Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.
Gluco-incretins control insulin secretion at multiple levels as revealed in mice lacking GLP-1 and GIP receptors.
复制标题
DOI：
10.1172/jci20518
复制
发表时间：
2004-02
期刊：
影响因子：
--
通讯作者：
F. Preitner;M. Ibberson;I. Franklin;C. Binnert;M. Pende;A. Gjinovci;Tanya Hansotia;D. Drucker;C. Wollheim;R. Burcelin;B. Thorens
中科院分区：
文献类型：
--
作者：
F. Preitner;M. Ibberson;I. Franklin;C. Binnert;M. Pende;A. Gjinovci;Tanya Hansotia;D. Drucker;C. Wollheim;R. Burcelin;B. Thorens
葡萄糖肠促胰岛素激素GIP和GLP-1在β细胞功能控制中的作用通过分析这些激素受体基因中的每一个或两者失活的小鼠来研究。我们的研究结果表明，葡萄糖耐受不良是在口服葡萄糖吸收时，两种受体失活的加成增加。腹膜内注射后，与单受体KO小鼠相比，双受体KO小鼠的葡萄糖耐受不良更严重，正葡萄糖钳夹显示正常的胰岛素敏感性，表明胰岛素分泌缺陷。当在体内或灌注胰腺中进行评估时，Glp-1 R（-/-）小鼠的胰岛素分泌显示缺乏第一时相，但Gipr（-/-）小鼠则没有。然而，在灌注实验中，第一时相胰岛素分泌存在于两种类型的胰岛中。在双KO胰岛中，胰岛素分泌的动力学是正常的，但其幅度降低了约50%，因为质膜去极化远端的缺陷。因此，葡萄糖肠促胰岛素激素控制胰岛素分泌（a）通过口服葡萄糖吸收后对β细胞的急性促胰岛素作用（B），通过GLP-1调节体内第一时相胰岛素分泌，可能是通过对胰岛外葡萄糖传感器的作用，和（c）通过保护分泌途径的功能，如两种受体失活时β细胞自主分泌缺陷所证明的。
The role of the gluco-incretin hormones GIP and GLP-1 in the control of beta cell function was studied by analyzing mice with inactivation of each of these hormone receptor genes, or both. Our results demonstrate that glucose intolerance was additively increased during oral glucose absorption when both receptors were inactivated. After intraperitoneal injections, glucose intolerance was more severe in double- as compared to single-receptor KO mice, and euglycemic clamps revealed normal insulin sensitivity, suggesting a defect in insulin secretion. When assessed in vivo or in perfused pancreas, insulin secretion showed a lack of first phase in Glp-1R(-/-) but not in Gipr(-/-) mice. In perifusion experiments, however, first-phase insulin secretion was present in both types of islets. In double-KO islets, kinetics of insulin secretion was normal, but its amplitude was reduced by about 50% because of a defect distal to plasma membrane depolarization. Thus, gluco-incretin hormones control insulin secretion (a) by an acute insulinotropic effect on beta cells after oral glucose absorption (b) through the regulation, by GLP-1, of in vivo first-phase insulin secretion, probably by an action on extra-islet glucose sensors, and (c) by preserving the function of the secretory pathway, as evidenced by a beta cell autonomous secretion defect when both receptors are inactivated.