EXENDIN-4 AS A TREATMENT FOR DIABETES MELLITUS

工作概要：胰腺的β细胞，它产生胰岛素， 2型糖尿病患者对葡萄糖的反应正常。与此同时， 尽管目前所有的治疗方法都可以治疗糖尿病β细胞 随着时间的推移，功能持续恶化。我们一直在为一些 GLP-1是一种天然存在的肽，由 肠道对食物的反应。它增强了胰岛素的释放能力， β细胞对食物的反应。令人感兴趣的是， 2型糖尿病GLP-1的药理学剂量可以使血糖正常化， 即，实现了电致发光。然而，GLP-1的生物半衰期为 只需4-6分钟，必须全身给药。这意味着它 必须持续注射才能维持正常的 希拉怪物是一种蜥蜴，生活在亚利桑那州。它的毒液中会产生 GLP-1的同系物，称为Exendin-4。当它被给予 对啮齿类动物全身而言，其生物半衰期为12-16小时。我们给 毒蜥外泌肽-4每日一次腹腔注射至db/db小鼠。Db/db小鼠发育 肥胖症和类似于人类2型糖尿病的糖尿病。 在给予Exendin-4的4天内， 糖尿病动物我们继续注射了10周。 血糖显示出在糖尿病动物中随着时间的推移而升高， Exendin-4，但它们仍然是未治疗组水平的至少一半。 动物血红蛋白A1 c是长期血糖控制的标志物， 给药动物中为5.7%，未给药动物中为9.1%。我们 正在扩大这个项目，以找到最小量的Exendin-4， 是抗糖尿病的，我们正在研究其机制， Exendin-4具有这种有益的长期效果。

Summary of work: 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. 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 4-6 minutes and has to be given systemically. This means that it would have to be given continuously in order to maintain euglycemia. The Hela monster is a lizard which lives in Arizona. It produces in its venom a homolog of GLP-1 which is 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. Db/db mice develop obesity and a type of diabetes resembling type 2 diabetes of humans. Within 4 days of giving Exendin-4 blood sugars were normalized in the diabetic animals. We continued the injections for a further 10 weeks. Blood sugars showed a rise over time in the diabetic animals treated with Exendin-4 but they remained at least half the level of the non-treated animals. Hemoglobin A1c, a marker of long-term control of blood sugars, was 5.7% in the treated animals and 9.1% in the non-treated animals. We are expanding on 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.