Studies on the in vitro effects of insulin on exocrine pancreatic function
Creators: name: Sinanan, Mika Narad
Publisher: name: University of British Columbia
Year: 2011

description: Endocrine and exocrine components of the pancreas coexist anatomically but have been considered to function independently. A vascular portal system leading from islets to the surrounding acinar tissue of the pancreas has been described but the physiological significance of this "insuloacinar" portal system is unclear. The underlying hypothesis of this work was that islet hormones, particularly insulin, are carried in high concentration to surrounding exocrine acinar tissue and modulate pancreatic secretion. The secretagogue dependency, magnitude, time course, and nature of insulin effects on the exocrine pancreas were investigated in two in vitro model systems, an isolated, perfused rat pancreas, and a preparation of dispersed rat pancreatic acini. The exocrine integrity of the model systems was investigated and verified in both systems for CCK, secretin, and VIP, and in acini, additionally, for methacholine dose responsive effects. In both systems, CCK proved to the most potent secretory stimulus for pancreatic exocrine secretion though maximal stimulation dosages of secretin and VIP resulted in greater exocrine secretion than CCK at any dose. Normal adult animals, animals of different ages, and animals treated to increase (hyperinsulinism) or decrease (experimental diabetes) circulating insulin levels were tested under a variety of acute insulin and secretagogue conditions for parameters determining the responsiveness to insulin. Endogenous and exogenous insulin clearly potentiated stimulated secretion in the isolated perfused pancreas though the potentiating effect was evident with some secretagogues (secretin and CCK) but not others (VIP). In contrast, insulin effects in isolated pancreatic acini were much less reproducible. Of greatest significance was the loss in absolute amylase cell content after development of diabetes with recovery towards normal amylase content and release after insulin treatment. This observation, however, was in response to chronic insulin treatment over several days. In the setting of more acute insulin treatment, high dosages of insulin seemed to actually inhibit CCK-stimulated secretion while in some but not all studies, acini from diabetic animals gained increased sensitivity to insulin. Conditions of increased circulating insulin negated any acute response to insulin. Acini from younger, more insulin sensitive animals, acini treated to deplete zymogen and induce protein synthesis, and acini treated with microtubule or protein synthesis inhibitors all failed to show any acute potentiation of stimulated secretion to insulin. However, acini harvested separately from ventral and dorsal pancreas, developed under the influence of islets having different compositions, did differ in secretory responsiveness. Although they seemed only a small contributing factor to the variability in insulin responsiveness of acini, islet fragments contaminating the purified acini preparation were assessed and appeared to be nonfunctional, releasing low concentrations of insulin only. Immunocytochemical studies provided a graphic correlation to the endocrine and exocrine changes induces by the various animal treatments and a pilot autoradiographic study of ¹²⁵I-insulin binding to acini in the perfused pancreas suggested that insulin from islets within the pancreas did reach at least the first four acini deep around the islet. These data suggest that insulin does reach surrounding exocrine tissue in high concentration and is capable of acutely modulating exocrine function in the intact gland. At the acinar level, either this response is in part indirect, or technical factors in the preparation of acini variably reduce responsiveness. Insulin in most cases potentiated secretion in stimulated normal and diabetic acini but at very high dosages during a prolonged preincubation, became inhibitory. It would appear that animal age, secretagogue dosage, calcium concentration, and a state of zymogen depletion were not important parameters in determining acinar responsiveness to insulin.