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 polymerase/nuclear factor kappa-B,PARP/NF-κB）表达的影响。方法：　SD大鼠84只,随机选12只作为正常组;其余大鼠均采用链脲佐菌素诱导建立DPN模型。建模成功后,抽取72只大鼠随机分为模型组,胰岛素组,甲钴胺组,利拉鲁肽低、中、高剂量组。正常组和模型组皮下注射等体积生理盐水,胰岛素组给予胰岛素治疗,甲钴胺组给予甲钴胺治疗,给药组给予不同剂量利拉鲁肽治疗,共治疗8周。记录各组大鼠体质量和血糖,测定神经反应速度,ELISA检测炎症因子,流式细胞术检测细胞凋亡,Western blot检测PARP-1、NF-κB蛋白表达,EMSA检测NF-κB转录活性。选择RSC96细胞建立高糖环境下细胞损伤模型,应用基因芯片预测PARP-靶基因,并通过转染PARP-1进行检验。结果：　与模型组比较,利拉鲁肽治疗后大鼠体质量显著增加,血糖显著降低,神经反应速度提高（P<0.05）;大鼠实验和细胞实验显示利拉鲁肽给药后细胞炎症因子含量及PARP和NF-κB蛋白表达较模型组显著降低,高剂量组降低幅度更明显（P<0.05）;大鼠神经细胞凋亡率较模型组显著降低（P<0.05）;利拉鲁肽抑制了NF-κB的转录活性;PARP-1转染组炎症因子和PARP-1、NF-κB蛋白水平显著高于中剂量组（P<0.05）,PARP-1/NF-κB是GLP-1对糖尿病神经病变大鼠抗炎症作用的重要靶点。结论：　利拉鲁肽可以降低DPN大鼠坐骨神经PARP-1和NF-κB的表达水平,从而降低大鼠坐骨神经损伤,起到防治糖尿病周围神经病变损伤的作用。     

Liraglutide: once-daily GLP-1 agonist for the treatment of type 2 diabetes

What is known and Objective: The prevalence of diabetes is increasing worldwide. Over the recent years, new discoveries have led to the development of new pharmacological agents targeting the incretin hormones gastric inhibitory peptide (GIP) and glucagon‐like peptide‐1 (GLP‐1). These agents, called incretin‐mimetics, are the newest agents added to the diabetes treatment options. The purpose of this article is to review the relevant literature on the chemistry, pharmacology, pharmacokinetics, metabolism, clinical trials, safety, drug interactions and place in therapy of liraglutide in the treatment of type 2 diabetes. Methods: An extensive search of the literature was performed with liraglutide and NN2211 as key terms. This article presents a review of the literature related to the chemistry, pharmacology, pharmacokinetics, drug interactions and safety and efficacy of liraglutide. Results and Discussion: Liraglutide, a subcutaneously administered GLP‐1 agonist, displays phamacodynamic and pharmacokinetic properties that allow for once‐daily administration. The agent has been shown to be efficacious as monotherapy, as well as in combination with glimperide, metformin and/or rosiglitazone, reducing glycoslyated haemoglobin (A1C) between 0·84% and 1·5%. The primary adverse event reported with liraglutide is transient nausea. What is new and conclusion: Liraglutide has been well studied in dual and triple combination therapies with sulfonylureas, metformin and rosiglitazone and appears safe and effective. For patients who cannot tolerate first‐line agents, metformin, insulin and sulfonylureas, liraglutide is a reasonable treatment option.     

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?     

Diagnostic and Therapeutic Uses of Intestinal Intubation

Intubation of the intestine is widely employed in the clinical management of patients. In this article are discussed some of the more important applications of this procedure in the diagnosis and treatment of intestinal, biliary and pancreatic diseases.     

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。     

Hormone-based therapies in the regulation of fuel metabolism and body weight

Background: The integrated central actions of hormones secreted from pancreatic islets, the gut and adipocytes regulate both energy homeostasis and body weight. Dysregulation in these neurohormonal pathways probably contributes to pathogenesis of obesity and type 2 diabetes. Objective: To examine hormone-based therapies targeting these interrelated pathways as potential treatments for obesity and diabetes. Methods: Preclinical and clinical data on therapies based on hormones secreted from the pancreas (glucagon, insulin, amylin and pancreatic polypeptide), gut (glucagon-like peptide-1, glucose dependent insulinotropic polypeptide, cholecystokinin and peptide YY) and adipose tissue (leptin and adiponectin) as potential treatments for diabetes and obesity are reviewed. Results/conclusions: In diabetes, hormone-based treatments have translated into new clinical platforms including insulin analogs, the GLP-1-like peptide receptor agonist exenatide and amylinomimetic pramlintide, which due to their complex interplay and the progressive nature of diabetes, can be utilized in different settings. Various peptide hormones and agonists/antagonists are currently under investigation as new approaches to treatment of obesity and diabetes.     

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。

     

CORE糖尿病模型预测利拉鲁肽联合二甲双胍治疗2型糖尿病的长期健康结果

目的预测利拉鲁肽联用二甲双胍治疗2型糖尿病的长期健康结果。方法临床数据来源于国际多中心随机对照双盲临床试验NCT00614120,入组对象为来自中国、印度和韩国的2型糖尿病患者。选取利拉鲁肽1.2 mg·d~(-1)组(n=233)、利拉鲁肽1.8 mg·d~(-1)组(n=234)和格列美脲4.0 mg·d~(-1)组(n=231)的患者作为研究对象,每组患者均联用二甲双胍1.5～2.0 g·d~(-1),3组完成试验分别为187例、175例和215例。应用CORE糖尿病模型,输入16 wk临床试验前后患者机体参数改变值,模拟患者终身(30年)治疗健康结果。结果与格列美脲4.0 mg·d~(-1)组相比,利拉鲁肽1.2 mg·d~(-1)组患者背景型视网膜病变、终末期肾病、首次足溃疡和充血性心力衰竭死亡的累积发病率分别降低0.195%、0.086%、0.020%和0.528%,存活率增加了0.32%,预期寿命增加0.018年,质量调整生命年增加0.11年;利拉鲁肽1.8 mg·d~(-1)组以上4种并发症的累积发病率分别降低0.607%、0.116%、0.337%和0.626%,存活率增加了0.42%,预期寿命增加0.051年,质量调整生命年增加0.108年。敏感度分析结果显示,当模拟时间跨度分别设为10年、20年、35年,贴现率分别设置为0和5%时,与格列美脲4.0 mg·d~(-1)组的模拟结果相比,利拉鲁肽1.2 mg·d~(-1)组和1.8 mg·d~(-1)组均获得较长的存活率、预期寿命和质量调整生命年。结论与格列美脲联用二甲双胍相比,利拉鲁肽联用二甲双胍能够延缓并减少2型糖尿病患者并发症的发生,增加存活率、预期寿命与质量调整生命年。