School of Biomedical Sciences, Ulster University, Coleraine, United Kingdom.
Front Endocrinol (Lausanne). 2021 May 18;12:689678. doi: 10.3389/fendo.2021.689678. eCollection 2021.
Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
最初作为胰岛素制剂中的杂质被发现，我们对高血糖激素胰高血糖素的认识在随后的几十年中发生了显著变化。随着前胰高血糖素原(proglucagon)的描述，我们现在认识到胰高血糖素只是第一个被表征的前胰高血糖素衍生肽(PGDP)。PGDP 家族的其他生物活性成员包括胰高血糖素样肽-1 和 -2(GLP-1 和 GLP-2)、胰高血糖素样肽-2(GLP-2)、胰高血糖素原相关肽(GIP)，这些肽是由前激素转化酶(PC)酶 PC1/3 和 PC2 对前胰高血糖素进行组织特异性加工产生的。PGDP 肽发挥独特的生理作用，影响代谢和能量调节，其中一些已被开发为长效、酶抗性类似物，用于治疗各种疾病。因此，肌肉内注射胰高血糖素已被广泛用于低血糖的抢救，而 GLP-2 类似物则用于治疗短肠综合征。此外，自 2005 年批准第一种用于 2 型糖尿病(T2DM)治疗的 GLP-1 类似物以来，由于对血糖、食欲控制和体重减轻的多方面和可持续改善，GLP-1 治疗已成为 T2DM 治疗的主要方法。最近，开发了更长作用时间的 PGDP 治疗药物，同时发现了对心脏保护、骨健康、肾功能和肝功能以及认知功能的新益处。在本文中，我们讨论了 PGDP 肽的生理学及其治疗应用，重点介绍了成功设计的类似物，包括目前正在临床开发的双重和三重 PGDP 受体激动剂。
