胰高糖素样肽-1类似物的进展与临床应用评价

目的:胰高糖素样肽-1类似物的问世为抗糖尿病药宝库中增添了一朵奇葩,其进展神速,作用途径独特,迂回在胰岛β细胞和胰岛素之外,本文总结其作用特点和临床评价。方法:对国内外近期文献进行分析。结果与结论:胰高糖素样肽-1类似物作用确切,在大量的临床研究中显示了良好效果和安全性,为糖尿病者的治疗展现了治疗前景,在延缓或逆转糖尿病自然病程的治疗策略中,为研发抗糖尿病新药提供了更为广阔的空间。     

Exenatide对多囊卵巢综合征大鼠胰腺组织SIRT1表达的影响

[目的]观察Exenatide对多囊卵巢综合征(PCOS)大鼠胰腺沉默信息调节因子1(SIRT1)表达的影响,探讨其对PCOS大鼠的干预治疗效果及可能机制.[方法]采用脱氢表雄酮(DHEA)诱导建立(n=50)PCOS雌性大鼠模型,随机分成Exenatide组(EX组,10只),给予EX颈部皮下注射;二甲双胍组(MF组,10只),给予MF无菌蒸馏水溶解灌胃;PCOS组(9只)及正常对照组(NC组,10只).连续给药4周后检测各组大鼠血清空腹胰岛素(FINS)、并进行糖耐量试验(OGTT),计算HOMA-IR指数.采用免疫组化及Real-time PCR法测定各组大鼠胰腺SIRT1的表达情况.[结果]①免疫组化和Q-PCR在蛋白水平和mRNA水平表明SIRT1表达于正常的胰腺内分泌组织中.PCOS组与NC组相比SIRT1表达明显降低(P＜0.05),经过药物干预后的EX和MF组与PCOS组相比表达均有不同程度升高(P＜0.05),而EX和MF之间相比没有统计学差异.②SIRT1表达与血清FPG、FINS、HOMA-IR呈明显负相关.[结论]Exenatide的干预改善了大鼠的血糖水平和胰岛素抵抗状态.SIRT1的表达下降可能在PCOS的发生发展中具有重要作用,Exenatide可能会通过上调SITR1的表达具有治疗PCOS的潜在作用.     

Retrospective cohort study evaluating exenatide twice daily and long-acting insulin analogs in a Veterans Health Administration population with type 2 diabetes

AimThis was a retrospective cohort study that evaluated the differences in glycated haemoglobin (HbA_1c) and body mass index (BMI) in veterans with type 2 diabetes mellitus (T2DM), prescribed exenatide twice daily (BID) versus long-acting insulin analog (LAIA) two years after initiation in the United States (US) veteran population.Materials and methodsPatients were included if they were ≥ 18 years old with T2DM, and initiated exenatide BID or LAIA at the Veterans Health Administration between January 1, 2006 and December 31, 2010. Multivariate models were used to evaluate the changes in HbA_1c and BMI between groups, controlling for potential confounders. Logistic regression was used to evaluate the odds of achieving ≥ 0.5% HbA_1c reduction based on baseline HbA_1c stratifications: low, < 7%; moderate, 7% to < 9%; and high, ≥ 9%.ResultsA total of 446 exenatide BID and 51,531 LAIA patients met inclusion/exclusion criteria. On average, exenatide BID patients were significantly older (64 versus 60 years) with a higher BMI (37.8 versus 32.9 kg/m²). Baseline HbA_1c was 8.2% and 8.8% for exenatide BID and LAIA patients, respectively (P < 0.001); otherwise, patients were similar for all other characteristics. Exenatide BID treatment was significantly associated with a 0.32% (95%CI: 0.18–0.47%) greater reduction in HbA_1c at two years compared with LAIA. Similar findings were observed for BMI reduction (0.68 kg/m²; 95%CI: 0.42–0.95 kg/m²). Exenatide BID patients with moderate baseline HbA_1c had significantly higher odds of achieving ≥ 0.5% HbA_1c reduction compared with LAIA patients (OR = 1.5; 95%CI: 1.2–2.0).ConclusionsVeterans treated with exenatide BID had significantly greater reduction in HbA_1c and BMI compared with patients treated with LAIA patients two years after initiation.     

Fatty liver-induced changes in stereotypic behavior in rats and effects of glucagon-like peptide-1 analog on stereotypy

Although understanding the relation between psychotic behavior and immune abnormalities has been the focus of research for many years, it remains to be elucidated whether the changes in cytokine levels are part of etiology or a result of the stress associated with the disorder. In accordance with previous studies on changes in cytokine levels due to metabolic changes and psychosis, we hypothesized that fatty liver may potentiate apomorphine-induced stereotypy in a rodent model and that a synthetic glucagon-like peptide-1 analog exenatide would ameliorate this effect. In this study, 18 male Sprague Dawley albino mature rats were used. We induced hepatosteatosis in these rats by feeding them with 30% fructose dissolved in drinking water for 8 weeks. The animals were divided into three groups, namely, the normal group, the intracerebroventricular (ICV) exenatide group, and the ICV NaCl group. Apomorphine-induced stereotypic behavior test was performed in all groups and the liver was removed for histopathological examination after all the rats were euthanized. In the nonalcoholic fatty liver (NAFL) group, stereotypy scores were significantly increased compared with the control group rats (p < 0.00001). A significant decrease in stereotypy scores were observed in the ICV exenatide group with NAFL when compared with the ICV saline group with NAFL (p < 0.005). In addition, brain malondialdehyde and tumor necrosis factor-α levels decreased in the ICV exenatide group. The results of this study showed that fatty liver enhances the effect of apomorphine on stereotypy, which was reversed by exenatide possibly by antioxidant and anti-inflammatory effects.     

Novel adjunctive treatments of myocardial infarction

Myocardial infarction is a major cause of death and disability worldwide and myocardial infarct size is a major determinant of prognosis. Early and successful restoration of myocardial reperfusion following an ischemic event is the most effective strategy to reduce final infarct size and improve clinical outcome,but reperfusion may induce further myocardial damage itself. Development of adjunctive therapies to limit myocardial reperfusion injury beyond opening of the coronary artery gains increasing attention. A vast number of experimental studies have shown cardioprotective effects of ischemic and pharmacological conditioning,but despite decades of research,the translation into clinical effects has been challenging. Recently published clinical studies,however,prompt optimism as novel techniques allow for improved clinical applicability. Cyclosporine A,the GLP-1 analogue exenatide and rapid cooling by endovascular infusion of cold saline all reduce infarct size and may confer clinical benefit for patients admitted with acute myocardial infarcts. Equally promising,three follow-up studies of the effect of remote ischemic conditioning(RIC) show clinical prognostic benefit in patients undergoing coronary surgery and percutaneous coronary intervention. The discovery that RIC canbe performed noninvasively using a blood pressure cuff on the upper arm to induce brief episodes of limb ischemia and reperfusion has facilitated the translation of RIC into the clinical arena. This review focus on novel advances in adjunctive therapies in relation to acute and elective coronary procedures.     

艾塞那肽对糖尿病自主神经病变患者氧化应激状态、血糖水平及心率变异性的影响

目的 探讨艾塞那肽对糖尿病自主神经病变（DAN）患者氧化应激、血糖及心率变异性的影响。方法 选取2015年4月—2017年4月在北京航天总医院治疗的DAN患者128例,根据患者最终选取的治疗方案分为观察组（n=67）和对照组（n=61）,对照组给予常规糖尿病治疗方案,观察组在对照组基础上给予sc艾塞那肽,2次/d,5 μg/次,总疗程12周。观察两组患者氧化应激、血糖及心率变异性情况。结果 观察组治疗后餐后2 h血糖（2h-PG）、糖化血红蛋白（HbA1c）和体质量指数（BMI）分别为（7.02±1.37）mmol/L、（6.71±1.82）%和（24.89±1.03）kg/m²,均显著低于对照组（P<0.05）。观察组治疗后丙二醛（MDA）、同型半胱氨酸（Hcy）分别为（2.51±0.91）mol/L和（12.03±3.11）μmmol/L,均显著低于对照组（P<0.05）,而超氧化物歧化酶（SOD）为（37.10±5.03）mU/L,显著高于对照组（P<0.05）。观察组治疗后总体标准差（SDNN）、差值均方的平方根（RMSSD）、爱丁堡指数（PNN50）、极频（VLF）、低频（LF）、高频（HF）分别为（50.25±8.10）ms、（26.02±5.55）ms、（12.01±1.32）%、（86.02±8.22）ms²、（71.14±7.05）ms²、（42.10±8.33）ms²,均显著高于对照组（P<0.05）,而LF/HF为（1.72±0.48）,显著低于对照组（P<0.05）。结论 艾塞那肽能有效控制DAN患者血糖,改善患者BMI和心率变异指标,减轻氧化应激反应。     

艾塞那肽治疗不同体质量指数的2型糖尿病患者的观察

目的观察艾塞那肽对不同体质量指数（BMI）的2型糖尿病患者的疗效及安全性。方法62例经口服降糖药物治疗而血糖控制不佳（HbAlC〉17．0％）的2型糖尿病患者,依据BMI分为3组,A组（正常组,19≤BMI〈24）,B组（超重组,24≤BMI〈28）,C组（肥胖组,BMIt〉28）。3组均加用艾塞那肽。12周后比较3组治疗前、后糖化血红蛋白（HbA1C）、空腹血糖（FPG）、餐后2h血糖（2hPG）、血脂、体质量、收缩压（SBP）、舒张压（DBP）的变化,记录低血糖发生的次数及不良反应。结果3组患者HbAlC、FPG、2hPG、血甘油三酯（TG）与治疗前相比均有明显降低（P〈0．01）,血高密度脂蛋白胆固醇（HDL—C）较治疗前明显升高（P〈0．05）,B组及C组体质量、BMI与治疗前相比也有明显下降（分别为P〈0．05,P〈0．01）,同时两组SBP、DBP也有显著降低（P〈0．05）。结论艾塞那肽更适用于超重及肥胖的2型糖尿病患者。     

艾塞那肽诱发大鼠胰腺组织病变的实验研究

目的 探讨艾塞那肽诱发大鼠胰腺组织病变的可能机制.方法 SD雄性大鼠30只按完全随机法分为艾塞那肽组、糖尿病组和对照组,每组10只.高糖、高脂喂养及腹腔注射链脲佐菌素（35 mg/kg体质量）方法诱导大鼠糖尿病模型,艾塞那肽组和糖尿病组每天2次皮下注射艾塞那肽5 μg/kg体质量,对照组皮下注射等容积生理盐水,实验周期为10周.大鼠处死后取胰腺组织,常规病理检查.免疫组化法检测胰腺组织α-平滑肌肌动蛋白（α-SMA）和Ⅲ型胶原蛋白表达,ELISA法检测胰腺组织基质金属蛋白酶2（MMP-2）和MMP-9含量.结果 对照组大鼠胰腺组织未见病理变化,艾塞那肽组大鼠胰腺组织出现慢性炎性改变,糖尿病组大鼠胰腺病变程度较艾塞那肽组严重,3组胰腺病理评分依次增高（P＜0.05）.对照组、艾塞那肽组和糖尿病组胰腺组织的MMP-2含量分别为（186.98±23.24）、（306.07±59.82）、（365.08±89.55） μg/L;MMP-9含量分别为（49.37±7.08）、（67.24±14.73）、（87.37±13.39） μg/L.艾塞那肽组和糖尿病组均显著高于对照组（P值均＜0.05）,但艾塞那肽组和糖尿病组间的差异无统计学意义.对照组、艾塞那肽组和糖尿病组大鼠高倍视野内胰腺组织的α-SMA阳性表达细胞数分别为（13.4±6.0）、（29.5±8.8）、（79.3±27.2）个,Ⅲ型胶原蛋白阳性表达细胞数分别为（10.6±4.9）、（29.3±13.0）、（56.0±27.2）个.艾塞那肽组阳性细胞数均显著多于对照组,糖尿病组阳性细胞数又显著多于艾塞那肽组（P值均＜0.05）.结论 长期皮下注射艾塞那肽可能激活胰腺星状细胞,表达α-SMA和Ⅲ型胶原蛋白,分泌MMP-2、MMP-9,诱发胰腺组织慢性炎性改变.     

艾塞那肽对糖尿病自主神经病变患者血清氧化应激和心率变异性的影响

目的 探讨艾塞那肽对糖尿病自主神经病变（DAN）患者氧化应激状态和心率变异性的影响.方法 选择2011年7月至2012年7月在武汉大学人民医院内分泌科住院的2型糖尿病自主神经病变患者62例,按照随机数字表法分为常规治疗组和艾塞那肽组,各31例.常规治疗组给予糖尿病药物治疗,艾塞那肽组在常规治疗的基础上给予艾塞那肽治疗.观察两组患者治疗前后血清氧化应激状态及心率变异性（HRV）的变化.结果 艾塞那肽组血清超氧化物歧化酶及还原性谷胱甘肽活性水平[（36.30±9.04） mU/L、（188.43±46.13） ng/L]较治疗前[（28.89±9.62） mU/L、（159.21±45.34） ng/L]显著升高（P＜0.05）,丙二醛水平[（2.59±0.89） mmol/L]较治疗前[（4.42±1.07） mmol/L]显著下降（P＜0.05）,心率变异性指标的改善显著优于对照组（P＜0.05）.结论 艾塞那肽对DAN有一定疗效,可改善心率变异指标,疗效可能与抗氧化作用有关.