Assessing the Role of Glucose-Dependent Insulinotropic Polypeptide to Mediate Improved Beta-Cell Function Following Bariatric Surgery

项目摘要 减肥手术，除了促进体重减轻，已被证明可以改善高血糖症， 糖尿病患者胃旁路手术等减肥手术后血糖控制的改善， 垂直袖状胃切除术（VSG）通过尚未描述的机制在体重减轻之前发生。 减轻手术后糖尿病的一种潜在机制是通过肠上皮细胞增加信号传导。 作用于胰岛的肽，称为肠促胰岛素，观察到接受VSG的患者显示 口服葡萄糖后刺激胰岛素分泌。建立了VSG小鼠模型 它模拟了手术对葡萄糖稳态和β细胞功能的临床影响， 刺激葡萄糖依赖性促胰岛素多肽（GIP）（一种重要的肠促胰岛素）的β细胞受体。它 尚不清楚VSG后β细胞中GIP的作用是如何调节的，或者GIPR是否介导葡萄糖 降低减肥手术的效果。因此，本提案的目标是检验改进的假设 减肥手术后的葡萄糖耐量和β细胞功能是由β细胞中增加的GIP作用介导的。 这一假设将通过两个相关的目标来解决。第一个目标是评估VSG驱动的变更， 通过测量VSG后胰岛素分泌对外源性GIP的响应，确定β细胞中的GIP敏感性。是 预测GIPR信号将在VSG之后增强。第二个目标是描述 β细胞GIPR改善VSG后胰岛功能的实验研究 手术后GIP受体的β细胞特异性缺失。据预测，GIPR删除将静音 VSG对血糖控制和β细胞功能的影响。该项目采用VSG在小鼠中的稳健效应 作为一个模型，不仅可以了解人类的代谢疾病，而且还可以确定 恢复正常的胰岛生理功能最后，该项目将提供丰富的培训经验， 生物学和翻译系统，为未来的独立研究奠定基础。

Project Summary Bariatric surgery, in addition to promoting weight loss, has been demonstrated to improve hyperglycemia in diabetic patients. Improvements in glucose control following bariatric procedures like gastric bypass and vertical sleeve gastrectomy (VSG) occur prior to weight loss through mechanisms that are not yet described. A potential mechanism for alleviating diabetes following surgery is that of increased signaling by enteric peptides that act on the islet, known as incretins, given observations that patients receiving VSG display stimulated insulin secretion following oral glucose administration. A mouse model of VSG has been developed that mimics the clinical effects of surgery on glucose homeostasis, β-cell function, and remarkably, shows stimulation of the β-cell receptor for glucose-dependent insulinotropic polypeptide (GIP), a prominent incretin. It is unknown how GIP action in the β-cell is regulated following VSG, or whether GIPR mediates the glucose lowering effects of bariatric surgery. Thus, the goal of this proposal is to test the hypothesis that improved glucose tolerance and β-cell function after bariatric surgery are mediated by increased GIP action in the β-cell. This hypothesis will be addressed through two related aims. The first aim is to assess VSG driven changes to GIP sensitivity in the β-cell by measuring post-VSG insulin secretion in response to exogenous GIP. It is predicted that GIPR signaling will be augmented following VSG. The second aim is to characterize the role of β-cell GIPR in improving islet function after VSG by measuring glucose tolerance and insulin secretion in mice with β-cell specific deletion of the GIP receptor following surgery. It is predicted that GIPR deletion will mute the VSG effects on glucose control and β-cell function. This project employs the robust effects of VSG in mice as a model not only to understand metabolic disease in humans, but also to identify mechanisms necessary for restoring proper islet physiology. Finally, the project will provide a rich training experience that merges cell biology and translational systems, laying a foundation for future, independent research.