Insulin protects pancreatic acinar cells during acute pancreatitis

Acute pancreatitis is a serious and sometimes fatal inflammatory disease whereby the pancreas digests itself. This is caused by bile acids, fatty acid/alcohol metabolites and oxidative stress. Recently, impaired metabolism and cytosolic Ca2+ ([Ca2+]i) overload have been suggested to be the cardinal events that trigger the disease regardless of the causative factor. We have shown that insulin, which is protective in animal models and clinical studies of human pancreatitis, protects pancreatic acinar cells from cytosolic Ca2+ overload, inhibition of the plasma membrane Ca2+ pump (PMCA), ATP depletion and necrotic cell death induced pancreatitis-causing agents. This was due to a metabolic switch from mitochondrial to glycolytic metabolism, sufficient to maintain ATP to fuel PMCA activity and thus prevent Ca2+ overload, even in the face of impaired mitochondrial function. The over-arching aim of this project is to determine the molecular mechanism for this insulin protection and in particular the specific glycolytic enzymes and signalling pathways responsible for the metabolic switch. The successful outcome of this project will further corroborate insulin, and related agents, as possible treatments for acute pancreatitis, regardless of the precise causative factor. It is hoped that this multidisciplinary approach from molecular mechanism to whole organism disease state will have major clinical implications for the treatment of acute pancreatitis. In addition this project may also reveal novel and more specific drug targets for the treatment of acute pancreatitis.