Vahl Torsten P, Paty Breay W, Fuller Bradley D, Prigeon Ronald L, D'Alessio David A
Division of Endocrinology, University of Cincinnati, Ohio 45267, USA.
J Clin Endocrinol Metab. 2003 Apr;88(4):1772-9. doi: 10.1210/jc.2002-021479.
Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue synthesized in the intestine and released in response to meal ingestion. It is secreted primarily in two forms, GLP-1-(7-37) and GLP-1-(7-36)NH(2), both of which bind to a specific GLP-1 receptor (GLP-1r) on the pancreatic beta-cell and augment glucose-stimulated insulin secretion. Once secreted, GLP-1-(7-36)NH(2) is rapidly metabolized to GLP-1-(9-36)NH(2), which is the predominant form of GLP-1 in postprandial plasma because of its relatively slower clearance. Although no clear biological role for GLP-1-(9-36)NH(2) in humans has been identified, recent studies in animals suggest two potential effects: to antagonize the effects of intact GLP-1 and to promote glucose disappearance in peripheral tissues. In the studies reported here we compared the independent effects of GLP-1-(7-36)NH(2), GLP-1-(7-37), and GLP-1-(9-36)NH(2) on parameters of iv glucose tolerance and determined whether GLP-1-(9-36)NH(2) inhibits the insulinotropic actions of GLP-1. Ten healthy subjects underwent 4 separate frequently sampled iv glucose tolerance tests during infusions of GLP-1-(7-37), GLP-1-(7-36)NH(2), GLP-1-(9-36)NH(2), or saline. Results from the iv glucose tolerance test were used to obtain indexes of beta-cell function (acute insulin response to glucose) and iv glucose tolerance (glucose disappearance constant), and the minimal model of glucose kinetics was used to obtain indexes of glucose effectiveness and insulin sensitivity. Compared with control studies, both GLP-1-(7-36)NH(2) and GLP-1-(7-37) significantly increased acute insulin response to glucose, glucose disappearance constant, glucose effectiveness, and glucose effectiveness at zero insulin, but did not change the insulin sensitivity index. In contrast, none of the parameters of glucose tolerance was measurably affected by GLP-1-(9-36) amide. In a second set of experiments, 10 healthy subjects had glucose-stimulated insulin secretion measured during an infusion of GLP-1-(7-36)NH(2) alone or with a simultaneous infusion of GLP-1-(9-36)NH(2) that increased plasma levels approximately 10-fold over those produced by unmetabolized GLP-1. Augmentation of glucose-stimulated insulin secretion by GLP-1-(7-36)NH(2) was not altered by the coadministration of GLP-1-(9-36)NH(2). Based on these results we conclude that GLP-1-(9-36)NH(2) does not regulate insulin release or glucose metabolism in healthy humans.
胰高血糖素样肽1（GLP-1）是一种在肠道合成的胰岛素促分泌剂，进食后会释放。它主要以两种形式分泌，即GLP-1-(7-37)和GLP-1-(7-36)NH₂，二者均可与胰腺β细胞上的特异性GLP-1受体（GLP-1r）结合，并增强葡萄糖刺激的胰岛素分泌。GLP-1-(7-36)NH₂一旦分泌，会迅速代谢为GLP-1-(9-36)NH₂，由于其清除相对较慢，它是餐后血浆中GLP-1的主要形式。尽管尚未确定GLP-1-(9-36)NH₂在人类中的明确生物学作用，但最近的动物研究表明有两种潜在作用：拮抗完整GLP-1的作用以及促进外周组织中的葡萄糖清除。在本文报道的研究中，我们比较了GLP-1-(7-36)NH₂、GLP-1-(7-37)和GLP-1-(9-36)NH₂对静脉注射葡萄糖耐量参数的独立影响，并确定GLP-1-(9-36)NH₂是否抑制GLP-1的促胰岛素作用。10名健康受试者在输注GLP-1-(7-37)、GLP-1-(7-36)NH₂、GLP-1-(9-36)NH₂或生理盐水期间进行了4次单独的频繁采样静脉注射葡萄糖耐量试验。静脉注射葡萄糖耐量试验的结果用于获得β细胞功能指标（对葡萄糖的急性胰岛素反应）和静脉注射葡萄糖耐量（葡萄糖清除常数），并使用葡萄糖动力学的最小模型来获得葡萄糖效能和胰岛素敏感性指标。与对照研究相比，GLP-1-(7-36)NH₂和GLP-1-(7-37)均显著增加了对葡萄糖的急性胰岛素反应、葡萄糖清除常数、葡萄糖效能以及零胰岛素状态下的葡萄糖效能，但未改变胰岛素敏感性指数。相比之下，GLP-1-(9-36)酰胺对葡萄糖耐量的各项参数均未产生可测量影响。在第二组实验中，10名健康受试者在单独输注GLP-1-(7-36)NH₂或同时输注GLP-1-(9-36)NH₂（使血浆水平比未代谢的GLP-1产生的水平增加约10倍）期间测量了葡萄糖刺激的胰岛素分泌。GLP-1-(9-36)NH₂的共同给药并未改变GLP-1-(7-36)NH₂对葡萄糖刺激的胰岛素分泌的增强作用。基于这些结果，我们得出结论，GLP-1-(9-36)NH₂在健康人类中不调节胰岛素释放或葡萄糖代谢。
