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肠促胰岛素肽，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。血浆水平升高后，GLP-1与β细胞上的GLP-1受体（GLP-1R）结合，通过腺苷酸环化酶（AC）激活和cAMP生成，增加PKA活性。在PKA活性增加的下游，葡萄糖诱导的胰岛素分泌增强。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。然而，胰岛内存在对β细胞分泌和增殖产生负面影响的细胞和激素机制，这不能用肠促胰岛素受体激动剂完全克服。另一种肠促胰岛素，GIP，也能增强葡萄糖诱导的胰岛素分泌，然而，与GLP-1不同的是，当以药理学浓度给予2型糖尿病患者时，它实际上会恶化餐后血糖，因为它也会增加胰高血糖素的分泌。至于胰岛素分泌的抑制剂，例如，胰岛中delta细胞产生的生长抑素可以抑制胰岛素分泌，尽管没有证据表明其在2型糖尿病中过度活跃，而且成人胰岛中delta细胞很少（β细胞与delta细胞的比例约为100:1）。我们寻找其他可能在胰岛内产生的潜在腺苷酸环化酶抑制剂，发现内源性大麻素仅在β细胞中产生。当大麻素1受体（CB1R）被抑制或基因移除时，胰岛素分泌和β细胞功能得到增强，因为对AC活性的抑制被解除了。我们目前正在评估仅在外周发挥作用的CB1R拮抗剂改善2型糖尿病β细胞功能的能力。

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 incretin 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 adenylyl cyclase (AC) activation and cAMP generation. Downstream of the increased PKA activity, glucose-induced insulin secretion is enhanced. 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. However, there are cellular and hormonal mechanisms within islets that negatively impact beta-cell secretion and proliferation, which cannot be fully overcome with incretin receptor agonists. Another incretin, GIP, also enhances glucose-induced insulin secretion, however, unlike GLP-1, when it is given in pharmacological concentrations to patients with type 2 diabetes it actually worsens post-prandial glucose because in also increases glucagon secretion. As regards inhibitors of insulin secretion, somatostatin production from delta cells in islets, for example, could serve to inhibit insulin secretion, though there is no evidence for its over-activity in type 2 diabetes and there are very few delta cells in adult islets to begin with ( about 100:1, beta to delta cells, respectively). We looked for other potential adenylyl cyclase inhibitors that may be produced within islets and found that endogenous cannabinoids are produced exclusively in beta cells. When cannabinoid 1 receptors (CB1R) are inhibited or genetically removed, insulin secretion and beta-cell function is enhanced because a brake on AC activity is lifted. We are now evaluating CB1R antagonists that have effects solely in the periphery for their ability to improve beta-cell function in type 2 diabetes.