A novel paracrine role for GLP-1 in the islet

项目摘要：GLP-1在胰岛中的新型旁分泌作用 前胰高血糖素原基因（Gcg）在肠、胰腺和脑中的一小群神经元中表达 后脑，以组织特异性方式编码多个肽。这些肽中的一种，胰高血糖素样 肽-1（GLP-1）在餐后增加，起到刺激胰岛素分泌的作用，并且对于 正常葡萄糖耐量教条是，生殖器衍生的GLP-1作为一种激素结合， 胰GLP-1受体（GLP-1 r）刺激胰岛素分泌。然而，在人类和啮齿动物中， 模型中，有新的体外和病理生理学证据支持GLP-1的产生， 内分泌胰腺我们的初步数据揭示了体内证据，不仅胰腺来源的 GLP-1的存在，但这种活性肽库在正常葡萄糖中起着必要的生理作用 宽容这些数据代表了我们对GLP-1系统理解的范式转变。该模型 内源性GLP-1的急性促胰岛素作用是旁分泌而非内分泌的，来源于胰岛α- 细胞并作用于β细胞GLP-1 r以刺激胰岛素分泌。这种模式将解决许多 在论证GLP-1对胰岛具有经典内分泌作用时面临的问题。受快速限制 在血管内代谢中，GLP-1的血浆浓度相对较低，仅为中等水平。 在进食时升高。有趣的是，有多种实验模型可以操纵 血浆和/或胰腺GLP-1，甚至更有趣的是，两个，特别是代表极端的β- 细胞功能链脲佐菌素诱导的糖尿病和减肥手术均升高血浆和/或胰腺GLP-1 对胰岛功能有相反的影响。在本提案中，我们将使用我们独特的遗传模型， 药理学和手术干预，以促进对体内作用的理解， 胰腺GLP-1，并在此过程中将有助于阐明围绕GLP-1的这种来源的许多争议。 我们建议在2个具体目标中做到这一点：具体目标1侧重于了解生理 胰腺GLP-1的功能，并将测试胰腺GLP-1刺激胰岛素的假设 通过旁分泌机制分泌和产生。具体目标2侧重于 胰腺GLP-1的药理学功能，并将检验以下假设： 在减肥手术和链脲佐菌素诱导的糖尿病中，胰腺GLP-1对β细胞的功能增加。

Project Summary: A novel paracrine role for GLP-1 in the islet The preproglucagon gene (Gcg), expressed in the intestine, the pancreas, and a small cluster of neurons in the hindbrain, encodes multiple peptides in a tissue-specific manner. One of these peptides, glucagon like peptide-1 (GLP-1) increases following meals, functions to stimulate insulin secretion, and is essential for normal glucose tolerance. The dogma is that intestinally-derived GLP-1 acts as a hormone binding to pancreatic GLP-1 receptors (GLP-1r) to stimulate insulin secretion. However, in both human and rodent models, there is emerging in vitro and pathophysiological evidence to support the production of GLP-1 in the endocrine pancreas. Our preliminary data reveal in vivo evidence that not only does a pancreatic source of GLP-1 exist, but that this pool of active peptide plays a necessary physiological role in normal glucose tolerance. These data represent a paradigm shift in our understanding of the GLP-1 system. In this model, the acute insulinotropic effects of endogenous GLP-1 are paracrine rather than endocrine, derived from islet α- cells and acting on β-cell GLP-1r to stimulate insulin secretion. This model would address many of the questions faced when arguing that GLP-1 has classical endocrine action on the islets. Limited by rapid intravascular metabolism, the plasma concentrations of GLP-1 are relatively low and are only modestly elevated during meal ingestion. Interestingly, there are multiple experimental models available that manipulate plasma and/or pancreatic GLP-1 and even more interesting is that two, in particular, represent extremes in β- cell function. Both streptozotocin-induced diabetes and bariatric surgery raise plasma and/or pancreatic GLP-1 with opposite effects on islet function. In this proposal, we will use our unique genetic models combined with pharmacological and surgical interventions in order to advance the understanding of the in vivo role of pancreatic GLP-1 and in the process will help elucidate many controversies surrounding this source of GLP-1. We propose to do this in 2 specific aims: Specific Aim 1 is focused on understanding the physiological function of pancreatic GLP-1 and will test the hypothesis that pancreatic GLP-1 stimulates insulin secretion and production through paracrine mechanisms. Specific Aim 2 is focused on the pharmacological function of pancreatic GLP-1 and will test the hypothesis that the contribution of pancreatic GLP-1 to β-cell function increases in bariatric surgery and streptozotocin-induced diabetes.