聚乙二醇化胰高血糖素样肽1类似物生物活性的报告基因法测定

目的:建立检测聚乙二醇化胰高血糖素样肽1类似物(polyethylene glycolylated glucagon-like peptide-1 analogue,PEG-GLP-1a)生物活性的报告基因法,并对该方法进行验证。方法:将人胰高血糖素样肽1受体表达载体和分泌型碱性磷酸酶(secreted alkalin...     

胰高血糖素样肽1类似物长效化的策略

胰高血糖素样肽1(GLP-1)是肠道细胞分泌的多肽激素,可促进胰岛素分泌,发挥葡萄糖浓度依赖性降糖作用.但GLP-1易被二肽基肽酶4降解且肾脏清除快,血浆半衰期短,大大限制了其临床应用.因此,氨基酸替换、脂肪酸修饰、融合蛋白、缓释给药等策略在长效GLP-1类似物的研发中被应用,目前已有多种GLP-1类似物制剂上市,但多...     

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。     

胰高血糖素样肽-1类似物的研究进展

该文主要介绍了近年来成为糖尿病治疗领域研究热点的胰高血糖素样肽-1(GLP-1)类似物的治疗药物及其临床研究应用进展.随着人们对GLP-1类似物及其治疗药物的进一步认识以及深入研究,将有望开发出更多治疗糖尿病的新型药物应用于临床,造福于广大患者.     

胰高血糖素样肽-1类似物研发进展

目的 总结胰高血糖素样肽-1(GLP-1)类似物的研发进展。方法 检索PubMed和Web of Science数据库自建库起至2024年2月20日的GLP-1类似物相关文献,从研发概况、单分子多靶点GLP-1受体激动剂（GLP-1RA）、除治疗糖尿病外的其他适应证及其药物研发新趋势方面,总结GLP-1类似物的研发进展。结果与结论 GLP-1类似物的研发经历了从短效到长效,从注射剂到口服剂,并扩展到多靶点治疗的过程。目前,多靶点GLP-1RA包括GLP-1R/葡萄糖依赖性促胰岛素释放多肽受体、GLP-1R/胰高血糖素受体（GCGR）、GLP-1R/GLP-2R、GLP-1R/胰淀素3受体（AMY3R）、GLP-1R/成纤维细胞生长因子21受体（FGF-21R）等双靶点激动剂,以及GLPR/GLP-1R/GCGR、GLP-1R/GCGR/FGF-21R等三靶点激动剂。GLP-1类似物展现了在2型糖尿病、超重、肥胖症、心血管疾病、多囊卵巢综合征、非酒精性脂肪性肝炎、慢性肾脏病等疾病治疗的巨大潜力,疗效优于单靶点的双靶点和三靶点GLP-1RA是近年来研发的重点。GLP-1类似物的重组腺相关病...     

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。     

新型胰高血糖素样肽-1类似物的合成及降糖活性

目的合成具有全新肽序的新型胰高血糖素样肽-1(GLP-1)受体激动剂非洲爪蟾GLP-1并对其(XenGLP-1)进行长效化修饰。方法先通过在其C端引入PSSGAPPPS序列以增加其降糖活性,再在XenGLP-1序列上引入半胱氨酸,进一步利用MAL-PEG2 000与其进行缀合。结果合成得到PEG2 000-ZF-1和PEG2 000-ZF-2 2个缀合肽,并对缀合肽进行长效化降糖活性研究。结论 2个PEG化缀合肽具有长效的降糖活性,具有很好的药物开发前景。     

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。     

人胰高血糖素样肽-1类似物的合理应用

传统2型糖尿病的治疗是在饮食、运动控制的基础上,使用多种口服药或者联合胰岛素治疗,本文着重介绍治疗成人2型糖尿病的新药人胰高血糖素样肽-1类似物利拉鲁肽在临床应用中的疗效及不良反应。大型LEAD系列研究以及在亚洲尤其是中国患者中展开的临床研究结果证实了利拉鲁肽具有葡萄糖依赖性降糖的特点,兼具有保护β细胞、降低体重、血压以及低血糖发生率低的优势,同时不良反应发生率低,为临床治疗2型糖尿病提供了新的治疗选择。     

胰高血糖素样肽-1及其类似物的生物学活性测定方法

胰高血糖素样肽-1(GLP-1)因其独特的生理功能成为治疗2型糖尿病最有潜力的药物之一,有很好的开发前景。本文对GLP-1及其类似物的生物学活性,如稳定性、免疫学活性、体外和体内生物学活性的测定方法进行了综述,为GLP-1及其类似物的应用开发研究提供参考。     

胰岛素、胰岛素原、胰岛素类似物和C肽

<正> 人类认识到糖尿病(DM)的现象已有数千年历史。然而由于科学技术和知识水平的限制,直到1921年才由加拿大学者Bantng和Best从狗的胰腺中提取出胰岛素,从此开辟了DM治疗的新时代。胰岛素制剂的开发和临床应用经历了许多具有历史意义的过程。最早使用的胰岛素是动物胰腺组织的粗提物,以     

Economic analysis of glucagon like peptide-1 receptor agonists from the Saudi Arabia payer perspective

ObjectivesTo perform a cost of control analysis of glucagon like peptide-1 receptor agonists (GLP1RA) in Saudi Arabia (SA) and determine the economic impact of adopting GLP1RAs.MethodsA budget impact model that captures the cost of control model was constructed to simulate hypothetical patient on six treatment options: a current mix of 60% liraglutide and 40% dulaglutide, semaglutide, liraglutide, dulaglutide, exenatide, and lixisenatide. We estimated the relative amounts of SAR spend to achieve HbA1c targets (≤6.5% or < 7.0%). For each treatment option, annual treatment cost, proportion of patients achieving HbA1c targets, and cost to treat major adverse cardiovascular events (MACE) were aggregated to estimate the cost of control per patient per year (CCPPPY) over 5-year horizon (2021–2025). Probabilistic sensitivity analysis (PSA) was performed as a confirmatory analysis.ResultsThe CCPPPY to achieve HbA1c ≤ 6.5%/<7.0% using current mix, semaglutide, liraglutide, dulaglutide, exenatide, and lixisenatide were SAR 17,097/SAR 14,113, SAR 12,889/SAR 11,123, SAR 15,594/SAR 12,892, SAR 19,184/SAR 15,940, SAR 580,211/SAR 380,936, and SAR 246,570/SAR 143,759, respectively. The relative amounts of SAR spend to achieve HbA1c ≤ 6.5%/<7.0% relative to 1 SAR on semaglutide in case of adopting current mix, liraglutide, dulaglutide, exenatide, and lixisenatide were SAR 1.42/SAR 1.18, SAR 1.30/SAR 1.07, SAR 1.60/SAR 1.33, SAR 48.33/SAR 31.73, and SAR 20.54/SAR 11.97, respectively. These results were confirmed in the PSA.ConclusionsSemaglutide 1 mg once weekly was the most economically favorable GLP1RA; associated with the least CCPPPY, and amount of SAR spent to achieve HbA1c of ≤6.50%/<7.00% versus all other GLP1RAs.     

重组人胰高糖素样多肽-1(7-36)对胰岛β细胞分泌功能影响的实验研究

目的观察重组人胰高糖素样多肽-1（7-36）（促胰岛素生成药）对大鼠血糖和胰岛β细胞功能的影响.方法12周龄OLETF大鼠随机分为给药组和模型组（n=10）,并以同种系非糖尿病LETO大鼠作为对照组;干预2,8周后,处死;于12,14及20周龄时,行口服葡萄糖耐量试验,测定血糖及血清胰岛素.结果经该药治疗,能降低2型糖尿病OLETF大鼠的进食量和体质量,增加血清胰岛素水平,部分改善葡萄糖耐量.结论重组人胰高糖素样多肽-1（7-36）能够改善OLETF大鼠分泌胰岛素的功能,降低血糖.     

A colorimetric protein phosphatase inhibition assay for the determination of cyanobacterial peptide hepatotoxins based on the dephosphorylation of phosvitin by recombinant protein phosphatase 1

A colorimetric protein phosphatase inhibition assay based on the dephosphorylation of phosvitin by recombinant protein phosphatase 1 was developed for analysis of waters for cyanobacterial hepatotoxins. The phosphate released in the assay was determined using a malachite green reagent. Good agreement with toxin concentrations determined by HPLC was obtained. The assay was capable of determining these toxins at concentrations around 1 μg/L with high precision and without sample concentration. This is of considerable benefit as the World Health Organisation specifies a provisional guideline of 1 μg/L for microcystin‐LR. There was evidence, however, that the sample matrix might affect quantification, leading to false positive results. Thus the assay should be viewed as a screening procedure, and confirmatory analyses by an alternative procedure should be carried out for positive results. Further work is required to resolve the question of matrix interferences if phosphatase inhibition assays are used directly for measuring toxin levels in water, especially if this information is used to check compliance with water quality guidelines. © 2001 John Wiley & Sons, Inc. Environ Toxicol 16: 242–252, 2001     

胰高血糖素样肽-1受体激动剂治疗2型糖尿病的研究进展

胰高血糖素样肽-1（GLP-1）为末端空肠、回肠及结肠中L细胞分泌的葡萄糖依赖性的内源性肠促胰岛素分泌激素,依其可与胰岛β细胞膜上受体特异性结合促进β细胞增殖、分化、抑制其凋亡,增加胰岛β细胞数量,改善胰岛β细胞功能的作用而被视为治疗2型糖尿病（T2DM）新靶点的又一突破性发现。本文就目前FDA批准上市的胰高血糖素样肽-1受体激动剂（GLP-1 RAs）有关受体分布特点、作用机制、临床疗效及不良反应作一综述。     

利拉鲁肽对ApoE基因缺陷小鼠动脉粥样硬化及相关危险因素的影响

目的观察长效胰高糖素样肽-1类似物利拉鲁肽对Apo E基因缺陷小鼠动脉粥样硬化及相关血清学指标的影响。方法高脂饲料喂养Apo E基因缺陷小鼠诱导动脉粥样硬化形成,并随机分为对照组(不给药,n=11)和利拉鲁肽组(30μg·d-1,皮下注射,共4周,n=12)。比较两组小鼠主动脉粥样硬化斑块面积/管腔面积、内膜厚度/中膜厚度、血脂、血清一氧化氮(NO)、肿瘤坏死因子α(TNF-α)、丙二醛(MDA)水平。结果对照组和利拉鲁肽组小鼠斑块面积/管腔面积、内膜厚度/中膜厚度无显著差异(P>0.05),两组中体重增加在中位数以下的小鼠进行亚组比较,利拉鲁肽组斑块面积/管腔面积、内膜厚度/中膜厚度均显著下降(P<0.05)。利拉鲁肽组总胆固醇、三酰甘油、低密度脂蛋白胆固醇、TNF-α水平显著低于对照组(P<0.05),NO水平显著高于对照组(P<0.05),两组间MDA水平无显著差异(P>0.05)。结论利拉鲁肽具有减轻体重、改善血脂水平,保护内皮功能及抑制炎症反应等作用,并可能通过减轻体重发挥潜在的抗动脉粥样硬化作用。     

Lateral allosterism in the glucagon receptor family: glucagon-like peptide 1 induces G-protein-coupled receptor heteromer formation

Activation of G-protein-coupled receptors (GPCRs) results in a variety of cellular responses, such as binding to the same receptor of different ligands that activate distinct downstream cascades. Additional signaling complexity is achieved when two or more receptors are integrated into one signaling unit. Lateral receptor interactions can allosterically modulate the receptor response to a ligand, which creates a mechanism for tissue-specific fine tuning, depending on the cellular receptor coexpression pattern. GPCR homomers or heteromers have been explored widely for GPCR classes A and C but to lesser extent for class B. In the present study, we used bioluminescence resonance energy transfer (BRET) techniques, calcium flux measurements, and microscopy to study receptor interactions within the glucagon receptor family. We found basal BRET interactions for some of the receptor combinations tested that decreased upon ligand binding. A BRET increase was observed exclusively for the gastric inhibitory peptide (GIP) receptor and the glucagon-like peptide 1 (GLP-1) receptor upon binding of GLP-1 that could be reversed with GIP addition. The interactions of GLP-1 receptor and GIP receptor were characterized with BRET donor saturation studies, shift experiments, and tests of glucagon-like ligands. The heteromer displayed specific pharmacological characteristics with respect to GLP-1-induced β-arrestin recruitment and calcium flux, which suggests a form of allosteric regulation between the receptors. This study provides the first example of ligand-induced heteromer formation in GPCR class B. In the body, the receptors are functionally related and coexpressed in the same cells. The physiological evidence for this heteromerization remains to be determined.