Regulation of Pancreatic Secretion

40.1.1

Basal Secretion

The rate of basal pancreatic exocrine secretion is generally expressed as a percent of the maximal amount that the pancreas can secrete when stimulated by a secretagogue such as cholecystokinin (CCK). When expressed as a percentage of the maximal pancreatic capacity to secrete enzymes, values for basal enzyme secretion range from 10% of maximal in cats to 20% in humans and 30% of maximal in rats. Basal secretion of bicarbonate, however, is often only 1%–2% of the maximal secretory rate compared to administration of exogenous secretin and there is considerably less species variation with the exception being the rat where basal bicarbonate secretion is 25% of maximal secretion. Therefore, the basal secretory rate of pancreatic enzymes may be adequate to prevent malabsorption of ingested nutrients since frank malabsorption generally appears only when pancreatic enzyme secretion is reduced to 10% or less.

Several different mechanisms are responsible for basal pancreatic exocrine secretion and could be due to (1) an automaticity of the gland, (2) regulation by low levels of gastrointestinal hormones such as CCK or secretin, or (3) due to the release of neurotransmitters such as acetylcholine. In vitro, pancreatic acinar cells demonstrate basal enzyme release, although it is unknown what is responsible for this basal exocytosis. In experimental animals such as dogs and rats, basal secretion is due primarily to cholinergic innervation as atropine blocks basal secretion and CCK receptor antagonists have repeatedly been shown to have no effect on basal pancreatic secretion. The inhibitory effects of anticholinergic drugs are probably due to the blockade of the muscarinic receptor on pancreatic acinar cells that block the effects of acetylcholine released from postganglionic pancreatic nerves. Moreover, basal levels of CCK are not sufficiently high to stimulate pancreatic exocrine secretion. Therefore, in contrast to secretin which appears to play a role in basal pancreatic secretion, there is strong evidence that CCK is not important in regulating basal pancreatic secretion in rats. In humans, however, varying reports have suggested that CCK and cholinergic inputs may contribute to basal pancreatic enzyme secretion. Profound inhibition of pancreatic secretion has been seen after atropine administration in humans and some reports indicate that CCK receptor antagonists may reduce pancreatic secretion. These findings indicate that low levels of circulating CCK or CCK acting locally on vagal afferent nerves are sufficient to stimulate human pancreatic secretion or that CCK released as a peptidergic transmitter from pancreatic neurons contributes to basal secretion. Recently, an alternative pathway for CCK-induced pancreatic secretion involving pancreatic stellate cells that lie in close proximity to acinar cells has been proposed. Human pancreatic stellate cells express CCK1 receptor and in primary culture it was shown that reasonably low levels of CCK (20 pM) stimulated acetylcholine release which induced amylase secretion from acini. This finding raises the possibility that CCK may regulate cholinergic stimulation of the pancreas through both neural and nonneural pathways.

Pancreatic bicarbonate secretion is largely regulated by secretin. Basal bicarbonate secretion correlates with plasma secretin levels, however, cholinergic inputs also affect bicarbonate release as atropine decreases both the basal and the secretin-stimulated bicarbonate secretion. It is likely that basal bicarbonate release is augmented by acetylcholine released from nerves locally in the pancreas.

Interestingly, the patterns of pancreatic secretion appear to be more complex if one examines secretory rates over time. Even under basal conditions, over several minutes, the secretory rate of pancreatic secretion varies. There are brief increases in bicarbonate and enzyme secretion that occur every 60–120 min. These bursts of pancreatic secretory activity coincide with periods of increased motor activity of the stomach and duodenum that are associated with the migrating motor complex (MMC) (25–27). Simultaneous with increases in pancreatic secretion, there are increases in gastric acid secretion and biliary flow into the duodenum. All of these actions are associated with increases in motilin levels in the blood. In addition, pancreatic polypeptide levels correlate well with the antral phase II motor activity and pancreatic enzyme secretion. These activities appear to be cholinergically mediated since atropine administration or ganglionic blockers abolish the periodic spikes in basal enzyme secretion. The administration of motilin prematurely initiates pancreatic secretion that is seen during the basal period and shortens the time between peaks of secretory activity. Conversely, immunoneutralization of motilin with specific antiserum abolishes the cyclic pattern of pancreatic secretion. The administration of pancreatic polypeptide (PP) inhibits basal pancreatic secretion and immunoneutralization with PP antiserum augments the peak in pancreatic secretion that is seen in the basal period. These findings are consistent with the overall belief that the MMC functions as a housekeeper to eliminate chyme, debris, and other secretions during the interdigestive period and to keep microbial populations in check. Although it is reduced, the periodic basal pattern of pancreatic secretion persists despite duodenectomy or autotransplantation of the pancreas indicating that independent of any obvious hormonal or neural influences the pancreas is able to generate an endogenous periodicity that is most likely due to activation of postganglionic cholinergic neural activity. These findings are consistent with electrophysiologic observations documenting spontaneous ganglionic neural activity. A circadian rhythm to pancreatic secretion has been described in rats where there is a peak in secretion during the dark phase of the day-night cycle.

40.1.2

Integrated Response of Meals

The major function of the exocrine pancreas is to facilitate the efficient digestion of food and absorption of micronutrients. The function of pancreatic enzymes is to break down macronutrients such as proteins to small peptides and amino acids, triglycerides to fatty acids and monoglycerides, and carbohydrates to sugars that can be easily absorbed from the small intestine. Pancreatic bicarbonate secretion is important for neutralizing gastric acid and creating an intraluminal environment with a pH that is hospitable to the action of enzymes especially in fat digestion. Unfortunately, very little is known about the actual pancreatic secretory process involved in the normal digestion of meals in humans. This problem is due in large part to difficulties in sampling intestinal secretions with and without food in the lumen without altering the normal physiologic function of the pancreas, biliary system, and intestine that together constitute an integrated response to a meal. Attempting to measure pancreatic juice free of biliary secretions requires cannulation of the pancreatic duct or diversion of pancreatic juice flow from the intestine. Diversion of pancreatic juice from the intestine disturbs the normal milieu by removing one or more factors that are either involved in neutralizing gastric acid or necessary for maintaining the proper intestinal environment in which intestinal releasing factors may function (mentioned later).

When pancreatic juice is diverted from the intestine, pancreatic bicarbonate is no longer present and the gastric acid entering the duodenum may avoid neutralization. Gastric acid is also a potent stimulus of secretin release which, in turn, stimulates pancreatic fluid and bicarbonate secretion. Interestingly, in dogs, the flow of pancreatic juice rich in bicarbonate increases following the diversion of pancreatic juice from the intestine. Although this fluid is rich in bicarbonate the amount of enzymes in the juice does not increase. In contrast, in rats diverting pancreatic juice stimulates pancreatic enzyme secretion to near-maximal amounts similar to that produced by exogenous CCK.

Quantifying pancreatic secretion associated with meals in humans is extremely difficult; therefore, there is very little quantitative information available. Sampling from the duodenum is fraught with hazards. Concentration measurements are notoriously unreliable because the volume of duodenal contents may vary. Moreover, duodenal bicarbonate is produced not only by the pancreas, but is secreted from the biliary tract and intestinal mucosa. There are also important species differences because pancreatic bicarbonate secretion in the pig is much less than biliary bicarbonate production, whereas pancreatic bicarbonate is the major source for neutralization of acid chyme in dogs. Maximum bicarbonate concentration in humans may be as high as 150 mM which is approximately twice as that in the rat. Measurement of trypsin is also difficult because it requires enzymatic activation of trypsinogen and the active form binds avidly to food making its quantification complex.

The physical nature of food is an important factor in the regulation of meal-stimulated pancreatic responses. When comparing a solid form of a meal to the same food homogenized to a liquid, the total pancreatic trypsin output is the same, however, the secretory response is prolonged, which is consistent with solid food emptying from the stomach at a slower rate than liquids. The maximal pancreatic enzyme response to fat occurs at low rates of fat delivery to the intestine. When the fat content of the meal was increased there was no further stimulation of pancreatic enzyme secretion; however, when the protein content was increased there was nearly a twofold increase in meal-stimulated pancreatic enzyme secretion.

The effects of food on gastric emptying rates appear to be important in regulating pancreatic secretory responses. The duration of pancreatic secretion correlates with the time required for the stomach to empty. As long as food was emptying from the stomach, pancreatic secretion was maintained at a high level; when the upper small intestine was free of food, pancreatic secretion declined. Importantly, delivery of food further down the intestine has an inhibitory effect on pancreatic secretion. Overall, meal-stimulated pancreatic secretion is 50%–60% of the maximal secretory capacity of the organ.

Meal-stimulated bicarbonate and enzyme responses are consistently found to be lower than maximal rates of secretion regardless of the species studied including dogs, rats, and humans. Although the reasons for this are not entirely clear they may be related to slow rates of gastric emptying. With delayed delivery of nutrients to the duodenum there may be submaximal pancreatic stimulation from the gastrointestinal hormones CCK and secretin. There also may be simultaneous or subsequent release of inhibitors of pancreatic secretion as food travels further down the intestine. Furthermore, as absorption of nutrients occurs they are no longer present in the lumen of the intestine to stimulate pancreatic responses. All of these possibilities may contribute to postprandial pancreatic secretion which is less than that can be induced by CCK alone.

40.2.1

Cephalic Phase

The cephalic phase of secretion results from inputs including the sight, smell, taste, and act of eating food and can account for up to 25% of the pancreatic exocrine secretion of a meal. Although we commonly think of these processes as stimulating pancreatic secretion they may also generate inhibitory signals when eating is associated with unpleasant features such as unattractive, malodorous, or bad tasting food. The cephalic phase of secretion has been produced in humans by presenting them with food that they see, smell, and taste but not swallow (a process known as modified sham feeding). In animals, food can be diverted from the esophagus by a surgically prepared esophageal or gastric fistula, and sham feeding can occur by allowing these animals to eat and swallow while preventing food from entering the stomach. In both dogs and humans, sham feeding stimulates low volumes of pancreatic secretions that are rich in enzymes but low in bicarbonate. The total pancreatic secretory response to sham feeding is approximately 25%–50% of maximal. Secretion of the islet hormone, pancreatic polypeptide, increases with sham feeding and has been used as an indicator of vagal innervation of the pancreas. In humans, the duration of pancreatic response to modified sham feeding is brief, lasting approximately 60 min, and ceases at the conclusion of sham feeding. If swallowing is included in sham feeding, the pancreatic secretory response is much greater. In contrast, in dogs, the pancreatic enzyme response to sham feeding lasts > 4 h.

There is substantial experimental data to support the concept that cephalic stimulation of pancreatic secretion is mediated by the vagus nerve. First, cholinergic agonists produce a pancreatic secretory response similar to that of cephalic stimulation. Second, the vagus nerve is the major source of cholinergic neurotransmitters to the pancreas. Third, electrical nerve stimulation to the vagus nerve or administration of 2-deoxyglucose (2-DG) which causes hypoglycemia (and initiates a vagal response) stimulated pancreatic juice flow similar to that of sham feeding. Finally, vagotomy blocked these responses. In anesthetized rats, pancreatic fluid and protein output following electrical nerve stimulation or 2-DG was partially blocked by atropine. Thus, although the vagus nerve carries fibers that bear peptidergic transmitters as well as acetylcholine, these data indicate that acetylcholine is the dominant neurotransmitter. The role of peptidergic efferent fibers in sham feeding is largely unknown.

Sham feeding is also a major stimulus of gastric secretion which may contribute to stimulation of pancreatic secretion through the release of secretin. Interestingly, it has been shown that mental stress produced by intense problem-solving can also stimulate pancreatic enzyme secretion in humans.

The regions of the dorsal and ventral anterior hypothalamus, including the medial hypothalamus, dorsomedial and ventromedial nuclei, and mammillary bodies, appear to generate signals for pancreatic secretion. Determination of the neurotransmitters and peptides that are involved in regulating these processes has been approached by examining effects of substances administered into the central nervous system. In rats, central administration of beta-endorphin, CGRP, and CRF inhibit pancreatic secretion. In contrast, TRH stimulates pancreatic secretion through the vagus nerve and involves both muscarinic and VIP receptors.

40.2.2

Gastric Phase

The gastric phase of pancreatic secretion has been difficult to study in unanesthetized intact animals and humans. Other than testing the effects of gastric distention by installing inert substances or balloon dilation of the stomach, it has been problematic to examine the effects of foods or other nutrients on pancreatic secretion because of the chemical properties of the nutrients themselves that stimulate neural reflexes and cause the release of hormones.

Gastrin is the best-studied gastrointestinal hormone and is a major regulator of gastric acid secretion. Although early reports suggested that gastrin was also a potent stimulus to pancreatic secretion these conclusions have been shown to be incorrect since plasma gastrin levels that are required for stimulation of pancreatic secretion are considerably higher than those that occur after a meal.

The gastric phase is responsible for about 10% of the pancreatic secretory response to a meal. This phase of pancreatic secretion is mediated primarily by gastropancreatic reflexes. Balloon distention of the stomach stimulates pancreatic secretion that is rich in pancreatic enzymes which is blocked by atropine or truncal vagotomy. Therefore, it appears that gastric contributions to pancreatic secretion are mediated by vagovagal cholinergic reflexes that originate in the stomach and terminate in the pancreas.

The stomach is also important in preparing food for delivery to the intestine where nutrients can stimulate the intestinal phase of pancreatic secretion. By the action of pepsin and gastric lipases, proteins are digested to peptides and triglycerides to fatty acids and monoglycerides, respectively. More extensive degradation of protein by enzymes other than pepsin does not further increase the pancreatic stimulatory activity of pepsin digests, suggesting that gastric digestion of protein is sufficient to produce protein products that initiate the intestinal phase of pancreatic secretion. In clinical situations, release of pancreatic enzymes is reduced in humans who have had gastric operations that alter gastric digestion or emptying. Of course, gastric emptying rates are critical for the delivery of nutrients to the intestine that is involved in the stimulation of neural reflexes and hormones that regulate pancreatic secretion.

40.2.3

Intestinal Phase

The intestinal phase of pancreatic secretion begins when food and chyme empty from the stomach into the intestine. Under normal conditions, the pancreas is already primed by cephalic and gastric influences that have increased blood flow to the pancreas and initiated secretion. The intestinal phase which accounts for 50%–80% of pancreatic exocrine secretion is easier to study than the other phases since solutions can be instilled directly into the intestinal lumen. The interactions of various food components such as fats, proteins, carbohydrates, and their breakdown products with neural and hormonal factors are complex. In the intestine, pancreatic secretions serve two major purposes. First, pancreatic bicarbonate neutralizes gastric acid delivered to the duodenum. Second, pancreatic enzymes break down proteins, fats, and carbohydrates to their constituent components that are ultimately absorbed but during the process can initiate processes that influence pancreatic secretion. The intestinal phase of pancreatic secretion can contribute as much as 70% to the postprandial secretory response.

40.2.4

Absorbed Nutrient Phase

The absorbed nutrient phase refers to the concept that nutrients once absorbed from the intestine may directly stimulate pancreatic secretion. Such an action would represent a direct effect of nutrients on the pancreas or an indirect effect through the ability of absorbed nutrients to stimulate the release of hormones or neurotransmitters that may affect pancreatic exocrine secretion.

40.3.1