1有97％同源,半衰期约12～14h,每天1次给药就能起到良好的降糖作用,并且可以显著减少低血糖发生率、减轻体重和降低收缩压,同时能够改善2型糖尿病患者的B细胞功能。     

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。     

利拉鲁肽和阿必鲁泰治疗2型糖尿病临床研究进展

利拉鲁肽和阿必鲁泰是治疗2型糖尿病的新靶点药物,较已有的口服降糖药降糖效果好、副作用较小,而且可以减轻体质量,因此有广阔的应用前景。作为新一代降糖新药,利拉鲁肽是一种短效胰高血糖素样肽-1（GLP-1）类似物,阿必鲁泰是一种长效GLP-1类似物,两者既有共同之处,又有区别。总结这二种抗糖尿病新药的临床应用和不良反应研究进展,为临床合理用药以及新药研发提供思路。     

胰高血糖素样肽1相关研究的进展

胰高血糖素样肽1(GLP-1)及其长效类似物作为糖尿病药物治疗领域研究的热点,已进行了深入的研究.本文将从GLP-1的生理学特征、生物学功能和基于GLP-1信号的糖尿病治疗药物相关进展进行阐述.     

胰高血糖素样肽-1类似物药物的研究进展

目的介绍胰高血糖素样肽-1（GLP-1）及其类似物药物在2型糖尿病治疗中的应用。方法通过归纳总结近年来国内外相关文献,介绍了GLP-1的序列结构及其生理功能,并对其类似物药物（如Exendin-4,Liraglutide等）的临床应用或研发进展,以及它们目前在临床应用上的缺陷及相应的修饰或改造途径进行了阐述。结果与结论与现有药物比较,GLP-1及其类似物药物对2型糖尿病有着显著的疗效,在糖尿病治疗领域有广泛的应用前景。     

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。     

糖尿病治疗新药——利拉鲁肽

人胰高糖素样肽-1（GLP-1）是人体内存在的一种生理性多肽，它能根据体内葡萄糖水平高低，按需促进胰岛8细胞分泌胰岛素，抑制胰岛素拮抗激素胰高血糖素的分泌，从而发挥降糖作用。然而，人体产生的GLP-1很不稳定，很快就会被体内的二肽基肽酶Ⅳ（DPP—IV）降解。利拉鲁肽（liraglutide）是诺和诺德公司开发的一种GLP-1类似物，是在天然GLP-1的分子结构上更换了一个氨基酸，并增加了一个16碳棕榈酰脂肪酸侧链，从而在保留天然GLP-1功效的同时克服了其易降解的缺点。通过这种分子改变，利拉鲁肽仅需每日1次注射就能起到良好的降糖作用，     

2型糖尿病合理用药策略

2型糖尿病是我国主要慢性疾病之一,而其控制状况不容乐观。降糖药物的使用是控制血糖的重要利器之一,糖尿病的药物治疗按作用机制和结构主要分为胰岛素促泌剂、双胍类、噻唑烷二酮类药物、糖苷酶抑制剂、DPP-Ⅳ抑制剂、GLP-1、胰岛素及其类似物等。本文概述临床常用降糖药物的药理机制、作用特点及其特性,并提出适时启用胰岛素、简单化原则、合理联用、个体化原则及兼顾安全性、性价比的合理使用降糖药物策略。     

激素、维生素及相关药物——开发中用于糖尿病治疗的GLP-1类药物Taspoglutide

由于肠降血糖素激动剂和类似物（仅在高血糖状态下）具有刺激胰岛素分泌的能力,所以它们作为潜在的抗糖尿病药越来越引起人们注意。开发肠降血糖素的作用以降低伴随许多抗糖尿病治疗的反弹性低血糖的风险。Taspoglutide是一种长效胰高血糖素样肽-1（GLP-1）类似物,有望用于2型糖尿病治疗。除了提高对蛋白酶二肽基肽酶4（DPP4）酶降解的抗力外,临床研究表明它能提高胰岛素水平和降低血糖。     

重组长效人胰高血糖素样肽1类似物研究进展

人胰高血糖素样肽1（glucagon-like peptide-1,GLP-1）是治疗2型糖尿病的主要药物,其长效性是一个重要指标。GLP-1化学合成工艺复杂、成本较高,因此通过基因工程获得重组长效GLP-1类似物成为目前的研究方向。此文对近年来通过基因工程获得重组长效GLP-1类似物的研究进行综述。     

胰高血糖素样肽-1长效注射微球的研究

目的制备载胰高血糖素样肽-1(GLP-1)的长效注射微球，并对其体外释放特性及药效学进行考察。方法采用复乳法(W/O/W)制备载GLP-1聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；在体动物法评价微球制备工艺和体外释放过程中GLP-1的生物学活性。在糖尿病模型小鼠体内考察了微球的降血糖作用。结果微球球形圆整，分散性好，包封率在80%以上；GLP-1微球1个月的体外累积释放可达85%，其释放行为符合近似零级释放模式；使用明胶溶液作为内水相，较好地保持了制备工艺过程中的GLP-1生物学活性，在体外释放过程中GLP-1的生物学活性略有下降；GLP-1微球可显著降低糖尿病模型小鼠的血糖水平，降糖作用可维持1个月。结论用可生物降解的聚合物PLGA作为载体材料，可以将GLP-1制备成缓释1个月的注射微球。     

The value of short- and long-acting glucagon-like peptide-1 agonists in the management of type 2 diabetes mellitus: experience with exenatide

Background:

Only about half of patients with type 2 diabetes treated with antihyperglycemic drugs achieve glycemic control (HbA1c <7%), most commonly due to poor treatment adherence. Glucagon-like peptide-1 (GLP-1) receptor agonists act on multiple targets involved in glucose homeostasis and have a low risk of causing hypoglycemia. While GLP-1 receptor (GLP-1R) agonists share the same mechanism of action, clinical profiles of individual agents differ, particularly between short- and long-acting agents. In this article, recent findings regarding the pharmacology of GLP-1 agonists are reviewed, and the clinical effects of short- versus long-acting agents are compared.

Data sources:

Relevant articles were identified through a search of PubMed using the keywords glucagon-like peptide-1, GLP-1, glucagon-like peptide-1 receptor agonist, GLP-1R agonist, and exenatide for publications up to 22 May 2015. Supporting data were obtained from additional searches for albiglutide, dulaglutide, liraglutide and lixisenatide as well as from the bibliographies of key articles.

Findings:

Short-acting GLP-1R agonists produce greater reductions in postprandial glucose levels by slowing gastric emptying, whereas long-acting GLP-1R agonists produce greater reductions in fasting blood glucose by stimulating insulin secretion from the pancreas. These characteristics can be exploited to provide individualized treatment to patients. A large body of evidence supports the benefits of short- and long-acting exenatide as add-on therapy in patients with inadequate glycemic control despite maximum tolerated doses of metformin and/or sulfonylurea. Exenatide is generally well tolerated and no new safety concerns were identified during long-term follow-up of up to 5 years. A limitation of this review of short-and long-acting GLP-1 receptor agonists is that it focuses on exenatide rather than all the drugs in this class. However, the focus on a single molecule helps to avoid any confusion that may be introduced as a result of differences in molecular structure and size.

Conclusions:

Short-acting GLP-1R agonists including exenatide are well suited to patients with type 2 diabetes with exaggerated postprandial glucose excursions and for co-administration with basal insulin therapy. Long-acting GLP-1R agonists including once weekly exenatide offer greater convenience and are well suited to patients who require specific control of fasting hyperglycemia.     

Effect of Urena lobataleaves extract on glucagon like peptide-1 serum level by inhibition of dipeptidyl peptidase-Ⅳ on diabetic rats

OBJECTIVE To investigate effect of Urenalobataleaves extract on glucagon like peptide-1(GLP-1)serum level by inhibition of dipeptidyl peptidase-Ⅳ(DPP-Ⅳ)on diabetic rat. METHODS This study uses control group post test only with male spraque dawley rats.Diabetic rats was induced by High Fructose Diet(HFD)and single dose streptozotocin 25mg·kg-1 bw intra peritoneal.The rat was administrated orally with ethanolic extract of U.lobataleaves in dose of 250,500 and 1000mg·kg-1 for 4weeks.Blood sample were collected from the tail vein at 15 min after oral glucose administration and then DPP-Ⅳserum level and GLP-1were examined using a rat elisa kits of DPP-Ⅳ and GLP-1.The data was analyzed using ANOVA test continued with LSD test(P<0.05).RESULTS The oral administration of U.lobataleaves extract at dose of 250,500 and 1000mg·kg-1 bw were able to prolong GLP-1 bioavaibility approximately 5,2and 2.5-fold respectively compared to diabetic group(P<0.05),while the DPP-Ⅳ serum level was decreased by 60%,50% and 40%(P<0.05),respectively.In diabetic groups,DPP-Ⅳ serum level was increased more and less 4-fold compared to normal group(P<0.05)while the GLP level were decreased by 8-fold(P<0.05).CONCLUSION U.lobataleaves extract could prolong GLP-1 bioavaibility by reducing of DPP-Ⅳserum level.This effect may be related to active compounds that act as an DPP-Ⅳinhibitor in U.lobata extract.     

已上市胰高血糖素样肽-1受体激动剂的研究进展

胰高血糖素样肽-1受体激动剂（GLP-1RAs）治疗2型糖尿病受到广泛关注,其不仅具有优异的降糖优势,还有控制体质量,调节血脂,改善胰岛β细胞功能等特点,同时低血糖或体质量增加的不良反应发生率较低。自2005年至今,已经有7个GLP-1RAs经美国食品药品监督管理局批准上市,即艾塞那肽、利拉鲁肽、艾塞那肽长效制剂、阿必鲁肽、度拉糖肽、利西拉来和索马鲁肽;在中国上市的有贝那鲁肽和洛塞那肽。对已经上市的9个GLP-1Ras治疗2型糖尿病的临床研究进展进行综述。     

新型口服降糖药——二肽基肽酶-Ⅳ抑制剂

胰高血糖素样肽（GLP-1）在调节血糖方面起着重要的作用,但其在体内可迅速被二肽基肽酶-Ⅳ（DPP-Ⅳ）降解失活。DPP-Ⅳ抑制剂可有效抑制GLP-1的降解,通过促进胰岛素分泌、抑制胰高血糖素释放、抑制食欲、减慢胃排空等作用调节血糖,具有不易引起严重低血糖事件、不引起体重增加等特点。本文对GLP-1和DPP-Ⅳ抑制剂的作用特点及已上市使用的西格列汀、维格列汀和沙格列汀的临床疗效、药代动力学以及不良反应等方面进行了综述。     

Glucagon-like peptide 1 as a regulator of food intake and body weight: therapeutic perspectives

After ingestion of carbohydrate- and fat-rich meals, the incretin hormone glucagon-like peptide 1 (GLP-1) is secreted from the L-cells in the distal put into the circulation. Its major physiological effect lies in a strongly glucose-dependent stimulation of insulin secretion from pancreatic B-cells. Furthermore, GLP-1 suppresses glucagon secretion, stimulates B-cell neogenesis as well as proinsulin biosynthesis and inhibits gastric emptying and acid secretion. Recently, GLP-1 could be shown to reduce caloric intake and to enhance satiety, most likely via specific receptors within the central nervous system, resulting in reduced weight gain in experimental animals. In nondiabetic and Type 2 diabetic human subjects, exogenous GLP-1 reduces hunger, caloric intake and body weight. Therefore, in addition to its well-characterized antidiabetogenic effect, the anorectic effect may offer GLP-1 a potential in the pharmacotherapy of obesity. It is still unknown whether the GLP-1 effect on caloric intake is sustained after long-term treatment. Furthermore, the exact mechanisms by which the peptide exerts its biological effects have not yet been clarified. Due to the rapid degradation of native GLP-1, its therapeutic application is limited by the short half-life. Therefore, suitable modes of administration are needed in order to reach stable plasma concentrations. The present review aims to describe the role of GLP-1 in the central regulation of feeding and to discuss its possible application in the pharmacotherapy of obesity.     

Glucagon-like peptide 1 and inhibitors of dipeptidyl peptidase IV in the treatment of type 2 diabetes mellitus

Proof-of-concept for the efficacy of a glucagon-like peptide 1 (GLP-1)-based therapy of patients with type 2 diabetes was provided in 2002 by means of prolonged continuous subcutaneous infusion of native GLP-1. Since then, several long-acting analogues of GLP-1, as well as inhibitors of dipeptidyl peptidase IV, the enzyme that rapidly inactivates endogenous GLP-1, have demonstrated efficacy in long term clinical trials.