Pancreatic Growth and Secretion. An Experimental Study on Growth Factors in Rat and Mouse

Abstract: The pancreas is a central organ in the digestion of food as well as in glucose metabolism. Its two major functions are exocrine and endocrine secretion. These are meticulously regulated processes that depend on hormonal response to gastrointestinal contents and blood glucose levels through feedback mechanisms, but also to the status of pancreas in health and diseases. The present thesis aimed at further defining regulators of pancreatic growth, maintenance and secretion. A certain focus was set on the role of epidermal growth factor (EGF). The main regulator of pancreatic integrity and growth is cholecystokinin (CCK), which is regulated by a feedback mechanism involving pancreatic juice and bile. Inducing high plasma levels of CCK for 4 weeks, by a pancreatic-biliary diversion in rats, resulted in an increase in pancreatic weight and content of DNA, but not in an increased capacity to secrete amylase. The contents of amylase and lipase in the pancreas were decreased. Continuous infusion of EGF to mouse was found to increase pancreatic weight but not the contents of protein or amylase. A strong mitogenic stimulus on all cell types in the exocrine pancreas was found, along with increased mucosal thickness in the small intestine. No effect was seen in colon. Transforming growth factor alpha (TGF-?), which binds to the same receptor as EGF, induced hypertrophy in pancreas without affecting DNA synthesis. TGF-? gave a strong response in cell number when administrated to a human pancreatic cancer cell line, an effect blocked by an EGF receptor tyrosine kinase inhibitor, tyrphostin. EGF infused to rats was excreted in the bile and increased the joint biliary and pancreatic secretion rate in a dose dependent manner, an effect that was absent when bile was diverted. The EGF receptor has been demonstrated on the ?-cells in rat. Injection of EGF decreased the blood insulin levels in rats. After glucose injection this effect was reversed. In summary, endogenous CCKemia stimulates pancreatic growth but decreases the content of pancraetic enzymes. Further, EGF probably, at least partly, exerts its effects on the pancreas and the proximal gastrointestinal tract in rats after excretion with bile. Bile and EGF seem to be important regulators of pancreatic growth and functions as well as the growth of the mucosa of the proximal gastrointestinal tract. EGF also affects blood insulin levels. EGF and TGF-? induce proliferation in a human pancreatic cell line, an effect inhibited by tyrphostins.