(MRC DTP) The diabetes-pancreatitis link: protective effects of insulin on pancreatic acinar cells

Acute pancreatitis is a serious and sometimes fatal inflammatory disease whereby the pancreas digests itself. This is caused by bile acids and ethanol/fatty acid metabolites. Recently, impaired metabolism and cytotoxic calcium overload have been suggested to be the cardinal events that trigger the disease regardless of the cause. There is strong clinical evidence linking diabetes (both type-1 and type-2) and the severity of pancreatitis. Our preliminary studies using two distinct experimental animal models (caerulein and fatty acid/ethanol-induced) show that pancreatitis is worse in type-1 diabetic (Akita mice) and PACIRKO mice, in which the insulin receptor has been genetically deleted specifically in pancreatic acinar cells. Moreover, the recovery and regeneration of the pancreas 7 days following pancreatitis was also impaired in PACIRKO mice. Furthermore, we have shown that insulin directly protects isolated pancreatic acinar cells from cellular injury induced by pancreatitis agents, including; ATP depletion, inhibition of the plasma membrane Ca2+ pump (PMCA), cytotoxic Ca2+ overload and necrosis(1,2). This was due to a metabolic switch towards glycolysis(2), sufficient to maintain ATP to fuel the PMCA and thus prevent Ca2+ overload, even in the face of impaired mitochondrial function(1,2). The over-arching aim of this project is to test the hypothesis that insulin directly protects pancreatic acinar cells from injury and facilitates their regeneration during acute pancreatitis. This will be directly and unambiguously tested in PACIRKO mice using cellular and in vivo models of pancreatitis, in which exogenous insulin is administered using a hyperinsulinaemic-euglycaemic clamp. In addition, the molecular mechanism for this insulin protection will be determined by investigating the signalling pathways and metabolic phenotype induced by insulin. 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.