Sustained release and pharmacologic evaluation of human glucagon-like peptide-1 and liraglutide from polymeric microparticles

Abstract

The GLP1-receptor agonists exert regulatory key roles in diabetes, obesity and related complications. Here we aimed to develop polymeric microparticles loaded with homologous human GLP1 (7-37) or the analogue liraglutide. Peptide-loaded microparticles were prepared by a double emulsion and solvent evaporation process with a set of eight polymers based on lactide (PLA) or lactide-glycolide (PLGA), and evaluated for particle-size distribution, morphology, in vitro release and pharmacologic activity in mice. The resulting microparticles showed size distribution of about 30–50?μm. The in vitro kinetic release assays showed a sustained release of the peptides extending up to 30–40?days. In vivo evaluation in Swiss male mice revealed a similar extension of glycemic and body weight gain modulation for up to 25?days after a single subcutaneous administration of either hGLP1-microparticles or liraglutide-microparticles. Microparticles-loaded hGLP1 shows equivalent in vivo pharmacologic activity to the microparticles-loaded liraglutide.     

利拉鲁肽对人HepG2肝细胞脂代谢的影响及作用机制

目的:建立HepG2肝细胞脂肪变性模型,了解利拉鲁肽是否可改善HepG2细胞内脂代谢状态,并对相关机制进行初步探讨?方法:软脂酸钠诱导建立HepG2肝细胞脂肪变性模型,并给予利拉鲁肽干预?油红O染色确定HepG2肝细胞脂肪变性模型的建立?Western blot检测HepG2 中脂质合成和分解关键酶蛋白水平的变化情况及HepG2 中PI3K信号通路活化情况?采用PI3K信号通路抑制剂预处理HepG2 细胞,观察PI3K信号通路在软脂酸钠诱导建立HepG2肝细胞脂肪变性中的作用?结果:油红O染色结果显示模型建立成功?Western blot结果显示,软脂酸钠诱导可显著升高HepG2中固醇调节元件结合蛋白1c(sterol regulatory element-binding protein1c,SREBP1c)?脂肪酸合成酶(fatty acid synthase,FAS)的蛋白水平,降低脂肪甘油三酯脂酶(adipose triglyceride lipase,ATGL)的蛋白水平(P < 0.01),并上调HepG2中PI3K信号通路活化水平;与软脂酸钠组相比,利拉鲁肽干预可显著降低HepG2中SREBP1c?FAS 的蛋白水平,升高ATGL的蛋白水平,并抑制HepG2中PI3K信号通路活化水平;阻断HepG2中的PI3K信号通路后,软脂酸钠诱导HepG2脂肪变性的能力显著降低(P < 0.01)?结论:利拉鲁肽可通过调节HepG2中的PI3K信号通路,进而改善HepG2细胞的脂代谢情况?     

达格列净对利拉鲁肽治疗后超重/肥胖2型糖尿病患者的疗效

 

目的 观察达格列净对利拉鲁肽治疗12周后超重/肥胖2型糖尿病患者(type 2 diabetic mellitus, T2DM)的疗效。方法 选取93例经利拉鲁肽治疗刚满12周的超重/肥胖T2DM患者,按1∶1随机分为利拉鲁肽(liraglutide,Lir)组46例和达格列净(dapagliflozin,Dap)组47例。Lir组继续应用利拉鲁肽,Dap组换用达格列净,继续治疗12周。比较两组治疗前后血糖、体重、腰围、血压变化。结果 治疗12周后,两组的血糖、体重、腰围、血压均较治疗前下降(P<0.01),其中空腹血糖(fasting blood glucose,FBP)[(1.0±0.6)vs(0.8±0.5)] mmol/L,餐后2 h血糖(2 hours postprandial blood glucose,2hBG)[(1.3±0.8)vs(1.4±0.9)]mmol/L,糖化血红蛋白(glycated hemoglobin,HbA₁c)[(1.0±0.5)vs(0.9±0.6)]%,体重[(1.5±1.4)vs(1.0±1.2)]kg,体重指数(body mass index,BMI)[(0.7±0.6)vs(0.5±0.4)]kg/m²,收缩压[(5.0±3.0)vs(5.0±2.5)]mmHg,舒张压[(3.0±1.0)vs(3.0±1.2)]mmHg,下降幅度无统计学差异(P＞0.05)。但Dap组腰围下降少于Lir组(P<0.01)。结论 对利拉鲁肽治疗后超重/肥胖的T2DM患者,换用达格列净,除腰围下降较少外,降糖、减重、降压的效果与继续原药治疗相同。

     

利拉鲁肽联合二甲双胍治疗肥胖型2型糖尿病的效果及对氧化应激指标的影响

目的 分析利拉鲁肽联合二甲双胍治疗肥胖型2型糖尿病的效果及对氧化应激指标的影响.方法 回顾性选取2019年1月至2021年1月本院收治的96例肥胖型2型糖尿病患者为研究对象,依据治疗方法将其分为利拉鲁肽联合二甲双胍治疗组(联合治疗组)和二甲双胍单独治疗组(单独治疗组),各48例.比较两组患者的BMI、血糖指标、临床疗效...     

GLP-1类似物利拉鲁肽对糖尿病神经病变大鼠坐骨神经PARP-1/NF-κB表达的影响

目的:通过构建大鼠糖尿病周围神经病变(diabetic peripheral neuropathy,DPN)模型探究胰高血糖素样肽1(glucagon-like peptide 1,GLP-1)类似物利拉鲁肽对DPN大鼠坐骨神经聚腺苷二磷酸核糖聚合酶/激活核因子-κB(poly ADP-ribose poly-mera...     

胰岛素泵与利拉鲁肽治疗老年超重2型糖尿病的疗效与安全性

目的:探讨胰岛素泵与利拉鲁肽治疗在老年超重2型糖尿病患者中的应用效果。方法:将68例老年超重2型糖尿病患者分为观察组(胰岛素泵)和对照组(利拉鲁肽)各34例,对比其治疗效果。结果:与对照组相比,观察组患者的治疗有效率(94.12%>73.53%)、SF-36评分((78.82±4.24)分>(69.14±5.16)分)相对更高(P<0.05),并发症发生率(8.82%<32.35%)、FBG((6.29±1.05)<(8.04±1.16)mmol/L)、2h PBG((8.74±1.38)<(10.39±1.57)mmol/L)、BMI((23.51±2.04)<(27.75±2.36)kg/m²)相对更低(P<0.05)。结论:老年超重2型糖尿病的临床治疗,胰岛素泵治疗在疗效和安全性方面具有显著优势。     

The incretin effect and its potentiation by glucagon-like peptide 1-based therapies: a revolution in diabetes management

The incretin effect is a phenomenon in which enteral glucose administration provokes greater insulin secretion than intravenous administration. The main incretins, glucose-dependent insulinotropic peptide and glucagon-like peptide (GLP)-1 are defective in Type 2 diabetes; whereas glucose-dependent insulinotropic peptide displays diminished effectiveness, GLP-1 secretion is decreased; thus, GLP-1 was a stronger candidate for a new class of anti-diabetic agents designed to potentiate the incretin effect. In the past decade, GLP-1 mimetics, peptidase inhibitors and GLP-1 have been developed. Early randomised trials show that these agents contribute to glucose homeostasis and enhance β-cell function, without causing hypoglycaemia or weight gain. This review includes an historical perspective, physiology of incretins, and discussions of the pathophysiology in Type 2 diabetes, pharmacology of the main agents and randomised clinical trials published to date.