Imaging beta cell function for metabolic surgery

 描述(申请人提供)：这项建议的目的是更好地了解Roux-en-Y胃旁路手术(RYGB)在快速逆转与胰岛素抵抗、糖尿病前期和T2 DM相关的高血糖中发挥作用的生理和分子机制。我们提出了一系列新的研究，集中在最近发现的葡萄糖刺激的胰岛素分泌抑制电路的研究，该抑制电路由存储在ç细胞囊泡和肠道中的多巴胺(DA)驱动。我们提供的证据表明，多巴胺(DA)和胰升糖素样肽1(GLP-1)代表了葡萄糖刺激的胰岛素分泌(GSIS)调节系统的两个相对的臂，并假设DA代表“抗胰岛素”假说，以解释减肥手术对T2 DM的有利影响。我们建议使用微创分子成像技术在动物模型中研究这些可能的回路。同时，我们将描述禁食和饮食刺激条件下肠道和胰腺中的多巴胺代谢，包括对一组接受RYGB手术的患者进行的有限的人类临床研究。从这一假说驱动的研究中获得的新信息可能直接影响我们对以下方面的理解：1)减肥手术后体重减轻前血糖稳态改善的机制，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小说方法的发展，通过成像β细胞功能和质量来实时定量评估。这种方法可能在糖尿病的治疗和管理和/或审查旨在保护或恢复疾病中的β细胞功能和质量的新药方面具有临床应用。

 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.