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。     

利拉鲁肽的药理及临床研究进展

 利拉鲁肽是一种酰化胰高血糖素样肽-1（GLP-1）类似物,通过激活GLP-1受体,以葡萄糖依赖性刺激胰岛素分泌并抑制胰高血糖素分泌,临床用于2型糖尿病的二线治疗,可与其他口服降糖药联合使用,但不用于1型糖尿病的治疗。文中通过Medline对利拉鲁肽进行文献检索,并对其药理作用、药动学、临床研究、安全性和药物相互作用等进行综述。     

糖尿病新靶点药物的研发进展

当前糖尿病临床治疗的热点是改善胰岛素抵抗、防止胰岛β-细胞衰竭.现就过氧化酶体增殖激活受体(PPAR)类药物、抑制糖异生促进外围组织对糖的摄取与利用的药物、胰高血糖素抑制剂等一些新的作用靶点糖尿病药物的研发进展及其在糖尿病治疗药物中的地位与前景进行讨论.     

治疗2型糖尿病的新颖化合物胰高血糖素样肽—1衍生物：NN2211在临床上的发展

胰高血糖素样肽-1（GLP-1）可促进胰岛素释放，降低血浆中的胰高血糖素水平，降低胃排空的速率，促进饱食感并刺激胰岛的生物合成和β细胞的增殖，因此，基于GLP-1的药物可用于2型糖尿病的治疗，在GLP-1任何C端用脂肪酸进行衍生，提高了与血浆蛋白的结合，从而提高基于GLP-1药物的作用时间，通过试验表明，多个化合物都具有较强的活性，并从中得到了活性最强的化合物NN2211，广泛的动物模型试验证明了NN2211具有降血糖和减轻体重的作用。同时还可增加或维持β细胞质量，NN2211在人体内降低血糖的长期作用正在进行Ⅱ期临床试验。     

胰高血糖素样肽1及其类似物治疗2型糖尿病的研究进展

目的:了解胰高血糖素样肽1(GLP-1)及其类似物治疗2型糖尿病的研究进展,为2型糖尿病的药物治疗提供参考。方法:查阅近年来国内外相关文献,就GLP-1及其类似物治疗2型糖尿病的研究进行归纳和总结。结果与结论:GLP-1类似物在2型糖尿病的治疗中使用广泛,其能促进葡萄糖依赖的胰岛素分泌,抑制胰高血糖素的合成,有效改善血糖水平。同时,GLP-1类似物还能够抑制机体餐后胃排空,减少热量摄入,减轻患者体质量。现有的GLP-1类似物中,艾塞那肽降血糖效果明显,患者依从性差,且存在恶心呕吐等不良反应;利拉鲁肽能很好地控制血糖,但存在胃肠道反应;阿必鲁肽降糖效果不及利拉鲁肽;度拉糖肽疗效与利拉鲁肽相当,是最具潜力的2型糖尿病治疗药物;利司那肽在美国还未被批准上市,但具有较好的临床应用前景。     

2型糖尿病治疗药物杜拉鲁肽的研究进展

杜拉鲁肽是一种长效胰高血糖素样肽-1(GLP-1)受体激动剂,能促进胰岛素分泌,保护胰岛β细胞,抑制胰高血糖素分泌,抑制胃排空,降低食欲;临床用于2型糖尿病(T2DM)和肥胖症的治疗;本品不适用于1型糖尿病,也不能替代胰岛素治疗。本文综述了近年来杜拉鲁肽的研究文献,从作用机制、药效学和药动学、临床研究、不良反应等方面介绍GLP-1受体激动剂杜拉鲁肽的研究进展,旨在为临床合理用药提供参考。     

治疗2型糖尿病的新靶点药物研究进展

糖尿病是一种代谢障碍性疾病,患病率逐年上升,已成为全球慢性非传染性疾病中最具流行性的疾病。糖尿病患者中以2型糖尿病患者为主,占比超过90%。现有糖尿病治疗药物主要包括磺脲类、双胍类、格列奈类、噻唑烷二酮类、α-葡萄糖苷酶抑制剂、胰高血糖素样肽-1(GLP-1)受体激动剂、二肽基肽酶IV(DPP-4)抑制剂和钠–葡萄糖协同转运蛋白2(SGLT2)抑制剂。它们在降糖控糖作用机制上各具特点和优势,但仍不能满足临床治疗的需求。随着研究人员的不断探索,一些治疗2型糖尿病的新靶点化合物已进入临床I、II期研究,并有多个化合物处于临床前研发中,有望成为2型糖尿病的治疗药物。介绍了葡萄糖激酶激动剂、胰高血糖素受体拮抗剂、G蛋白偶联受体119(GPR119)激动剂、腺苷酸活化蛋白激酶(AMPK)激动剂、游离脂肪酸受体1(FFAR1)激动剂、蛋白酪氨酸磷酸酶-1B(PTP-1B)抑制剂和11β-羟类固醇脱氢酶1(11β-HSD1)抑制剂的作用机制、研发进程和注意事项,希望为2型糖尿病治疗药物的研发提供参考。     

G蛋白偶联受体：激活B类GPCR的新开关

胰高血糖素样肽1（GLP1）受体属于难以被小分子药物靶向作用的G蛋白偶联受体（GPCR）。Bjerre-Knudsen等发现了一个能刺激胰高血糖素依赖性胰岛素释放的小分子GLP1受体激动剂，这可能对研究治疗糖尿病的口服GLP1激动剂有帮助。     

基于肠促胰岛素的抗糖尿病药物发展概况

肠促胰岛素的发现为糖尿病治疗提供了一个新的途径,各大制药公司已相继推出了自己的药品,根据作用机制可分为二肽基肽酶-4抑制剂和胰高血糖素样肽-1类似物或受体激动剂。这些药物具有有效降低血糖、安全性和耐受性良好以及不增加体重等优点,是2型糖尿病治疗的新选择。     

Exendin-4及其类似物的研究近况

Exendin-4是一种胰高血糖素样肽-1(GLP-1)受体的长效激动剂,与GLP-1具有53%的序列同源性,具有促进葡萄糖依赖性的胰岛素分泌、促进β细胞增殖、减慢胃排空、抑制食物摄取和减轻体重等作用,有望成为治疗2型糖尿病的理想药物。综述Exendin-4的结构、药理作用、制备方法、结构修饰改造的策略,介绍首个用于临床的Exendin-4类药物Exenatide,并对Exendin-4及其类似物的发展前景进行了展望。     

Glucagon as a target for the treatment of Type 2 diabetes

Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeu-tic agents to target glucagon action as a treatment for Type 2 diabe-tes.     

Glucagon: Its evolving role in the management of hypoglycemia

More than 10% of the United States population has diabetes, characterized by hyperglycemia. Insulin and other agents used to treat diabetes predispose people to hypoglycemia, which can be life threatening. Glucagon is an emergency medication that can save lives by quickly raising glucose in people who are unconscious or unable to consume glucose due to severe hypoglycemia. Although glucagon has been commercially available since 1960, earlier formulations required reconstitution of a dry powder with diluent immediately prior to injection, due to lack of long-term stability once reconstituted. Glucagon has been underutilized due to the lack of confidence or ability to administer in emergency situations. More recently, new formulations including a nasal powder glucagon and liquid-stable glucagon have become available. This article discusses the evidence surrounding new glucagon formulations compared with the original glucagon emergency kit including ease of use, efficacy, and safety with a focus on important patient counseling points and relevant clinical information on hypoglycemia.     

Glucagon is absorbed from the rectum but does not hasten recovery from hypoglycaemia in patients with type 1 diabetes

AIMS

A failure to secrete glucagon during hypoglycaemia is near universal in patients with type 1 diabetes 5 years after disease onset and may contribute to delayed counter-regulation during hypoglycaemia. Rectal glucagon delivery may assist glucose recovery following insulin-induced hypoglycaemia in such patients and has not been previously studied.

METHODS

Six male patients (age 21–38 years) with type 1 diabetes (median duration 10 years) without microvascular complications, were studied supine after an overnight fast on two separate occasions at least 14 days apart. After omission of their usual morning insulin and 45 min rest, hypoglycaemia was induced by an intravenous insulin infusion which was terminated when capillary glucose concentration reached 2.5 mmol l⁻¹. Subjects were randomized to insert a rectal suppository containing 100 mg indomethacin alone (placebo) or 100 mg indomethacin plus 1 mg glucagon at the hypoglycaemic reaction. Serial measurements were made for 120 min.

RESULTS

In the two groups, mean (SD) plasma glucose concentrations fell to a similar nadir of 1.8 (0.7) mmol l⁻¹ (placebo) and 2.1 (1.2) mmol l⁻¹ (glucagon). Peak plasma glucagon following hypoglycaemia was higher in the glucagon group; 176 (32) ng l⁻¹vs. 99 (22) ng l⁻¹ after placebo (P = 0.006). However, the glucose recovery rate over 120 min after hypoglycaemia did not differ significantly.

CONCLUSIONS

Our results provide evidence for the absorption of glucagon from the rectum. They also indicate that 1 mg does not constitute a useful mode of therapy to hasten recovery from hypoglycaemia in patients with type 1 diabetes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Patients with type 1 diabetes experience recurrent hypoglycaemia and have abnormal glucose counter regulatory responses with a failure to secrete glucagon. It is unknown if rectal glucagon is absorbed and what effect this may have on counter regulation from hypoglycaemia.

WHAT THIS STUDY ADDS

• A rectal suppository of glucagon results in a rise in plasma glucagon with metabolic effects in normal subjects. Similarly rectal glucagon results in a rise in plasma glucagon in patients with type 1 diabetes, but 1 mg does not improve recovery rates from experimental hypoglycaemia when compared with placebo.
• Larger doses of glucagon per rectum may provide pharmacological circulating concentrations with resulting therapeutic benefit during recovery from hypoglycaemia and deserves further study.

     

Glucagon and glucagon-like peptide receptors as drug targets

Glucagon and the glucagon-like peptides are derived from a common proglucagon precursor, and regulate energy homeostasis through interaction with a family of distinct G protein coupled receptors. Three proglucagon-derived peptides, glucagon, GLP-1, and GLP-2, play important roles in energy intake, absorption, and disposal, as elucidated through studies utilizing peptide antagonists and receptor knockout mice. The essential role of glucagon in the control of hepatic glucose production, taken together with data from studies employing glucagon antagonists, glucagon receptor antisense oligonucleotides, and glucagon receptor knockout mice, suggest that reducing glucagon action may be a useful strategy for the treatment of type 2 diabetes. GLP-1 secreted from gut endocrine cells controls glucose homeostasis through glucose-dependent enhancement of beta-cell function and reduction of glucagon secretion and gastric emptying. GLP-1 administration is also associated with reduction of food intake, prevention of weight gain, and expansion of beta-cell mass through stimulation of beta-cell proliferation, and prevention of apoptosis. GLP-1R agonists, as well as enzyme inhibitors that prevent GLP-1 degradation, are in late stage clinical trials for the treatment of type 2 diabetes. Exenatide (Exendin-4) has been approved for the treatment of type 2 diabetes in the United States in April 2005. GLP-2 promotes energy absorption, inhibits gastric acid secretion and gut motility, and preserves mucosal epithelial integrity through enhancement of crypt cell proliferation and reduction of epithelial apoptosis. A GLP-2R agonist is being evaluated in clinical trials for the treatment of inflammatory bowel disease and short bowel syndrome. Taken together, the separate receptors for glucagon, GLP-1, and GLP-2 represent important targets for developing novel therapeutic agents for the treatment of disorders of energy homeostasis.     

A Semi-mechanistic Model for the Effects of a Novel Glucagon Receptor Antagonist on Glucagon and the Interaction Between Glucose,Glucagon, and Insulin Applied to Adaptive Phase II Design

A potent novel compound (MK-3577) was developed for the treatment of type 2 diabetes mellitus (T2DM) through blocking the glucagon receptor. A semi-mechanistic model was developed to describe the drug effect on glucagon and the interaction between glucagon, insulin, and glucose in healthy subjects (N = 36) during a glucagon challenge study in which glucagon, octreotide (Sandostatin), and basal insulin were infused for 2 h starting from 3, 12, or 24 h postdose of a single 0–900 mg MK-3577 administration. The drug effect was modeled by using an inhibitory E_max model (I_max = 0.96 and IC₅₀ = 13.9 nM) to reduce the ability of glucagon to increase the glucose production rate (GPROD). In addition, an E_max model (E_max = 0.79 and EC₅₀ = 575 nM) to increase glucagon secretion by the drug was used to account for the increased glucagon concentrations prechallenge (via compensatory feedback). The model adequately captured the observed profiles of glucagon, glucose, and insulin pre- and postchallenge. The model was then adapted for the T2DM patient population. A linear model to correlate fasting plasma glucose (FPG) to weighted mean glucose (WMG) was developed and provided robust predictions to assist with the dose adjustment for the interim analysis of a phase IIa study.KEY WORDS: glucagon challenge, glucagon receptor antagonist, glucose and insulin, modeling and simulation, type 2 diabetes     

Glucagon as a target for the treatment of Type 2 diabetes

Glucagon is the key counter-regulatory hormone that opposes the action of insulin. In states of relative hypoglycaemia, glucagon acts to increase blood glucose by stimulating hepatic glycogen breakdown and gluconeogenesis to achieve euglycaemia. Type 2 diabetes is characterised by inappropriate regulation of hepatic glucose production, which is due, at least in part, to an imbalance in the bihormonal relationship between plasma levels of glucagon and insulin. The glucose-lowering effects of glucagon peptide antagonists and antiglucagon neutralising antibodies first demonstrated the potential of glucagon receptor (GCGR) antagonism as a treatment for hyperglycaemia. In recent years, the development of GCGR antisense oligonucleotides and small molecular weight GCGR antagonists have been pursued as possible therapeutic agents to target glucagon action as a treatment for Type 2 diabetes.     

Progress towards glucagon receptor antagonist therapy for Type 2 diabetes

Peptidal glucagon receptor antagonists and antiglucagon monoclonal antibodies lower glucose levels in diabetic rodent models, suggesting a potential to treat hyperglycaemia in Type 2 diabetics through the inhibition of glucagon function. Several research groups have discovered small molecule glucagon antagonists from multiple chemical series and at least one has been clinically evaluated. Although multiple compounds have blocked the rise in blood glucose levels in response to a glucagon challenge, no preclinical or clinical efficacy data from chronic studies have been reported. In general, drug candidate potency, pharmacokinetics, physical properties and cross-species potency have hindered progress and preclinical efficacy assessment. Recently, antisense oligonucleotides against the glucagon receptor have been described, providing a guiding post for the type of activity a small molecule glucagon antagonist may possess, as well as offering a potential therapeutic strategy.     

2型糖尿病患者胰高血糖素水平检测的临床意义

目的探讨2型糖尿病患者空腹及馒头餐后血浆中胰高血糖素水平变化及意义。方法采用放射免疫法对140例2型糖尿病患者进行空腹及馒头餐后血浆胰高血糖素、血清胰岛素水平进行检测,并对二者不同时相结果进行比较。结果糖尿病患者空腹及餐后各时相胰高血糖素偏高比例均明显高于胰岛素水平低下患者比例（P〈0.05）。糖尿病患者空腹及餐后各时相胰高血糖素偏高者百分比与胰岛素水平低下者百分比分别为：空腹胰高血糖素为60%,（150±33）pg/ml,P〈0.01,胰岛素为4.29%,（4.4±0.8）mIU/L,P〈0.01;餐后1h胰高血糖素为91.86%,（154±37）pg/ml,P〈0.01,胰岛素为72.86%,（20.2±5.9）mIU/L,P〈0.01;餐后2h胰高血糖素为91.43%,（144±31）pg/ml,P〈0.01,胰岛素为38.57%,（15.1±3.4）mIU/L,P〈0.01;餐后3h胰高血糖素为71.43%,（141±30）pg/ml,P〈0.01,胰岛素2.86%,（4.1±0.74）mIU/L,P〈0.01。结论胰高血糖素异常升高是导致2型糖尿病患者血糖偏高的重要因素,检测胰高血糖素水平有助于临床准确判断糖尿病患者病情。     

胰高血糖素与2型糖尿病及糖调节异常相关性的研究

目的研究胰高血糖素(GC)与2型糖尿病(T2DM)及糖调节异常(IGR)的相关性。方法 T2DM组(45例)、IGR组(28例)、对照组(30例)三组对象皆采取空腹糖尿量试验(OGTT)与左旋精氨酸试验(L-ArG)检测,对比分析三组检测结果。结果 T2DM组患者与IGR组患者在FBG、F、GC上与对照组有显著性差异(P<0.05);T2MD组患者FFA明显高于IGR组与对照组(P<0.05);T2DM组患者F明显低于对照组与IGR组(P<0.05)。结论 2型糖尿病与糖调节异常患者其血糖水平、胰高血糖素及游离脂肪酸水平皆明显高于正常人群,可见胰高血糖素与2型糖尿病及糖调节异常有着一定的相关性。     

初诊2型糖尿病患者胰高血糖素水平的变化及临床意义

目的探讨初诊断2型糖尿病胰高血糖素水平的变化和其与胰岛素抵抗的关系。方法98例初诊断2型糖尿病患者和20例血糖正常的健康人,分别为糖尿病组和正常对照组,两组患者均行标准馒头餐试验,分别测定餐前0min和餐后30、60、120rain时点的血糖、胰岛素和胰高血糖素水平。结果（1）糖尿病组餐前0rain和餐后30、60、120rain的胰高血糖素水平与正常对照组对应的各时点比较,均显著增高,两组间差异有统计学意义。（2）糖尿病组餐后各时点胰高血糖素水平与胰岛素抵抗指数HOMA-IR相关。结论胰高血糖素分泌紊乱是2型糖尿病患者发生高血糖的重要因素,胰岛α细胞存在胰岛素抵抗。