利拉鲁肽用于超重和肥胖患者有效性的系统评价

目的：采用Meta分析系统评价利拉鲁肽治疗超重和肥胖患者的有效性。方法采用计算机检索英文数据库( MEDLINE、EMbase、CENTRAL)和中文数据库(万方数据库、中国知网、维普数据库),查找利拉鲁肽治疗超重和肥胖患者的随机对照试验( RCT),检索时限截至2015年3月。由2位研究者根据纳入与排除标准独立筛选文献、提取资料并评价质量后,采用RevMan5.3.0版软件进行Meta分析。结果最终纳入12个RCT,其中英文文献11篇,中文文献1篇。结果显示在降低患者体质量方面,利拉鲁肽组优于安慰药组、胰岛素组、艾塞那肽组、格列美脲组,且差异均有统计学意义[RR=-0.91,95％CI(-1.01,-0.81),P<0.00001]、[RR=-2.88,95％CI(-3.37,-2.39),P<0.00001]、[RR=-1.12,95％CI(-1.32,-0.92),P<0.00001]、[RR=0.45,95％CI(-0.62,-0.27),P<0.00001]。利拉鲁肽在降低超重和肥胖患者糖化血红蛋白c、收缩压都有明显的效果。结论利拉鲁肽能有效控制超重和肥胖患者的体质量。其远期疗效有待开展更多高质量、大样本、长期随访的RCT加以验证。     

利拉鲁肽治疗血糖控制不佳超重2型糖尿病的疗效

目的 观察利拉鲁肽治疗血糖控制不佳超重2型糖尿病( T2DM)患者的临床效果. 方法 40例口服降糖药物联合胰岛素治疗后血糖控制不佳的超重T2DM患者,在原治疗方案不变的基础上加用利拉鲁肽注射液,连用12周. 观察治疗前、治疗后4周和12周空腹血糖(FPG)、餐后2h血糖(2hPG)、空腹胰岛素(FINS)、空腹C肽、糖化血红蛋白(HbA1c)、体重指数(BMI)、血脂的变化情况. 结果 治疗后FPG、2hPG、空腹C肽、HbA1c、BMI较治疗前均明显下降(P<0.05),随着时间的增加,上述各指标均逐渐降低(P<0.05);治疗前后患者总胆固醇、高密度胆固醇、低密度胆固醇、甘油三酯、脂联素、瘦素水平比较,差异无统计学意义(P>0.05).40 例患者平均HbA1c、体重由治疗前的8.6%、74.4 kg,下降至治疗12周后的7.6%、71.1 kg,分别减少了1.0%、3.3 kg. HbA1c下降幅度与患者治疗前HbA1c水平呈正相关(P<0.05),与患者既往使用胰岛素呈负相关(P<0.05),与其他指标无明显相关性(P>0.05). 治疗期间无低血糖、无胰腺炎及不良免疫反应等发生. 结论 利拉鲁肽对血糖控制不佳超重2型糖尿病(T2DM)患者的治疗效果好,可明显降低体重,改善血糖.     

Complex vasoactivity of liraglutide. Contribution of three gasotransmitters

BackgroundIncretine hormone glucagon-like peptide-1 (GLP-1) causes dose-dependent relaxation of the thoracic aorta of rats and other arteries via nitric oxide (NO), cAMP and ATP-sensitive potassium channels, however, through a mechanism not thoroughly described. Hereby we aimed to determine the mediators involved in the vasoactive effect of liraglutide.MethodsIsolated rat aortic rings and segments of the femoral artery were mounted in a wire myograph to study the vasoactive effect of liraglutide. Vessels were preincubated either with inhibitors of gasotransmitter-, prostaglandin- or reactive oxygen species-formation, or with inhibitors of protein kinases, potassium channels or the Na⁺/Ca²⁺-exchanger.ResultsAccording to our findings, liraglutide activates endothelial cells and vascular smooth muscle cells leading to the production of NO, carbon monoxide, hydrogen sulphide, superoxide anion, and hydrogen peroxide. Increased production of such relaxing factors promotes the activation of protein kinase– A and –G, resulting in the activation of potassium channels (ATP-sensitive-, voltage-gated-, large-conductance-calcium activated), which profoundly contributes to the activation of the Na⁺/Ca²⁺-exchanger, thereby leading to calcium efflux and smooth muscle relaxation and vasorelaxation.ConclusionsWe reveal the contribution of all gasotransmitters in the vasorelaxation induced by liraglutide. We provide ex vivo evidence that liraglutide is capable of causing vasodilatation in the central and peripherial vessels, thereby supporting the clinical observation that it lowers blood pressure.     

利拉鲁肽对高糖条件下HepG2细胞胆固醇流出的影响

目的研究利拉鲁肽对高糖条件下HepG2细胞胆固醇流出的影响,检测相关蛋白表达并探讨其分子机制。方法体外培养HepG2细胞,以高糖刺激并以不同浓度利拉鲁肽干预,采用BODIPY-胆固醇荧光法检测利拉鲁肽对高糖条件下HepG2细胞胆固醇流出的影响,通过Western blot法分析三磷酸腺苷结合盒转运体A1(ABCA1)、ABCG1与清道夫受体B1蛋白表达及细胞外调节蛋白激酶1/2(ERK1/2)信号通路变化。结果利拉鲁肽可显著降低高糖(50 mmol/L)条件下HepG2细胞内荧光密度,增加ABCA1蛋白的表达,且增强ERK1/2的磷酸化水平。结论利拉鲁肽增强高糖条件下HepG2细胞中胆固醇流出,其机制可能与调控ERK1/2信号通路进而上调ABCA1表达有关。     

SIRT1/AMPK通路在利拉鲁肽早期干预缓解高脂饮食导致的大鼠非酒精性脂肪性肝病中的作用

目的:探讨胰高血糖素样肽1(GLP-1)受体激动剂利拉鲁肽(Lira)早期干预对高脂饮食(HFD)诱导的非酒精性脂肪性肝病(NAFLD)大鼠的影响及沉默信息调节因子1(SIRT1)/AMP活化蛋白激酶(AMPK)通路在其中的作用。方法:SPF级雄性SD大鼠随机分为普通饮食(ND)组、HFD组和HFD+Lira组,每组8只。适应性饲养1周后,按不同分组给药,HFD+Lira组大鼠每日固定时间皮下注射Lira(200μg/kg),其余2组注射等体积生理盐水。干预期间注意观察大鼠体重、毛发、食欲、大小便及活动情况,以便及时调整药量。每周记录体重、进食量和血糖,第16周行葡萄糖耐量实验;第18周末麻醉后行高胰岛素-正葡萄糖钳夹实验,该实验结束后颈动脉取血,处死后取肝脏及不同部位的脂肪组织。血清检测丙氨酸转氨酶(ALT)和天冬氨酸转氨酶(AST)等指标;HE染色法观察肝组织病理损伤变化;油红O染色法观察肝组织脂质蓄积程度;马松染色和天狼星红染色法观察肝脏纤维化程度;活性氧簇(ROS)染色观察肝脏氧化应激情况;免疫荧光染色观察肝脏GLP-1受体表达情况;免疫组织化学染色法观察SIRT1和第172位苏氨酸磷酸化的AMPK[p-AMPK(Thr172)]的表达及定位;Western blot法检测肝组织AMPK、p-AMPK(Thr172)、SIRT1、第372位丝氨酸磷酸化的固醇调节元件结合蛋白1c[p-SREBP-1c(Ser372)]、第79位磷酸化的乙酰辅酶A羧化酶[p-ACC(Ser79)]、肉毒碱棕榈酰转移酶1A(CPT1A)和脂肪酸合成酶(FAS)的蛋白水平。结果:HE和油红O染色结果证实HFD组肝组织结构紊乱,脂质蓄积严重,马松和天狼星红染色显示纤维化程度严重,提示NAFLD大鼠模型建立成功。与ND组相比,HFD组血清总胆固醇(TC)、甘油三酯(TG)、AST和ALT,以及肝组织丙二醛(MDA)、TC、TG和ROS水平均显著升高(P<0.01),超氧化物歧化酶(SOD)活性显著降低(P<0.01),肝组织p-AMPK(Thr172)、SIRT1、p-SREBP-1c(Ser372)、p-ACC(Ser79)和CPT1A蛋白水平显著降低(P<0.05或P<0.01),FAS表达显著增加(P<0.01);与HFD组比较,HFD+Lira组大鼠肝组织脂质蓄积和纤维化程度明显减轻,血清TG、TC、AST和ALT,以及肝组织MDA、TC、TG和ROS水平均显著降低(P<0.05或P<0.01),SOD活性增强(P<0.05),肝组织p-AMPK(Thr172)、SIRT1、p-SREBP-1c(Ser372)、p-ACC(Ser79)和CPT1A蛋白水平显著升高(P<0.05或P<0.01),FAS表达显著减少(P<0.01)。结论:Lira能够减轻HFD诱导的NAFLD大鼠胰岛素抵抗、肝纤维化和氧化应激程度,并改善肝脏脂质代谢,其作用可能与SIRT1/AMPK通路有关。     

利拉鲁肽治疗非酒精性脂肪性肝病合并2型糖尿病患者血脂、血管内皮功能和肝纤维化指标的变化*

目的 探讨应用利拉鲁肽治疗非酒精性脂肪性肝病(NAFLD)合并2型糖尿病(T2DM)患者血脂、血管内皮功能和血清肝纤维化指标的变化。方法 2014年1月～2018年12月我院收治的NAFLD合并T2DM患者90例,被随机分为对照组45例和观察组45例,分别给予二甲双胍或二甲双胍联合利拉鲁肽治疗12周。检测空腹血糖(FPG)、餐后 2 h 血糖(2hPPG)和糖化血红蛋白(HbA1c),使用高分辨超声诊断仪检测肱动脉内径变化,记录血管舒张内径达到最大值所需的时间(T₁)和舌下含化硝酸甘油后血管达最大内径所需的时间(T₂),计算肱动脉血流介导的内皮依赖性血管舒张功能(EDR)和硝酸甘油介导的内皮非依赖性血管舒张功能(END)。采用放射免疫分析法检测血清透明质酸(HA)、 层粘连蛋白(LN)、 IV型胶原(CIV)和 III型前胶原(PIIIP)。结果 在治疗结束时,观察组和对照组FPG分别为(7.3±1.9)mmol/L对(8.6±1.8)mmol/L,2hPPG分别为(9.8±2.3)mmol/L对(11.4±2.2)mmol/L,HbA1c水平分别为(7.2±1.0)%对(8.3±1.2)%,差异显著(P＜0.05);血清TC分别为(4.8±0.9)mmol/L对(5.6±1.2)mmol/L、TG分别为(1.5±0.4)mmol/L对(2.0±0.6)mmol/L、LDL-C分别为(2.0±0.6)mmol/L对(2.9±0.7)mmol/L和HDL-C分别为(1.6±0.3)mmol/L对(1.3±0.2)mmol/L,差异显著(P＜0.05);T₁分别为(56.1±6.5)s对(62.9±5.8)s,EDR分别为(7.8±1.0)%对(5.2±0.8)%和END分别为(21.3±2.9)%对(17.2±2.5)%,差异显著(P＜0.05);血清HA分别为(70.3±9.2)ng/ml对(85.9±10.3)ng/ml, CIV分别为(50.2±0.7)ng/ml对(67.3±0.9)ng/ml和PIIIP分别为(6.2±0.6)ng/ml对(8.3±0.5)ng/ml,差异显著(P＜0.05)。结论 应用利拉鲁肽治疗NAFLD合并2 型糖尿病患者能有效降低血糖,改善血管内皮功能,纠正脂代谢紊乱,对预防糖尿病患者大血管并发症可能有益。     

利拉鲁肽对2型糖尿病肥胖患者胰岛细胞功能及NLRP3炎症小体、IL-1β、IL-18的影响

目的 探讨利拉鲁肽对2型糖尿病肥胖患者核苷酸结合寡聚化结构域(NOD)样受体家族3(NLRP3)炎症小体、白细胞介素1β（IL 1β）、白细胞介素18（IL 18）及稳态模型胰岛素抵抗指数（HOMA IR）、胰岛β细胞功能指数（HOMA β）的影响。方法 选取2型糖尿病肥胖患者44例,按随机数字表法分为观察组和对照组各22例,对照组给予口服二甲双胍降糖方案,观察组在对照组基础上给予利拉鲁肽降糖方案。分析两组治疗前和治疗后空腹胰高血糖素、C肽、空腹血糖、HbA1c、总胆固醇水平、NLRP3 mRNA、IL 1β、IL 18及HOMA IR、HOMA β的变化。结果 治疗前两组各指标均没有显著性差异。治疗后观察组患者BMI、空腹血糖、餐后2小时血糖及HbA1c均显著降低,且显著低于对照组;30min、60minC肽及AUC C肽显著增大,30min、60min、120min胰高血糖素及AUC 胰高血糖素显著下降;两组NLRP3 mRNA、IL 1β、IL 18均显著性降低,且观察组显著低于对照组;两组患者HOMA IR均显著性降低,且观察组HOMA IR显著低于对照组,而HOMA β均显著性升高,且观察组HOMA β显著高于对照组。 结论 利拉鲁肽可以抑制NLRP3激活减小IL 1β、IL 18炎症因子的释放,改善胰岛β细胞功能。     

Effects of Dietary Self-Monitoring,Physical Activity,Liraglutide 3.0 mg,and Placebo on Weight Loss in the SCALE IBT Trial

IntroductionIndividuals who enroll in intensive behavioral therapy (IBT) programs are asked to make several lifestyle changes simultaneously. However, few studies have examined the relative effects of adherence to different treatment components on weight loss.ObjectiveThis secondary analysis of the SCALE IBT trial assessed adherence to the medication regimen, dietary self-monitoring, and physical activity recommendations and their relative contributions to weight change in individuals with obesity who were provided with IBT combined with either liraglutide 3.0 mg or placebo.MethodsSCALE IBT was a double-blinded, multicenter, randomized controlled trial comparing 56-week weight losses in individuals with obesity who received liraglutide 3.0 mg (n = 142) or placebo (n = 140), as an adjunct to IBT. Adherence to dietary self-monitoring, physical activity, and medication usage (liraglutide or placebo) were measured during the 56-week treatment period. A regression model was used to estimate the relative contribution of adherence to each treatment component to weight loss at week 56.ResultsThe proportion of individuals who adhered to each intervention component decreased over time. Compared with non-adherence, complete adherence to dietary self-monitoring and physical activity recommendations were associated with estimated weight changes of −7.2% (95% CI −10.4 to −4.0; p < 0.0001) and −2.0% (95% CI −3.2 to −0.8; p = 0.0009), respectively. Complete adherence to liraglutide predicted an additional weight loss of −6.5% (95% CI −10.2 to −2.9; p = 0.0005) relative to individuals who did not adhere to the medication regimen, while adherence to placebo did not have a statistically significant effect on weight loss (p = 0.33).ConclusionsHigh adherence to dietary self-monitoring and use of liraglutide 3.0 mg was associated with clinically relevant weight loss with IBT and adjunctive pharmacotherapy. The effect of adherence to physical activity was significant but smaller.