Drug Development of GLP-1 receptor agonists

当出现2型糖尿病时，胰腺中制造和分泌胰岛素的β细胞不会像非糖尿病受试者那样做出反应。具体地说，患有2型糖尿病的受试者对葡萄糖的反应是第一时相迟钝甚至完全丧失，第二时相胰岛素释放严重迟钝。与此同时，尽管目前有所有治疗糖尿病的方法，但随着时间的推移，β细胞功能继续恶化。使用英国前瞻性糖尿病研究(9月1日)的数据。1998)这一点被更有力地带回了家。尽管对参与研究的患者进行了持续的监测，但由于β细胞功能下降，即使进行强化治疗，正常血糖也无法维持。我们研究GLP-1已经有一段时间了，GLP-1是一种自然产生的多肽，通过肠道产生并释放出来，对食物做出反应。令人非常感兴趣的是，发现在2型糖尿病中，药物剂量的GLP-1可以使血糖正常化，即实现正常血糖。然而，GLP-1的生物半衰期只有2-4分钟，必须系统地给药。其短暂的半衰期部分是由于二肽基肽酶IV(DPP IV)迅速使其失活，从而分解前两个氨基酸。这意味着为了维持正常血糖，必须持续给药。吉拉怪兽是一种蜥蜴，其自然栖息地在亚利桑那州。它在唾液中产生一种名为exendin-4的多肽，它是GLP-1的同源物。给啮齿动物系统给药，生物半衰期为12-16小时。我们每天只给db/db小鼠一次腹腔注射exendin-4，结果显示，长期控制血糖的标志物--血红蛋白A1c在治疗的动物中为5.7%，在未治疗的动物中为9.1%，并且它的效力大约是GLP-1的10倍(Diabetologia 42：45-50,1999)。我们正在扩大这个项目，以寻找抗糖尿病的exendin-4的有效浓度，我们正在寻找exendin-4具有如此有益的长期影响的机制。我们还在致力于将exendin-4人源化，这样我们就可以获得一个尽可能接近GLP-1的多肽，同时仍然保持exendin-4的效力和生物半衰期。这使得它比GLP-1更有优势，甚至比其他多肽更有优势，如果我们发现Exendin-4在人类身上可以控制血糖(参见Exendin-4是治疗2型糖尿病的药物Z01AG00907)，我们将进一步扩大这一发现。至于使GLP-1对DPP IV产生抗性，我们已经表明，在第一和第二个氨基酸之间放置间隔区会抑制DPP IV的功能(内分泌学142：4462-4468,2001)。目前，Amylin Corp.(圣地亚哥)正在生产Exendin-4的透皮制剂，这种制剂可能只需每两周或每月更换一次。我们也一直在研究Exendin-4 C末端的九个氨基酸加成的功能。

Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. In conjunction with this, and despite all treatments currently available to treat diabetes, beta cell function continues to deteriorate over time. With the data now available from the United Kingdom Prospective Diabetes Study (Sept. 1998) this point was brought home even more forcefully. Despite continual monitoring of patients enrolled in the study, euglycemia could not be maintained even with intensive therapy, because of declining beta cell function. We have been working for some time with GLP-1, a naturally occurring peptide produced and released from the gut in response to food. Of great interest is the finding that in type 2 diabetes, pharmacological doses of GLP-1 can normalize blood sugars, i.e. euglycemia is achieved. However, GLP-1 has a biological half-life of only 2-4 minutes and has to be given systemically. Its short half-life is partially due to rapid inactivation of the peptide by dipeptidyl peptidase IV (DPP IV) which cleaves off the first 2 amino acids. This means that it would have to be given continuously in order to maintain euglycemia. The Gila monster is a lizard whose natural habitat is in Arizona. It produces a peptide, called exendin-4, in its saliva which is a homolog of GLP-1. When it is given systematically to rodents, its biological half-life is 12-16 hours. We gave exendin-4 intraperitoneally, only once daily, to db/db mice and showed that the hemoglobin A1c, a marker of long-term control of blood glucose, was 5.7% in the treated animals vs. 9.1% in the non-treated animals and that it was about 10-fold more potent that GLP-1 (Diabetologia 42:45-50, 1999). We are expanding this project to find the effective concentration of exendin-4 that is anti-diabetogenic and we are looking at the mechanisms whereby exendin-4 has such beneficial long-term effects. We are also working on "humanizing" exendin-4 so that we can have a peptide as close as possible to GLP-1 but still retain the potency and biological half-life of exendin-4. This gives it a major advantage over GLP-1 and indeed over other peptides and if we find that exendin-4, in humans, can control blood glucose (see Exendin-4 is a Treatment for Type 2 Diabetes Z01AG00907) we will expand further on this finding. As regards rendering GLP-1 DPP IV resistant we have shown that placing a spacer between the first and second amino acids inhibits DPP IV function (Endocrinology 142:4462-4468, 2001). Currently, Amylin Corp. (San Diego) is involved in manufacturing a transdermal preparation of Exendin-4 which may only have to be replaced biweekly or monthly even. We have also been investigating the function of the nine amino acid addition that is at the C-terminal end of exendin-4.