EXENDIN-4 AS A TREATMENT FOR DIABETES MELLITUS

当2型糖尿病患者出现时，胰腺的β细胞（制造和分泌胰岛素）不会像非糖尿病患者那样做出反应。具体来说，患有2型糖尿病的受试者对第一阶段和第二阶段胰岛素释放的感觉迟钝甚至绝对迟钝。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。根据英国前瞻性糖尿病研究（1998年9月）的现有数据，这一点得到了更有力的论证。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，即使进行强化治疗，也无法维持血糖正常。我们研究GLP-1已经有一段时间了，这是一种自然产生的肽，在肠道对食物的反应中产生和释放。在2型糖尿病中，药理学剂量的GLP-1可以使血糖正常化，即达到正常血糖，这一发现非常有趣。然而，GLP-1的生物半衰期只有2-4分钟，必须全身给予。这意味着必须连续给药以维持血糖正常。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叫做exendin-4的肽，它是GLP-1的同源物。当系统地给啮齿动物服用时，其生物半衰期为12-16小时。我们每天只给db/db小鼠腹腔注射一次exendin-4，结果显示，治疗动物的糖化血红蛋白（长期血糖控制的标志）为5.7%，而未治疗动物为9.1%，其效力约为GLP-1的10倍（Diabetologia 42:45- 50,1999）。我们正在扩大这个项目，以找到抗糖尿病的有效浓度，我们正在研究exendin-4具有如此有益的长期效果的机制。我们也在努力使exendin-4人源化，这样我们就可以得到尽可能接近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exendin-4是一种非常稳定的化合物，无论是口服还是鼻用制剂。这使得exendin-4比GLP-1和其他多肽更有优势，如果我们发现exendin-4在人类中可以控制血糖（见exendin-4是治疗2型糖尿病的药物Z01AG00907），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，多肽，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