Novel metabolic actions of GIP

工作总结 胰岛素样生长因子包括葡萄糖依赖的促胰岛素多肽(GIP)和胰升糖素样肽1(GLP-1)。 肠道衍生的调节餐后代谢的激素。INTING系统占高达 健康人餐后胰岛素分泌的70%，2型患者减少到约30% 糖尿病(T2D)。了解胰岛素调节胰岛素分泌的机制，以及这是如何实现的 随着代谢应激而变得功能障碍，这是理解T2D病理生理学的核心。我们有 最近发现来自阿尔法细胞的前胰高血糖素产物对正常的β细胞功能是必不可少的 这种现象被称为阿尔法到贝塔细胞通讯。具体地说，我们发现细胞内的音调是由 由原胰高血糖素肽输入产生的cAMP水平。损害α-β细胞间的通讯 极大地减少胰岛素的分泌，并在代谢应激的情况下导致葡萄糖不耐受。GIP 受体(GIPR)和GLP-1受体(GLP-1R)在β细胞上表达，并增强葡萄糖刺激 胰岛素分泌。另一方面，α细胞只表达GIPR而不表达GLP-1R。事实上，GIP 促进胰升糖素的分泌，而GLP-1R则减少它的分泌。这个项目的目标是了解 GIPR在α细胞中的活性及其在健康和疾病中对代谢调节的潜在贡献 各州。我们最近发现，α细胞产生的胰升糖素是营养刺激的胰岛素所必需的 分泌，支持阿尔法细胞中GIPR活性增强α-β细胞通讯的假说。 这一假说的一个推论是，阿尔法细胞中的GIPR活性对脑内胰岛素的作用有意义 通过增加胰岛素分泌来改善餐后状况。此外，限制GIPR在阿尔法地区活动的干预措施 预计细胞会减少胰岛素分泌，损害葡萄糖耐量。检验这一假说 将我们的INTIN效应的概念扩展到β细胞活动之外的可能性，将α细胞合并为 这是一个至关重要的组成部分。此外，阐明阿尔法细胞中GIPR的活性可以提供对新的 结合GIPR活性的抗糖尿病药物的产生，潜在地解释了 这些化合物的功效超过了GLP-1R单激动剂。

Summary of Work Incretins, glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1), are intestinally derived hormones that regulate postprandial metabolism. The incretin system accounts for up to 70% of postprandial insulin secretion in healthy individuals and diminishes to ~30% in people with type 2 diabetes (T2D). Understanding the mechanisms that regulate incretin control of insulin secretion, and how this becomes dysfunctional with metabolic stress, is central to understanding the pathophysiology of T2D. We have recently discovered that proglucagon products from alpha-cells are essential for normal beta-cell function – a phenomenon termed alpha-to-beta cell communication. Specifically, we found that intra--cell tone is dictated by the level of cAMP generated by input from proglucagon peptides. Impairing alpha-to-beta cell communication greatly diminishes insulin secretion and results in glucose intolerance in the context of metabolic stress. The GIP receptor (GIPR) and GLP-1 receptor (GLP-1R) are expressed on beta-cells and potentiate glucose-stimulated insulin secretion. On the other hand, alpha cells only express the GIPR and not the GLP-1R. Indeed, GIP stimulates glucagon secretion, while GLP-1R decreases it. The goal of this project is to understand the importance of GIPR activity in alpha cells and the potential contribution to metabolic regulation in both healthy and diseased states. Our recent discovery that glucagon production from alpha cells is necessary for nutrient stimulated insulin secretion, support the hypothesis that GIPR activity in alpha cells enhances alpha-to-beta cell communication. A corollary to this hypothesis is that GIPR activity in alpha cells contribute meaningfully to the incretin effect in a postprandial situation by enhancing insulin secretion. Moreover, interventions that limit GIPR activity in alpha cells would be expected to decrease insulin secretion and impair glucose tolerance. Testing this hypothesis has the potential to extend our concept of the incretin effect beyond beta cell activity to incorporate the alpha cell as a vital component. Furthermore, clarification of GIPR activity in alpha cells can provide insight into the new generation of anti-diabetic medications that incorporate GIPR activity, potentially explaining the increased efficacy achieved by these compounds above and beyond GLP-1R monoagonism.