Exendin-4 Is A Treatment For Type 2 Diabetes

继续Z 01 AG 00905 -04 LCI，我们收到了FDA的研究者IND，用于研究糖尿病患者中的exendin-4。1998年12月，我们在非糖尿病（n=12）和糖尿病（n=12）受试者中开始了毒蜥外泌肽-4（RPN：GRC 98 -10-26-01）的急性研究，以观察其是否（1）促胰岛素，（2）寿命长，（3）比GLP-1更有效，（4）在糖尿病状态下有效，以及（5）有效控制餐后葡萄糖升高（这是2型糖尿病的主要问题，由于第一时相胰岛素分泌不足）。我们发现这五个方面都是如此。我们还发现，毒蜥外泌肽-4在非糖尿病和糖尿病人群中均为拟胰岛素（增加葡萄糖摄取）。这证实了我们在Z 01 AG 00906 -04 LCI中概述的怀疑，其中我们假设GLP-1是拟胰岛素。使用更有效的exendin-4，我们可以清楚地阐明这一发现。随后，我们又启动了两项临床研究（RPN：GRC 99 -02-09-01和GRC 99 -07-07-01）。我们给2型糖尿病患者每天皮下注射exendin-4长达一个月，在30天的治疗前后监测胰岛素分泌和葡萄糖摄取。为了证明exendin-4是一种真正的拟胰岛素药物，我们将在1型糖尿病受试者中进行exendin-4的急性研究。由于它们没有内源性胰岛素分泌，我们观察到的对葡萄糖摄取的任何影响都应该是由于exendin-4的施用而不是由于内源性胰岛素分泌。我们认为exendin-4，或我们正在开发的它的类似物之一，将是未来治疗糖尿病的方法。我们还希望exendin-4可以以经皮方式使用，以消除皮下注射的需要。

Continuing Z01AG00905-04 LCI, we received an Investigators' IND from the FDA to study exendin-4 in diabetic humans. In December 1998, we started an acute study of exendin-4 (RPN:GRC98-10-26-01 in non-diabetic (n=12) and diabetic (n=12) subjects to see if it was (1) insulinotropic, (2) long-lived, (3) more potent than GLP-1, (4) effective in the diabetic state, and (5)effective in controlling post-prandial glucose elevations (which are a major problem in type 2 diabetes due to deficient first phase insulin secretion). We found all five aspects to be the case. We also found that exendin-4 was insulinomimetic (increases glucose uptake) in both non-diabetic and diabetic humans. This confirms what we suspected as outlined in Z01AG00906-04 LCI in which we hypothesized GLP-1 was insulinomimetic. Using the more potent exendin-4, we could clearly elucidate this finding. Subsequently, we initiated two more clinical studies(RPN: GRC99-02-09-01 and GRC99-07-07-01). We gave exendin-4 daily subcutaneously to type 2 diabetic subjects for up to one month, with measures of insulin secretion and glucose uptake monitored before and after the 30-day treatment. In order to prove that exendin-4 is a true insulinomimetic agent, we will carry out an acute study of exendin-4 in type 1 diabetic subjects. As they have no endogenous insulin secretion, any effect we see on glucose uptake should be due to the administration of exendin-4 and not due to endogenous insulin secretion. We think that exendin-4, or one of its analogs which we are developing, will be a future treatment for diabetes. We are also hoping that exendin-4 may be used in a transdermal fashion to eliminate the need for subcutaneous injection.