Enyew Belay Kibret, Jemal Rebil Heiru, Tuyizere Aloys
Department of Internal Medicine, Endocrinology and Metabolism Unit, Bahir Dar University, Bahir Dar 6000, Ethiopia.
Department of Internal Medicine, Adama Hospital Medical College, Adama 1000, Ethiopia.
J Endocr Soc. 2024 Nov 6;8(12):bvae197. doi: 10.1210/jendso/bvae197. eCollection 2024 Oct 29.
Obesity poses a significant global health challenge, with an alarming rise in prevalence rates. Traditional interventions, including lifestyle modifications, often fall short of achieving sustainable weight loss, ultimately leading to surgical interventions, which carry a significant burden and side effects. This necessitates the exploration of effective and relatively tolerable pharmacological alternatives. Among emerging therapeutic avenues, glucagon-based treatments have garnered attention for their potential to modulate metabolic pathways and regulate appetite. This paper discusses current research on the physiological mechanisms underlying obesity and the role of glucagon in energy homeostasis. Glucagon, traditionally recognized for its glycemic control functions, has emerged as a promising target for obesity management due to its multifaceted effects on metabolism, appetite regulation, and energy expenditure. This review focuses on the pharmacological landscape, encompassing single and dual agonist therapies targeting glucagon receptors (GcgRs), glucagon-like peptide-1 receptors (GLP-1Rs), glucose-dependent insulinotropic polypeptide receptors (GIPRs), amylin, triiodothyronine, fibroblast growth factor 21, and peptide tyrosine tyrosine. Moreover, novel triple-agonist therapies that simultaneously target GLP-1R, GIPR, and GcgR show promise in augmenting further metabolic benefits. This review paper tries to summarize key findings from preclinical and clinical studies, elucidating the mechanisms of action, safety profiles, and therapeutic potential of glucagon-based therapies in combating obesity and its comorbidities. Additionally, it explores ongoing research endeavors, including phase III trials, aimed at further validating the efficacy and safety of these innovative treatment modalities.
肥胖是一项重大的全球健康挑战，患病率呈惊人的上升趋势。包括生活方式改变在内的传统干预措施往往难以实现可持续的体重减轻，最终导致需要进行手术干预，而手术干预会带来重大负担和副作用。这就需要探索有效且相对可耐受的药物替代方案。在新兴的治疗途径中，基于胰高血糖素的治疗因其调节代谢途径和控制食欲的潜力而受到关注。本文讨论了肥胖潜在生理机制的当前研究以及胰高血糖素在能量平衡中的作用。胰高血糖素传统上因其血糖控制功能而被认可，由于其对代谢、食欲调节和能量消耗具有多方面影响，已成为肥胖管理的一个有前景的靶点。本综述聚焦于药理学领域，包括针对胰高血糖素受体（GcgRs）、胰高血糖素样肽 -1 受体（GLP -1Rs）、葡萄糖依赖性促胰岛素多肽受体（GIPRs）、胰岛淀粉样多肽、三碘甲状腺原氨酸、成纤维细胞生长因子 21 和肽酪氨酸酪氨酸的单激动剂和双激动剂疗法。此外，同时靶向 GLP -1R、GIPR 和 GcgR 的新型三联激动剂疗法在增强进一步的代谢益处方面显示出前景。这篇综述文章试图总结临床前和临床研究的关键发现，阐明基于胰高血糖素的疗法在对抗肥胖及其合并症方面的作用机制、安全性概况和治疗潜力。此外，它还探讨了正在进行的研究工作，包括旨在进一步验证这些创新治疗方式有效性和安全性的 III 期试验。
