胰高血糖素样肽-1受体激动剂对中枢神经系统的作用

胰高血糖素样肽-1受体(GLP-1R)激动剂通过GLP-1R刺激胰岛素分泌并改善胰岛细胞的状态,现已成为糖尿病领域研究热点.已证实GLP-1R在中枢神经系统有广泛表达,中枢应用GLP-1R激动剂后其可发挥保护神经细胞、调节食欲、调节认知功能等一系列作用,体现了其在中枢神经系统应用的潜质与价值.     

胰高血糖素样肽-1受体激活在脑缺血中的神经保护作用

胰高血糖素样肽-1（glucagon-likepeptide1,GLP-1）是肠促胰岛素的重要成员。经口进食可刺激末端回肠和结肠L 细胞分泌GLP-1。 GLP-1与特异性受体GLP-1受体（ GLP-1 receptor, GLP-1R）结合后发挥促进葡萄糖依赖的胰岛素分泌、抑制胰高血糖素分泌和降低血浆胰高血糖素水平等作用。 GLP-1具有分子质量相对较小,可直接透过血脑屏障,且中枢和外周神经系统均有GLP-1R表达。 GLP-1可显著改善神经功能缺损和缩小梗死体积,其可能通过抑制炎症反应、氧化应激和细胞凋亡等机制发挥神经保护作用。文章就GLP-1的发现、生物学特性和在脑缺血中的神经保护作用进行了综述。     

胰高血糖素样肽-1类似物改善肌肉萎缩的研究进展

胰高血糖素样肽-1(GLP-1)是由肠道L细胞分泌的一种肠促胰素,其主要功能是促进胰岛素分泌和抑制胰高血糖素分泌从而降低血糖,其制剂在临床上广泛用于糖尿病的治疗。近年来有研究发现,GLP-1类似物有改善肌肉萎缩的功能,该作用与抑制肌肉生长抑制素和肌萎缩因子表达、增强肌源性因子表达、改善骨骼肌微循环和胰岛素抵抗有关。     

胰高血糖素样肽-1受体激动剂在心血管疾病中的研究进展

近年来新型降血糖药在心血管疾病治疗中获益显著。胰高血糖素样肽-1受体激动剂(GLP-1RA)是新一代降血糖药，除有较为明显的降糖作用外，还通过提高肠促胰岛素的活性在心血管系统中发挥保护作用。基础与临床研究表明，GLP-1RA具有抑制免疫反应、抑制平滑肌细胞增生和改善动脉粥样硬化形成等作用，在心血管临床研究中受到广泛关注。现对GLP-1RA在心血管疾病中直接或间接的影响进行综述，为临床防治提供理论基础。     

胰高血糖素样肽1的胰腺外作用研究进展

胰高血糖素样肽1(GLP-1)是体内重要的肠肽激素,在调节体内葡萄糖稳态中起重要作用.它通过促进胰岛素分泌、抑制胰高血糖素产生以及减慢餐后胃排空降低血糖.在胰腺外组织它也可通过调节葡萄糖代谢来参与全身血糖的调节.一方面通过激活磷脂酰肌醇3激酶、蛋白激酶B、蛋白激酶C、1型蛋白磷酸酶和丝裂原活化蛋白酶等增加糖原合酶a活性,促进糖原合成和糖利用.另一方面,在脂肪组织直接促进葡萄糖利用或增强胰岛素对葡萄糖的利用.此外,GLP-1还具有其它生物学作用包括舒张血管、保护血管内皮功能并激活垂体前叶激素分泌等.exendin-4是GLP-1的长效类似物,具有比GLP-1更持久的生物学活性和更强的降血糖作用,是一种治疗2型糖尿病的新型药物.     

GLP-1在摄食和胃肠道生理功能中的作用

早期研究发现胰高血糖素样肽-1(GLP-1)作为一种肠道肽,具有葡萄糖依赖的胰岛素释放作用,后来在中枢神经系统中亦发现它的存在,消化道和脑中的GLP-1行使着多种生理功能,包括传递神经信号,调节摄食和饮水,调节体温和能量代谢,抑制胃肠分泌和运动,调节细胞的增殖和存活等.本文主要从GLP-1的合成与分泌,在脑中的分布,GLP-1对摄食和胃肠运动的影响,以及其临床应用潜力对它进行阐述.     

GLP-1在2型糖尿病诱发的阿尔茨海默病治疗中的作用

2型糖尿病是诱发阿尔茨海默病的高危因素.胰高血糖素样肽-1(GLP-1)可诱导胰岛β细胞再生和增殖,可以呈葡萄糖依赖性地促进胰岛素分泌.另外,GLP-1在治疗神经退行性病变中也有重要的作用,能降低脑内β淀粉样蛋白斑块沉积,减少氧化应激引起的神经细胞损伤,还可以调节突触的传递,增加突触的可塑性,刺激轴突生长,影响长时程增强,从而改善记忆并提高认知水平.     

GLP-1RA对2型糖尿病合并心血管疾病的影响

心血管疾病(CVD)是2型糖尿病最常见的并发症，血糖的升高以及高血压、高血脂、超重肥胖等危险因素会导致糖尿病人的动脉粥样硬化。胰高血糖素样肽1(GLP-1)受体激动剂(GLP-1RA)是与天然GLP-1的高度同源类似物，不仅具有降低血糖、改善胰岛功能的作用，还可以改善血管内皮功能，降血压、降血脂、减重等，降低并发CVD的概率，从而延缓T2DM远期并发症的发生。     

GLP-1通过调节巨噬细胞泡沫化抑制ApoE-/-小鼠动脉粥样硬化的作用机制研究

目的 研究胰高血糖素样肽1(GLP-1)是否能抑制高脂饮食喂养的载脂蛋白E基因敲除(ApoE-/-)小鼠动脉粥样硬化(AS)进程,从巨噬细胞泡沫化角度探讨相关作用机制.方法 选择6周龄雄性ApoE-/-小鼠40只,随机分为对照组(普通饮食)、模型组(高脂饮食)、GLP-1组(高脂饮食+GLP-1)和GLP-1阻断组(高...     

GLP-1及其类似物治疗糖尿病的研究进展

胰高血糖素样肽-1(GLP-1)是一种肠源性激素,具有促进胰岛素分泌、抑制胰高血糖素释放,改善胰岛β细胞功能,促进胰岛β细胞增殖并抑制其凋亡、延缓胃排空以及保护心血管等重要作用。天然的GLP-1在体内被二肽基肽酶-4(DPP-4)迅速降解,因此很难在临床中直接应用。GLP-1类似物可以抵抗DPP-4的降解,增强与GLP-1受体的结合,有效延长作用时间,具有很好地应用前景。该文就GLP-1及其类似物的作用特点、临床应用、潜在风险和不良反应等最新研究进展作一综述。     

Incretin based therapies: A novel treatment approach for non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease is considered a hepatic manifestation of metabolic syndrome (MS). The current treatment of non-alcoholic fatty liver disease (NAFLD) principally includes amelioration of MS components by lifestyle modifications but the lack of success in their implementation and sustainment arises the need for effective pharmacological agent in fatty liver treatment. Incretins are gut derived hormones secreted into the circulation in response to nutrient ingestion that enhances glucose-stimulated insulin secretion. Glucagon-like peptide-1 (GLP-1) is the most important incretin. Its receptor agonist and inhibitors of dipeptidyl peptidase-4 (DPP-4) are used in treatment of type 2 diabetes mellitus. DPP-4 serum activity and hepatic expression are shown to be elevated in several hepatic diseases. There are several experimental and clinical trials exploring the efficacy of incretin based therapies in NAFLD treatment. They suggest that GLP-1 analogues might have beneficial effect on hepatic steatosis acting as insulin sensitizers and directly by stimulating GLP-1 receptors expressed on hepatocytes. The use of DPP-4 inhibitors also results in hepatic fat reduction but the mechanism of action remains unclear. There is growing evidence that incretin based therapies have beneficial effects on hepatocytes, however further study analysis are needed to assess the long term effect of incretin based therapies on NAFLD.     

胰升糖素样肽1对胰岛β细胞作用的研究进展

胰升糖素样肽1(GLP-1)是由小肠内L细胞分泌的肠道促胰岛激素,GLP-1与其特异性受体GLP-1受体(GLP-1R)结合后可激活腺苷酸环化酶,生成cAMP,并激活蛋白激酶A及鸟嘌呤核苷酸交换因子(GEF)信号途径,另外GLP-1还可通过不同的方式激活钙调蛋白通路及丝裂原活化蛋白激酶和磷脂酰肌醇3激酶通路,产生多种生理效应.GLP-1可促进胰岛素的1相和2相分泌,增加胰岛素的合成,此外GLP-1还可促进胰岛β细胞的增殖及分化,减少β细胞凋亡,减轻内质网应激对β细胞的损伤作用,增加β细胞存活.     

肠促胰素在2型糖尿病治疗中的作用

肠促胰素是经食物刺激后由肠道细胞分泌入血、具有促进胰岛素分泌作用的一类激素;人体中,胰升糖素样肽1(GLP-1)和糖依赖性胰岛素释放肽(GIP)发挥肠促胰素效应.根据近期发表的研究,本文回顾了肠促胰素的生理作用,同时阐述了 GIP和GLP-1在2型糖尿病治疗中的特点.     

胰升糖素样肽-1的研究进展

胰升糖素样肽-1(GLP-1)是由肠道内分泌L细胞分泌的肠促胰岛素,具有促进胰岛素分泌、胰岛细胞生长、增殖和分化并抑制胰岛β细胞凋亡等多种作用,可用来预防和治疗糖尿病,辅助进行胰岛细胞移植,且不引起体重增加和低血糖。但GLP-1可很快被二肽基肽酶Ⅳ降解,限制了其临床应用。目前对长效的GLP-1类似物、二肽基肽酶Ⅳ抑制剂和GLP-1基因治疗的研究已成为热点。     

The evolving story of incretins (GIP and GLP-1) in metabolic and cardiovascular disease: A pathophysiological update

The incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) have their main physiological role in augmenting insulin secretion after their nutrient-induced secretion from the gut. A functioning entero-insular (gut-endocrine pancreas) axis is essential for the maintenance of a normal glucose tolerance. This is exemplified by the incretin effect (greater insulin secretory response to oral as compared to “isoglycaemic” intravenous glucose administration due to the secretion and action of incretin hormones). GIP and GLP-1 have additive effects on insulin secretion. Local production of GIP and/or GLP-1 in islet α-cells (instead of enteroendocrine K and L cells) has been observed, and its significance is still unclear. GLP-1 suppresses, and GIP increases glucagon secretion, both in a glucose-dependent manner. GIP plays a greater physiological role as an incretin. In type 2-diabetic patients, the incretin effect is reduced despite more or less normal secretion of GIP and GLP-1. While insulinotropic effects of GLP-1 are only slightly impaired in type 2 diabetes, GIP has lost much of its acute insulinotropic activity in type 2 diabetes, for largely unknown reasons. Besides their role in glucose homoeostasis, the incretin hormones GIP and GLP-1 have additional biological functions: GLP-1 at pharmacological concentrations reduces appetite, food intake, and—in the long run—body weight, and a similar role is evolving for GIP, at least in animal studies. Human studies, however, do not confirm these findings. GIP, but not GLP-1 increases triglyceride storage in white adipose tissue not only through stimulating insulin secretion, but also by interacting with regional blood vessels and GIP receptors. GIP, and to a lesser degree GLP-1, play a role in bone remodelling. GLP-1, but not GIP slows gastric emptying, which reduces post-meal glycaemic increments. For both GIP and GLP-1, beneficial effects on cardiovascular complications and neurodegenerative central nervous system (CNS) disorders have been observed, pointing to therapeutic potential over and above improving diabetes complications. The recent finding that GIP/GLP-1 receptor co-agonists like tirzepatide have superior efficacy compared to selective GLP-1 receptor agonists with respect to glycaemic control as well as body weight has renewed interest in GIP, which previously was thought to be without any therapeutic potential. One focus of this research is into the long-term interaction of GIP and GLP-1 receptor signalling. A GLP-1 receptor antagonist (exendin [9-39]) and, more recently, a GIP receptor agonist (GIP [3-30] NH₂) and, hopefully, longer-acting GIP receptor agonists for human use will be helpful tools to shed light on the open questions. A detailed knowledge of incretin physiology and pathophysiology will be a prerequisite for designing more effective incretin-based diabetes drugs.     

艾塞那肽临床研究新进展

肠促胰素是肠道在进餐后分泌的激素,能促进胰岛素的分泌.胰高糖素样肽1(GLP-1)是主要的肠促胰素,通过葡萄糖依赖的方式促进胰岛素分泌、抑制胰高糖素分泌以及延缓胃排空、增加饱腹感等作用维持体内血糖的稳定.另外,在2型糖尿病患者中,它还可改善β细胞功能.但是天然的GLP-1半寿期很短,无法用于临床治疗.艾塞那肽是从希拉巨蜥唾液中分离得到的一种多肽,它可与GLP-1受体结合,产生与GLP-1相似的生理效应,但它的半寿期远比GLP-1长,因此每天两次皮下注射即可产生满意的疗效.临床研究显示艾塞那肽可显著降低2型糖尿病患者HbA_(1C)、空腹血糖及餐后血糖,并降低体重.动物研究表明艾塞那肽还可改善β细胞功能、增加β细胞量.由于GLP-1受体激动剂的独特疗效,新近的糖尿病治疗指南已将其列入2型糖尿病的治疗药物.     

Glucagon-like peptide-1: from extract to agent. The Claude Bernard Lecture, 2005

The incretin hormones are intestinal polypeptides that enhance postprandial insulin secretion. Gastric inhibitory polypeptide (GIP) was initially thought to regulate gastric acid secretion, whereas glucagon-like peptide-1 (GLP-1) was discovered as a result of a systematic search for intestinal insulinotropic products of proglucagon gene expression. The incretin effect is markedly impaired or absent in patients with type 2 diabetes because of decreased secretion of GLP-1 and a loss of the insulinotropic effects of GIP. Metabolic control can be restored or greatly improved by administration of exogenous GLP-1, but this peptide is almost immediately degraded by dipeptidyl peptidase IV (DPP-IV), and therefore has little clinical value. DPP-IV-resistant analogues (incretin mimetics) have been identified or developed, and inhibitors of DPP-IV have also proved effective in protecting endogenous GLP-1 (and GIP) from degradation. Both principles have been tested in clinical studies. The incretin mimetics, administered by sc injection, have demonstrated lasting improvement in HbA₁c in patients insufficiently treated with conventional oral therapy, and their use has been associated with steady weight loss for up to 2 years. The DPP-IV inhibitors, given once or twice daily by mouth, also appear to provide lasting improvement in HbA₁c, but are weight-neutral. The first incretin mimetic has reached the market in the US, and applications for approval of the first inhibitors are expected to be filed early in 2006.     

Impact of glucagon-like peptide-1 on endothelial function

Cardiovascular (CV) disease is the major cause of mortality and morbidity in individuals with diabetes. Individuals with diabetes often have a variety of factors such as hyperglycaemia, dyslipidaemia, hypertension, insulin resistance and obesity, which increase their risks of endothelial dysfunction and CV disease. The incretin hormones, such as glucagon-like peptide-1 (GLP-1), induce the glucose-dependent secretion of insulin, improve beta-cell function and induce slowing of gastric emptying and feelings of satiety – which result in reduced food intake and weight loss. Therapeutic treatments targeting the incretin system, such as GLP-1 receptor agonists, offer the potential to address beta-cell dysfunction (one the underlying pathogenic mechanisms of type 2 diabetes), as well as the resulting hyperglycaemia. Initial evidence now suggests that incretins could have beneficial effects on endothelial function and the CV system through both indirect effects on the reduction of hyperglycaemia and direct effects mediated through GLP-1 receptor–dependent and –independent mechanisms. If these initial findings are confirmed in larger clinical trials, GLP-1 receptor antagonists could help to address the major CV risks faced by patients with diabetes.     

Incretins, insulin secretion and Type 2 diabetes mellitus

When glucose is taken orally, insulin secretion is stimulated much more than it is when glucose is infused intravenously so as to result in similar glucose concentrations. This effect, which is called the incretin effect and is estimated to be responsible for 50 to 70% of the insulin response to glucose, is caused mainly by the two intestinal insulin-stimulating hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). Their contributions have been confirmed in mimicry experiments, in experiments with antagonists of their actions, and in experiments where the genes encoding their receptors have been deleted. In patients with Type 2 diabetes, the incretin effect is either greatly impaired or absent, and it is assumed that this could contribute to the inability of these patients to adjust their insulin secretion to their needs. In studies of the mechanism of the impaired incretin effect in Type 2 diabetic patients, it has been found that the secretion of GIP is generally normal, whereas the secretion of GLP-1 is reduced, presumably as a consequence of the diabetic state. It might be of even greater importance that the effect of GLP-1 is preserved whereas the effect of GIP is severely impaired. The impaired GIP effect seems to have a genetic background, but could be aggravated by the diabetic state. The preserved effect of GLP-1 has inspired attempts to treat Type 2 diabetes with GLP-1 or analogues thereof, and intravenous GLP-1 administration has been shown to be able to near-normalize both fasting and postprandial glycaemic concentrations in the patients, perhaps because the treatment compensates for both the impaired secretion of GLP-1 and the impaired action of GIP. Several GLP-1 analogues are currently in clinical development and the reported results are, so far, encouraging.Abbreviations GLP-1 Glucagon-like peptide-1 - GIP glucose-dependent insulinotropic polypeptide - FPG fasting plasma glucose     

Real-time trafficking and signaling of the glucagon-like peptide-1 receptor

The glucagon-like peptide-1 incretin receptor (GLP-1R) of family B G protein-coupled receptors (GPCRs) is a major drug target in type-2-diabetes due to its regulatory effect on post-prandial blood-glucose levels. The mechanism(s) controlling GLP-1R mediated signaling are far from fully understood. A fundamental mechanism controlling the signaling capacity of GPCRs is the post-endocytic trafficking of receptors between recycling and degradative fates. Here, we combined microscopy with novel real-time assays to monitor both receptor trafficking and signaling in living cells. We find that the human GLP-1R internalizes rapidly and with similar kinetics in response to equipotent concentrations of GLP-1 and the stable GLP-1 analogues exendin-4 and liraglutide. Receptor internalization was confirmed in mouse pancreatic islets. GLP-1R is shown to be a recycling receptor with faster recycling rates mediated by GLP-1 as compared to exendin-4 and liraglutide. Furthermore, a prolonged cycling of ligand-activated GLP-1Rs was observed and is suggested to be correlated with a prolonged cAMP signal.