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.

当出现2型糖尿病时，胰腺中制造和分泌胰岛素的β细胞不会像非糖尿病受试者那样做出反应。具体地说，患有2型糖尿病的受试者对葡萄糖的反应是第一时相迟钝甚至完全丧失，第二时相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。使用英国前瞻性糖尿病研究(9月1日)的数据。1998)这一点被更有力地带回了家。尽管对参与研究的患者进行了持续的监测，但由于β细胞功能下降，即使进行强化治疗，正常血糖也无法维持。我们研究GLP-1已经有一段时间了，GLP-1是一种自然产生的胰岛素多肽，在肠道中产生并释放出来，对食物做出反应。释放的量取决于摄入的葡萄糖和脂肪的量。血浆GLP-1水平升高后，GLP-1与β细胞上的GLP-1受体(GLP-1R)结合，通过腺苷环化酶(AC)的激活和cAMP的生成，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加。最终结果是血糖恢复到基线水平。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紧张的研究中。一种自然产生的GLP-1R激动剂exendin-4现在可以用于治疗。然而，胰岛内有细胞和激素机制对β细胞的分泌和增殖产生负面影响，这不能用胰岛素受体激动剂完全克服。另一种胰岛素，GIP，也可以增强葡萄糖诱导的胰岛素分泌，然而，与GLP-1不同的是，当它以药物浓度给2型糖尿病患者时，它实际上会恶化餐后血糖，因为它还会增加高血糖素的分泌。至于胰岛素分泌的抑制剂，例如，胰岛中的三角洲细胞产生的生长抑素可以抑制胰岛素的分泌，尽管没有证据表明它在2型糖尿病中过度活跃，而且成人胰岛中最初只有很少的三角洲细胞(大约100：1，分别是β细胞和三角洲细胞)。我们寻找可能在胰岛内产生的其他潜在的腺酰环化酶抑制剂，发现内源性大麻素只在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细胞功能增强，因为AC活性的刹车被解除。我们现在正在评估CB1R拮抗剂对改善2型糖尿病患者β细胞功能的能力，这些拮抗剂只在外周有效。