胰高血糖素样肽-1--2型糖尿病治疗的新策略

胰高血糖素样肽-1(GLP-1)由胰岛α细胞和肠道L细胞分泌,具有葡萄糖依赖性促胰岛素分泌、抑制胰高血糖素产生、增加β细胞数量及延缓胃排空等作用。易被二肽基肽酶IV(DPP-IV)降解,半衰期(t1/2)仅数分钟。近来,GLP-1类似物和DPP-IV抑制剂的研发为2型糖尿病的治疗提供了新策略。     

非酒精性脂肪肝患者口服葡萄糖后血浆胰高血糖素样肽和葡萄糖依赖性促胰岛素多肽水平的变化

目的 考察非酒精性脂肪肝(nonalcoholic fatty liver,NAFLD)患者口服葡萄糖后胰高血糖素样肽(glucagon- likepeptide-1,GLP-1)和葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic ploypeptide,GIP)分泌的特征。方法 选取34例非酒精性脂肪肝和42例健康人群,行口服糖耐量试验后在120 min内测定血GLP-1、GIP、血糖、血胰岛素、胰高血糖素含量进行比较。结果 NAFLD患者经葡萄糖诱导后GLP-1分泌量明显低于正常对照组(P<0.01),而GIP没有明显改变,但是所有患者均存在胰岛素抵抗。与正常对照组相比,NAFLD患者空腹胰岛素水平和葡萄糖诱导后的胰岛素水平均明显升高,血糖降低缓慢,而空腹胰高血糖素水平明显升高。结论 NAFLD患者经葡萄糖诱导分泌GLP-1功能缺陷,GIP分泌无异常。NAFLD患者存在胰岛素抵抗、高胰岛素血症和胰高血糖素血症。     

葡萄糖依赖性促胰岛素多肽/胰高血糖素样肽-1双受体激动剂在血糖控制中的作用研究进展

葡萄糖依赖性促胰岛素多肽(glucose-dependent insulinotropic ploypeptide,GIP)及胰高血糖素样肽(glucagon-like peptide,GLP)-1是两种主要的肠促胰岛素,二者均能增加葡萄糖依赖的胰岛素分泌,发挥降糖作用。近年来,GLP-1受体激动剂对2型糖尿病(diabetes mellitus type 2,T2DM)的疗效得到广泛认可,但关于GIP对T2DM的疗效仍未完全明确。当GIP与GLP-1在单分子双重激动剂中结合时,可表现出显著协同作用。现主要概述GIP/GLP-1双受体激动剂在T2DM患者血糖控制中的作用,及从临床前研究和临床研究中获得的新发现,旨在为临床提供参考。     

基于肠促胰岛素治疗糖尿病的药物研究进展

肠促胰岛素包括胰高血糖素样肽-1(Glucagon-like peptide-1,GLP-1)和葡萄糖依赖性促胰岛素释放多肽(Glucose-dependent insulinotropic polypeptide, GIP)两种分子,能够在肠道摄入食物后通过血糖依赖机制促进胰岛素的分泌。胰高血糖素样肽-1受体激动剂(Glucagon-like peptide-1 receptor agonists, GLP-1RAs)类药物凭借其良好的降糖活性、显著的体重控制作用以及明显的心血管收益在糖尿病的治疗中占据重要地位,基于另一肠促胰岛素GIP的疗法能否在糖尿病患者中发挥降糖作用仍不确定。GIP/GLP-1双重受体激动剂在临床试验中展现出了较好的治疗效果,针对糖尿病这一复杂的综合代谢性疾病,单分子多重受体激动剂似乎更具有潜力。文章介绍了基于肠促胰岛素的已上市药物,综述近年来处于临床试验阶段的基于肠促胰岛素治疗糖尿病的分子,以期为基于肠促胰岛素治疗糖尿病提供更多研究思路。     

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。     

肠促胰岛素激素类2-型糖尿病药物研究进展

近年来糖尿病患者递增,糖尿病已经成为严重危害人类健康的疾病。新型2-型糖尿病药物的研发已成为当前药物研究的一大热点。研究表明葡萄糖依赖性促胰岛素分泌多肽（glucose-dependent-insulinotropie polypeptide,GIP）和胰高血糖素样肽-1（glucagons like peptide-1.GLP-1）是人类重要的肠促胰岛素激素,GLP-1和GIP对于保持人体葡萄糖稳态平衡意义重大。目前根据GLP-1和GIP的作用机制研发出胰高血糖素样肽-l类似物和受体激动剂以及二肽基肽酶-4（DPP-4）抑制剂,均具有广阔的临床价值及市场前景。     

DPP-4抑制剂对2型糖尿病患者骨代谢的影响及其分子机制

糖尿病患者骨质疏松及骨折的发生风险增加。二肽基肽酶4(DPP-4)抑制剂是一种广泛应用于临床的降血糖药，有研究发现其对2型糖尿病患者的骨代谢有潜在的有益作用，但不同DPP-4抑制剂的作用存在差异。DPP-4抑制剂对骨代谢的作用可能通过降低血糖，影响胰高血糖素样肽1 (GLP-1)、葡萄糖依赖性促胰岛素多肽（GIP）等底物，改变维生素D水平，影响能量代谢,抑制脂肪分化、炎症等多种途径实现，但其对骨代谢的确切作用及与剂量的关系，以及对糖尿病以外人群的作用等有待进一步研究。     

基于胰高血糖素样肽-1的Ⅱ型糖尿病治疗研究进展

Ⅱ型糖尿病的治疗是现今研究关注的热点。现有的抗糖尿病药物由于副作用以及对病程恶化无显著改善而限制了其临床应用。基于胰高血糖素样肽-1(GLP-1)的药物为Ⅱ型糖尿病治疗提供了新的思路,主要包括GLP-1类似物及二肽基肽酶-IV(DPP-IV)抑制剂,其安全性和有效性已被大量的临床试验证明。GLP-1能够葡萄糖依赖地促进胰岛素分泌,且能够促进胰岛细胞的增殖,降低糖化血红蛋白浓度。文章就GLP-1及二肽基肽酶抑制剂用于Ⅱ型糖尿病治疗的研究作了综述。     

2型糖尿病的药物治疗进展

2型糖尿病是一种进展性疾病,由于胰岛素抵抗、对胰岛素反应低和β细胞代偿性分泌增加所致。近五年新的降糖药取得了进展。如胰高糖素样肽促进剂(GLP-1),二肽基肽酶(DPP-IV)抑制剂sitagliptin、vild-agliptin,减肥药Rimonabant,以及非注射型性胰岛素。该综述回顾这些新药的作用方式和临床应用。     

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。     

From the bench to the bedside: dipeptidyl peptidase IV inhibitors, a new class of oral antihyperglycemic agents

New therapeutic agents are needed to combat the ever-increasing prevalence of diabetes. The two incretins glucagon-like peptide-1 (7-36) (GLP-1(7-36)) amide and glucose-dependent insulinotropic peptide (GIP) are released from the small intestine in response to the ingestion of nutrients and regulate glucose homeostasis in a glucose-dependent fashion; however, the action of both incretins is terminated by the rapid N-terminal cleavage of two amino acid residues of GLP-1 and GIP by dipeptidyl peptidase-IV (DPP-IV). The preservation of active GLP-1 and GIP by inhibiting DPP-IV activity is an attractive strategy for the treatment of diabetes in patients who exhibit a reduced incretin response. This strategy has resulted in the launch of two DPP-IV inhibitor drugs; sitagliptin in North America, several European territories, and various other countries, and vildagliptin in the EU as well as various countries. This article provides an overview of the recent advances in and the lessons learned from the design of potent and selective small-molecule inhibitors of DPP-IV for the treatment of type 2 diabetes.     

Gut peptides in the treatment of diabetes mellitus

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPPIV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.     

Gut peptides in the treatment of diabetes mellitus

It has been known for at least one century that agents secreted from the intestine during meal absorption regulates glucose assimilation. Extensive research during the past three decades has identified two gut hormones, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, also known as gastric inhibitory polypeptide) that are important in postprandial glucose metabolism. Both peptides are incretins; they are secreted during carbohydrate absorption and increase insulin secretion. Since they are potent insulin secretagogues, GIP and GLP-1 have received considerable attention as potential diabetes therapeutics. However, only GLP-1 exerts insulinotropic properties when administered to patients with Type 2 diabetes. Both GLP-1 and GIP are rapidly inactivated in the circulation by the enzyme dipeptidyl peptidase IV (DPP-IV). The application of GLP-1 into clinical practice has been delayed due to the need to develop compounds that overcome this rapid inactivation. Two approaches have been taken to utilise the insulinotropic and glucose-lowering actions of GLP-1 as an antidiabetic agent: the development of DPP-IV-resistant analogues and the inhibition of DPP-IV. This review focuses on the physiology of GLP-1 and GIP and the advances that have been made thus far in developing treatments based on these physiological incretins for Type 2 diabetes.     

Current advances and therapeutic potential of agents targeting dipeptidyl peptidases-IV, -II, 8/9 and fibroblast activation protein

Dipeptidyl peptidase-IV (DPP-IV), a serine protease that specifically cleaves the N-terminal dipeptide with a preference for L-proline or L-alanine at the penultimate position, is involved in the degradation of incretin hormones, including glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). GLP-1 regulates glucose homeostasis by stimulating insulin secretion, inhibiting glucagon release, and delaying gastric emptying. Intravenous GLP-1 has been shown to increase insulin secretion in response to elevated glucose levels and offers therapeutic benefit for patients with type 2 diabetes. However, the therapeutic application of GLP-1 is severely compromised by its lack of oral activity and its rapid degradation by plasma DPP-IV. Consequently, small-molecule DPP-IV inhibitors that could extend the duration of action of GLP-1 and prolong its beneficial effects have been investigated as potential therapeutics for type 2 diabetes. This review summarizes important structural classes of DPP-IV inhibitors, focusing mainly on their inhibitory potency and selectivity for DPP-IV over other related peptidases such as DPP-II, DPP8, DPP9, and FAP. Because inhibition of DPP8 and/or DPP9 has been shown to cause severe toxicity in preclinical species, high selectivity is an important criterion in selecting DPP-IV inhibitors for clinical development. As of today, several DPP-IV inhibitors have completed phase III clinical studies for the treatment of type 2 diabetes. A brief overview of clinical efficacy data on these inhibitor drugs is provided here. In addition, biological activities of other related dipeptidyl peptidases (DPP-II, DPP8, DPP9, and FAP) will be summarized. Selective inhibitors for these peptidases and their therapeutic potential will be discussed.     

Synthetic and phytocompounds based dipeptidyl peptidase-IV (DPP-IV) inhibitors for therapeutics of diabetes

Currently antidiabetic therapeutic strategies are mainly based on synthetic hypoglycemic agent. Antidiabetic drugs are associated with significant adverse effects of hypoglycemia, dysfunction of insulin and weight gain. Nowadays, the novel Dipeptidyl peptidase-IV (DPP-IV) inhibitors unique approach for the management of diabetes has been considered to be safe, as DPP-IV inhibitors reduce blood glucose level by monitoring hyperglycemia including positive effects on body weight as it remains neutral, improves glycated hemoglobin levels and do not induce hypoglycemia. Inhibitors help to protect degradation of Glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), gut hormones which helps to suppresses postprandial glucagon release, delay gastric emptying and regulate satiety. Therefore, the innovation of DPP-IV inhibitor based drugs regulates activity of incretin hormones such as GLP-1 and GIP. Commercially available DPP-IV inhibitors are chemically synthesized with good therapeutic value. However, the durability and long-term safety of DPP-IV inhibitors remains to be established. On the other hand, phytocompounds-based DPP-IV inhibitors are alternative and safe to use as compared to synthetic. Numerous novel antidiabetic compounds and group of compounds emerging in clinical development are through DPP-IV inhibition. This review summarized recent progress made on DPP-IV inhibitors from both synthetic as well as from natural sources.     

Dipeptidyl peptidase IV inhibitors and the incretin system in type 2 diabetes mellitus

As understanding of type 2 diabetes mellitus pathophysiology expands, treatments continue to evolve and new pharmacologic targets emerge. Patients with type 2 diabetes exhibit deficiencies of the incretin system; thus, methods for increasing insulinotropic hormones have become a popular target for therapy. A new class of oral antidiabetics has emerged-the dipeptidyl peptidase IV (DPP-IV) inhibitors. Unlike conventional oral antidiabetic agents, these agents promote glucose homeostasis through inhibition of DPP-IV, the enzyme responsible for degradation of two key glucoregulatory hormones: glucagon-like peptide-1 (GLP-1), which extends the action of insulin while also suppressing the release of glucagon, and glucose-dependent insulinotropic peptide (GIP). Other proposed mechanisms of action of GLP-1 and thus DPP-IV inhibitors include satiety, increased beta-cell production, and inhibition of apoptosis of beta cells. Clinical studies have evaluated the potential for DPP-IV inhibition to reduce glucagon levels, delay gastric emptying, and stimulate insulin release. The DPP-IV inhibitors appear to have excellent therapeutic potential in the management of type 2 diabetes as monotherapy or in combination with existing agents, such as metformin. Their pharmacokinetic and pharmacodynamic profiles support once-daily dosing, with sustainable reductions in glycosylated hemoglobin levels and relatively few adverse effects. Their distinctive mechanism of action and adverse-event profiles may offer advantages over existing therapies, including low risk for hypoglycemia and possible augmentation of pancreatic beta-cell regeneration.     

KR-62436, 6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile, is a novel dipeptidyl peptidase-IV (DPP-IV) inhibitor with anti-hyperglycemic activity

Dipeptidyl peptidase-IV (DPP-IV) is involved in the inactivation of glucagon-like peptide-1 (GLP-1), a potent insulinotropic peptide. Thus, DPP-IV inhibition can be an effective approach to treat type 2 diabetes mellitus by potentiating insulin secretion. This study describes the biological effects of a new DPP-IV inhibitor, KR-62436 (6-{2-[2-(5-cyano-4,5-dihydropyrazol-1-yl)-2-oxoethylamino]ethylamino}nicotinonitrile) in vitro and in vivo. KR-62436 inhibited rat plasma DPP-IV, porcine kidney DPP-IV as well as human DPP-IV (Caco-2) with IC50 values of 0.78, 0.49, 0.14 microM, respectively. In addition, the compound (10 microM) almost completely inhibited DPP-IV-mediated degradation of GLP-1 in vitro. KR-62436 inhibited the enzyme in a competitive manner, and exhibited selectivity against several proteases including proline-specific proteases. In vivo efficacy of the compound was examined by using normal C57BL/6J mice and ob/ob mice, a type 2 diabetes animal model. Administration of KR-62436 to C57BL/6J mice either orally or subcutaneously resulted in the suppression of plasma DPP-IV activity, increase in intact GLP-1 and insulin levels in plasma. Furthermore, the plasma glucose concentrations during oral glucose tolerance test (OGTT) were reduced upon oral administration of KR-62436. This study demonstrates that KR-62436 could be a good lead compound for further development as a new anti-diabetic agent.     

Dipeptide boronic acid inhibitors of dipeptidyl peptidase IV: determinants of potency and in vivo efficacy and safety

Dipeptidyl peptidase IV (DPP-IV; E.C. 3.4.14.5), a serine protease that degrades the incretin hormones GLP-1 and GIP, is now a validated target for the treatment of type 2 diabetes. Dipeptide boronic acids, among the first, and still among the most potent DPP-IV inhibitors known, suffer from a concern over their safety. Here we evaluate the potency, in vivo efficacy, and safety of a selected set of these inhibitors. The adverse effects induced by boronic acid-based DPP-IV inhibitors are essentially limited to what has been observed previously for non-boronic acid inhibitors and attributed to cross-reactivity with DPP8/9. While consistent with the DPP8/9 hypothesis, they are also consistent with cross-reactivity with some other intracellular target. The results further show that the potency of simple dipeptide boronic acid-based inhibitors can be combined with selectivity against DPP8/9 in vivo to produce agents with a relatively wide therapeutic index (>500) in rodents.     

Chitosan-based therapeutic nanoparticles for combination gene therapy and gene silencing of in vitro cell lines relevant to type 2 diabetes

Glucagon like peptide 1 (GLP-1), a blood glucose homeostasis modulating incretin, has been proposed for the treatment of type 2 diabetes mellitus (T2DM). However, native GLP-1 pharmacokinetics reveals low bioavailability due to degradation by the ubiquitous dipeptydil peptidase IV (DPP-IV) endoprotease. In this study, the glucosamine-based polymer chitosan was used as a cationic polymer-based in vitro delivery system for GLP-1, DPP-IV resistant GLP-1 analogues and siRNA targeting DPP-IV mRNA. We found chitosans to form spherical nanocomplexes with these nucleic acids, generating two distinct non-overlapping size ranges of 141-283 nm and 68-129 nm for plasmid and siRNA, respectively. The low molecular weight high DDA chitosan 92-10-5 (degree of deacetylation, molecular weight and N:P ratio (DDA-Mn-N:P)) showed the highest plasmid DNA transfection efficiency in HepG2 and Caco-2 cell lines when compared to 80-10-10 and 80-80-5 chitosans. Recombinant native GLP-1 protein levels in media of transfected cells reached 23 ng/L while our DPP-IV resistant analogues resulted in a fivefold increase of GLP-1 protein levels (115 ng/L) relative to native GLP-1, and equivalent to the Lipofectamine positive control. We also found that all chitosan-DPP-IV siRNA nanocomplexes were capable of DPP-IV silencing, with 92-10-5 being significantly more effective in abrogating enzymatic activity of DPP-IV in media of silenced cells, and with no apparent cytotoxicity. These results indicate that specific chitosan formulations may be effectively used for the delivery of plasmid DNA and siRNA in a combination therapy of type 2 diabetes.     

GLP-1 based therapy for type 2 diabetes.

Type 2 diabetes mellitus is a major and growing health problem throughout the world. Current treatment approaches include diet, exercise, and a variety of pharmacological agents including insulin, biguanides, sulfonylureas and thiazolidinediones. New therapies are still needed to control metabolic abnormalities, and also to preserve beta-cell mass and to prevent loss of beta-cell function. Glucagon-like peptide 1 (GLP-1) is a drug candidate which potentially fulfils these conditions. GLP-1 is an incretin hormone secreted by intestinal L-cells in response to meal ingestion is a novel pharmacological target with multiple antihyperglycemic actions. GLP-1 glucoregulatory actions include glucose-dependent enhancement of insulin secretion, inhibition of glucagon secretion, slowing of gastric emptying and reduction of food intake. GLP-1 is rapidly inactivated by amino peptidase, dipeptidyl peptidase IV (DPP-IV) and the utility of DPP-IV inhibitors are also under investigation. There is a recent upsurge in the development of GLP-1 mimetics and DPP-IV inhibitors as potential therapy for type 2 diabetes. However, both the strategies are having their own advantages and limitations. The present review summarizes the concepts of GLP-1 based therapy for type 2 diabetes and the current preclinical and clinical development in GLP-1 mimetics and DPP-IV inhibitors. Further, the potential advantages and the limitations of both the strategies are discussed.