Drug Development of GLP-1 receptor agonists

当存在2型糖尿病时，制造和分泌胰岛素的胰腺β细胞不像非糖尿病受试者的β细胞那样响应。 具体地，患有2型糖尿病的受试者响应于葡萄糖而具有第一时相的钝化或甚至绝对损失和严重钝化的第二时相胰岛素释放。 与此同时，尽管目前有所有治疗糖尿病的方法，β细胞功能仍会随着时间的推移而恶化。 根据英国前瞻性糖尿病研究（9月11日）的数据，1998年，这一点被更有力地带回家。 尽管对参加研究的患者进行了持续监测，但由于β细胞功能下降，即使采用强化治疗也无法维持正常。 我们已经研究GLP-1一段时间了，GLP-1是一种天然存在的肠促胰岛素肽，在食物反应中从肠道产生和释放。 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-1 R）结合，并因腺苷酸环化酶（AC）激活和cAMP生成而增加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。 最终结果是血糖恢复至基线水平。 因此，GLP-1类似物和GLP-1 R激动剂作为2型糖尿病的治疗正在进行深入研究。 一种天然存在的GLP-1 R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，当它以药理学浓度给予2型糖尿病患者时，它实际上会降低餐后葡萄糖，因为它也会增加胰高血糖素分泌。关于胰岛素分泌的抑制剂，例如，来自胰岛中δ细胞的生长抑素产生可用于抑制胰岛素分泌，尽管没有证据表明其在2型糖尿病中过度活性，并且在成人胰岛中几乎没有δ细胞可开始（β细胞与δ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（CB 1 R）被抑制或基因去除时，胰岛素分泌和β细胞功能增强，因为AC活性的制动被解除。我们现在正在评估CB 1 R拮抗剂，这些拮抗剂仅在外周发挥作用，以改善2型糖尿病患者的β细胞功能。

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.