PRO-SOMATOSTATIN RELATED PEPTIDES

生长抑素原相关肽

基本信息

批准号：
3232732
负责人：
JOHN W ENSINCK
金额：
$ 22.49万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
1984
资助国家：
美国
起止时间：
1984-09-01 至 1993-03-31
项目状态：
已结题

项目摘要

The overall hypothesis is that insulinotropic peptides from the and somatostatin-28 [S-28], a "decretin", act in concert to modulate insulin secretion on during absorption and assimilation of nutrients. Specific questions include: 1) Do "ineretine" and S-28 differentially alter the periodicity and threshold of glucose-mediated insulin secretion in vitro and in vivo? 2) Do S-28 and "incretins" module periodicity and kinetice of insulin secretion during nutrient absorption and is there a hierarchal order of importance amongst the putative "ineretins"? 3) Do elevated levels of S-28, contribute to defective insulin secretion in diabetes sellitue? The hypothesis is based on emerging information that enteric peptides including secretion, CCK, GIP and GLP-1 (7-36) potentiate the release of insulin, whereas, S-28 also from the gut, way inhibit insulin secretion. From pancreatic islet models, insulin appears to be released at varying glucose threabolds and it is plausible that "incretins" and S-28 may shift the threshold and rate of insulin release by glucose and also alter the periodicity and/or amplitude of its cyclic release. Since glucone-mediated first-phase insulin secretion [equated with threshold sensitivity] is deficient in Type II diabetes mellitus, it is possible that S-28 may adversely shift the sensitivity threshold in this disorder. To address these questions, we will evaluate the effects of secretion, CCK, GIP and GLP-1 (7-36) and S-28, separately and together, on the threshold and rate of insulin release in the perfused rat pancreas and in man. Periodicity and amplitude of insulin release will also be used. To evaluate the "physiologic" role of "incretine" and S-28 in modulating insulin secretion in vivo, baboons will be studied before and after immunoneutralization of circulating "incretins" and S-28, separately and together, during nutrient intake. To evaluate the role of S-28 on insulin secretion in defective B-cells, baboons, treated with small doses of streptozocin to induce early changes in insulin secretion, and the Goto rat model of Type II diabetes mellitus vill be examined. Insulin secretion before and after immunoneutralization with S-28 monoclonal antibodies during nutrient absorption will be tested. The results of these experiments should provide a more comprehensive view of the physiologic importance of the entero-insular axis in modulating insulin secretion.

总体假设是，来自和的促胰岛素肽生长抑素-28 [S-28]，一种“促胰岛素”，协同调节胰岛素营养物质吸收和同化过程中的分泌。具体的问题包括：1）“ineretine”和 S-28 是否会不同地改变体外葡萄糖介导的胰岛素分泌的周期和阈值以及体内？ 2) S-28和“肠促胰素”模块的周期性和动力学营养吸收过程中胰岛素的分泌是否存在假定的“ineretins”之间的重要性等级顺序？ 3）做 S-28 水平升高，导致胰岛素分泌缺陷糖尿病好不好？该假设基于新出现的信息肠肽，包括分泌肽、CCK、GIP 和 GLP-1 (7-36) 增强胰岛素的释放，而 S-28 也来自肠道抑制胰岛素分泌。从胰岛模型中，胰岛素出现以不同的葡萄糖阈值释放，这似乎是合理的 “肠降血糖素”和 S-28 可能会改变胰岛素释放的阈值和速率通过葡萄糖并且还改变其循环的周期性和/或幅度发布。由于葡萄糖酮介导的第一阶段胰岛素分泌[等同于 [具有阈值敏感性]在 II 型糖尿病中缺乏， S-28 可能会对灵敏度阈值产生不利影响在这种混乱中。为了解决这些问题，我们将评估分泌、CCK、GIP 和 GLP-1 (7-36) 和 S-28 的影响，分别和一起，关于灌注中胰岛素释放的阈值和速率大鼠胰腺和人类。胰岛素释放的周期性和幅度也将被使用。评价“肠促胰岛素”的“生理”作用 S-28调节体内胰岛素分泌，狒狒将进行研究循环“肠促胰岛素”免疫中和之前和之后 S-28，在营养摄入期间单独和一起。评估 S-28 对有缺陷的 B 细胞、狒狒的胰岛素分泌的作用用小剂量的链佐星诱导胰岛素的早期变化分泌，建立 II 型糖尿病 Goto 大鼠模型检查了。免疫中和前后的胰岛素分泌将测试营养吸收过程中的 S-28 单克隆抗体。这些实验的结果应该提供更全面的肠岛轴在生理学中的重要性调节胰岛素分泌。