Drug Development of GLP-1 receptor agonists

GLP-1受体激动剂的药物开发

• 批准号: 8736642
• 负责人: Josephine Egan
• 金额: $ 49.99万
• 依托单位: NATIONAL INSTITUTE ON AGING
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8736642
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Adenylate Cyclase; Adult; Agonist; Back; Beta Cell; Binding; Cannabinoids; Cell Proliferation; Cell physiology; Cell secretion; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; D Cells; Data; Diabetes Mellitus; Disease; Endocannabinoids; Enrollment; Fatty acid glycerol esters; Food; GNAI2 gene; Generations; Glucagon; Glucose; Home environment; Hormonal; Injection of therapeutic agent; Insulin; Insulin Antagonists; Lifting; Ligands; Non-Insulin-Dependent Diabetes Mellitus; Patient Monitoring; Patients; Pattern; Peptides; Pharmaceutical Preparations; Phase; Plasma; Production; Somatostatin; Structure of beta Cell of islet; Time; United Kingdom; Work; analog; drug development; exenatide; glucagon-like peptide 1; improved; inhibitor/antagonist; insulin secretion; islet; non-diabetic; prospective; receptor; response; restoration

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.

当存在 2 型糖尿病时，产生和分泌胰岛素的胰腺 β 细胞不会像非糖尿病受试者那样做出反应。 具体地，患有2型糖尿病的受试者响应葡萄糖的第一相胰岛素释放减弱甚至完全丧失，并且第二相胰岛素释放严重减弱。 与此同时，尽管目前可以使用所有治疗糖尿病的方法，但β细胞功能随着时间的推移继续恶化。 根据英国前瞻性糖尿病研究（1998 年 9 月）提供的数据，这一点更加明显。 尽管对参与该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正常血糖。 一段时间以来，我们一直在研究 GLP-1，这是一种天然存在的肠促胰岛素肽，由肠道响应食物而产生和释放。 释放的量取决于摄入的葡萄糖和脂肪的量。 血浆水平增加后，GLP-1 与 β 细胞上的 GLP-1 受体 (GLP-1R) 结合，并由于腺苷酸环化酶 (AC) 激活和 cAMP 生成而增加 PKA 活性。 PKA 活性增加的下游，葡萄糖诱导的胰岛素分泌增强。 最终结果是血浆葡萄糖恢复至基线。 因此，GLP-1 类似物和 GLP-1R 激动剂作为 2 型糖尿病的治疗方法正在进行深入研究。 一种天然存在的 GLP-1R 激动剂 Exendin-4 现在可用于治疗。然而，胰岛内的细胞和激素机制会对 β 细胞的分泌和增殖产生负面影响，而肠促胰岛素受体激动剂无法完全克服这种影响。另一种肠促胰素 GIP 也能增强葡萄糖诱导的胰岛素分泌，但与 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，因为它还会增加胰高血糖素分泌。例如，就胰岛素分泌抑制剂而言，胰岛中 δ 细胞产生的生长抑素可用于抑制胰岛素分泌，尽管没有证据表明其在 2 型糖尿病中过度活跃，而且成年胰岛中的 δ 细胞很少首先（大约 100:1，β 到 δ 细胞分别）。我们寻找可能在胰岛内产生的其他潜在的腺苷酸环化酶抑制剂，并发现内源性大麻素仅在β细胞中产生。当大麻素 1 受体 (CB1R) 受到抑制或从基因上去除时，胰岛素分泌和 β 细胞功能就会增强，因为对 AC 活性的抑制被解除。我们现在正在评估仅在外周起作用的 CB1R 拮抗剂改善 2 型糖尿病中 β 细胞功能的能力。