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升糖素。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)和专门的血管和神经供应。在胰岛内，三角洲(δ)细胞分泌抑制激素生长抑素(Sst)，该激素与其他类型细胞上发现的各种*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，但这些受体在新陈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释放会受到影响，而在低血糖时，SST水平会显著影响胰高血糖素的释放。这表明SST在抵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、轻度低血糖和正常血糖等不同条件下，SST信号对包括胰岛素、胰淀素、胰升糖素、胰多肽和Ghrelin在内的各种胰岛激素的释放有何影响尚不清楚。这项发现基金旨在阐明胰岛细胞之间的局部串扰，重点放在所谓的“正常”生理过程中的SST信号。主要使用活体方法(啮齿动物模型)和新开发的SSTR激动剂和拮抗剂文库，*我们将阐明SST严格调节胰岛*功能以维持能量平衡的正常机制。利用新的药理学药物和体内的新方法，这项研究将集中于SST信号在调节肝脏、骨骼肌和脂肪组织的胰岛激素释放和底物代谢方面的潜在直接作用。目标1将侧重于使用不同的激动剂和拮抗剂，根据五种受体亚型的特异性来确定SST信号如何在基础条件下(禁食、休息状态)和在各种刺激条件下(摄食、运动)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。目标2将研究体内和分离的胰岛中SST释放的潜在触发因素*，包括各种营养物质(葡萄糖、脂类、氨基酸)、其他激素、神经肽、肌肉因子/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的SST信号直接影响肝脏、脂肪组织和骨骼肌的能量代谢(葡萄糖、脂肪和蛋白质)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、胰岛分离和灌流胰岛。

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.