GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion
GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion
复制标题
DOI：
10.1152/ajpendo.00452.2001
复制
发表时间：
2002-04-01
影响因子：
5.1
通讯作者：
Holst, JJ
中科院分区：
文献类型：
--
作者：
Deacon, CF;Plamboeck, A;Holst, JJ
胰升糖素样肽1(GLP-1)是一种有效的抗高血糖激素，目前正在研究其治疗潜力。然而，由于二肽基肽酶IV(DPP IV)的快速降解限制了其代谢稳定性，并丧失了其促胰岛素活性，因此无法在体内评估其真正的疗效。在氯醛糖麻醉的猪中，给予valine-pyrrolide(阻断内源性DPP IV的活性)，观察GLP-1-(7-36)酰胺对葡萄糖和静脉注射葡萄糖的胰岛素反应的独立作用，并研究DPP IV产生的代谢物GLP-1-(9-36)酰胺对这些反应的影响。GLP-1-(7-36)酰胺促进胰岛素分泌(P<；0.03 vs VS)，但GLP-1-(9-36)酰胺单独或与GLP-1-(7-36)酰胺合用均无作用。相反，GLP-1-(9-36)酰胺确实影响血糖反应(P<；0.03)。生理盐水(12 1+/-17mmol.l(-1).min)较GLP-1-(9-36)酰胺(73+/-19mmol.l(-1).min；P<；0.0 5)、GLP-1-(7-36)酰胺(62+/-13 mmol.L(-1)·min；P<；0.02)或GLP-1-(7-36)酰胺+GLP-1-(9-36)酰胺(50+/-13mmol.l(-1).min；P<；0.02)大；P<；0.005)。GLP-1-(7-36)酰胺+(9-36)酰胺(10.3+/-1.2%/m in)组的葡萄糖清除率高于GLP-1-(7-36)酰胺(7.0+/-0.9%/m in；P<；0.04)、GLP-1-(9-36)酰胺(6.8+/-1.0%/m in；P<；0.03)或生理盐水(5.4+/-1.2%/m in；P<；0.005)。胰高血糖素浓度未受影响。这些结果表明，GLP-1-(9-36)酰胺在体内既不刺激胰岛素的分泌，也不拮抗GLP-1-(7-36)酰胺的促胰岛素作用。此外，代谢产物本身具有抗高血糖作用，支持选择性DPP IV作用在血糖稳态中重要的假说。
Glucagon-like peptide 1 (GLP-1) is a potent anti-hyperglycemic hormone currently under investigation for its therapeutic potential. However, due to rapid degradation by dipeptidyl peptidase IV (DPP IV), which limits its metabolic stability and eliminates its insulinotropic activity, it has been impossible to assess its true efficacy in vivo. In chloralose-anesthetized pigs given valine-pyrrolidide (to block endogenous DPP IV activity), the independent effects of GLP-1-(7-36) amide on glucose and insulin responses to intravenous glucose were assessed, and the metabolite generated by DPP IV, GLP-1-( 9-36) amide, was investigated for any ability to influence these responses. GLP-1-(7-36) amide enhanced insulin secretion (P < 0.03 vs. vehicle), but GLP-1-(9-36) amide was without effect, either alone or when coinfused with GLP-1-(7-36) amide. In contrast, GLP-1-(9-36) amide did affect glucose responses (P < 0.03). Glucose excursions were greater after saline (121 +/- 17 mmol.l(-1).min) than after GLP-1-(9-36) amide (73 +/- 19 mmol.l(-1).min; P < 0.05), GLP-1-(7-36) amide (62 +/- 13 mmol•l(-1)•min; P < 0.02) or GLP-1-(7-36) amide + GLP-1-(9-36) amide (50 +/- 13 mmol.l(-1).min; P < 0.005). Glucose elimination rates were faster after GLP-1-(7-36) amide + (9-36) amide (10.3 +/- 1.2%/min) than after GLP-1-(7-36) amide (7.0 +/- 0.9%/ min; P < 0.04), GLP-1-(9-36) amide (6.8 +/- 1.0%/ min; P < 0.03), or saline (5.4 +/- 1.2%/min; P < 0.005). Glucagon concentrations were unaffected. These results demonstrate that GLP-1-(9-36) amide neither stimulates insulin secretion nor antagonizes the insulinotropic effect of GLP-1-(7-36) amide in vivo. Moreover, the metabolite itself possesses anti-hyperglycemic effects, supporting the hypothesis that selective DPP IV action is important in glucose homeostasis.