Taste receptor signaling in beta cells and role in postprandial insulin secretion

β细胞中的味觉受体信号传导及其在餐后胰岛素分泌中的作用

基本信息

批准号：
8152145
负责人：
George Kyriazis
金额：
$ 5.39万
依托单位：
SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-12-01 至 2012-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8152145
关键词：
ATP sensitive potassium channel complex Address Agonist Amino Acids Beta Cell Biosensor Calcium Calcium Channel Cells Cellular Stress Chronic Complications of Diabetes Mellitus Data Endoplasmic Reticulum Enteroendocrine Cell Exocytosis Failure Glucose Goals Health Hormones In Vitro Inositol Insulin Ion Channel Islets of Langerhans Knock-out Knockout Mice Mediating Membrane Metabolic Metabolic Pathway Monosaccharides Mus Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Nutrient Pancreas Pathway interactions Phenotype Physiological Receptor Activation Receptor Signaling Regulation Regulatory Pathway Reporting Role Signal Pathway Signal Transduction Structure of beta Cell of islet System Taste Perception Tongue blood glucose regulation design detection of nutrient glucose metabolism in vivo insulin secretion islet novel oxidation prevent receptor research study response sensory system sweet taste perception therapeutic target uptake

项目摘要

DESCRIPTION (provided by applicant): We recently discovered that pancreatic beta-cells express a signaling system complementary to the traditional glucose-induced metabolic pathway that participates in the stimulation of insulin release. Taste receptors (TRs) and their signaling machinery that are traditionally involved in taste perception on the tongue are also expressed in pancreatic islets. We found that TR agonists stimulate insulin secretion in primary pancreatic islets, and that these responses can be blocked using antagonists and knock out strategies targeting TR signaling components. This proposal addresses the physiological relevance of these findings. We hypothesize that the TR machinery in beta-cells is an important sensory system that modulates insulin secretion in response to ingested nutrients, such as monosaccharides and amino acids. We propose that TR signaling in beta-cells contributes to postprandial glucose homeostasis by modulating the effects of glucose-stimulated insulin secretion (GSIS). Our experimental plan evaluates the role of TRs in beta-cells, and elucidates the downstream signaling pathway induced by physiological TR agonists. We will use T1R3 knock out (KO) mice to investigate the role of TRs in the regulation of insulin secretion in vitro and glucose homeostasis in vivo. We will compare in vitro GSIS between wild type and T1R3 KO islets in static and perifusion experiments, and assess the in vivo metabolic phenotype of T1R3 KO mice subjected to beta-cell stress. We will also identify postprandial sweet taste nutrients that act through TRs to potentiate insulin release. Finally, we will elucidate the TR signaling pathway by evaluating the activation of PLC using a PLC-biosensor (PHPLC4-GFP), and analyze dynamic changes in ER calcium using a specific ER calcium biosensor (D1ER cameleon). Results from these studies will greatly enhance our understanding of the regulation of insulin release and confirm a novel regulatory pathway mediated by TRs present in beta-cells.

描述（由申请人提供）：我们最近发现，胰腺β细胞表达了一种互补的信号系统，该信号系统与传统的葡萄糖诱导的代谢途径互补，该途径参与刺激胰岛素释放。传统上参与舌头味觉感知的味觉受体（TR）及其信号传导机制也在胰岛中表达。我们发现，TR激动剂刺激原发性胰岛中的胰岛素分泌，并且可以使用拮抗剂阻止这些反应并淘汰针对TR信号成分的策略。该建议涉及这些发现的生理相关性。我们假设β细胞中的TR机械是一个重要的感觉系统，它可以调节胰岛素分泌，以响应摄入的营养素，例如单糖和氨基酸。我们建议通过调节葡萄糖刺激的胰岛素分泌（GSIS）的作用来导致β细胞中的TR信号传导导致餐后葡萄糖稳态。我们的实验计划评估了TR在β细胞中的作用，并阐明了生理TR激动剂引起的下游信号传导途径。我们将使用T1R3敲除（KO）小鼠来研究TR在体内体外和葡萄糖稳态调节体内胰岛素分泌中的作用。我们将比较静态和渗透实验中野生型和T1R3 KO胰岛之间的体外GSI，并评估受β细胞应力的T1R3 KO小鼠的体内代谢表型。我们还将确定通过TRS起作用以增强胰岛素释放的餐后甜味味。最后，我们将使用PLC生物传感器（PHPLC4-GFP）评估PLC的激活来阐明TR信号通路，并使用特定的ER钙生物传感器（D1ER Cameleon）分析ER钙中的动态变化。这些研究的结果将大大增强我们对胰岛素释放的调节的理解，并确认由β细胞中存在的TR介导的新型调节途径。