Role of somatostatin signalling on pancreatic islet function and energy homeostasis

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（α、β、γ、δ、ε）和专门的血管和神经供应。在胰岛内，δ (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。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”生理期间的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将研究体内和离体胰岛中SST释放的潜在触发因素，包括各种营养物质（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Aim 3中，我们将研究哺乳动物中SST信号直接影响肝脏、脂肪组织和骨骼肌能量代谢（葡萄糖、脂质和蛋白质）的可能性。将使用多种体内和原位技术，包括啮齿动物插管（肝静脉和门静脉、颈动脉和颈静脉）、血糖钳、胰岛分离和胰岛周围灌注。

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.