Abstract：
The rapidly rising incidence of obesity, coupled with type 2 diabetes mellitus (T2DM), is a growing concern. Glucagon-like peptide 1 (GLP-1), an endogenous peptide secreted by enteroendocrine L-cells, demonstrates exceptional pharmacological potential for the treatment of T2DM and obesity, primarily through its pivotal roles in regulating glucose homeostasis, stimulating glucose-dependent insulin secretion, and promoting satiety. Considering its proven efficacy in glucoregulation and weight loss, GLP-1 receptor agonists (GLP-1RAs) have emerged as a revolutionary breakthrough in the arena of diabetes management and weight control. Additional gastrointestinal hormones, such as glucose-dependent insulinotropic peptide (GIP) and glucagon, exhibit structural similarities to GLP-1 and work synergistically to lower blood glucose levels or aid in weight loss. Today, various classes of gut hormone receptor multiple agonists are steadily progressing through development and clinical trials, including dual GLP-1/glucagon receptor agonists (first discovered in 2009), dual GLP-1/GIP receptor agonists (first described in 2013), and triple GLP-1/GIP/glucagon receptor agonists (initially designed in 2015). The GLP-1/GIP receptor co-agonist, tirzepatide, was approved by the U.S. Food and Drug Administration (FDA) for the treatment of T2DM, outperforming basal insulin or selective GLP-1RAs by providing superior HbA1c reductions. Remarkably, tirzepatide also facilitated unprecedented weight loss of up to 22.5% in non-diabetic individuals living with obesity. This result is comparable to those achieved with certain types of bariatric surgery. Therefore, the advent of gut hormone multi-agonists signifies the dawn of an exciting new era in peptide-based therapy for obesity and T2DM. This review offers a comprehensive summary of the various types of gut hormone multiple agonists, including their discovery, development, action of mechanisms, and clinical effectiveness. We further delve into potential hurdles, limitations, and prospective advancements in the field.
摘要：
肥胖的发病率迅速上升,伴有2型糖尿病（T2DM），越来越令人担忧。胰高血糖素样肽-1(GLP-1),由肠内分泌L细胞分泌的内源性肽，显示了治疗T2DM和肥胖症的特殊药理学潜力。考虑到其在葡萄糖调节和减肥方面的功效，GLP-1受体激动剂（GLP-1RAs）已成为糖尿病管理和体重控制领域的革命性突破。额外的胃肠激素，如葡萄糖依赖性促胰岛素肽（GIP）和胰高血糖素，表现出与GLP-1的结构相似性,并且协同作用以降低血糖水平或帮助体重减轻。今天,各类肠道激素受体多重激动剂正在通过开发和临床试验稳步推进，包括双重GLP-1/胰高血糖素受体激动剂，双重GLP-1/GIP受体激动剂，和三联GLP-1/GIP/胰高血糖素受体激动剂。GLP-1/GIP受体共激动剂，泰西帕肽,被美国食品和药物管理局（FDA）批准用于治疗T2DM，通过提供优异的HbA1c降低，优于基础胰岛素或选择性GLP-1RAs。值得注意的是,在患有肥胖症的非糖尿病患者中,替瑞帕肽还促进了高达22.5%的前所未有的体重减轻.该结果与某些类型的减肥手术所获得的结果相当。因此,肠道激素多激动剂的出现标志着基于肽的肥胖和2型糖尿病治疗新时代的到来.这篇综述提供了各种类型的肠道激素多重激动剂的全面总结，包括他们的发现,发展,机制的作用，和临床有效性。我们进一步深入研究潜在的障碍，局限性,以及该领域的未来进展。
