胰高血糖素样肽1与糖尿病的治疗

胰高血糖素样肽1(glucagon-like peptide-1,GLP-1)是由肠道L细胞分泌的一种重要的肠促胰岛素激素,其在体内的主要生理作用有刺激胰岛素的分泌和释放、抑制胰高血糖素的分泌、促进胰腺β细胞的增殖并抑制其凋亡、抑制胃的排空、促进饱食感的产生等。GLP-1对糖尿病和肥胖具有很好的治疗前景。由于GLP-1在体内很快被二肽酰基肽酶Ⅳ降解,血浆半衰期很短,因而限制了其临床应用。现已发现了促进GLP-1分泌的物质,开发了多种GLP-1的衍生物和二肽酰基肽酶Ⅳ抑制剂,为开发新型糖尿病治疗药物开辟了新的天地。     

Selective targeting of glucagon-like peptide-1 signalling as a novel therapeutic approach for cardiovascular disease in diabetes

Glucagon-like peptide-1 (GLP-1) is an incretin hormone whose glucose-dependent insulinotropic actions have been harnessed as a novel therapy for glycaemic control in type 2 diabetes. Although it has been known for some time that the GLP-1 receptor is expressed in the CVS where it mediates important physiological actions, it is only recently that specific cardiovascular effects of GLP-1 in the setting of diabetes have been described. GLP-1 confers indirect benefits in cardiovascular disease (CVD) under both normal and hyperglycaemic conditions via reducing established risk factors, such as hypertension, dyslipidaemia and obesity, which are markedly increased in diabetes. Emerging evidence indicates that GLP-1 also exerts direct effects on specific aspects of diabetic CVD, such as endothelial dysfunction, inflammation, angiogenesis and adverse cardiac remodelling. However, the majority of studies have employed experimental models of diabetic CVD and information on the effects of GLP-1 in the clinical setting is limited, although several large-scale trials are ongoing. It is clearly important to gain a detailed knowledge of the cardiovascular actions of GLP-1 in diabetes given the large number of patients currently receiving GLP-1-based therapies. This review will therefore discuss current understanding of the effects of GLP-1 on both cardiovascular risk factors in diabetes and direct actions on the heart and vasculature in this setting and the evidence implicating specific targeting of GLP-1 as a novel therapy for CVD in diabetes.     

Pleiotropic effects of glucagon-like peptide-1 (GLP-1)-based therapies on vascular complications in diabetes

Accelerated atherosclerosis and microvascular complications are the leading causes of coronary heart disease, end-stage renal failure, acquired blindness and a variety of neuropathies, which could account for disabilities and high mortality rates in patients with diabetes. Glucagon-like peptide-1 (GLP-1) belongs to the incretin hormone family. L cells in the small intestine secrete GLP-1 in response to food intake. GLP-1 not only enhances glucose-evoked insulin release from pancreatic β-cells, but also suppresses glucagon secretion from pancreatic α-cells. In addition, GLP-1 slows gastric emptying. Therefore, enhancement of GLP-1 secretion is a potential therapeutic target for the treatment of type 2 diabetes. Dipeptidyl peptidase-4 (DPP-4) is a responsible enzyme that mainly degrades GLP-1, and the half-life of circulating GLP-1 is very short. Recently, DPP-4 inhibitors and DPP-4-resistant GLP-1 receptor (GLP-1R) agonists have been developed and clinically used for the treatment of type 2 diabetes as a GLP-1-based medicine. GLP-1R is shown to exist in extra-pancreatic tissues such as vessels, kidney and heart, and could mediate the diverse biological actions of GLP-1 in a variety of tissues. So, in this paper, we review the pleiotropic effects of GLP-1-based therapies and its clinical utility in vascular complications in diabetes.     

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.     

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.     

胰高血糖素样肽1受体激动剂在2型糖尿病治疗中的研究进展

胰高血糖素样肽1受体激动剂（glucagon‐like peptide‐1 receptor agonist ,GLP‐1RA）是近年来2型糖尿病药物开发领域的研究热点。作为一种降血糖药物,GLP‐1RA 在增强患者血糖调控能力的同时,还能降低患者低血糖风险,减轻体重,保护心血管系统。此文对已上市和部分正处于临床试验阶段的 GLP‐1RA 的疗效及安全性做一综述,并对 GLP‐1RA 药物的发展趋势进行探讨。     

胰高血糖素样肽-1及其对糖尿病的治疗研究进展

胰高血糖素原包含2种胰高血糖素样肽，即胰高血糖素样肽-1(Glucagon-like peptide-1，GUL-1)和胰高血糖素样肽-2(GUL-2)。GLP-1主要是由小肠和大肠的内分泌细胞和脑的神经细胞分泌，通过复杂的机制调节血糖，其中包括对胰岛素和胰高血糖素的分泌、胃的排空及外周胰岛素敏感性的调节，而且可以调节脂肪组织和肌肉的糖原合成，增加胰岛β细胞数量及抑制其凋亡。     

Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is a peptide hormone released from the gut mucosa in response to meal ingestion. Its actions include stimulation of all steps of insulin gene expression, as well as β-cell growth, inhibition of glucagon secretion, inhibition of hepatic glucose production, inhibition of gastrointestinal secretion and motility, and inhibition of appetite and food intake. Physiologically, therefore, GLP-1 is thought to act as an incretin hormone (intestinal hormones that enhance meal-related insulin secretion) and as one of the hormones of the ileal brake mechanism (endocrine inhibition of gastrointestinal motility and secretion in the presence of nutrients in the lower small intestine). However, because of these same actions, the hormone can normalise the blood glucose of patients with Type 2 diabetes mellitus, and, in contradistinction to insulin and sulphonylurea, it does not cause hypoglycaemia. Therefore, treatment of Type 2 diabetes based on GLP-1 is currently being investigated. As a peptide, it must be administered parenterally, and, in addition, it is metabolised extremely rapidly. However, several methods to circumvent these problems have already been developed. A GLP-1- based therapy of diabetes mellitus and perhaps also obesity is therefore likely to become a realistic alternative to current therapies of these disorders.     

Treatment of Type 2 diabetes mellitus based on glucagon-like peptide-1

Glucagon-like peptide-1 (GLP-1) is a peptide hormone released from the gut mucosa in response to meal ingestion. Its actions include stimulation of all steps of insulin gene expression, as well as beta-cell growth, inhibition of glucagon secretion, inhibition of hepatic glucose production, inhibition of gastrointestinal secretion and motility, and inhibition of appetite and food intake. Physiologically, therefore, GLP-1 is thought to act as an incretin hormone (intestinal hormones that enhance meal-related insulin secretion) and as one of the hormones of the ileal brake mechanism (endocrine inhibition of gastrointestinal motility and secretion in the presence of nutrients in the lower small intestine). However, because of these same actions, the hormone can normalise the blood glucose of patients with Type 2 diabetes mellitus, and, in contradistinction to insulin and sulphonylurea, it does not cause hypoglycaemia. Therefore, treatment of Type 2 diabetes based on GLP-1 is currently being investigated. As a peptide, it must be administered parenterally, and, in addition, it is metabolised extremely rapidly. However, several methods to circumvent these problems have already been developed. A GLP-1- based therapy of diabetes mellitus and perhaps also obesity is therefore likely to become a realistic alternative to current therapies of these disorders.     

胰升糖素样肽1类似物治疗2型糖尿病有效性和安全性的系统评价

目的 系统评价胰升糖素样1肽(GLP-1)类似物治疗2型糖尿病的有效性和安全性.方法 计算机检索Pubmed、Ovid、SpringerLink、Cochrane图书馆、中国生物医学文献数据库(CBM)及万方数据库.检索时间由建库截至2010年9月.按Cochrane系统评价的方法 评价研究的质量,应用RevMan4.2软件进行Meta分析;不能合并的数据,进行描述性分析.结果 本研究共纳入23个随机对照试验进行分析.Meta分析结果 显示在降低糖化血红蛋白[加权均数差(WMD)=-0.89,95%可信区间(CI)-1.02～-0.77,P＜0.01]和降低体重方面(WMD=-1.16,95% CI-1.75～-0.56,P＜0.01),GLP-1类似物组均优于安慰剂组或其他降糖药组.GLP-1类似物组的低血糖事件发生率高于安慰剂组(RR=1.81,95%CI 1.32～2.49,P＜0.01),但与其他降糖药组相当(RR=0.59,95%CI 0.34,1.01,P=0.06).GLP-1类似物组的胃肠道的不良反应率高于安慰剂组(RR=3.30,95%CI2.43～4.49,P＜0.01).结论 现有的临床证据显示,GLP-1类似物治疗2型糖尿病疗效较好,且相对安全,主要的不良反应为胃肠道不良反应.     

胰升糖素样肽1类似物治疗2型糖尿病有效性和安全性的系统评价

目的 系统评价胰升糖素样1肽(GLP-1)类似物治疗2型糖尿病的有效性和安全性.方法 计算机检索Pubmed、Ovid、SpringerLink、Cochrane图书馆、中国生物医学文献数据库(CBM)及万方数据库.检索时间由建库截至2010年9月.按Cochrane系统评价的方法 评价研究的质量,应用RevMan4.2软件进行Meta分析;不能合并的数据,进行描述性分析.结果 本研究共纳入23个随机对照试验进行分析.Meta分析结果 显示在降低糖化血红蛋白[加权均数差(WMD)=-0.89,95%可信区间(CI)-1.02～-0.77,P＜0.01]和降低体重方面(WMD=-1.16,95% CI-1.75～-0.56,P＜0.01),GLP-1类似物组均优于安慰剂组或其他降糖药组.GLP-1类似物组的低血糖事件发生率高于安慰剂组(RR=1.81,95%CI 1.32～2.49,P＜0.01),但与其他降糖药组相当(RR=0.59,95%CI 0.34,1.01,P=0.06).GLP-1类似物组的胃肠道的不良反应率高于安慰剂组(RR=3.30,95%CI2.43～4.49,P＜0.01).结论 现有的临床证据显示,GLP-1类似物治疗2型糖尿病疗效较好,且相对安全,主要的不良反应为胃肠道不良反应.     

胰高血糖素样肽-1类似物对2型糖尿病患者血脂的影响

目的探讨胰高血糖素样肽-1(GLP-1)对2型糖尿病患者血脂变化的影响。方法选择2013年1月至2014年6月间我院收治的2型糖尿病患者108例,根据随机数字表将所有患者分成对照组(口服二甲双胍)和观察组(注射百泌达),连续应用12周,观察两组患者血糖、血脂变化情况及影响血脂变化的指标。结果治疗后,两组空腹血糖、餐后2 h血糖、糖化血红蛋白水平和BMI与治疗前比较,差异有统计学意义(P<0.05),观察组与对照组比较,差异有统计学意义(P<0.05)。治疗后,两组三酰甘油、总胆固醇、低密度脂蛋白和高密度脂蛋白水平与治疗前比较,差异有统计学意义(P<0.05),观察组与对照组比较,差异有统计学意义(P<0.05)。患者BM I、血糖、糖化血红蛋白、血清胰岛素和胰岛素抗体水平均为影响GLP-1类似物致2型糖尿病患者血脂变化的因素。结论 GLP-1类似物可改善2型糖尿病患者的血脂情况,降低三酰甘油、总胆固醇、低密度脂蛋白含量,提高高密度脂蛋白含量,但在临床中仍需要结合患者自身因素进行临床治疗,以取得理想疗效。     

胰高血糖素样肽-1长效注射微球的研究

目的制备载胰高血糖素样肽-1(GLP-1)的长效注射微球，并对其体外释放特性及药效学进行考察。方法采用复乳法(W/O/W)制备载GLP-1聚乳酸-羟基乙酸嵌段共聚物(PLGA)的微球；考察微球的粒径大小、外观及包封率等理化特性；以HPLC法测定微球的体外释放速率；在体动物法评价微球制备工艺和体外释放过程中GLP-1的生物学活性。在糖尿病模型小鼠体内考察了微球的降血糖作用。结果微球球形圆整，分散性好，包封率在80%以上；GLP-1微球1个月的体外累积释放可达85%，其释放行为符合近似零级释放模式；使用明胶溶液作为内水相，较好地保持了制备工艺过程中的GLP-1生物学活性，在体外释放过程中GLP-1的生物学活性略有下降；GLP-1微球可显著降低糖尿病模型小鼠的血糖水平，降糖作用可维持1个月。结论用可生物降解的聚合物PLGA作为载体材料，可以将GLP-1制备成缓释1个月的注射微球。     

胰高血糖素样肽-1的心血管益处及机制

心血管疾病是2型糖尿病患者的主要死亡原因之一。新近研究发现胰高血糖素样肽-1(GLP-1)不仅通过葡萄糖依赖的方式刺激胰岛素分泌和抑制糖原的不适当分泌,延缓胃排空,增加饱食感等方式调节血糖;还能通过GLP-1R和受体以外的方式发挥心血管保护作用,包括心肌、内皮细胞和血管等。越来越多的动物和临床研究显示,GLP-1和GLP-1R激动剂都能改善内皮细胞功能、促进钠的排泄、改善缺血损伤的心肌和心功能的恢复,减少心血管风险的危险因素和标志物。文中综述有关动物和人类研究中GLP-1对心血管系统的作用以及可能机制。     

Vascular protective effects of diabetes medications that mimic or increase glucagon-like peptide-1 activity

The incidence of type 2 diabetes (T2DM) is increasing rapidly worldwide and is a strong risk factor for cardiovascular disease (CVD) events. Although hyperglycemia is associated with increased CVD, intensive glycemic control with current diabetes medications has failed in recent large clinical trials to reduce macrovascular disease, demonstrating that intensive glucose control alone is insufficient to reduce major CVD events. A new approach to lowering glucose takes advantage of the incretin system and medications that raise or mimic glucagon-like peptide-1 (GLP-1). These agents not only improve glycemic control by mechanisms that minimize hypoglycemia, but also improve lipoprotein profiles, blood pressure control and weight loss. There is also increasing evidence that at least pharmacologic concentrations of GLP-1 or GLP-1 mimetics may improve endothelial function and have direct vascular-protective effects. Importantly, these benefits transpired even before the improvements in weight and overall glucose control occurred. It remains to be seen whether the chronic effects of GLP-1 activity on glucose, CVD risk factors and vascular function will lead to lasting beneficial effects on CVD risk. If preliminary findings on the vasculoprotective effects of GLP-1 agents are validated and confirmed in longitudinal clinical trials, this class of drugs may represent a paradigm shift in the treatment of vascular disease in both patients with diabetes and in non-diabetic individuals at high risk for CVD. Recent patents regarding GLP-1 agents are discussed in this review article.     

Dipeptidyl peptidase IV inhibitors as new therapeutic agents for the treatment of Type 2 diabetes

Type 2 diabetes is the most prevalent form of diabetes. Incretin hormones play an important role in normal and pathological blood glucose homeostasis. The role of dipeptidyl peptidase IV (DPP IV) in the inactivation of glucagon-like peptide-1 (GLP-1), one of the most important incretins, is wellestablished. Therefore, DPP IV inhibitors are investigated as new therapeutic agents for the treatment of Type 2 diabetes. A summary of DPP IV inhibitors reported until 1998 and a more extensive discussion of more recent inhibitors found in literature and patent applications will be provided. The therapeutic potential of several aminoacyl pyrrolidides, aminoacyl thiazolidides and aminoacyl pyrrolidine-2-nitriles will be reviewed.