Pancreatic proteolytic enzymes: Role of the insulo-acinar and entero-acinar axes

Abstract

The endocrine pancreas and the gastrointestinal tract are involved in the regulation of pancreatic proteolytic enzymes, and these are termed the ‘insulo-acinar axis’ and ‘entero-acinar axis’. When any of these signaling pathways are compromised it affects function of the exocrine pancreas. For example, insulin one of the numerous hormones released from the pancreatic islets has a trophic effect on the exocrine pancreas, as evidenced by the pancreatic proteolytic enzymes (in particular trypsin and chymotrypsin). However, the evidential base for this notion is largely limited to studies done in individuals with hypoinsulinaemia. Whether it holds true in individuals with hyperinsulinaemia is largely unknown. Moreover, little is known about the relationship between pancreatic proteolytic enzymes and gastrointestinal humoral factors. The first aim of this thesis was to investigate the associations between pancreatic proteolytic enzymes and insulinaemia, and to determine whether other pancreatic hormones (glucagon, pancreatic polypeptide, and somatostatin) contribute to this association. The second aim was to investigate the associations between pancreatic proteolytic enzymes and gastrointestinal humoral factors. Further, in a sub-group analysis, the effect of risk factors such as, chronic alcohol consumption on the above associations was investigated. The study cohort comprised of 93 patients following an episode of pancreatitis, in whom the above associations were investigated adjusting for various patient-related, metabolism-related, and pancreatitis-related factors in several statistical models. The key results of this thesis show, for the first time, that one, chymotrypsin is significantly associated with hyperinsulinaemia, and that this association appears to be affected by the pattern of glucagon and pancreatic polypeptide expressed in individuals with hyperinsulinaemia. Two, chymotrypsin is also significantly associated with gastrointestinal humoral factors such as gastrin, cholecystokinin, and vasoactive intestinal peptide. These humoral factors result in increased concentration of chymotrypsin. Further, this increase in chymotrypsin concentration was more prominent in individuals with alcoholrelated pancreatitis. This thesis provides deeper insights into the mechanism underlying the complex interaction between the endocrine pancreas and exocrine pancreas as well as the gastrointestinal tract.