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Endocrine Society members Sign in via society site. During interdigestive periods, very little secretion takes place, but as food enters the stomach and, a little later, chyme flows into the small intestine, pancreatic secretion is strongly stimulated.
Like the stomach, the pancreas is innervated by the vagus nerve, which applies a low level stimulus to secretion in response to anticipation of a meal. However, the most important stimuli for pancreatic secretion comes from three hormones secreted by the enteric endocrine system :.
Stop and think about this for a minute - control of pancreatic secretion makes perfect sense. Fat-mediated pancreatic secretion was blocked by proglumide, a CCK receptor antagonist, implicating the importance of CCK in stimulating pancreatic secretion Both C12 and C18 fatty acids augment the effects of secretin-induced bicarbonate secretion In humans, introduction of different concentrations of oleic acid into the duodenum induce pancreatic secretion, although the threshold for CCK stimulation is much lower than for secretin Secretin release is physiologically important since injection of anti-secretin antibodies in conscious rats greatly reduce fat-mediated protein and bicarbonate secretion Fatty acids with less than ten carbon atoms did not augment secretion.
This dependence on fatty acid chain length is similar to that observed previously for in vivo CCK release in humans. In addition to the fatty acid carbon chain length, a free carboxyl terminus is also important as esterification of the carboxylic terminus abolished CCK secretion, while modification of the methyl terminus had no effect Two cell surface receptors have been identified and demonstrated to promote fat-mediated CCK release.
The recently discovered immunoglobulin-like domain containing receptor ILDR is expressed in I cells of the duodenum. Thus fats and fatty acids are important regulators of pancreatic secretion.
Experimental evidence suggests that the degree and extent of acinar and ductal cell activation may vary depending on the animal species and the route of fat administration. Studies performed in dogs, rats, and humans have shown that proteins, peptides, and amino acids stimulate pancreatic secretion while the magnitude of this effect may be dependent on the species being evaluated In dogs, intact, undigested proteins such as casein, albumin, and gelatin did not stimulate pancreatic secretion, whereas protease digests of these proteins were very effective In contrast, studies in rats suggested that intestinal administration of hydrolyzed casein produced a smaller response than some of the other proteins which potently stimulated pancreatic enzyme secretion, suggesting that the amino acid composition of a protein is relevant in determining the extent of stimulation 96, Although intravenous infusion of amino acids in humans stimulated pancreatic enzyme and bicarbonate secretion, a mixture of L-amino acids when infused intravenously in dogs was not effective.
In contrast to intravenous infusion, intraduodenal delivery of amino acids in dogs induced pancreatic fluid, bicarbonate and protein secretion which was comparable to an elemental diet suggesting the importance of the route of administration on pancreatic secretion , Only L-amino acids stimulate pancreatic secretion which is consistent with the overall physiological importance of these stereoisomers.
Of all the amino acids, aromatic amino acids such as phenylalanine and tryptophan have the greatest potency 76, , Although aromatic amino acids are highly effective in stimulating pancreatic secretion, peptides may be more physiologically relevant as they are more abundant than amino acids in the intestinal lumen Oligopeptides and longer peptides containing the amino acids phenylalanine and tryptophan are effective stimulants of pancreatic secretion , Acidification of amino acid , and peptide 76 preparations with hydrochloric acid potentiates the bicarbonate response but pancreatic enzyme secretion is not influenced beyond that observed in the absence of acid.
Aromatic amino acids are capable of inducing maximal secretory response as potentiation of pancreatic enzyme secretion is not observed when amino acids or peptides are administered concomitantly with lipid molecules such as oleate or monoolein 75, The pancreatic secretory response to intraduodenal administration of amino acids appears to be concentration dependent. A minimal concentration of 8 mM is necessary for stimulation by most amino acids although the more potent aromatic amino acids such as tryptophan stimulate secretion at concentrations as low as 3 mM The length of the intestine exposed to amino acids also plays a critical role in pancreatic secretion.
In dogs, exposure of the first 10 cm was least effective, while perfusion of the whole intestine produced significant enzyme output suggesting that the pancreatic response was dependent upon the entire load of nutrients, not just their concentration. The majority of stimuli responsible for pancreatic stimulation originate in the proximal small intestine. In humans, amino acids stimulated pancreatic secretion only when perfused into the duodenum and no response was observed upon perfusion in the ileum Therefore, similar to fats, the primary mechanisms that stimulate pancreatic secretion are limited to the proximal regions of the small intestine.
The amount of bicarbonate released by intraluminal administration of tryptophan is similar to that produced by maximal doses of exogenously infused CCK indicating that release of CCK by tryptophan leads to pancreatic secretion 52, , Similarly, intraduodenal administration of liver extracts in dogs mediated CCK release along with pancreatic enzyme and bicarbonate secretion, both of which were blocked by CCK receptor antagonists Bile acids released from the gallbladder can significantly inhibit pancreatic stimulation induced by intraluminal amino acids.
This inhibition of pancreatic secretion by bile acids appears to be due to inhibition of CCK release and serves as a feedback mechanism in regulating pancreatic and gallbladder function By using a sensitive bioassay for CCK measurement, it was shown that one of the pathways by which proteins stimulate CCK release is by their ability to inhibit intraluminal trypsin activity Another mechanism by which aromatic amino acids mediate CCK release is by activation of the calcium sensing receptor CaSR , a known nutrient sensor , , , In addition to stimulating the release of hormones such as CCK and secretin, amino acids also activate cholinergic neural mechanisms which regulate pancreatic bicarbonate secretion Hence proteins, peptides, and amino acids stimulate pancreatic secretion but the magnitude of stimulation depends upon the mode of administration and the species being evaluated.
Bile is produced by hepatocytes as a complex mixture of bile acids, cholesterol, and organic molecules. It is stored and concentrated in the gall bladder and released into the duodenum upon entry of chyme. Bile acids such as cholate, deoxycholate, and chenodeoxycholate are conjugated with glycine or taurine amino acids which increase their solubility.
In the intestine, bile acids assist in the emulsification and absorption of fatty acids, monoacylglycerols, and lipids and stimulate lipolysis by facilitating binding of pancreatic lipase with its co-lipase. Under basal conditions, intraduodenal administration of physiological concentrations of bile or the bile salt sodium taurocholate, elevated plasma secretin and stimulated pancreatic fluid secretion in cats , Secretin was released only in response to perfusion of sodium taurocholate in the duodenum.
Perfusion in the upper jejunum produced a significantly diminished pancreatic response, while no response was observed upon ileal perfusion Pancreatic fluid secretion was stimulated by the free ionized form of taurocholate and was not dependent on its detergent properties In humans, infusion of bovine bile augmented secretin release along with pancreatic exocrine secretions of fluid, bicarbonate, and enzymes , In addition to secretin, infusion of bovine bile and bile acids in humans and dogs was shown to stimulate the release several hormones and neuropeptides such as CCK, neurotensin, VIP, gastric inhibitory peptide GIP , PP, and somatostatin 34, 42, , Fluid and bicarbonate release was enhanced when elevated levels of VIP were present in the plasma, suggesting that bile activates peptidergic nerves resulting in pancreatic secretion.
Additionally, cholinergic mechanisms are also important as atropine blocked bile- and taurocholate-stimulated exocrine pancreatic secretion The composition of bile is important in mechanisms regulating this secretory response as some differences in hydrokinetic and ecbolic responses were observed with administration of bile versus various bile acids However, a stimulatory effect of bile acids on pancreatic fluid secretion was not observed in the presence of digestive intraluminal contents In some studies where bile acids were administered concomitantly with amino acids or fat, an inhibition of pancreatic enzyme secretion was observed.
The mechanism underlying this observation is not completely understood, although it is possible that bile acids inhibit CCK release by a negative feedback mechanism which helps to relax and refill the gallbladder 24, , , Chemical sequestration of bile acids in dogs augmented the release of CCK and pancreatic enzyme secretion in response to amino acids and addition of taurocholate reversed this effect Long term diversion of bile in dogs also augmented basal and oleate-stimulated pancreatic fluid, bicarbonate, and enzyme secretion along with plasma CCK levels, further supporting the role of bile acids in inhibiting CCK release Other studies have shown that the bile salt chenodeoxycholate when infused in humans, inhibited bombesin- and CCK-stimulated gallbladder emptying along with elevation of plasma CCK levels.
These results led the authors to hypothesize that chenodeoxycholate, by a yet unknown mechanism, reduced the sensitivity of the gall bladder to stimulation by bombesin and CCK In contrast to many species including mice and humans, rats do not possess a gallbladder and multiple pancreatic ducts join the lower end of the common bile duct.
In rats, diversion of bile and pancreatic juice stimulates the release of pancreatic enzymes. This augmentation of enzyme secretion has been suggested to compensate for the increased degradation of proteolytic enzymes in the absence of bile. Thus exocrine secretion in rats is regulated by a luminal feedback mechanism 93, Additional experiments have shown that certain bile salts stimulate bicarbonate secretion via CCK release whereas other bile salts inhibit exocrine secretion , , Two inhibitory mechanisms have been proposed — one dependent on the stabilization of luminal proteases and the other independent of protease activity The physiological role of bile and bile salts in regulating pancreatic secretions is not completely understood and appears to be dependent on multiple factors, including the chemical properties of bile salts, the animal model being evaluated, and prandial status of the animal being studied Once nutrients are absorbed from the intestinal lumen, they may directly stimulate pancreatic secretion leading to the absorbed nutrient phase.
Nutrients can either directly stimulate pancreatic acinar cells, or they may indirectly activate hormonal and neural pathways to further regulate exocrine secretion. Little conclusive evidence is available for intravenous lipids and glucose in stimulating pancreatic secretion However, intravenous administration of amino acids increases the amount of trypsin and chymotrypsin secretion, but not lipase or amylase Amino acids appear to have a substantial indirect effect on pancreatic secretion, since intraduodenal administration of amino acids produces large increases in pancreatic secretion , , The role of nutrients after absorption on pancreatic secretion is not well understood and additional studies are needed to fully investigate these effects.
One effect is to stimulate synthesis of new digestive enzymes to replenish the pancreatic supply. Feedback Regulation of Pancreatic Secretion. The concept of feedback regulation of pancreatic secretion emanated from a series of studies demonstrating that 1 instillation of trypsin inhibitor into the upper small intestine or 2 surgical diversion of the bile-pancreatic duct removing bile and pancreatic juice from the duodenum of rats stimulated pancreatic enzyme secretion Conversely, infusion of trypsin into the duodenum during bile-pancreatic juice diversion suppressed pancreatic enzyme release.
Thus, the protease concentration in the upper small intestine appears to be intimately linked to pancreatic secretion through a negative feedback system in which active proteases within the duodenum limit pancreatic secretion but reduced protease activity stimulates pancreatic secretion.
When assays for CCK became available, it was shown that CCK mediated the effects of proteases on pancreatic secretion through protease-sensitive CCK releasing factors , see Figure 1.
In the absence of proteases, CCK releasing factor can stimulate CCK cells, but in the presence of proteases, the releasing factors are inactivated and CCK secretion is low. Negative feedback regulation of pancreatic secretion has been shown to exist in many species although other proteases such as elastase may be more important in regulating pancreatic secretion in humans. Figure 1. Feedback regulation of pancreatic exocrine secretion is mediated by positive and negative mechanisms.
Positive feedback: Monitor peptide is secreted by acinar cells and directly stimulates CCK cells in the small intestine and amplifies pancreatic secretion once it has been initiated. Pancreatic exocrine secretion is also influenced through a positive feedback mechanism. Monitor peptide is a 61 amino acid peptide produced by pancreatic acinar cells and possessing CCK releasing activity. Although monitor peptide has modest trypsin inhibitor capability, its ability to stimulate CCK is independent of this action because monitor peptide can directly stimulate CCK secretion from isolated CCK cells in vitro 28, Monitor peptide is secreted in pancreatic juice, therefore, it does not stimulate CCK secretion unless pancreatic secretion is underway.
Thus, monitor peptide cannot account for the increase in CCK in during bile-pancreatic juice diversion, but it may serve to reinforce pancreatic secretion once the process has been initiated. The exocrine pancreas delivers its secretions of digestive enzymes, fluid, and bicarbonate ions to the duodenum following ingestion of food. The pancreas is composed of both endocrine and exocrine components. These specialized cells secrete the hormones insulin, glucagon, somatostatin, ghrelin, amylin, and pancreatic polypeptide into the blood, which exert endocrine and paracrine actions within the pancreas.
Ninety percent of the pancreas is composed of acinar cells which secrete digestive enzymes such as trypsin, chymotrypsin, and amylase for digestion of food in the small intestine. The acinar cells are triangular in shape and arranged in clusters with the apex of the cell opening into a centrally located terminal duct. The terminal or intercalated ducts merge to form interlobular ducts, which in turn congregate to form the main pancreatic duct.
The pancreatic duct delivers exocrine secretions into the duodenum. The ductal cells secrete fluid and bicarbonate ions, which neutralize acinar cell secretions, as well as the acidic gastric contents entering the duodenum The pancreas is heavily innervated by sympathetic and parasympathetic peripheral nerves and contains a dense network of blood vessels which regulate blood flow and modulate pancreatic secretion. Pancreatic exocrine secretion is a highly integrated process mediated by neural and hormonal signals arising from the gut as well as by factors secreted by other tissues and hormones released from pancreatic islets.
The secretory pathways can be stimulatory or inhibitory in nature, and represent a highly regulated system that responds to ingestive signals. The agents that modulate pancreatic exocrine secretion are discussed below Table 1.
The pancreas is innervated by parasympathetic nerve fibers, postganglionic sympathetic neurons, as well as a network of intrapancreatic nerves. The pancreatic ganglia receive input from pre- and post-ganglionic nerve fibers and regulate exocrine and endocrine secretion. Intrapancreatic postganglionic neurons are activated by central input during the cephalic phase and by vagovagal responses initiated during the gastric and intestinal phases of stimulation.
They stimulate enzyme and bicarbonate secretion primarily by releasing acetylcholine, which activates muscarinic receptors located on acinar and duct cells. The dorsal vagal complex in the brainstem is comprised of the nucleus of the solitary tract and the dorsal motor nucleus of the vagus DMV and exerts parasympathetic control on pancreatic secretion.
Information relayed by sensory vagal afferent nerves innervating the pancreas is first processed in the nucleus of the solitary tract, which then projects onto the preganglionic motor neurons of the DMV. The DMV receives inputs from other regions of the brain such as the hypothalamus and from numerous hormones and neuropeptides through the afferent limb of the vagus nerve. Parasympathetic preganglionic efferent vagal nerves innervating the pancreas originate primarily from the DMV and terminate in the pancreatic ganglion.
Electrical and chemical stimulation of the DMV induces rapid pancreatic secretion, and this response is inhibited by vagotomy or blockade of muscarinic receptors by atropine It has been suggested that vagal cholinergic neurons mediate pancreatic secretion during low loads of intestinal stimulants whereas hormones mediate the response during high loads of intestinal stimuli , CCK affects pancreatic secretion through both a direct effect on pancreatic acinar cells and an indirect effect on the vagus nerve Figure 2.
However, the effects on the vagus nerve are complex and the firing response of neurons in the DMV complex appears to be dictated by their spatial location. In one study, neurons in the caudal region were activated, those in the rostral region were unaffected, while neurons in the intermediate region were inhibited by a direct action of CCK The exocrine pancreas is regulated directly by the vagus.
Studies with muscarinic receptor knockout mice demonstrated that both M1 and M3 receptors mediate amylase release from dispersed acini.
It is likely that M3 receptors are more relevant physiologically since the level of M3 receptor expression was significantly higher in acinar cells 87 and M1 receptors were found to have only a minor effect on bicarbonate secretion in conscious dogs These receptors are located on excitatory and inhibitory pre-synaptic terminals of pancreas-projecting DMV neurons 10 that are also activated by CCK and pancreatic polypeptide.
VIP is a 28 amino acid neuropeptide that is found throughout the body. Immunocytochemical evidence suggests that VIP is localized in pancreatic nerve fibers and functions as a vagal neurotransmitter.
In the chick, VIP immunoreactive nerve endings are found in close proximity to acinar cells and epithelial cells of arterioles. Small clear vesicles were present in VIP-positive nerves indicating that these neurons are were also cholinergic in nature Figure 2.
CCK stimulates pancreatic secretion through hormonal and neuronal pathways. CCK is released from I cells of the small intestine and diffuses into the blood stream where it is carried to the pancreas. CCK binds to receptors on acinar cells to stimulate pancreatic enzyme secretion. Vagal afferent signals are integrated in the dorsal vagal complex which also receives signals from other regions of the brain e. Vagal efferent fibers transmit cholinergic signals to the pancreas to stimulate pancreatic secretion.
In normal human pancreas, autonomic ganglia receive an abundant supply of VIP-positive fiber plexi, and VIP-positive nerves and appeared to innervate acinar cells, ducts, and blood vessels After atropine treatment, electrical stimulation of the vagus still increased bicarbonate secretion concurrent with detection of VIP in pancreatic venous effluent suggesting that VIP release is coupled with bicarbonate secretion The effects of VIP are especially prominent in the pig as perfusion of the pancreas with VIP antibodies inhibited fluid and bicarbonate secretion, and treatment of rats with a VIP antagonist reduced bicarbonate secretion concomitant with vasodepression further supporting a direct relationship , High and low affinity VIP receptors have been identified on pancreatic acinar membranes.
The high affinity receptors are coupled to cAMP-mediated amylase release, while activation of low affinity receptors did not cause cAMP elevation or amylase release, suggesting that only high affinity receptors are important in protein secretion These effects of VIP were attenuated by somatostatin and galanin, which reduced VIP-mediated fluid and protein output One ofthe main functions of VIP appears to be increasing blood flow by vasodilation, and as a result its effects on pancreatic secretion independent of blood flow in the pancreas are difficult to evaluate 9, Gastrin releasing peptide GRP is a 27 amino acid neuropeptide that is present in post-ganglionic vagal afferents and has been detected in neurons innervating the feline, porcine, rodent, and human pancreas Receptors responsive to GRP have been identified in rat pancreatic membranes and cancer cells where they mediate enzyme secretion , In the cat, GRP is present in intrapancreatic ganglia, acinar and stromal regions, and occasionally on the vasculature and ducts In humans, the pattern of GRP expression was similar to that of VIP; GRP was localized on nerve fibers in proximity to pancreatic acini, capillaries, ductules, and arterial walls Several studies in different species have demonstrated that GRP modulates exocrine secretion Vagal stimulation of porcine pancreas resulted in GRP release which enhanced pancreatic exocrine secretion In isolated perfused rat pancreatic preparations, electrical field-stimulated GRP release potentiated secretin-mediated fluid and amylase secretion through a non-cholinergic pathway Neuromedin C, a decapeptide of GRP, also enhanced pancreatic secretion by direct action on canine acinar cells as well as indirectly by stimulating CCK release , However, since bombesin GRP analog does not stimulate pancreatic secretion in dogs, it appears that its effects may be dependent on the species being evaluated For more details on bombesin see Neurotensin: Neurotensin is a 13 amino acid neuropeptide that is widely expressed in the central nervous system and is also present in pancreatic nerves.
It stimulates amylase secretion and its effects are potentiated by carbachol a cholinergic agonist , secretin, and caerulein a CCK analog 11, Other studies demonstrated that neurotensin stimulates bicarbonate, but not protein secretion in dogs and may act indirectly by stimulating dopamine release Substance P: Substance P is expressed in periductal nerves in the guinea pig pancreas and inhibits ductal bicarbonate secretion by modulating neurokinin 2 and 3 receptors , , It enhanced caerulein-stimulated enzyme secretion in isolated perfused pancreas as well as in anesthetized rodents The effect of CGRP on exocrine secretion is not clear and may be species specific.
Interaction of CGRP with receptors on guinea pig acinar cells led to amylase release, although its effect was not as potent as VIP In rat acinar cell preparations, CGRP inhibited amylase release by a mechanism involving cholinergic muscarinic neural pathways NPY: NPY, a 36 residue peptide, is expressed in intrapancreatic ganglia and nerve fibers that surround exocrine pancreatic tissue
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