胰高血糖素样肽-1/葡萄糖依赖性促胰岛素多肽双受体激动剂替西帕肽

新型胰高血糖素样肽-1/葡萄糖依赖性促胰岛素多肽(GLP-1/GIP)双受体激动剂替西帕肽,临床显示具有较强的降糖效果,并且减轻体质量效果非常显著,可以提高胰岛素敏感性,同时具有优越的心血管保护作用和改善非酒精性脂肪性肝病/非酒精性脂肪性肝炎(NAFLD/NASH)的作用,并且副作用小,依从性好。替西帕肽作为双肠道激素激动剂对改善代谢水平显示出强大的潜力。该文就GLP-1/GIP双受体激动剂替西帕肽的作用机制和临床研究进行综述。     

超重或肥胖2型糖尿病患者的注射降糖治疗策略

随着自然病程的进展,2型糖尿病患者常需进行起始注射降糖治疗。对于超重或肥胖的2型糖尿病患者,选择注射降糖治疗时常会面临诸多的挑战。与胰岛素相比,胰高血糖素样肽-1(glucagon-like peptide-1,GLP-1)受体激动剂有相似的降糖疗效,且可显著减轻体重,改善胰岛素抵抗,保护胰岛β细胞功能,降低血压,改善血脂异常及非酒精性脂肪性肝病等。因此,在超重或肥胖的2型糖尿病患者中,GLP-1受体激动剂具有改善多重代谢异常的综合益处。     

胰高血糖素样肽-1受体激动剂的研究进展

在健康人中,肠降血糖素胰高血糖素样肽-1(GLP-1)是在进食后分泌,并通过增加胰岛素分泌和抑制胰高血糖素释放而降低葡萄糖浓度。天然GLP-1在体内降解时间约为2~3 min,因此需要开发各种GLP-1受体激动剂以延长其体内作用时间。已开发出的GLP-1受体激动剂分为短期受体激活的化合物(例如艾塞那肽)和GLP-1受体的长效化合物(例如阿必鲁肽和利拉鲁肽等),以及小分子非肽类药物。这些GLP-1受体激动剂的个体性质可能使基于肠降血糖素的2型糖尿病治疗满足每个患者的需要。本文对当前GLP-1激动剂类药物的研究进行了综述。     

GLP-1R激动剂及正变构调节剂研究进展

胰高血糖素样肽-1受体(glucagon-like peptide-1 receptor, GLP-1R)是治疗2型糖尿病的重要靶标，作为一种G蛋白偶联受体可通过胰高血糖素样肽-1介导胰岛素分泌。该文对胰高血糖素样肽-1和GLP-1R的结构与功能进行综述，并对肽类GLP-1R激动剂、非肽类小分子GLP-1R激动剂和GLP-1R正变构调节剂的设计开发进行讨论，旨在为进一步探寻2型糖尿病的治疗方案提供思路。     

胰高血糖素样肽-1受体激动剂药理作用的研究进展

胰高血糖素样肽-1是经胰高血糖素原基因编码、肠道L细胞分泌的多肽类物质,在营养物质、细胞因子、神经信号等刺激下通过促进胰岛素的分泌而发挥降糖作用。近年来,胰高血糖素样肽-1受体激动剂在2型糖尿病治疗方面已获肯定,与传统降糖药物相比,其除可以稳定降糖外,还具有减重、降压、调脂、心血管和肾脏保护等益处。主要对GLP-1受体激动剂药理作用的研究进展进行综述。     

胰高血糖素样肽-1受体激动剂治疗2型糖尿病的研究进展

糖尿病目前已经成为继心血管疾病和肿瘤之后的第三位主要非传染性疾病,其中90%为2型糖尿病患者。作为肠促胰素激素之一的胰高血糖素样肽1（GLP-1）受体激动剂具有集多效于一身的降糖作用,已成为2型糖尿病治疗新热点。利拉鲁肽与人体内天然GLP-1保持了高度同源性（97%）,成为新一代人GLP-1类似物研发的亮点。我国科学家最近在非肽类小分子胰高血糖素样肽-1受体激动剂的研究领域取得了令世人瞩目的开创性研究成果。     

治疗非酒精性脂肪性肝病的调节代谢类药物临床试验研究进展

非酒精性脂肪性肝病(NAFLD)是一种慢性疾病,全球患病率高达25%。由于该病的发病机制复杂,到目前为止尚无特效药治疗。大多数NAFLD新药是通过作用于某一靶点调节糖脂代谢改善症状,进而阻止非酒精性脂肪性肝炎(NASH)甚至肝硬化等更严重疾病的发生。本文通过检索美国临床试验注册中心(https://clinicaltrials.gov/)、中国临床试验注册中心(https://www.chictr.org.cn/)及药物临床登记与信息公示平台(http://www.chinadrugtrials.org.cn/),就作用于法尼醇X受体(FXR)、过氧化物酶体增殖物激活受体(PPARs)及胰高血糖素样肽-1(GLP-1)这3类受体的调节代谢类候选药物的临床注册试验进行综述,期望为非酒精性脂肪性肝病的临床治疗提供循证依据。     

GLP-1 受体激动剂治疗非酒精性脂肪肝的新进展

非酒精性脂肪性肝病（NAFLD）是在世界范围内最常见的一种肝脏疾病, 然而目前尚无特异性的治疗药物。胰升糖素样肽-1 受体激动剂 （GLP-1Ra） 是基于肠促胰素为靶点治疗 2 型糖尿病的一类新药物。近期, 动物和临床研究证实 GLP-1Ra 类药物能够有效减少肝脏脂肪沉积, 减轻脂肪变性, 是治疗 NAFLD 的一类最有希望的药物。本文将 GLP-1Ra 类药物改善 NAFLD 基础和临床研究证据及作用机制综述如下。     

胰高血糖素样肽1及其受体激动剂研究进展

胰高血糖素样肽1 (Glucagon-like Peptide-1,GLP-1) 是一种由肠道Ｌ细胞分泌的多肽激素,其与GLP-1受体结合后具有促进胰岛素分泌和生物合成,抑制胰高血糖素的分泌,促进胰岛?细胞增殖,抑制胰岛?细胞凋亡,保存?细胞对血糖的敏感性等多种生理功能,但是其在体内的半衰期很短 (<2 min),在临床应用上很受限制。根据GLP-1及其受体设计GLP-1类似物是目前开发糖尿病新药的前沿靶点之一,旨在寻找能够耐受二肽基肽酶4(DPP4)降解并具有GLP-1生理活性的长效肽类及非肽类化合物。本文对GLP-1及其受体激动剂的研究成果综述如下。     

胰高血糖素样肽-1受体激动剂对改善2型糖尿病伴代谢相关脂肪性肝病患者糖脂水平及肝脏脂肪含量的影响

目的 研究探讨胰高血糖素样肽-1(GLP-1)受体激动剂对改善2型糖尿病(T2DM)伴代谢相关脂肪性肝病(MAFLD)患者糖脂水平及肝脏脂肪含量的影响,为后续的治疗总结临床经验.方法 选取广州医科大学附属第四医院及广州中医药大学深圳医院(福田)2019年1月至2020年1月收治的90例T2DM伴MAFLD患者为研究对象...     

非酒精性脂肪性肝病发病机制的研究进展

非酒精性脂肪性肝病（NAFLD）是指与过量饮酒无关的临床综合征,主要病理改变包括肝细胞弥漫性脂肪变性和脂肪堆积。NAFLD动物模型表现出显著的肝脏微循环障碍,关于其形成机制,被广为接受的为＂二次打击＂学说。该学说认为肥胖、胰岛素抵抗等因素作为＂第一次打击＂,导致肝脏中脂质堆积,形成单纯性脂肪肝,增加了＂第二次打击＂造成的肝脏损伤的易感性,这些因素包括炎症、枯否细胞功能障碍、氧化应激、线粒体障碍、脂肪因子调节紊乱等,导致非酒精性脂肪性肝炎甚至纤维化等更严重疾病的发生。     

Are statins ‘IDEAL’ for non-alcoholic fatty liver disease?

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease and cause of elevated serum liver enzyme activities in the developed world1. Obesity, diabetes mellitus (DM), and dyslipidaemia, common components of the metabolic syndrome (MetS), are frequently associated with NAFLD; 75–100% of patients with MetS or DM have NAFLD2. NAFLD is characterized by hepatic triglyceride (TG) infiltration in the absence of alcohol abuse or chronic liver disease1. NAFLD includes a spectrum of conditions varying from steatosis to steatosis with inflammation [steatohepatitis (NASH)], necrosis, fibrosis or cirrhosis that rarely progresses to hepatocellular carcinoma3. NAFLD and NASH are the hepatic manifestations of MetS and are associated with increased cardiovascular disease (CVD) risk4. Most NAFLD/NASH patients die from CVD rather than from liver disease4,5. There is no universally accepted treatment for NAFLD1-5.     

Impairment of reproductive function in a male rat model of non-alcoholic fatty liver disease and beneficial effect of N-3 fatty acid supplementation

Non-alcoholic fatty liver disease (NAFLD) is closely associated with reduced levels of testosterone, which may affect fertility. Herein, we investigated whether NAFLD impairs the reproductive function of male rats. Male Sprague-Dawley rats were fed a high fat diet (HFD) until they developed NAFLD. N-3 polyunsaturated fatty acid (PUFA) was then given for 4 weeks to prevent hepatic steatosis. Testes weight and serum and testicular testosterone were significantly lower in rats with NAFLD compared with healthy controls. Testicular pathological changes in NAFLD rats included markedly reduced sperm number and motility, and the number of apoptotic spermatogenic cells was higher, which was consistent with a reduction in the number of tetraploid cells. Breeding experiments indicated that paternal NAFLD affected neither the sperm morphology nor the development of fetuses and offspring, but did prolong the days required for insemination. However, administration of N-3 PUFA alleviated the impairment of reproductive function. These results suggest that NAFLD impairs reproductive function in male rats by decreasing testicular testosterone synthesis, and N-3 PUFA treatment may have a beneficial therapeutic effect.     

Novel role of NPC1L1 in the regulation of hepatic metabolism: potential contribution of ezetimibe in NAFLD/NASH treatment

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in Western countries and also in other parts of the world. NAFLD encompasses a histological spectrum ranging from simple steatosis to steatohepatitis, advanced fibrosis and inflammatory changes. It frequently occurs with features of the metabolic syndrome including obesity, type 2 diabetes mellitus, dyslipidemia and hypertension. In fact, the metabolic syndrome is a strong predictor of NAFLD. Recently, Niemann-Pick C1-like 1 (NPC1L1) has been shown to play a pivotal role in cholesterol absorption. Unlike mouse NPC1L1 protein, predominantly expressed in the intestines, human and rat NPC1L1 is also abundantly expressed in the liver. Though the exact functions of hepatic NPC1L1 remain unknown, NPC1L1 may facilitate the hepatic accumulation of cholesterol. This raises a potential possibility that ezetimibe may improve fatty liver formation. In this review, potential role of lipid metabolism in NAFLD and its possible modulation through NPC1L1 blockade is discussed.     

炎症小体介导的细胞焦亡在非酒精性脂肪肝病中的作用及机制

非酒精性脂肪肝病包含单纯性脂肪肝、非酒精性脂肪肝炎和肝硬化等一系列病变,是造成肝硬化、肝细胞癌症的主要因素和肝脏器官移植的重要诱因。非酒精性脂肪肝的发病机制尚不明确,除了加强运动、改善饮食习惯外,目前尚无公认有效的药物治疗方式。细胞焦亡是一种新发现的程序性细胞死亡方式,依赖于天冬氨酸特异性半胱氨酸蛋白酶1（caspase-1）或caspase-11等介导的炎性小体的激活。细胞焦亡过程中常伴有炎症反应的发生,而炎症小体则是细胞产生焦亡和炎症反应所必需的多聚体蛋白复合物,其主要功能是活化caspase-1,从而间接调控炎症因子白介素1（IL-1）和IL-18的表达和分泌。最近的研究表明,细胞焦亡和炎症小体在非酒精性脂肪肝病的发生发展中起重要作用。针对该领域的最新研究进行综述,以期为非酒精性脂肪肝的防治提供新的科学认识和信息。     

Blood oxidative stress markers are unreliable markers of hepatic steatosis

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) and viral hepatitis are associated with hepatic oxidative stress, which is partially dependent on the amount of hepatic fat. AIM: To determine whether the circulating lipid and oxidative stress parameters could be non-invasive markers of hepatic steatosis. METHODS: Sixty-four patients with NAFLD or viral hepatitis were tested for lipid peroxidation products and antioxidant defence systems, lipid parameters and liver function tests. RESULTS: Hepatic steatosis was correlated with lipids, gamma-glutamyltranspeptidase, thiobarbituric acid-reactive substances, superoxide dismutase and superoxide dismutase/erythrocyte glutathione peroxidase ratio. gamma-Glutamyltranspeptidase, triglycerides and low-density lipoprotein cholesterol were significantly higher in the presence of steatosis. No difference in blood oxidative stress markers was observed according to the presence or absence of steatosis except for the superoxide dismutase/erythrocyte glutathione peroxidase ratio. Total cholesterol, triglycerides and low-density lipoprotein cholesterol were significantly higher in the NAFLD group (n = 17, 60% mean steatosis grade) than in the viral hepatitis group (n = 20, 13% mean steatosis grade). Only superoxide dismutase was lower and vitamin E higher in NAFLD than in viral hepatitis patients. CONCLUSIONS: Standard blood oxidative stress markers do not predict the extent of hepatic steatosis as they probably do not accurately reflect intrahepatic oxidative stress. Serum lipid levels were best correlated with hepatic steatosis.     

非酒精性脂肪性肝病的治疗进展

目前全球非酒精性脂肪性肝病的发病率增加,并与代谢综合征,尤其是肥胖及糖尿病密切相关.越来越多的证据表明,胰岛素抵抗是代谢综合征患者发生脂肪性肝炎的关键病因,其可增加脂肪变性及肝脏游离脂肪酸聚集,刺激氧化应激反应,促进脂质过氧化及炎症细胞因子产生.非酒精性脂肪性肝病的治疗以改善代谢综合征为主,尚缺乏已验证的疗效理想的治疗药物.近年来随着对其发病机制的深入理解,一些尚处于动物试验及前期临床研究的新药值得关注.     

The development of non-peptide glucagon-like peptide-1 receptor agonist for the treatment of type 2 diabetes

Glucagon-like peptide-1 (GLP-1) is the main member of the incretin family and stimulates insulin secretion by binding with its specific receptor on pancreatic β-cells. In addition, GLP-1 exerts broad beneficial effects on the glucose regulation by suppressing food intake and delaying stomach emptying. Now, long acting GLP-1 analogs including exenatide and liraglutide have been approved for the treatment of diabetes mellitus type 2, however long-term injection can limit their use for these chronic patients. In this report, the authors provide a review on the development of non-peptide GLP-1 receptor agonists and introduce a novel agonist DA-15864.