Imaging beta cell function for metabolic surgery

代谢手术中β细胞功能成像

基本信息

批准号：
9041585
负责人：
Paul E Harris
金额：
$ 54.85万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9041585
关键词：
Abdomen Affect Amphetamines Anabolism Animal Model Asses Bariatrics Beta Cell Binding Biochemical Biochemistry Biological Blood Glucose Body Weight decreased Cell physiology Cell surface Cells Clinical Research Clinical Trials DRD2 gene Development Diabetes Mellitus Diagnostic Imaging Discipline of Nuclear Medicine Disease Dopa Dopamine Duodenum Endocrine Environment Event Failure Family suidae Fasting GIPR gene Gastric Bypass Gastric Inhibitory Polypeptide Gastrointestinal tract structure Glucose Goals Health Human Hyperglycemia Image Imaging Techniques In Situ Ingestion Insulin Insulin Resistance Interdisciplinary Study Intestines Islets of Langerhans Kinetics Label Lead Ligands Location Maps Measurement Measures Mediating Metabolic Metabolism Methods Modeling Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Organ Pancreas Pathogenesis Pharmacotherapy Physiological Positron-Emission Tomography Prediabetes syndrome Primitive foregut structure Production Rattus Regulation Research Series Serum Services Signal Transduction Source Stomach Structure of beta Cell of islet System Techniques Testing Time Tissues Tracer Tyrosine Upper digestive tract structure Vesicle Work arm autocrine bariatric surgery base blood glucose regulation cell type clinical application diabetes management dietary manipulation glucagon-like peptide glucagon-like peptide 1 imaging modality improved in vivo inhibitor/antagonist insight insulin granule insulin secretagogues insulin secretion interest islet metabolic phenotype metabolomics minimally invasive molecular imaging novel novel diagnostics novel therapeutics paracrine patient population pre-clinical profiles in patients receptor response reuptake success uptake vesicular monoamine transporter

项目摘要

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.

描述（由申请人提供）：本提案的目的是更好地了解 Roux-en-Y 胃绕道手术 (RYGB) 手术介导的快速逆转与胰岛素抵抗、糖尿病前期和 T2DM 相关的高血糖的生理和分子机制我们提出了一系列新颖的研究，重点研究最近认识到的由存储在 ß 细胞囊泡中的多巴胺 (DA) 驱动的葡萄糖刺激胰岛素分泌的抑制回路以及我们提供的证据表明，多巴胺 (DA) 和胰高血糖素样肽 1 (GLP-1) 代表了葡萄糖刺激胰岛素分泌 (GSIS) 调节系统的两个对立分支，并且谦虚地表示 DA 代表“抗肠促胰岛素”，它们竞相解释其有益作用。我们建议在动物模型中使用微创分子成像技术研究这些假定的回路，同时我们将描述肠道和胰腺中的多巴胺代谢。禁食和进餐刺激条件，包括对接受 RYGB 手术的患者群体中的多巴胺代谢进行有限的人体临床研究，从这一假设驱动的研究中获得的新信息可能会直接影响我们对以下方面的理解：1）改善葡萄糖稳态的机制。减肥手术后减肥前观察到的现象，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，我们的研究可能会开发出通过对β细胞功能进行成像来实时定量评估的新方法。此类方法可在糖尿病的治疗和管理和/或审查旨在保持或恢复疾病中的β细胞功能和质量的新药物方面具有临床应用。