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).
作為靶心的胰高血糖素類似肽1（ GLP-1 ）
以上討論過GLP-1合成和激活有關的問題?；仡櫼幌隆LP-1從腸子內分泌L細胞釋放的，對他的主要代謝反應是，抑制胰高血糖素分泌，增加從胰腺的釋放的葡萄糖依賴的胰島素，二者都導致游離血糖減少。如上所示，GLP-1的激素作用是，通過一種DPP IV使酶分裂（降解）的結果，作用快速終止
最近的臨床證明顯示，無論GLP-1的灌注還是DPP IV的抑制，能顯著降低血漿葡萄糖和糖化血紅蛋白的濃度，并改善胰腺?細胞的功能。因此，二者都表現(xiàn)出潛在的目標，防止糖尿病和胰島素功能損害伴隨來的高血糖

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.
當前探討 GLP-1治療糖尿病的作用 ，有利有弊?，F(xiàn)在用GLP-1的模擬物或受體物(GLP-1R)，集中在肽或改良肽，而且必須注射。這種長期注射的治療方法是病人接受的問題。最有希望的受體物，是最近獲得批準的BYETTA （由阿姆林藥業(yè)集團Amylin Pharmaceuticals a和禮來公司Eli Lilly and Co開發(fā)）Byetta 是由exenatide 組成，exenatide是稱作exendin-4. Exenatide的蜥蜴唾液肽 ，其氨基酸水平，有53%與GLP-1相同，并與GLP-1R.結合并激活。作為一種治療，exenatide的優(yōu)勢是通過
DPP IV，，.抗拒分裂和滅活。最近一項2型糖尿病的試驗中，Byetta不僅降低血糖和糖化血紅蛋白水平，同時病人的體重減輕。另一個有希望的GLP-1R是liraglutide.，是GLP-1和脂肪酸連接的衍生物，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.
雖然能抑制DPP IV酶作用的靶復合物，似乎是治療不能控制的糖尿病的理想藥物，但對DPP IV抑制劑，知之甚少。 DPP IV抑制劑有幾項未知數(shù)，其中之一是，GLP-1 和 GIP僅僅是許多已知的DPP IV分裂酶作用物中的兩種，這樣DPP IV酶活性的延長抑制，可能有一個與高血糖控制無關的想不到的結果。 默克Merck,公司，不管這種尚未知曉的潛在能力，還是開發(fā)了Januvia (sitagliptin), 該藥最近獲得批準單獨使用或與甲福明或噻嗪類合用。只用Januvia (sitagliptin),治療的病人用藥18個星期，血紅蛋白明顯降低，?細胞功能改善，體重沒有變化。
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最初被認為是lymphocyte cell surface antigen CD26.淋巴細胞表面抗原CD26.，在人類 CD26通過多種途徑起作用，與其肽酶活性沒有直接聯(lián)系。含有腺苷脫氨基酶粘合adenosine deaminase-binding (ADA)的特性，并與細胞外組織有牽連。對免疫系統(tǒng)的重要性，T 細胞的激活增強CD26的表達與活性。CD26與其他淋巴細胞表面抗原ADA, CD45和chemokine receptor CXCR4相互作用（值得注意的是 CXCR4是一種HIV的T細胞的附屬部分）還沒有清楚地描繪，是否DPP IV的酶活性對T細胞的活性很重要，并對CD26.有再刺激的功能。這個問題必須在DPP IV抑制劑長期處理好以前，才能應用于臨床。

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.
應用DPP IV抑制劑的主要優(yōu)點是，當前的試驗都是口服。病人更愿意口服而不是注射。藥品NVPDPP728顯示明顯的DPP IV抑制作用，引起2型糖尿病人的血糖和糖化血紅蛋白明顯降低。第二代DPP IV抑制劑LAF237正在進行臨床試驗

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