Drug Development of GLP-1 receptor agonists

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）的反应与非糖尿病患者不同。具体来说，患有2型糖尿病的受试者对葡萄糖的第一阶段胰岛素释放迟钝甚至完全丧失，第二阶段胰岛素释放严重迟钝。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。释放的量取决于摄入的葡萄糖和脂肪的量。在其血浆水平升高后，GLP-1与β细胞上的GLP-1受体（GLP-1R）结合，并由于cAMP的生成而增加PKA活性。在PKA活性增加的下游，胰岛素释放也以葡萄糖依赖的方式发生，血浆葡萄糖因进食而升高。最终的结果是血浆葡萄糖恢复到基线。因此，GLP-1类似物和GLP-1R激动剂作为治疗2型糖尿病的药物正在深入研究中。一种天然存在的GLP-1R激动剂exendin-4现在可用于治疗。它与GLP-1R结合的速度是天然GLP-1的十倍。它含有许多与GLP-1同源的氨基酸，有趣的是，它含有一个独特的9个氨基酸的c端。我们通过研究将c端添加到GLP-1的c端时对GLP-1的影响，以及通过从exendin-4中按顺序和三联体删除9个氨基酸，广泛地研究了c端的功能意义。它与GLP-1的结合提高了其与自身受体的结合亲和力，而从exendin-4中删除则消除了其对GLP-1R的增强亲和力。另一种促胰岛素肽GIP也会在进食后从肠道中释放出来，但根据BLSA的数据，一旦血糖超过126毫克/分升，胰腺的β细胞就会对其产生抵抗作用。此外，使用外源性GIP的人体体内实验方案表明，β细胞对外源性GIP的反应不会增加胰岛素分泌。GIP也容易被二肽基肽酶1V快速分解。因此，我们目前正在2型糖尿病患者中测试二肽基肽酶1v抗性GIP肽是否能够成功地增加β细胞的胰岛素分泌。这项研究涉及24名受试者，这些受试者的肽浓度不断增加，最高可达20 ng/kg/min。该协议现在已经完成，数据正在分析中。

Beta cells of the pancreas, which make and secrete insulin, do not respond like those of non-diabetic subjects when type 2 diabetes is present. Specifically, subjects suffering from type 2 diabetes have a blunted or even absolute loss of first phase and a severely blunted second phase insulin release in response to glucose. 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. The amount released depends on the amount of glucose and fat that has been ingested. After its plasma levels increase, GLP-1 binds to the GLP-1 receptor (GLP-1R) on beta cells, and increases PKA activity because of cAMP generation. Downstream of the increased PKA activity, insulin release occurs also in a glucose-dependent manner, plasma glucose having risen because of the meal. The end result is a restoration of plasma glucose back to baseline. Consequently, GLP-1 analogs and GLP-1R agonists are under intense study as treatments for type 2 diabetes. A naturally occurring GLP-1R agonist, exendin-4, is now available for treatment. It binds to GLP-1R with ten times more avidity than does native GLP-1. It contains many amino acids homologous to GLP-1 and, interestingly, contains a unique 9 amino acid C-terminus. We have extensively investigated the functional significance of the C-terminus by studying the effects on GLP-1 when it is added to the C-terminus of GLP-1 and by deleting the 9 amino acids sequentially and in triads from exendin-4. Its addition to GLP-1 improved its binding affinity to its own receptor and its deletion from exendin-4 abrogated its increased affinity for GLP-1R. Another insulinotropic peptide, GIP, is also released from the gut after eating, but, based on BLSA data, beta cells of the pancreas appear resistant to its effects once blood glucose exceed 126 mg/dl. Additionally, in vivo experimental protocols in humans using exogenous GIP have shown that beta cells do not increase insulin secretion in response to exogenous human GIP. GIP is also subject to rapid breakdown by dipeptidyl peptidase 1V. Therefore, we are currently testing in type 2 diabetic humans if a dipeptidyl peptidase 1V-resistant GIP peptide might be successful at increasing insulin secretion from beta cells. This study involves 24 subjects to which increasing concentrations of the peptide have been given up to a maximum of 20 ng/kg/min. This protocol is now finished and the data is being analyzed.