基于ROS-NLRP3炎症小体介导的细胞焦亡探究利拉鲁肽对糖尿病肾病大鼠肾损伤的保护作用

目的 探究利拉鲁肽对糖尿病肾病大鼠的作用及其调控机制。方法 采取多次小剂量ip链脲佐菌素40 mg/kg构建糖尿病肾病大鼠模型,分为模型组、利拉鲁肽组、活性氧簇（ROS）抑制剂（NAC）组、利拉鲁肽+NAC组,另设置对照组,每组10只。利拉鲁肽组大鼠sc 200μg/(kg·d)的利拉鲁肽;NAC组大鼠ip 20 mg/(kg·d)的NAC;利拉鲁肽+NAC组大鼠sc 200μg/(kg·d)的利拉鲁肽的同时ip 20 mg/(kg·d)的NAC;对照组和模型组大鼠sc等量的生理盐水,1次/d,连续治疗4周。全自动分析仪检测24 h尿微量蛋白排泄率（MAER）;血糖仪测定空腹血糖（FBG）;试剂盒检测血清肌酐（Scr）、尿素氮（BUN）水平;HE染色、Masson染色观察肾组织病理变化;二氢乙锭（DHE）荧光探针检测肾组织活性氧（ROS）水平;化学比色法检测肾组织丙二醛（MDA）含量、谷胱甘肽过氧化物酶（GSH）和超氧化物歧化酶（SOD）活性;Western blotting检测肾组织NOD样受体蛋白3(NLRP3)炎症小体和焦亡相关蛋白表达。结果 与模型组相比,利拉鲁肽组和NAC组大...     

Current perspectives in treatment of angina pectoris

Intravenous immunoglobulin is an important method of treating idiopathic thrombocytopenic purpura, especially when a rapid platelet response is desired. Dr Besa explains how to use this therapy in acute and chronic purpura in both children and adults. He also describes the four preparations available and discusses efficacy, cost, and safety.     

Liraglutide protects Rin‐m5f β cells by reducing procoagulant tissue factor activity and apoptosis prompted by microparticles under conditions mimicking Instant Blood‐Mediated Inflammatory Reaction

Instant Blood‐Mediated Inflammatory Reaction (IBMIR) occurs at the vicinity of transplanted islets immediately after intraportal infusion and is characterized by cytokine secretion, tissue factor (TF) expression, and ß cell loss. Microparticles (MPs) are cellular effectors shed from the plasma membrane of apoptotic cells. Modulation of the properties of ß cell‐derived MPs by liraglutide was assessed in a cellular model designed to mimic IBMIR oxidative and inflammatory conditions. Rin‐m5f rat β cells were stimulated by H₂O₂ or a combination of IL‐1β and TNF‐α. Cell‐derived MPs were applied to naive Rin‐m5f for 24 h. Apoptosis, MP release, TF activity, P‐IκB expression, and MP‐mediated apoptosis were measured in target cells. Direct protection by liraglutide was shown by a significant decrease in the oxidative stress‐induced apoptosis (18.7% vs. 7.6%, P < 0.0001 at 1 μm liraglutide) and cellular TF activity (?40% at 100 nm liraglutide). Indirect cytoprotection led to 20% reduction in MP generation, thereby lowering MP‐mediated apoptosis (6.3% vs. 3.7%, P = 0.022) and NF‐κB activation (?50%) in target cells. New cytoprotective effects of liraglutide were evidenced, limiting the expression of TF activity by ß cells and the generation of noxious MPs. Altogether, these data suggest that liraglutide could target pro‐apoptotic and pro‐inflammatory MPs in transplanted islets.     

Investigational glucagon-like peptide-1 agonists for the treatment of obesity

Introduction: Obesity is a worldwide problem predisposing to type 2 diabetes mellitus (T2DM), hypertension, cardiovascular disease, cancer and other comorbidities. Lifestyle modification is the first line intervention but adjunctive pharmacotherapy is often required. The GLP-1 receptor agonists (GLP-1RAs) were developed primarily for T2DM and they also reduce body weight. Liraglutide was approved for the treatment of obesity and other GLP-1RAs are likely to be suitable for this indication.

Areas covered: This review describes the GLP-1RAs that have been approved for the treatment of T2DM as potential candidates for the treatment of obesity and the new agents currently under development which may have advantages in patient adherence.

Expert opinion: The GLP-1RAs offer a welcome addition to obesity pharmacotherapy. They appear to be free of serious adverse effects although uncertainty remains about possible risks of pancreatitis and neoplasms. However, they have frequent gastrointestinal side effects, particularly nausea, which limits their tolerability. Cardiovascular outcome studies in T2DM support their use and this is likely to increase in both T2DM and obesity. Other GLP-1RAs which can be given by subcutaneous injection once weekly or less frequently or by oral administration would have advantages especially if nausea is less frequent than with liraglutide.     

Liraglutide,a once‐daily human GLP‐1 analogue,improves pancreatic B‐cell function and arginine‐stimulated insulin secretion during hyperglycaemia in patients with Type 2 diabetes mellitus

Aims To assess the effect of liraglutide, a once‐daily human glucagon‐like peptide‐1 analogue on pancreatic B‐cell function. Methods Patients with Type 2 diabetes (n = 39) were randomized to treatment with 0.65, 1.25 or 1.9 mg/day liraglutide or placebo for 14 weeks. First‐ and second‐phase insulin release were measured by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Arginine‐stimulated insulin secretion was measured during a hyperglycaemic clamp (20 mmol/l). Glucose effectiveness and insulin sensitivity were estimated by means of the insulin‐modified frequently sampled intravenous glucose tolerance test. Results The two highest doses of liraglutide (1.25 and 1.9 mg/day) significantly increased first‐phase insulin secretion by 118 and 103%, respectively (P < 0.05). Second‐phase insulin secretion was significantly increased only in the 1.25 mg/day group vs. placebo. Arginine‐stimulated insulin secretion increased significantly at the two highest dose levels vs. placebo by 114 and 94%, respectively (P < 0.05). There was no significant treatment effect on glucose effectiveness or insulin sensitivity. Conclusions Fourteen weeks of treatment with liraglutide showed improvements in first‐ and second‐phase insulin secretion, together with improvements in arginine‐stimulated insulin secretion during hyperglycaemia.     

老年2型糖尿病患者经利拉鲁肽治疗后外周血IGF-1及IGF-1R的表达变化

目的 观察老年2型糖尿病患者经利拉鲁肽治疗后胰岛素样生长因子1(IGF-1)及胰岛素样生长因子1受体(IGF-1R)的表达变化情况,以探讨利拉鲁肽治疗老年2型糖尿病的价值。方法 选取2017年1月-2019年2月期间于我院门诊82例老年2型糖尿病患者,采用数字奇偶法将入选者分为观察组(奇数)与对照组(偶数),各41例。所有入选者均接受常规治疗并联合使用二甲双胍,在此基础上为观察组患者联合利拉鲁肽治疗,均治疗6个月;分别于治疗前、治疗6个月后检测并比较两组IGF-1及IGF-1R水平、记录两组身体质量指数(BMI)及腰围并比较、检测并比较两组胰岛功能[空腹C肽(FC-P)、餐后两小时C肽(2hC-P)]、脂联素及抵抗素水平;治疗期间记录并比较两组不良反应发生情况。结果 治疗6个月后,两组IGF-1及IGF-1R水平均较治疗前降低,且观察组各水平均低于对照组,差异有统计学意义(P＜0.05);治疗6个月后,对照组BMI、腰围、FC-P水平、2hC-P、胰岛素抵抗指数(HOMA-IR)水平、脂联素水平、抵抗素水平较治疗前无明显变化,各指标组内比较差异无统计学意义(P＞0.05);治疗6个月后,观察组BMI值、抵抗素水平较治疗前降低、腰围较治疗前缩小,FC-P、2hC-P、HOMA-IR、脂联素水平均较治疗前升高,且BMI、抵抗素水平低于对照组、腰围小于对照组、FC-P、2hC-P、HOMA-IR、脂联素水平均高于对照组,差异有统计学意义(P＜0.05);治疗期间组间不良反应发生率比较差异无统计学意义(P＞0.05)。结论 老年2型糖尿病患者经利拉鲁肽治疗获益明显,患者外周血IGF-1及IGF-1R水平明显改善,有利于调节患者胰岛功能、降低BMI、缩小腰围,患者脂联素、抵抗素水平显著改善,临床应用价值高。     

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。