Overall View of Pancreatic Secretion Regulation
Pancreatic secretory activity related to meal ingestion occurs in cephalic (20-25%), gastric (10%), and intestinal phases (~60-70%). Pancreatic secretion is activated by a combination of neural and hormonal effectors. During the cephalic and gastric phases, secretions are low in volume with high concentrations of digestive enzymes, reflecting stimulation primarily of acinar cells. This stimulation arises from cholinergic vagal input during the cephalic phase, and vago-vagal reflexes activated by gastric distension during the gastric phase. During the intestinal phase, on the other hand, ductular secretion is strongly activated, resulting in the production of high volumes of pancreatic juice with decreased concentrations of protein, although the total quantity of enzymes secreted during this phase is actually also markedly increased. Ductular secretion during this phase is driven primarily by the endocrine action of secretin on receptors localized to the basolateral pole of duct epithelial cells. The inputs to the acinar cells during the intestinal phase include CCK and 5-HT from the intestine as well as neurotransmitters including ACh and GRP. The large magnitude of the intestinal phase is also attributable to amplification by so-called enteropancreatic reflexes transmitted via the enteric nervous system.
- Cholinergic vagal input – cephalic phase – acinar secretion
- Vago-vagal reflexes – gastric phase – acinar secretion
- Secretin – intestinal phase – ductular (cells) secretion
- CCK (via vago-vagal reflexes and non-ACh neurotransmitters) by CCK-RP and monitor peptide – intestinal phase – acinar cells
- 5-HT (via vago-vagal reflexes) – intestinal phase – acinar cells
- ACh – cephalic, gastirc, and intestinal phases – acinar cells
- GRP – cephalic, gastirc, and intestinal phases – acinar cells
- Enteropancreatic reflexes transmitted via the enteric nervous system – intestinal phase – ?
Mechanisms of Regulation of Pancreatic Secretion (Primarily the Intestinal Phase)
CCK can be considered a master regulator of the duodenal cluster unit, of which the pancreas is an important component. CCK is a potent stimulus of acinar secretion, acting predominantly via CCK1 receptor-dependent stimulation of vagal afferents close to its site of release in the duodenum, thereby evoking vago-vagal reflexes that stimulate acinar cell secretion via cholinergic and non-cholinergic neurotransmitters (GRP, VIP). Threre are also CCK1 receptors on the basolateral pole of acinar cells, but it now seems likely that these are only activated if circulating concentrations of CCK rise to supraphysiologic levels.
In addition to its effects on the pancreas, CCK coordinates the activity of other GI seggments and draining organ, including by contract the gallbladder, relaxing the sphincter of Oddi, and slowing gastric motility to retard gastric emptying and thereby control the rate of delivery of partially digested nutrients to more distal segments of the gut. Finally, CCK can modulate the activity of other neurohumorla regulators in a synergistic fashion. For example, CCK itself is a weak agonist of pancreatic ductular secretion of bicarbonate, but it markedly potentiates the effect of secretin on this transport mechanism.
CCK is synthesized and stored by endocrine cells located predominantly in the duodenum, labeled in some sources as "I" cells. Control of CCK release from these cells is carefully regulated to match the body's needs for CCK bioactivity. In part, this is accomplished by the activity of two luminally active CCK releasing factors, which are small peptides. One of these peptides is derived from cells in the duodenum, called CCK-releasing peptide (CCK-RP). It is likely release into the lumen in response to specific nutrients, including fatty acids and hydrophobic amino acids. The other luminal peptide that controls CCK secretion is monitor peptide, which is a product of pancreatic acinar cells. Release of monitor peptide can be neurally mediated, including by the release of ACh and GRP in the vicinity of pancreatic acinar cells during the cephalic phase, and mediated by subsequent vago-vagal reflexes during the gastric and intestinal phases of the response to a meal. Likewise, once CCK release has been stimulated by CCK-RP, it too can cause monitor peptide release via the mechanisms of vago-vagal reflexes.
When meal proteins and oligopeptides are present in the lumen in large quantities, they compete for the action of trypsin and other proteolytic enzymes, meaning that CCK-RP and monitor peptide are degraded only slowly. Thus, CCK release is sustained, causing further secretion of proteases and other components of the pancreatic juice. On the other hand, once the meal has been fully digested and absorbed, CCK-RP and monitor peptide will be degraded by the pancreatic proteases. This then lead to the termination of CCK release, and thus a marked reduction in the secretion of pancreatic enzymes.
- CCK-RP by duodenum cells
- Monitor peptide by acinar cells
5-HT, released from intestinal enterochromaffin cells in response to nutrients, activates a vagovagal reflex that mirrors and augments that of CCK itself. It has been calculated that CCK and 5-HT are each responsible for about 50% of pancreatic enzyme secretion during the intestinal phase.
The other major regulator of pancreatic secretion is secretin, which is released from S cells in the duodenal mucosa. When the meal enters the small intestine from the stomach, the volume of pancreatic secretions increases rapidly, shifting from a low-volume, protein-rich fluid to a high volume secretion in which enzymes are present at lower concentrations (although in greater absolute amounts, reflecting the effect of CCK and neural effectors on acinar cell secretion). As the secretory rate rises, the pH and bicarbonate concentration in the pancreatic juice rises, with a reciprocal fall in the concentration of chloride ions. These latters effects on the composition of the pancreatic juice are mediated predominately by the endocrine mediator, secretin.
The S cells in the duodenal mucosa can be considered to act functionally as pH meters, sensing the acidity of the luminal contents. As the pH falls, due to the entry of gastric acid, secretin is released from the S cells and travels through the bloodstream to bind to receptors on pancreatic duct cells, as well as on epithelial cells lining the bile ducts and the duodenum itself. These cells, in turn, are stimulated to secrete bicarbonate into the duodenal lumen, thus causing a rise in pH that will eventually shut off secretin release. The pancreas is quantitatively the most important in the bicarbonate secretory response, although the ability of duodenal epithelial cells to secrete bicarbonate may be critically important to protect them from gastric acid, especially in the first part of the duodenum, which is proximal to the site of entry of the pancreatic juice and bile. In fact, patients suffering from duodenal ulcers have abnormally low levels of duodenal bicarbonate secretion both at rest and in response to luminal acidification.
The threshold for secretin release appears to be a luminal pH of less than 4.5. The mechanism by which the S cells sense the change in luminal acidity, and whether secretin release requires a peptide releasing factor and/or the function of mucosal sensory nerve endings is currently unclear. However, while other meal components, such as fatty acids, have been shown in experimental studies to evoke secretin release, the response to acid appears to be the most important physiologically. Subjects who are unable to secrete gastric acid (achlorhydric) secondary to disease or the administration of proton pump inhibitors, or in whom gastric contents have been neutralized by the oral administration of bicarbonate, fail to release secretin postprandially no matter what type of meal is given.