利拉鲁肽治疗2型糖尿病的临床研究进展

利拉鲁肽是一种新型胰高糖素样肽-1 GLP-1类似物,能迅速、高效、持久地降低血糖及糖化血红蛋白,具有改善胰岛β细胞功能、调节收缩压、保护心血管、降低血脂、减轻体重、延迟胃排空、增加饱腹感等作用。此外,利拉鲁肽具有葡萄糖依赖的促胰岛素分泌作用,仅在机体血糖水平高时刺激胰岛素的释放,但当患者体内血糖浓度恢复至正常时,GLP-1分泌促胰岛素的作用便消退,因而发生低血糖事件的几率较低,能有效地改善糖尿病患者的病情,已成为目前2型糖尿病治疗领域的研究热点。本文主要就利拉鲁肽治疗2型糖尿病的临床研究进展进行综述。     

利拉鲁肽治疗2型糖尿病的研究进展

利拉鲁肽是一种胰高糖素样肽-1(GLP-1)类似物,作为一种新型的2型糖尿病治疗药物,具有降低体质量、改善胰岛β细胞功能、降低收缩压,减少低血糖发生率的作用。本文通过对近期国内外文献中关于利拉鲁肽研究进展的归纳和分析,从其药理作用研究、动物实验研究、临床研究、安全性和耐受性等方面进行阐述,为今后的研究提供参考和依据。     

取代环丁烷结构的非肽类胰高血糖素样肽-1受体激动剂

应用胰高血糖素样肽-1（glucagon-like peptide-1,GLP-1）及其类似物治疗2型糖尿病是代谢性疾病研究领域近年来的热点,尤其是胰高血糖素样肽-1独特的作用机制倍受业界的关注。它能同时作用于2型糖尿病的多个发病环节,在有效降低血糖的同时,避免低血糖的发生并能减轻体重。但这类药物因其多肽性质而存在诸多的使用限制（如需反复注射）。简要介绍一类取代环丁烷结构的新型非肽类胰高血糖素样肽-1受体小分子激动剂的发现过程、基本药理学特征和体内抗糖尿病和抗肥胖症效应。     

GLP-1类似物蛋白结构及功能研究进展

基于胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)结构改变得到的GLP-1类似物,能迅速、高效、持久地降低血糖及糖化血红蛋白,具有改善胰岛β细胞功能、调节收缩压、保护心血管、降低血脂、减轻体重、延迟胃排空、增加饱腹感等作用,成为近年来2型糖尿病治疗领域研究的热点。本文对GLP-1及其类似物的结构、功能、不良反应、蛋白质结构研究的方法作一综述。     

酪酸梭菌活菌胶囊联合利拉鲁肽对2型糖尿病患者的疗效及对肠道菌群的影响

目的探究酪酸梭菌活菌胶囊联合利拉鲁肽对2型糖尿病患者的治疗效果及其对肠道菌群的影响,为该类患者的治疗提供参考。方法选取2017年11月至2019年3月于我院接受治疗的120例2型糖尿病患者为研究对象,随机分为利拉鲁肽组和联合治疗组,各60例。利拉鲁肽组患者使用利拉鲁肽进行治疗,联合治疗组患者使用酪酸梭菌活菌胶囊联合利拉鲁肽进行治疗。采用血糖检测仪对两组患者空腹血糖(FBG)、餐后两小时血糖(2hPG)、糖化血红蛋白(HbA1c)水平进行检测。采用酶联免疫吸附实验检测总胆固醇(TC)、三酰甘油(TG)、血清趋化素(Chemerin)水平。采用免疫透射比浊法检测谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)、丙二醛(MDA)水平,使用光冈法对两组患者肠道菌群进行检测,对比两组患者治疗效果。结果治疗半年后联合治疗组患者FBG、2hPG、HbA1c水平均低于利拉鲁肽组(均P0.05)。治疗后利拉鲁肽组患者TC、TG、Chemerin水平均低于联合治疗组(均P0.05)。治疗后联合治疗组患者血清GSH-Px、SOD水平高于利拉鲁肽组,MDA水平低于利拉鲁肽组(均P0.05)。治疗后联合治疗组患者肠道乳杆菌、双歧杆菌数量高于利拉鲁肽组,肠球菌、肠杆菌数量低于利拉鲁肽组(均P0.05)。联合治疗组患者治疗总有效率显著高于利拉鲁肽组(95.00%vs 83.33%,χ~2=4.227,P=0.040)。结论酪酸梭菌活菌胶囊联合利拉鲁肽能够改善2型糖尿病患者糖代谢指标水平以及血脂水平,提升患者抗氧化能力,调节患者肠道菌群,治疗效果显著。     

贝那鲁肽与利拉鲁肽对2型糖尿病患者长期结局影响的对比研究

摘要 目的：对比分析贝那鲁肽与利拉鲁肽对2型糖尿病患者长期结局的影响，为二甲双胍和磺脲类药物治疗后血糖不能达标的患者应用胰高糖素样肽-1（GLP-1） 受体激动剂提供临床依据。方法：选取2018年3月～2019年3月在我院就诊的使用二甲双胍或者二甲双胍联合磺脲类药物血糖未达标的2型糖尿病患者150例作为研究对象，随机分为观察组和对照组，每组各75例。观察组使用贝那鲁肽注射液治疗，对照组使用利拉鲁肽注射液治疗，所有患者均连续治疗24周。比较两组患者治疗前后空腹血糖（FPG）、餐后2 h血糖（2hPG）、糖化血红蛋白（HbA1c）、收缩期血管峰值血流( PSV)、血管内膜中层厚度(IMT) 、肌酐（Scr）和尿素氮（BUN）水平，两年内的不良事件发生率、心血管相关死亡率和全因死亡率。结果：两组患者之间治疗前、后FPG、2hPG、HbA1c、PSV、IMT、Scr和BUN水平无统计学差异（P>0.05）, 观察组的不良事件总发生率（8.00%）较对照组（20.00%）明显降低（P<0.05），两组患者心血管相关死亡率和全因死亡率相比，差异无统计学意义（P>0.05）。结论：在使用二甲双胍或者二甲双胍联合磺脲类药物血糖未达标的2型糖尿病患者中，与利拉鲁肽相比，贝那鲁肽在降低血糖、改善下肢血管功能、肾功能和死亡率方面无明显差异，但不良事件发生率更低。     

GLP-1与2型糖尿病的研究进展

胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)具有促进胰岛素分泌、保护胰岛β细胞、降低食欲等多种重要功能,在控制体内血糖平衡的过程中发挥重要作用。2型糖尿病的发生伴随着胰高血糖素样肽-1生物应答功能受损。胰高血糖素样肽-1类似物、胰高血糖素样肽-1受体激动剂和胰高血糖素样肽-1降解酶抑制剂等糖尿病治疗药物已在临床上表现出很好的应用前景。     

胰升血糖素样肽-1及其受体与 2 型糖尿病的治疗

胰岛素对治疗 2 型糖尿病有一定效果,但长期使用会引起低血糖反应;双胍类药物降糖疗效显著,但会引起消化道不良反应 . 因此,寻找一种安全有效的药物是 2 型糖尿病治疗的当务之急 . 胰升血糖素样肽-1 作为一种胰岛素分泌促进剂和胰岛素增敏剂越来越受人们的关注,将它用于治疗糖尿病不会产生低血糖,对 1 型和 2 型糖尿病都有疗效 . 讨论胰升血糖素样肽-1及其受体的最新研究状况 .     

抗糖尿病药物GLP-1在阿尔茨海默病中的神经保护作用及其分子机制研究进展

随着世界人口老龄化的加剧,阿尔茨海默病(Alzheimer's disease,AD)已成为日益严重的公众健康问题。大量证据表明,AD和2型糖尿病(type 2 diabetes mellitus,T2DM)在发病机制、病理生理过程及治疗等方面关系密切。近年来,已有不少有关T2DM最新药物胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)用于AD治疗的基础与临床研究报道,GLP-1及其类似物极有可能成为防治AD的一个新策略。本文将就AD和T2DM的相关性、GLP-1及其类似物、GLP-1受体分布及生理作用、GLP-1神经保护作用分子机制的研究进展作一综述。     

利拉鲁肽抑制高糖诱导的小鼠胰岛细胞损伤

利拉鲁肽(liraglutide,Lira)是胰高血糖素样肽-1的类似物,在糖尿病治疗中发挥重要作用,但利拉鲁肽通过改善胰岛β细胞的功能实现治疗糖尿病的具体机制尚未完全阐明。本研究采用高糖(33 mmol/L)诱导胰岛MIN6细胞48 h建立高糖损伤模型,CCK-8检测发现,与对照组相比,高糖组MIN6细胞活力下降(P <0.05),利拉鲁肽作用高糖组细胞活力升高(P <0.05);小鼠胰岛素和ATP含量检测发现,与对照组相比,高糖组胰岛素分泌降低(P <0.01),ATP含量减少(P <0.001),利拉鲁肽作用高糖组胰岛素释放量增加(P <0.05)和细胞内ATP含量增加(P <0.001);采用活体细胞线粒体膜通道孔(MPTP)荧光检测发现,与对照组相比,高糖组绿色荧光强度降低(P <0.001),利拉鲁肽作用高糖组绿色荧光强度增加(P <0.001);DCFH-DA探针联合流式细胞仪检测细胞活性氧簇(ROS)含量发现,与对照组相比,高糖组ROS水平升高(P <0.001),利拉鲁肽作用高糖组ROS水平降低(P <0.01);细胞内丙二醛(MDA)含量、超氧化物歧化酶(SOD)和过氧化氢酶(CAT)以及细胞上清中乳酸脱氢酶(LDH)活性测定发现,与对照组相比,高糖组MDA和LDH水平升高(P <0.05),SOD和CAT水平降低(P ＜0.01),利拉鲁肽作用高糖组细胞内MDA含量和LDH活性降低(P <0.05),SOD和CAT活性增加(P <0.05);Western印迹检测解偶联蛋白2(uncoupling protein 2,UCP2)的表达发现,与对照组相比,高糖组UCP2表达上调(P <0.01),利拉鲁肽作用高糖组UCP2表达降低(P <0.05)。结果表明,利拉鲁肽对高糖诱导MIN6细胞的线粒体损伤、氧化应激以及胰岛素分泌具有重要作用,其作用机制可能与下调UCP2的表达相关,为利拉鲁肽更好地应用于临床提供了理论依据。     

Glucagon-like peptide-1 relaxes rat conduit arteries via an endothelium-independent mechanism

A lot of interest has engendered in glucagon-like peptide-1 (GLP-1) as an emerging new drug in the treatment of type 2 diabetes. GLP-1 exerts several effects that reduce glycemia in type 2 diabetes patients. We recently also demonstrated that GLP-1 ameliorates endothelial dysfunction in type 2 diabetes mellitus patients with established coronary heart disease, suggesting a new important cardioprotective role for GLP-1. Because hypertension is overrepresented in diabetes and is adversely influencing survival, we have now investigated direct GLP-1 effects on vascular beds in a rat organ bath model. It was found that GLP-1 relaxed femoral artery rings in a dose-response manner. The relaxant effect from GLP-1 was completely inhibited by the specific GLP-1 receptor antagonist, exendin(9-39). Neither the specific nitric oxide (NO) synthase inhibitor, N-nitro-L-arginine, nor removing of endothelium, affected the GLP-1 relaxant effect. In conclusion, we now report a direct vascular action of GLP-1, relaxing conduit vessels independently of NO and the endothelium.     

GLP-1 for type 2 diabetes

Glucagon-like peptide-1 (GLP-1)-based therapy of type 2 diabetes is executed either by GLP-1 receptor agonists, which stimulate the GLP-1 receptors, or by dipeptidyl peptidase-4 (DPP-4) inhibitors, which prevent the inactivation of endogenous GLP-1 thereby increasing the concentration of endogenous active GLP-1. GLP-1 activates pancreatic receptors resulting in improved glycemia through glucose-dependent stimulation of insulin secretion and inhibition of glucagon secretion. There is also a potential beta cell preservation effect, as judged from rodent studies. GLP-1 receptors are additionally expressed in extrapancreatic tissue, having potential for the treatment to reduce body weight and to potentially have beneficial cardio- and endothelioprotective effects. Clinical trials in subjects with type 2 diabetes have shown that in periods of 12 weeks or more, these treatments reduce HbA_1c by ≈ 0.8–1.1% from baseline levels of 7.7–8.5%, and they are efficient both as monotherapy and in combination therapy with metformin, sulfonylureas, thiazolidinediones or insulin. Furthermore, GLP-1 receptor agonists reduce body weight, whereas DPP-4 inhibitors are body weight neutral. The treatment is safe with very low risk for adverse events, including hypoglycaemia. GLP-1 based therapy is thus a novel and now well established therapy of type 2 diabetes, with a particular value in combination with metformin in patients who are inadequately controlled by metformin alone.     

Glucagon-like peptide-1 (GLP-1) inhibits advanced glycation end product (AGE)-induced up-regulation of VCAM-1 mRNA levels in endothelial cells by suppressing AGE receptor (RAGE) expression

Glucagon-like peptide-1 (GLP-1) is one of the incretins, a gut hormone secreted from L cells in the intestine in response to food intake. It has been proposed as a potential therapeutic target for the treatment of patients with type 2 diabetes. However, the direct effects of GLP-1 on vascular injury in diabetes are largely unknown. Since there is a growing body of evidence that advanced glycation end products (AGE) and their receptor RAGE axis plays an important role in vascular complications in diabetes, this study investigated whether and how GLP-1 blocked the deleterious effects of AGE on human umbilical vein endothelial cells (HUVEC). GLP-1 receptor (GLP-1R) was expressed in HUVEC. GLP-1 dose-dependently inhibited RAGE gene expression in HUVEC, which was blocked by small interfering RNAs raised against GLP-1R. An analogue of cyclic AMP also decreased RAGE mRNA level in HUVEC. Further, GLP-1 decreased reactive oxygen species generation and subsequently reduced vascular cell adhesion molecule-1 mRNA levels in AGE-exposed HUVEC. Our present study suggests that GLP-1 directly acts on HUVEC via GLP-1R and it could work as an anti-inflammatory agent against AGE by reducing RAGE expression via activation of cyclic AMP pathways.     

胰高血糖素样肽1受体--治疗糖尿病新药的研究热点

胰高血糖素样肽l(glucagon—like peptide—l,GLP-1)与胰岛素分泌和糖代谢调节密切相关。GLP-1与其受体(GLP-1receptor,GLP-1R)结合后,主要通过cAMP和P13K两条信号途径,促进胰岛素的分泌,刺激胰岛β细胞的增殖和分化。对GLP-1R结构和信号传导机制的研究,有助于了解其在糖尿病病理进程中的作用,为开发新型糖尿病治疗药物指明方向。     

GLP-1 C-terminal structures affect its blood glucose lowering-function.

Glucagon-like peptide-1 (GLP-1), which is an endogenous insulinotropic peptide that can stimulate islet cells to secret insulin, is a promising new drug candidate for the treatment of type 2 diabetes. However, due to the very short half-life of this peptide, the clinical value of GLP-1 is restricted. A GLP-1 peptide analog that had been altered by deletion of five amino acids from the C-terminus (sGLP-1) was selected and investigated in vivo for the therapeutic effect on GK rats with type II DM (T2DM). The results revealed that sGLP-1 exhibited decreased blood glucose-lowering ability compared to GLP-1 in the first week, as measured after once-daily administration. However, after drug administration for 2 weeks, the blood glucose-lowering effect of sGLP-1 became superior to that of GLP-1. sGLP-1 reduced apoptosis of the old islets, enhanced insulin production, and promoted new islets replication. sGLP-1 is a shorter but more efficient GLP-1 analog for type 2 diabetes management. Because sGLP-1 prolonged the proliferation and recovery of islet cells, the ability to maintain blood glucose (BG) within a normal range was still present 2 weeks after drug withdrawal. These results confirmed the importance of the C-terminus of GLP-1 molecule, and further demonstrated that GLP-1 (7-37) can be truncated till the 32nd amino acid to have a better long-term BG lowing function. This result may imply for the presence of glucagon family clearance receptors in vivo and demonstrates that the C-terminus participates in GLP-1 clearance.     

Novel AGLP-1 albumin fusion protein as a long-lasting agent for type 2 diabetes

Glucagon like peptide-1 (GLP-1) regulates glucose mediated-insulin secretion, nutrient accumulation, and β-cell growth. Despite the potential therapeutic usage for type 2 diabetes (T2D), GLP-1 has a short half-life in vivo (t_1/2 ＜2 min). In an attempt to prolong half-life, GLP-1 fusion proteins were genetically engineered: GLP-1 human serum albumin fusion (GLP-1/HSA), AGLP-1/HSA which has an additional alanine at the N-terminus of GLP-1, and AGLP-1-L/HSA, in which a peptide linker is inserted between AGLP-1 and HSA. Recombinant fusion proteins secreted from the Chinese Hamster Ovary-K1 (CHO-K1) cell line were purified with high purity (＞96%). AGLP-1 fusion protein was resistant against the dipeptidyl peptidase-IV (DPP-IV). The fusion proteins activated cAMP-mediated signaling in rat insulinoma INS-1 cells. Furthermore, a C57BL/6N mice pharmacodynamics study exhibited that AGLP-1-L/HSA effectively reduced blood glucose level compared to AGLP-1/HSA. [BMB Reports 2013; 46(12): 606-610]     

The role of GLP-1 in the regulation of islet cell mass

Glucagon-like peptide-1 (GLP-1) is an incretin hormone capable of restoring euglycemia in glucose-intolerant subjects and improving glucose control in individuals with type 2 diabetes. Whether the antidiabetic properties of GLP-1 are exclusively the result of its acute postprandial action is being investigated. A GLP-1-dependent differentiation of pancreatic precursor cells into mature β-cells has been proposed. In addition, GLP-1 has been shown to have antiapoptotic activity in cultured insulin-secreting cells and in an animal model in which diabetes occurs as a consequence of an excessive rate of β-cell apoptosis. Studies from our laboratory, and others, lead us to propose that GLP-1 is a growth factor for pancreatic cells and it is a regulator of islet cell mass. The aim of this article is to review those reports that have emphasized the role of GLP-1 as a regulator of islet cell mass as well as its insulin secretory action.