Insulin protects pancreatic acinar cells during pancreatitis

急性胰腺炎是一种严重的，有时甚至是致命的炎症性疾病，胰腺借此消化自己。这是因为外分泌胰腺的主要功能是将强大的消化酶分泌到肠道中，以帮助消化食物。如果这个过程出错，那么这些酶可以在细胞内被激活，并释放到周围的组织中，在那里它们开始消化胰腺。这会导致广泛的组织损伤和炎症，在严重的情况下，酶可以进入血流并开始攻击远处的器官，如肺部。胰腺细胞内细胞内钙浓度的变化刺激这些消化酶以一种非常受控的方式释放到肠道中，对激素和神经递质做出反应。这是通过维持细胞内非常低的钙浓度来实现的，这主要是由细胞膜上的钙泵调节的。这种钙泵使用来自营养新陈代谢的化学能，将钙泵出细胞，以维持这种低钙。在正常情况下，激素或神经递质会刺激钙迅速泄漏到细胞内部，从而刺激消化酶的分泌。然后，钙泵迅速恢复低钙，因为长期升高的钙对细胞是有害的。急性胰腺炎的主要原因包括酒精代谢产物、过量饮酒和胆结石导致的胆汁酸反流。这些因素会抑制细胞的化学能量工厂，进而抑制钙泵，从而导致这一过程出错。这最终会导致细胞内的“不受控制的钙超载”，这是有毒的，可能会导致消化酶的激活和组织损伤的螺旋，从而导致胰腺炎。我们先前的研究表明，胰岛素通常是从靠近胰腺外分泌细胞的内分泌细胞中释放出来的，它可以保护外分泌细胞免受细胞损伤。胰岛素恢复了细胞能量平衡，保护了钙泵。因此，本项目的总体目标是研究实验性胰腺炎动物体内胰岛素保护的确切机制。这将在胰岛素受体基因缺失的小鼠身上实现，特别是在外分泌胰腺中。因此，该项目的成功结果可能揭示胰岛素作为一种潜在的治疗胰腺炎的方法。此外，该项目还可能揭示治疗急性胰腺炎的新的、更特异的药物靶点。

Acute pancreatitis is a serious and sometimes fatal inflammatory disease whereby the pancreas digests itself. This is because the major function of the exocrine pancreas is to secrete powerful digestive enzymes into the gut to aid the digestion of food. If this process goes wrong then the enzymes can be activated inside the cells and released into the surrounding tissue where they start to digest the pancreas. This causes extensive tissue damage, inflammation and in severe cases, enzymes can enter the blood stream and start to attack distant organs, such as the lungs. Changes in cellular calcium concentration inside pancreatic cells stimulate the release of these digestive enzymes into the gut in response to hormones and neurotransmitters in a very controlled manner. This is achieved by maintaining very low calcium concentration inside cells, which is primarily regulated by calcium pumps on the cell membrane. This calcium pump uses chemical energy, derived from nutrient metabolism, to pump calcium out of the cell to maintain this low calcium. Under normal situations hormones or neurotransmitters stimulate a very rapid leak of calcium into the cell interior to stimulate secretion of digestive enzymes. The calcium pump then rapidly restores low calcium because prolonged elevated calcium is toxic to cells. The major causes of acute pancreatitis include alcohol metabolites, from excessive alcohol consumption and bile acid reflux from gall stones. These can cause this process to go wrong by inhibiting the chemical energy factories of the cells, which in turn inhibit the calcium pumps. This eventually leads to "uncontrolled calcium overload" within the cell, which is toxic and can lead to activation of digestive enzymes and the spiral of tissue damage that leads to pancreatitis. Our previous study showed that insulin, which is normally released from endocrine cells in close proximity to the exocrine cells of the pancreas, protects the exocrine cells from cellular injury. The insulin restored the cellular energy balance and protected the calcium pump. Therefore, the overall aim of this project is to investigate the precise mechanism for this insulin protection in animals with experimental pancreatitis. This will be achieved using mice in which the insulin receptor has been genetically deleted specifically in the exocrine pancreas. The successful outcome of this project could therefore reveal insulin as a potential treatment for pancreatitis. In addition this project may also reveal novel and more specific drug targets for the treatment of acute pancreatitis