Plaisancie P, Bernard C, Chayvialle J A, Cuber J C
INSERM U-45, Hôpital E. Herriot, Lyon, France.
Endocrinology. 1994 Dec;135(6):2398-403. doi: 10.1210/endo.135.6.7988423.
Glucagon-like peptide-1 (GLP-1) is promptly released from endocrine cells of the distal part of the gut after oral ingestion of a meal. To test the possibility that hormones produced by the proximal small intestine or transmitters of the enteric nervous system may be involved in the early phase of meal-induced GLP-1 secretion, various intestinal regulatory peptides and neurotransmitters of the gut were administered intraarterially in the isolated vascularly perfused rat colon preparation. The release of GLP-1 in the portal effluent was measured by a specific RIA. Intraarterial infusion of glucose-dependent insulinotropic peptide (GIP) over the concentration range 0.25-1 nM evoked a dose-dependent release of GLP-1, with a maximal response of 350% of the basal value. Tetrodotoxin did not modify the GIP-induced release of GLP-1. Secretin or cholecystokinin did not stimulate the secretion of GLP-1. Bombesin (10(-9)-10(-7) M) provoked a dose-dependent release of GLP-1, consisting of an early peak, followed by a sustained response. Calcitonin gene-related peptide (5 x 10(-8) M) induced a dramatic rise of GLP-1 immunoreactivity in the portal effluent (peak at 800% of the basal value 10 min after the start of infusion). Similarly, the beta-adrenergic agonist isoproterenol at concentrations of 10(-7) and 10(-6) M provoked a pronounced release of GLP-1 (peak at 500% of the basal value with 10(-6) M isoproterenol). Finally, the muscarinic cholinergic agonist bethanechol at a concentration of 10(-4) M evoked a gradual increase in GLP-1 immunoreactivity, which reached a maximal value (900% over basal) at the end of the 30-min infusion period. The lowest concentration of bethanechol used in the present study (10(-5) M) did not increase portal GLP-1 immunoreactivity over the basal value. Tetrodotoxin did not modify the bethanechol-, isoproterenol-, calcitonin gene-related peptide-, or bombesin-induced GLP-1 release. In conclusion, the present study conducted with the isolated vascularly perfused rat colon shows that there are interactions between the two most potent incretins, GIP and GLP-1, probably through an enteroendocrine pathway. Additionally, several transmitters of the gut are potent stimulants of GLP-1 release and, therefore, represent potential tools in the treatment of the noninsulin-dependent diabetes mellitus.
口服进食后，胰高血糖素样肽-1（GLP-1）会迅速从肠道远端的内分泌细胞中释放出来。为了测试近端小肠产生的激素或肠神经系统的递质是否可能参与进食诱导的GLP-1分泌的早期阶段，在分离的血管灌注大鼠结肠制备物中动脉内给予各种肠道调节肽和肠道神经递质。通过特异性放射免疫分析法（RIA）测量门静脉流出液中GLP-1的释放。在0.25 - 1 nM的浓度范围内动脉内输注葡萄糖依赖性促胰岛素多肽（GIP）可引起GLP-1的剂量依赖性释放，最大反应为基础值的350%。河豚毒素不会改变GIP诱导的GLP-1释放。促胰液素或胆囊收缩素不会刺激GLP-1的分泌。蛙皮素（10⁻⁹ - 10⁻⁷ M）引起GLP-1的剂量依赖性释放，包括一个早期峰值，随后是持续反应。降钙素基因相关肽（5×10⁻⁸ M）在门静脉流出液中诱导GLP-1免疫反应性急剧升高（输注开始后10分钟达到基础值的800%峰值）。同样，浓度为10⁻⁷和10⁻⁶ M的β-肾上腺素能激动剂异丙肾上腺素引起GLP-1的显著释放（10⁻⁶ M异丙肾上腺素时峰值为基础值的500%）。最后，浓度为10⁻⁴ M的毒蕈碱胆碱能激动剂氨甲酰甲胆碱引起GLP-1免疫反应性逐渐增加，在30分钟输注期结束时达到最大值（比基础值高900%）。本研究中使用的最低浓度的氨甲酰甲胆碱（10⁻⁵ M）不会使门静脉GLP-1免疫反应性超过基础值。河豚毒素不会改变氨甲酰甲胆碱、异丙肾上腺素、降钙素基因相关肽或蛙皮素诱导的GLP-1释放。总之，本研究在分离的血管灌注大鼠结肠上进行，结果表明两种最有效的肠促胰岛素GIP和GLP-1之间存在相互作用，可能通过肠内分泌途径。此外，几种肠道递质是GLP-1释放的有效刺激物，因此是治疗非胰岛素依赖型糖尿病的潜在工具。
