Targeting glucagon-like peptide-1 (GLP-1): The synthesis and activities associated with GLP-1 were discussed above. As review, the primary metabolic responses to GLP-1 release from the enteroendocrine L-cells of the gut are inhibition of glucagon secretion and enhancement of glucose-dependent insulin release from the pancreas, both effects lead to ，decreased glycemic excursion. As indicated above, the hormonal action of GLP-1 is rapidly terminated as a consequence of enzymatic cleavage by DPP IV. Recent clinical evidence has shown that either infusion of GLP-1 or inhibition of DPP IV can result in dramatic reductions in plasma glucose concentrations, reductions in HbA1c and improvement in pancreatic ?-cell function. Thus, both represent potential targets for the prevention of the hyperglycemia associated with diabetes and impaired insulin function (see the DPP IV review site maintained by Dr. Daniel J. Drucker).
作为靶心的胰高血糖素类似肽1（ GLP-1 ）
以上讨论过GLP-1合成和激活有关的问题。回顾一下。GLP-1从肠子内分泌L细胞释放的，对他的主要代谢反应是，抑制胰高血糖素分泌，增加从胰腺的释放的葡萄糖依赖的胰岛素，二者都导致游离血糖减少。如上所示，GLP-1的激素作用是，通过一种DPP IV使酶分裂（降解）的结果，作用快速终止
最近的临床证明显示，无论GLP-1的灌注还是DPP IV的抑制，能显著降低血浆葡萄糖和糖化血红蛋白的浓度，并改善胰腺?细胞的功能。因此，二者都表现出潜在的目标，防止糖尿病和胰岛素功能损害伴随来的高血糖
There are advantages and disadvantages with the current therapeutic approaches to targeting GLP-1 action in diabetic patients. Current use of GLP-1 mimetics and/or GLP-1 receptor (GLP-1R) agonists focus on peptides or modified peptides and these must be injected. The need for chronic injection as a means of therapy always runs into the problem of patient compliance. One of the most promising GLP-1R agonists that has recently been approved for use is BYETTA (developed by Amylin Pharmaceuticals and Eli Lilly and Co.). Byetta is composed of exenatide which is the lizard salivary peptide called exendin-4. Exenatide is 53% identical to GLP-1 at the level of amino acids and binds to and activates the GLP-1R. The advantage of exenatide as a therapeutic is that it is resistant to cleavage and inactivation by DPP IV. In a recent trial in patients with type 2 diabetes, Byetta was shown not only to lower blood glucose levels and HbA1c, but patients also had an associated weight loss. Another promising GLP-1R agonist is liraglutide. This compound is a fatty acid-linked derivative of GLP-1 that is resistant to DPP IV cleavage.
当前探讨 GLP-1治疗糖尿病的作用 ，有利有弊。现在用GLP-1的模拟物或受体物(GLP-1R)，集中在肽或改良肽，而且必须注射。这种长期注射的治疗方法是病人接受的问题。最有希望的受体物，是最近获得批准的BYETTA （由阿姆林药业集团Amylin Pharmaceuticals a和礼来公司Eli Lilly and Co开发）Byetta 是由exenatide 组成，exenatide是称作exendin-4. Exenatide的蜥蜴唾液肽 ，其氨基酸水平，有53%与GLP-1相同，并与GLP-1R.结合并激活。作为一种治疗，exenatide的优势是通过
DPP IV，，.抗拒分裂和灭活。最近一项2型糖尿病的试验中，Byetta不仅降低血糖和糖化血红蛋白水平，同时病人的体重减轻。另一个有希望的GLP-1R是liraglutide.，是GLP-1和脂肪酸连接的衍生物，抗拒DPP IV的分裂。
Although targeting compounds that can inhibit the enzymatic action of DPP IV would seem like ideal candidates for treating the hyperglycemia of uncontrolled diabetes, there are several unknowns associated with DPP IV inhibition. One of these issues is the fact that GLP-1 and GIP are only two of the many known substrates for DPP IV cleavage. Thus, prolonged inhibition of DPP IV enzymatic activity may have unexpected consequences unrelated to control of hyperglycemia. Despite the potential for as yet unknown effects, the DDP IV inhibitor developed by Merck, Januvia (sitagliptin), has recently been approved for use alone or in combination with either metformin or the thiazolidinediones. Treatment of patients with Januvia as the only therapeutic agent for 18 weeks produced significant reductions of HbA1c, along with an improvement of ?-cell function and no change in body weight.
虽然能抑制DPP IV酶作用的靶复合物，似乎是治疗不能控制的糖尿病的理想药物，但对DPP IV抑制剂，知之甚少。 DPP IV抑制剂有几项未知数，其中之一是，GLP-1 和 GIP仅仅是许多已知的DPP IV分裂酶作用物中的两种，这样DPP IV酶活性的延长抑制，可能有一个与高血糖控制无关的想不到的结果。 默克Merck,公司，不管这种尚未知晓的潜在能力，还是开发了Januvia (sitagliptin), 该药最近获得批准单独使用或与甲福明或噻嗪类合用。只用Januvia (sitagliptin),治疗的病人用药18个星期，血红蛋白明显降低，?细胞功能改善，体重没有变化。
DPP IV was originally identified as the lymphocyte cell surface antigen CD26. In humans CD26 functions in many pathways that are not directly related to its peptidase activity. It harbors adenosine deaminase-binding (ADA) properties and is involved in extracellular matrix binding. Of importance to the immune system, CD26 expression and activity are enhanced upon T-cell activation. CD26 interacts with other lymphocyte cell surface antigens including ADA, CD45 and the chemokine receptor CXCR4 (notable is the fact that CXCR4 is a T-cell attachment site for HIV). As yet it has not been clearly delineated as to whether the enzymatic activity of DPP IV is essential for the T-cell activating and co-stimulatory functions assigned to CD26. This issue must be resolved before chronic administration of DPP IV inhibitors can be applied in the clinic. Of significance, however, is that in gene knock-out mice lacking CD26 there is enhanced insulin secretion and improved glucose tolerance.
DPP IV最初被认为是lymphocyte cell surface antigen CD26.淋巴细胞表面抗原CD26.，在人类 CD26通过多种途径起作用，与其肽酶活性没有直接联系。含有腺苷脱氨基酶粘合adenosine deaminase-binding (ADA)的特性，并与细胞外组织有牵连。对免疫系统的重要性，T 细胞的激活增强CD26的表达与活性。CD26与其他淋巴细胞表面抗原ADA, CD45和chemokine receptor CXCR4相互作用（值得注意的是 CXCR4是一种HIV的T细胞的附属部分）还没有清楚地描绘，是否DPP IV的酶活性对T细胞的活性很重要，并对CD26.有再刺激的功能。这个问题必须在DPP IV抑制剂长期处理好以前，才能应用于临床。
The major clinical advantages to the use of DPP IV inhibitors is that the ones in current trials are orally delivered. Compliance in patients is much higher with orally delivered drugs than with those that require injection. The drug NVPDPP728 was shown to have significant DPP IV inhibitory action and led to significant lowering of blood glucose and HbA1c levels in type 2 diabetics. A second generation DPP IV inhibitor LAF237 is currently in clinical trials.
应用DPP IV抑制剂的主要优点是，当前的试验都是口服。病人更愿意口服而不是注射。药品NVPDPP728显示明显的DPP IV抑制作用，引起2型糖尿病人的血糖和糖化血红蛋白明显降低。第二代DPP IV抑制剂LAF237正在进行临床试验
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