Role of somatostatin signalling on pancreatic islet function and energy homeostasis

90多年来，胰腺内分泌的研究主要局限于胰岛素和胰高血糖素。然而，完整的 * 胰岛作为一个完整的器官系统，具有五种不同的细胞类型 *（α，β，γ，δ，ε）和专用的血管系统和神经供应。在胰岛内，δ细胞分泌抑制性激素生长抑素（SST），其与在其他细胞类型上发现的各种 * G偶联蛋白SST受体（SSTR 1 -5）结合。SSTR 1/2在许多影响能量代谢的其他组织中表达，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。我们已经发现，在低、正常和高血糖 * 水平期间，胰岛的SST释放 * 受到影响，并且SST水平显著影响低血糖期间胰高血糖素的 * 释放。这表明SST在低血糖的调节防御中起着关键的调节作用。然而，在各种条件下，包括运动、轻度高血糖、轻度低血糖 * 和正常血糖，SST信号传导对各种胰岛 * 激素（包括胰岛素、胰淀素、胰高血糖素、胰肽和生长素释放肽 *）的释放有何影响仍不清楚。这项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。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，我们将阐明SST对胰岛功能的严格调节以维持能量稳态的正常机制。使用新的药理学试剂和 * 新的体内方法，这项研究 * 将集中在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。目标1将集中于使用各种激动剂和拮抗剂，选择它们对五种受体亚型中的每一种的特异性，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、生长激素释放肽和SST）进入门静脉循环，使用基础条件（禁食、休息状态）和各种刺激条件（进食、运动）。目标2将检查SST在体内和分离的胰岛中释放的潜在触发因素，* 包括各种营养素（葡萄糖、脂质、氨基酸）、其他激素、* 神经肽、肌因子/细胞因子和神经递质。最后，在目标3中，我们将研究哺乳动物中SST信号直接影响肝脏、脂肪组织和骨骼肌中能量代谢（葡萄糖、脂质和蛋白质）的可能性。将使用各种体内 * 和原位技术，包括啮齿动物插管（肝和门静脉、颈动脉和 * 颈静脉）、血糖钳夹、胰岛分离和灌注胰岛 *。

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*(α, β, γ, δ, ε) and a dedicated vasculature and neural supply. Within the islet, the delta (δ) 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 and in isolated islets,*including various nutrients (glucose, lipids, amino acids), other hormones,*neuropeptides, myokines/cytokines and neurotransmitters. Finally, in Aim 3, we will*examine the possibility that SST signalling in mammals directly impacts energy*metabolism (glucose, lipid and protein) in the liver, adipose tissue and*skeletal muscle. A variety of in vivo*and in situ techniques including rodent cannulations (hepatic and portal veins, carotid artery and*jugular vein), glycemic clamps, islet isolations and perifused pancreatic*islets will be used.