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.     

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.     

治疗肥胖症药——利拉鲁肽

利拉鲁肽(liraglutide,商品名SAXENDA)是由丹麦诺和诺德公司研制的用于肥胖治疗的人胰高血糖素样肽-1(GLP-1)类似物。至2014年12月,FDA批准作为治疗慢性肥胖的药物后,2015年1月欧洲药品管理局(EMA)人用医药产品委员会(CHMP)也已建议批准。在长期临床试验表明,利拉鲁肽(3mg)结合饮食和锻炼,能够有效减轻患者体重,同时也显著改善了肥胖相关合并症,是目前唯一的减肥针剂。笔者从利拉鲁肽的基本信息、作用机制、药动学、药效学、临床试验、不良反应及国内研发动态等方面进行评述,希望能给医院临床合理用药提供帮助。     

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。     

Current treatments and strategies for type 2 diabetes: Can we do better with GLP-1 receptor agonists?

Abstract

Diet, lifestyle modification, and pharmacotherapy with metformin are appropriate initial treatments for many patients with type 2 diabetes (T2DM). However, most individuals do not maintain glycemic control with metformin alone. Addition of other oral antidiabetes drugs (OADs), including sulfonylurea, meglitinide, or thiazolidinedione, is often the next step. Newer options, including incretin-based glucagon-like peptide-1 (GLP-1) receptor agonists (RAs) and dipeptidyl peptidase-4 (DPP-4) inhibitors, offer important benefits as monotherapies or in combination with OADs, with low risk for hypoglycemia. Reductions in glycated hemoglobin (A1C) have been reported among patients treated with GLP-1 RAs (exenatide, ?0.8 to ?1.1%; liraglutide, ?0.8 to ?1.6%), as has weight loss (exenatide, ?1.6 to ?3.1 kg; liraglutide, ?1.6 to ?3.2 kg). GLP-1 RAs also stimulate β-cell responses and have positive effects on cardiovascular risk factors often present in patients with T2DM. The most common adverse events associated with GLP-1 RAs are nausea, which diminishes over time, and hypoglycemia (when used in combination with a sulfonylurea). A large number of trials demonstrated benefits of GLP-1 RAs, suggesting they could provide suitable treatment options for patients with T2DM.     

利拉鲁肽对大鼠心肌微血管内皮细胞缺氧复氧损伤的影响

 目的 探究胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)类似物利拉鲁肽(GLP-1 analogue,Liraglutide)对大鼠心肌微血管内皮细胞(cardiac microvascular endothelial cells, CMEC)缺氧复氧损伤的影响。方法 双酶消化法体外分离培养SD大鼠CMEC,实验的细胞分为正常对照组、Liraglutide(0~100 nM)组、H/R组、H/R+Liraglutide组。建立缺氧复氧模型(hypoxia/reoxygenation model,H/R)诱导的细胞氧化应激凋亡模型,流式细胞学检测细胞凋亡率,DCFHDA荧光探针检测胞内ROS的变化免疫荧光染色和Western Blot检测XO、caspase3等蛋白分子的表达情况,通过比较各组中XO、ROS以及凋亡相关蛋白caspase3的表达情况阐明Liraglutide在抗细胞氧化应激过程中的保护作用机制。结果 与正常对照组细胞相比,H/R模型条件诱导细胞中XO表达增加,生成过量ROS及凋亡蛋白的表达,最终导致凋亡细胞数量显著提高至20.66%±1.30%。Liraglutide预处理12 h抑制了H/R诱导的XO的激活,最终降低胞浆过量ROS并将细胞的凋亡数量降低至8.36±1.19%。结论 H/R模型导致XO-ROS激活,生成过量胞浆ROS,最终介导了CMEC的线粒体凋亡通路激活,而予以Liraglutide预处理可以逆转上述过程。     

影响患者利拉鲁肽降糖疗效因素的回顾分析

目的：为促进利拉鲁肽合理应用提供依据,回顾性分析影响2型糖尿病（type 2 diabetic mellitus,T2DM）患者使用利拉鲁肽降糖疗效的因素。方法：以华东医院2019年1月至2020年8月间使用利拉鲁肽的T2DM患者为研究对象,采用回顾性分析方法,观察和比较患者首次使用利拉鲁肽3个月及以上前后的糖化血红蛋白（HbA1c）、BMI （身体质量指数）和体质量的差异,分成疗效达标（治疗后HbA1c<7%或下降幅度>1%）和疗效未达标组。通过独立样本t检验和卡方检验分析组间基线数据差异,包括基本信息、检验指标,还有合并用药情况,Logistic回归法筛选出降糖疗效的影响因素。结果：在所有纳入研究的患者中,HbA1c、BMI和体质量指标分别下降（1.13±2.04）%、（0.77±1.48） kg·m^-2、（2.41±4.04） kg。140例（60.9%）患者达到预期的降糖目标,90例（39.1%）未达标。研究还发现2组患者的年龄、DM病程、体质量、性别和联用胰岛素的差异具有统计学意义（P=0.005、P=0.000、P=0.044、P=0.016、P=0.011）,Logistic回归分析显示年龄和联用胰岛素对利拉鲁肽降糖疗效影响有显著意义[P=0.004,OR=0.907,95% CI （0.848,0.969）;P=0.000,OR=0.151,95% CI （0.058,0.396）]。结论：首次使用利拉鲁肽时,患者的年龄、DM病程、体质量、性别和联用胰岛素与其降糖疗效达标相关,年龄和联用胰岛素是影响利拉鲁肽疗效的主要因素。临床个体化用药时,可评估以上因素对疗效的影响。     

Liraglutide treatment improves endothelial function in the Ldlr−/− mouse model of atherosclerosis and affects genes involved in vascular remodelling and inflammation

Recent clinical intervention studies have shown that the GLP1 analogue liraglutide lowers cardiovascular risk, but the underlying mechanism has not yet been fully elucidated. This study investigated the effects of liraglutide on endothelial function in the Ldlr?/? mouse model. Mice (n = 12/group) were fed Western diet (WD) or chow for 12 weeks followed by 4 weeks of treatment with liraglutide (1 mg/kg/day) or vehicle subcutaneously. Weight loss, blood lipid content, plaque burden, vasomotor function of the aorta and gene expression pattern in aorta and brachiocephalic artery were monitored. Liraglutide treatment significantly induced weight loss (P < .0001), decreased blood triglycerides (P < .0001) and total cholesterol (P < .0001) in WD‐fed mice but did not decrease plaque burden. Liraglutide also improved endothelium‐mediated dilation of the distal thoracis aorta (P = .0067), but it did not affect phenylephrine or sodium nitroprusside responses. Fluidigm analyses of 96 genes showed significantly altered expression of seven genes related to inflammation, vascular smooth muscle cells and extracellular matrix composition in liraglutide‐treated animals. We conclude that treatment with liraglutide decreased endothelial dysfunction and that this could be linked to decreased inflammation or regulation of vascular remodelling.