Role of somatostatin signalling on pancreatic islet function and energy homeostasis

生长抑素信号传导对胰岛功能和能量稳态的作用

• 批准号: RGPIN-2018-05933
• 负责人: Riddell, Michael
• 金额: $ 2.91万
• 依托单位: York University
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2019
• 资助国家: 加拿大
• 起止时间: 2019-01-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=688015
• 关键词: Role; somatostatin; signalling; pancreatic; islet

For*over 90 years, the study of the endocrine pancreas has mainly been limited to insulin*and glucagon. However, the intact*pancreatic islet acts as a complete organ system with five different cell types*(, , , , ) and a dedicated vasculature and neural supply. Within the islet, the delta () cell secretes the inhibitory hormone somatostatin (SST) that binds to various*G-coupled protein SST receptors (SSTR1-5) found on the other cell types. SSTR1/2 are expressed in a number*of other tissues that impact energy metabolism, including the adipose tissue,*liver and skeletal muscle, but the role of these receptors on metabolism is unclear. We have discovered that SST release*from pancreatic islets is impacted during low, normal and high blood glucose*levels and that SST levels dramatically influences the*release of glucagon during hypoglycemia. This suggests that SST plays a critical*regulatory role in the regulatory defence against hypoglycemia. However, it is*still unclear what impact SST signalling has in the release of various islet*hormones including insulin, amylin, glucagon, pancreatic peptide and ghrelin*under various conditions including exercise, mild hyperglycemia, mild hypoglycemia*and euglycaemia. This Discovery Grant aims to elucidate the local cross-talk among islet cells, with an emphasis on SST signalling during so called normal'*physiology. Using primarily in vivo*approaches (rodent models) and a library of newly developed SSTR agonists and antagonists,*we will elucidate the normal mechanisms for SST's tight regulation of islet*function to maintain energy homeostasis. Using novel pharmacological agents and*new in vivo approaches, this research*will focus on the potential direct role of SST signalling in regulating islet*hormone release and substrate metabolism in liver, skeletal muscle and adipose*tissue. Aim 1 will focus on using various agonists and antagonists, chosen for*their specificity for each of the five receptor subtypes, to determine how SST signalling impacts islet function and hormone release (insulin, glucagon, amylin,*pancreatic polypeptide, ghrelin and SST) into the portal circulation using under*basal conditions (fasting, rested state) and under various stimulated conditions*(feeding, exercise). Aim 2 will examine the potential triggers of SST release in vivo

90多年来，对内分泌胰腺的研究主要局限于胰岛素和胰高血糖素。然而，完整的胰岛是一个完整的器官系统，有五种不同的细胞类型（,,,,）和专门的脉管系统和神经供应。在胰岛内，δ（）细胞分泌抑制激素生长抑素（SST），该激素与其他细胞类型上发现的各种* g偶联蛋白SST受体（SSTR1-5）结合。SSTR1/2在其他影响能量代谢的组织中也有表达，包括脂肪组织、肝脏和骨骼肌，但这些受体在代谢中的作用尚不清楚。我们发现在低血糖、正常血糖和高血糖时胰岛的SST释放*受到影响，低血糖时SST水平显著影响胰高血糖素的释放*。这表明SST在对抗低血糖的调节防御中起着关键的调节作用。然而，在运动、轻度高血糖、轻度低血糖和低血糖等不同情况下，SST信号传导对胰岛素、胰淀素、胰高血糖素、胰肽和胃饥饿素等多种胰岛激素的释放有何影响尚不清楚。该发现基金旨在阐明胰岛细胞之间的局部串扰，重点是所谓的正常生理过程中的SST信号传导。我们将主要使用体内方法（啮齿动物模型）和新开发的SSTR激动剂和拮抗剂库，阐明SST严格调节胰岛功能以维持能量稳态的正常机制。利用新的药物和新的体内方法，本研究将关注SST信号在调节肝脏、骨骼肌和脂肪组织中胰岛激素释放和底物代谢中的潜在直接作用。目的1将重点使用各种激动剂和拮抗剂，根据其对五种受体亚型的特异性选择，以确定SST信号传导如何影响胰岛功能和激素释放（胰岛素、胰高血糖素、胰淀素、胰多肽、胃饥饿素和SST）在基础条件（禁食、休息状态）和各种刺激条件（进食、运动）下进入门静脉循环。目的2将研究体内SST释放的潜在触发因素