Role of somatostatin signalling on pancreatic islet function and energy homeostasis

为 90多年来，对胰腺内分泌的研究主要局限于胰岛素。 和胰高血糖素。然而，完好无损的 胰岛作为一个完整的器官系统，有五种不同的细胞类型 (，，，)和专门的血管和神经供应。在胰岛内，Delta()细胞分泌抑制激素生长抑素(SST)，该激素与各种 G-偶联蛋白SST受体(SSTR1-5)存在于其他类型的细胞中。SSTR1/2用数字表示 影响能量代谢的其他组织，包括脂肪组织， 肝脏和骨骼肌，但这些受体在新陈代谢中的作用尚不清楚。我们发现SST释放 在低血糖、正常血糖和高血糖时，来自胰岛的影响 海温水平极大地影响了 低血糖时高血糖素的释放。这表明海温在海温变化中起着关键作用。 在针对低血糖的调节性防御中的调节作用。然而，它是 仍然不清楚SST信号在各种胰岛的释放中有什么影响 胰岛素、胰淀素、胰升糖素、胰多肽和胃促生长素等激素 在各种情况下，包括运动、轻度高血糖、轻度低血糖 和正常血糖。这项发现赠款旨在阐明胰岛细胞之间的局部串扰，重点是在所谓的正常期间的SST信号。 生理学。主要在体内使用 方法(啮齿动物模型)和新开发的SSTR激动剂和拮抗剂的库， 我们将阐明SST对胰岛严格调控的正常机制 维持能量平衡的功能。使用新的药理制剂和 新的活体方法，这项研究 将重点放在SST信号在调节胰岛方面的潜在直接作用 肝脏、骨骼肌和脂肪的激素释放和底物代谢 组织。目标1将重点使用各种激动剂和拮抗剂，选择用于 它们对五种受体亚型中每一种的特异性，以确定SST信号如何影响胰岛功能和激素释放(胰岛素、胰升糖素、胰淀素、 胰多肽、Ghrelin和SST)进入门静脉循环 基础条件(空腹、休息状态)和各种刺激条件 (喂食、锻炼)。AIM 2将研究体内SST释放的潜在触发因素

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