Baggio Laurie L, Drucker Daniel J
Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Treat Endocrinol. 2002;1(2):117-25. doi: 10.2165/00024677-200201020-00005.
Glucagon-like peptide-1 (GLP-1) is synthesized from proglucagon in enteroendocrine cells and regulates glucose homeostasis via multiple complementary actions on appetite, gastrointestinal motility and islet hormone secretion. GLP-1 is secreted from the distal gut in response to food ingestion, and levels of circulating GLP-1 may be diminished in patients with type 2 diabetes mellitus. GLP-1 administration stimulates glucose-dependent insulin secretion, inhibits glucagon secretion, and lowers blood glucose in normal and diabetic rodents and in humans. GLP-1 exerts additional glucose-lowering actions in patients with diabetes mellitus already treated with metformin or sulfonylurea therapy. GLP-1 inhibits gastric emptying in healthy individuals and those with diabetes mellitus, and excess GLP-1 administration may cause nausea or vomiting in susceptible individuals. Chronic GLP-1 treatment of normal or diabetic rodents is associated with bodyweight loss and GLP-1 agonists transiently inhibit food intake and may prevent bodyweight gain in humans. The potential for GLP-1 therapy to prevent deterioration of beta-cell function is exemplified by studies demonstrating that GLP-1 analogs stimulate proliferation and neogenesis of beta-cells, leading to expansion of beta-cell mass in diabetic rodents. The rapid N-terminal inactivation of bioactive GLP-1 by dipeptidyl peptidase-IV (DPP-IV) limits the utility of the native peptide for the treatment of patients with diabetes mellitus, and has fostered the development of more potent and stable protease-resistant GLP-1 analogs which exhibit longer durations of action. The importance of DPP-IV for glucose control is illustrated by the phenotype of rodents with genetic inactivation of DPP-IV which exhibit reduced glycemic excursion and increased levels of circulating GLP-1 in vivo. Inhibitors of DPP-IV potentiate incretin action by preventing degradation of GLP-1 and glucose-dependent insulinotropic peptide, and lower blood glucose in normal rodents and in experimental models of diabetes mellitus. Hence, orally available DPP-IV inhibitors also represent a new class of therapeutic agents that enhance incretin action for the treatment of patients with type 2 diabetes mellitus.
胰高血糖素样肽-1（GLP-1）由肠内分泌细胞中的胰高血糖素原合成，并通过对食欲、胃肠蠕动和胰岛激素分泌的多种互补作用来调节葡萄糖稳态。GLP-1在食物摄入后从肠道远端分泌，2型糖尿病患者的循环GLP-1水平可能会降低。在正常和糖尿病啮齿动物以及人类中，给予GLP-1可刺激葡萄糖依赖性胰岛素分泌、抑制胰高血糖素分泌并降低血糖。在已经接受二甲双胍或磺脲类药物治疗的糖尿病患者中，GLP-1还具有额外的降血糖作用。GLP-1可抑制健康个体和糖尿病患者的胃排空，过量给予GLP-1可能会使易感个体出现恶心或呕吐。对正常或糖尿病啮齿动物进行慢性GLP-1治疗与体重减轻有关，GLP-1激动剂可短暂抑制食物摄入，并可能防止人类体重增加。研究表明GLP-1类似物可刺激β细胞增殖和新生，导致糖尿病啮齿动物的β细胞量增加，这例证了GLP-1疗法预防β细胞功能恶化的潜力。二肽基肽酶-IV（DPP-IV）对生物活性GLP-1的快速N端失活限制了天然肽在糖尿病患者治疗中的应用，并促进了更有效、更稳定的蛋白酶抗性GLP-1类似物的开发，这些类似物具有更长的作用持续时间。DPP-IV基因失活的啮齿动物的表型表明了DPP-IV对血糖控制的重要性，这些动物在体内表现出血糖波动减少和循环GLP-1水平升高。DPP-IV抑制剂通过防止GLP-1和葡萄糖依赖性促胰岛素多肽的降解来增强肠促胰岛素作用，并降低正常啮齿动物和糖尿病实验模型中的血糖。因此，口服可用的DPP-IV抑制剂也代表了一类新型治疗药物，可增强肠促胰岛素作用以治疗2型糖尿病患者。
