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: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=757808
• 关键词: Role; somatostatin; signalling; pancreatic; islet

Forover 90 years, the study of the endocrine pancreas has mainly been limited to insulinand glucagon. However, the intactpancreatic 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 variousG-coupled protein SST receptors (SSTR1-5) found on the other cell types. SSTR1/2 are expressed in a numberof 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 releasefrom pancreatic islets is impacted during low, normal and high blood glucoselevels and that SST levels dramatically influences therelease of glucagon during hypoglycemia. This suggests that SST plays a criticalregulatory role in the regulatory defence against hypoglycemia. However, it isstill unclear what impact SST signalling has in the release of various islethormones including insulin, amylin, glucagon, pancreatic peptide and ghrelinunder various conditions including exercise, mild hyperglycemia, mild hypoglycemiaand 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 vivoapproaches (rodent models) and a library of newly developed SSTR agonists and antagonists,we will elucidate the normal mechanisms for SST's tight regulation of isletfunction to maintain energy homeostasis. Using novel pharmacological agents andnew in vivo approaches, this researchwill focus on the potential direct role of SST signalling in regulating islethormone release and substrate metabolism in liver, skeletal muscle and adiposetissue. Aim 1 will focus on using various agonists and antagonists, chosen fortheir 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 underbasal 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，完整的胰岛作为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在许多其他影响能量代谢的组织中表达，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。我们发现胰岛的SST释放在低血糖、正常血糖和高血糖时受到影响，并且SST水平显著影响低血糖时胰高血糖素的释放。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条件下，SST信号传导对胰岛素、胰高血糖素、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。这项发现资助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。本研究将使用新的药物和新的体内方法，重点研究SST信号在调节肝脏、骨骼肌和脂肪组织中岛激素释放和底物代谢中的潜在直接作用。目的1将着重于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，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、胰胰肽、胰多肽、胃饥饿素和SST）在基础条件下（禁食、休息状态）和各种刺激条件下（进食、运动）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