Duke Molecular Physiology Institute, Durham, NC, USA.
Novo Nordisk Research Center, Indianapolis, IN, USA.
Nat Metab. 2023 Jun;5(6):945-954. doi: 10.1038/s42255-023-00811-0. Epub 2023 Jun 5.
The incretins glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) mediate insulin responses that are proportionate to nutrient intake to facilitate glucose tolerance. The GLP-1 receptor (GLP-1R) is an established drug target for the treatment of diabetes and obesity, whereas the therapeutic potential of the GIP receptor (GIPR) is a subject of debate. Tirzepatide is an agonist at both the GIPR and GLP-1R and is a highly effective treatment for type 2 diabetes and obesity. However, although tirzepatide activates GIPR in cell lines and mouse models, it is not clear whether or how dual agonism contributes to its therapeutic benefit. Islet beta cells express both the GLP-1R and the GIPR, and insulin secretion is an established mechanism by which incretin agonists improve glycemic control. Here, we show that in mouse islets, tirzepatide stimulates insulin secretion predominantly through the GLP-1R, owing to reduced potency at the mouse GIPR. However, in human islets, antagonizing GIPR activity consistently decreases the insulin response to tirzepatide. Moreover, tirzepatide enhances glucagon secretion and somatostatin secretion in human islets. These data demonstrate that tirzepatide stimulates islet hormone secretion from human islets through both incretin receptors.
肠促胰岛素包括葡萄糖依赖性胰岛素释放肽 (GIP) 和胰高血糖素样肽 1 (GLP-1)，它们介导的胰岛素反应与营养摄入成比例，有助于葡萄糖耐量。GLP-1 受体 (GLP-1R) 是治疗糖尿病和肥胖症的既定药物靶点，而 GIP 受体 (GIPR) 的治疗潜力仍存在争议。替西帕肽同时激动 GIPR 和 GLP-1R，是治疗 2 型糖尿病和肥胖症的高效药物。然而，尽管替西帕肽在细胞系和小鼠模型中激活 GIPR，但尚不清楚双重激动作用是否以及如何有助于其治疗益处。胰岛β细胞表达 GLP-1R 和 GIPR，而胰岛素分泌是肠促胰岛素激动剂改善血糖控制的既定机制。在这里，我们表明在小鼠胰岛中，替西帕肽主要通过 GLP-1R 刺激胰岛素分泌，这归因于对小鼠 GIPR 的效力降低。然而，在人胰岛中，拮抗 GIPR 活性始终会降低对替西帕肽的胰岛素反应。此外，替西帕肽增强人胰岛中的胰高血糖素分泌和生长抑素分泌。这些数据表明，替西帕肽通过两种肠促胰岛素受体刺激人胰岛的胰岛激素分泌。
