Glucagon-like peptide-1 (GLP-1) is a gastrointestinal hormone secreted from L cells in the distal small intestine and proximal colon after a meal that acts as an incretin to augment the insulin response, while also inhibiting glucagon and slowing gastric emptying. These characteristics of GLP-1, as well as its ability to reduce islet beta cell apoptosis and expand beta cell mass and its cardioprotective and neuroprotective effects, provide a broad spectrum of actions potentially useful for the management of type-2 diabetes mellitus. GLP-1 also has the added advantage of having its incretin effects dependent on the level of serum glucose, only acting in the presence of hyperglycaemia, and thereby preventing hypoglycemic responses. Although natural GLP-1 has a very short half-life, limiting its therapeutic usefulness, a variety of analogues and formulations have been developed to provide extended actions and to limit side effects. However, all of these peptides require parenteral administration. Potentially orally active small-molecule agonists acting at the GLP-1 receptor are also being developed, but have not yet been approved for clinical use. Recent insights into the molecular nature of the class B G-protein-coupled GLP-1 receptor has provided insights into the modes of binding these types of ligands, as well as providing opportunities for rational enhancement. The advantages and disadvantages of each of these agents and their possible clinical utility will be explored.

胰高血糖素样肽-1 (GLP-1) 是一种胃肠激素，在餐后由远端小肠和近端结肠的 L 细胞分泌，可作为肠促胰岛素增加胰岛素反应，同时抑制胰高血糖素和减缓胃排空。GLP-1 的这些特性，以及其减少胰岛 β 细胞凋亡和扩大 β 细胞质量的能力及其心脏保护和神经保护作用，提供了可能对 2 型糖尿病的管理有用的广泛作用。GLP-1 还具有额外的优势，即其肠促胰岛素作用取决于血清葡萄糖水平，仅在高血糖存在时起作用，从而防止低血糖反应。虽然天然 GLP-1 的半衰期很短，限制了它的治疗用途，已经开发了多种类似物和制剂以提供延长作用并限制副作用。然而，所有这些肽都需要肠胃外给药。作用于 GLP-1 受体的潜在口服活性小分子激动剂也正在开发中，但尚未被批准用于临床。最近对 B 类 G 蛋白偶联 GLP-1 受体分子性质的深入了解提供了对结合这些类型配体的模式的深入了解，并为合理增强提供了机会。将探讨这些药物中的每一种的优点和缺点以及它们可能的临床效用。作用于 GLP-1 受体的潜在口服活性小分子激动剂也正在开发中，但尚未被批准用于临床。最近对 B 类 G 蛋白偶联 GLP-1 受体分子性质的深入了解提供了对结合这些类型配体的模式的深入了解，并为合理增强提供了机会。将探讨这些药物中的每一种的优点和缺点以及它们可能的临床效用。作用于 GLP-1 受体的潜在口服活性小分子激动剂也正在开发中，但尚未被批准用于临床。最近对 B 类 G 蛋白偶联 GLP-1 受体分子性质的深入了解提供了对结合这些类型配体的模式的深入了解，并为合理增强提供了机会。将探讨这些药物中的每一种的优点和缺点以及它们可能的临床效用。