EXENDIN-4 AS A TREATMENT FOR DIABETES MELLITUS

胰腺中制造胰岛素的β细胞可以 2型糖尿病患者对葡萄糖的反应不正常。结合 有了这一点，尽管目前有所有可用的治疗方法 糖尿病，随着时间的推移，β细胞的功能继续恶化。使用 现在可以从英国获得的数据预期 糖尿病研究(9月这一点甚至被带回家了 更有力地。尽管持续监测参加 研究中的正常血糖不能维持，即使在强化的情况下 治疗，因为β细胞功能下降。我们一直在 研究了一段时间的GLP-1，一种自然产生的多肽， 产生并从肠道释放出来的对食物的反应。它 增强胰岛β细胞的胰岛素释放能力 食物。令人感兴趣的是，在2型糖尿病患者中 药理剂量的GLP-1可以使血糖正常化，即， 达到了正常血糖。然而，GLP-1具有生物半衰期 只有2-4分钟，而且必须系统地给予。这意味着 它将不得不不断地给予，以保持 正常血糖。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毒液，这种毒液是 GLP-1，称为Exendin-4。当它被系统地给予啮齿类动物时 其生物半衰期为12-16小时。我们给了Exendin-4 给db/db小鼠每天一次的腹腔注射，结果表明 长期控制血糖的标志物--血红蛋白A1c 治疗组为5.7%，非治疗组为9.1%。 我们正在扩展这个项目，以找到最小数量的 Exendin-4是抗糖尿病的，我们正在研究 Exendin-4具有如此有益的长期机制 效果。我们已经获得了Exendin-4的抗体，以便开发 以测量其在血浆中的浓度。一个 FDA的调查IND刚刚被授予我们，所以 我们可以开始给糖尿病患者服用Exendin-4 以监测其皮下给药后的疗效 浓度各不相同。我们计划在下一个月开始研究。 年。

Beta cells of the pancreas, which make insulin, do not respond normally to glucose in type 2 diabetes. 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. It augments the insulin-releasing capacity of beta cells in response to food. Of great interest is the finding that in type 2 diabetes pharmacological doses of GLP-1 can normalize blood sugars, ie, 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 continuously in order to maintain euglycemia. The Gila monster is a lizard whose natural habitat is in Arizona. It produces a venom in its saliva which is a homolog of GLP-1, called Exendin-4. When it is given systemically to rodents its biological half-life is 12-16 hours. We gave Exendin-4 intraperitoneally, 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. We are expanding this project to find the minimal amount of Exendin-4 that is anti-diabetogenic and we are looking at the mechanisms whereby Exendin-4 has such beneficial long-term effects. We have obtained antibodies to exendin-4 so as to develop assays in order to measure its concentrations in plasma. An Investigational IND from the FDA has just been granted to us so that we can begin to administer Exendin-4 to diabetic subjects in order to monitor its efficacy after subcutaneous administration at various concentrations. We plan to begin the studies in the next year.