Imaging beta cell function for metabolic surgery

 描述（由申请方提供）：本提案的目的是更好地了解Roux-en-Y胃旁路（RYGB）手术介导的胰岛素抵抗、前驱糖尿病和T2 DM相关高血糖快速逆转的生理和分子机制。我们提出了一个新的一系列的研究集中在最近公认的抑制电路葡萄糖刺激胰岛素分泌的多巴胺（DA）存储在胰岛细胞囊泡和肠道驱动的研究。我们提供的证据表明，多巴胺（DA）和胰高血糖素样肽1（GLP-1）代表葡萄糖刺激的胰岛素分泌（GSIS）调节系统的两个相反的武器，并假设DA代表“抗肠促胰岛素”，假设解释减肥手术对T2 DM的有益影响。我们建议在动物模型中使用微创分子成像技术来研究这些假定的电路。同时，我们将在禁食和膳食刺激条件下表征肠道和胰腺中的多巴胺代谢，包括在接受RYGB手术的患者人群中进行的多巴胺代谢的有限人体临床研究。从这一假设驱动的研究中获得的新信息可能直接影响我们对以下内容的理解：1）减肥手术后体重减轻前葡萄糖稳态改善的机制，以及2）葡萄糖刺激胰岛内胰岛素分泌的调节。在实践层面上，我们的研究可能会导致新的方法的发展，定量评估在真实的时间通过成像β细胞功能以及质量。这样的方法可以在治疗和管理糖尿病和/或用于审查旨在保留或恢复疾病中的β细胞功能和质量的新药中具有临床应用。

 DESCRIPTION (provided by applicant): The objective of this proposal is to better understand the physiological and molecular mechanisms at work in the Roux-en-Y gastric bypass (RYGB) surgery mediated rapid reversal of the hyperglycemia associated with insulin resistance, prediabetes and T2DM. We propose a novel series of studies focused on the study of a recently recognized inhibitory circuit of glucose stimulated insulin secretion driven by dopamine (DA) stored in ß cell vesicles and the gut. We provide evidence that dopamine (DA) and Glucagon like peptide 1 (GLP-1) represent two opposing arms of a glucose stimulated insulin secretion (GSIS) regulatory system and hypothesize that DA represents the "anti incretin" hypothesized to explain the beneficial effects of bariatric surgery on T2DM. We propose to study these putative circuits using minimally invasive molecular imaging techniques in an animal model. Concurrently, we will characterize dopamine metabolism in the gut and pancreas under fasting and meal stimulated conditions, including a limited human clinical study of dopamine metabolism in a population of patients who have undergone RYGB surgery. The new information obtained from this hypothesis driven research may directly impact our understanding of: 1) the mechanisms underlying improved glucose homeostasis seen before weight loss following bariatric surgery, and 2) the regulation of glucose stimulated insulin secretion within islets. On a practical level, our studies may result in the development of novels methods to quantitatively asses in real time by imaging both beta cell function as well as mass. Such methods may have clinical application in the treatment and management of diabetes and/or for vetting new drugs aimed preserving or restoring beta cell function and mass in disease.