Laboratory of Molecular and Cellular Medicine, Departments of Cellular and Physiological Sciences and Surgery, Life Sciences Institute, University of British Columbia, Vancouver, Canada.
Pharmacol Ther. 2012 Sep;135(3):247-78. doi: 10.1016/j.pharmthera.2012.05.009. Epub 2012 Jun 1.
Diabetes is a debilitating disease characterized by chronic hyperglycemia and is often associated with obesity. With diabetes and obesity incidence on the rise, it is imperative to develop novel therapeutics that will not only lower blood glucose levels, but also combat the associated obesity. The G protein-coupled receptors (GPCRs) for glucose-dependent insulinotropic polypeptide (GIP), glucagon-like peptide-1 (GLP-1) and glucagon are emerging as targets to treat both hyperglycemia and obesity. GIP is rapidly released from intestinal K-cells following food intake and stimulates glucose-dependent insulin secretion from β-cells and the storage of fat in adipocytes. Both GIP receptor agonists and antagonists have been demonstrated to display therapeutic potential to treat diabetes and obesity. Similar to GIP, GLP-1 is released from intestinal L-cells following food intake and potentiates glucose-dependent insulin secretion from β-cells. In addition, GLP-1 reduces glucagon levels, suppresses gastric emptying and reduces food intake. As such, GLP-1 receptor agonists effectively lower blood glucose levels and reduce weight. Finally, glucagon is released from α-cells and raises blood glucose levels during the fasting state by stimulating gluconeogenesis and glycogenolysis in the liver. Thus, molecules that antagonize the glucagon receptor may be used to treat hyperglycemia. Given the structural similarity of these peptides and their receptors, molecules capable of agonizing or antagonizing combinations of these receptors have recently been suggested as even better therapeutics. Here we review the biology of GIP, GLP-1 and glucagon and examine the various therapeutic strategies to activate and antagonize the receptors of these peptides.
糖尿病是一种以慢性高血糖为特征的消耗性疾病，常与肥胖有关。随着糖尿病和肥胖症发病率的上升，开发不仅能降低血糖水平，还能对抗相关肥胖症的新型疗法迫在眉睫。葡萄糖依赖性胰岛素释放多肽 (GIP)、胰高血糖素样肽-1 (GLP-1) 和胰高血糖素的 G 蛋白偶联受体 (GPCR) 已成为治疗高血糖和肥胖症的靶点。进食后，肠道 K 细胞迅速释放 GIP，刺激β细胞葡萄糖依赖性胰岛素分泌和脂肪在脂肪细胞中的储存。已经证明 GIP 受体激动剂和拮抗剂都具有治疗糖尿病和肥胖症的潜力。与 GIP 相似，GLP-1 在进食后从肠道 L 细胞释放，并增强β细胞葡萄糖依赖性胰岛素分泌。此外，GLP-1 降低胰高血糖素水平，抑制胃排空并减少食物摄入。因此，GLP-1 受体激动剂有效地降低血糖水平并减轻体重。最后，胰高血糖素由α细胞释放，并通过刺激肝脏中的糖异生和糖原分解在禁食状态下升高血糖水平。因此，拮抗胰高血糖素受体的分子可用于治疗高血糖症。鉴于这些肽及其受体的结构相似性，最近有人提出能够激动或拮抗这些受体组合的分子作为更好的治疗方法。在这里，我们回顾了 GIP、GLP-1 和胰高血糖素的生物学特性，并研究了激活和拮抗这些肽受体的各种治疗策略。
