EXENDIN-4 AS A TREATMENT FOR DIABETES MELLITUS

当存在2型糖尿病时，胰腺的β细胞（其产生和分泌胰岛素）不像非糖尿病受试者的β细胞那样响应。具体地，患有2型糖尿病的受试者具有钝的或甚至绝对的第一阶段感觉和钝的第二阶段胰岛素释放。与此同时，尽管目前有所有治疗糖尿病的方法，β细胞功能仍会随着时间的推移而恶化。根据英国前瞻性糖尿病研究（9月11日）的数据，1998年，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监测，但由于β细胞功能下降，即使采用强化治疗也无法维持正常。我们已经研究GLP-1一段时间了，GLP-1是一种天然存在的肽，在食物反应中从肠道产生和释放。非常令人感兴趣的是，在2型糖尿病中，药理学剂量的GLP-1可以使血糖正常化，即实现血糖正常化。然而，GLP-1的生物半衰期只有2-4分钟，必须全身给药。这意味着它将不得不不断给予，以维持健康。吉拉怪物是一种蜥蜴，其自然栖息地在亚利桑那州。它在唾液中产生一种称为exendin-4的肽，它是GLP-1的同系物。当它被系统地给予啮齿动物时，其生物半衰期为12-16小时。我们将毒蜥外泌肽-4腹膜内给予db/db小鼠，每天仅一次，并显示血红蛋白A1 c（血糖长期控制的标志物）在治疗的动物中为5.7%，而在未治疗的动物中为9.1%，并且其效力是GLP-1的约10倍（Diabetologia 42：45-50，1999）。我们正在扩大这个项目，以找到抗糖尿病的exendin-4的有效浓度，我们正在研究exendin-4具有这种有益的长期作用的机制。我们还在研究exendin-4的人源化，这样我们就可以获得尽可能接近GLP-1的肽，但仍然保留exendin-4的效力和生物半衰期。我们还发现，毒蜥外泌肽-4是一个相当稳定的化合物时，采取的口或作为鼻制剂。这使它比GLP-1和其他肽具有主要优势，如果我们发现Exendin-4在人体中可以控制血糖（参见Exendin-4是2型糖尿病的治疗Z 01 AG 00907），我们将进一步扩展这一发现。我们目前正在开发一种可以从口腔粘膜吸收的制剂。- Exendin-4，2型糖尿病，肽类，分化，人源化

Beta cells of the pancreas, which make and secrete insulin, do not respond as do those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute sense of first phase and a blunted second phase insulin release. 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. 19998) 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. This means that it would have to be given continously 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. We also found that exendin-4 is quite a stable compound when taken by mouth or as a nasal preparation. 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. We are currently developing a preparation which can be absorbed from the buccal mucosa. - Exendin-4, Type 2 diabetes, Peptides, Differentiation, Humanization