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Stimulation ofPancreatic Secretion 67

doses)

(Physiologic

Downloaded from https://onlinelibrary.wiley.com/doi/ by Universität Bern, Wiley Online Library on [22/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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controversial. Invitro studies using dispersed rat pancre- atic acini show that CCK- stimulated amylase release is insensitive to atropine or tetrodotoxin, indicating a direct action on pancreatic acini[31]. However, invivo studies of humans and dogs have shown that atropine can block CCK- stimulated pancreatic secretion, implying involvement of cholinergic pathways [31]. Furthermore, enzyme output in response to low- dose CCK is reduced after vagotomy[31]. It appears that CCK can act through atropine- sensitive and atropineinsensitive pathways to stimulate pancreatic exocrine secretion. Human studies have shown that CCK- 8infusions at physiological doses can stimulate pancreatic enzyme output predominately in an atropine- sensitive fashion [31]. Furthermore, studies in rats indicate that physiological doses of CCK act through stimulation of vagal afferent pathways originating from the duodenal mucosa[31] (Fig.7.2). CCK receptors have been detected in the rat vagus nerve using invitro autoradiography[16]. Vagal CCK

receptors exist in high- and low- affinity

states[16]. Under physiological conditions, CCK appears to act through high- affinity vagal CCK1 receptors to mediate pancreatic enzyme secretion [16]. In contrast, the effect of CCK on satiety is mediated by low- affinity vagal CCK receptors [16]. These findings suggest that different affinity states of the vagal CCK receptors mediate different digestive functions. Under physiological

conditions, CCK seems to stimulate postprandial pancreatic enzyme secretion through cholinergic pathways rather than through direct action on pancreatic acinar cells. M1 and M3 muscarinic receptors on pancreatic acini appear to mediate these responses[32,33] (Fig.7.2). The molecular cloning of the CCK receptor gene and subsequent recognition that its expression is virtually absent in human pancreas [16,34] suggests that CCK acts at an extrapancreatic site. One study indicates that human acini do not respond to CCK agonists, although they respond to a muscarinic agonist [16]. In contrast, acini responded to CCK agonists after adenovirusmediated CCK receptor gene transfer[16]. Quantitative reverse transcription–polymerase chain reaction showed that CCK1 receptor mRNA expression was ~30- fold lower than that for CCK2 receptors, and ~10- fold lower than for M

muscarinic receptors. In situ hybridization

did not detect CCK1 receptor mRNAs in adult human pancreas, supporting the concept that CCK acts at an extrapancreatic site to stimulate enzyme secretion. By contrast, a study of isolated human pancreatic acini showed that physiological levels of CCK induced Ca2+ signaling, activated mitochondrial function, and stimulated enzyme secretion[35]. The physiological relevance of these observations is unclear. CCK1 receptors are expressed in human pancreatic stellate cells, which lie near acinar cells[36]. Low CCK concentrations (20 pM)

Serotonin

CCK

doses)

Figure7.2 Sites and mechanisms of action of stimulatory and inhibitory hormones to modulate pancreatic enzyme secretion. Dosages of

cholecystokinin- 8 (CCK- 8) that produce physiological plasma CCK levels act through stimulation of the vagal afferent pathway, which originates from the gastroduodenal mucosa. In contrast, dosages that produce supraphysiological plasma CCK levels act on intrapancreatic neurons and, to a lesser extent, on pancreatic acini. Serotonin (5HT) another stimulatory hormone also acts via vagal afferent pathway to evoke pancreatic enzyme secretion. In contrast, most of the inhibitory hormones such as PP, SRIF, PYY, and Pancreastatin act at a central vagal site to inhibit pancreatic secretion. ACh: acetylcholoine; PP: pancreatic polypeptide; SRIF: somatostatin; PYY: pancreatic polypeptide YY.

Nodose ganglion

Afferent

Vagal

SRIF

PYY

Pancreastatin

ACh

Efferent Vagal

Intrinsi

neuron

CCK

(Supraphysiologic

Neurohormonal andHormonal Control ofPancreatic Secretion

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stimulate acetylcholine release, which evokes enzyme secretion from pancreatic acini. Thus, it appears that CCK may regulate cholinergic stimulation of the pancreas through both neural and nonneural pathways.

Serotonin

Apart from CCK, intestinal serotonin (5- HT) appears to play an important role in mediating postprandial pancreatic enzyme secretion [16]. Although 5- HT is found in the myenteric plexus, the major source of 5- HT in the gastrointestinal tract appears to be mucosal enterochromaffin cells[37]. 5- HT is released in response to various stimuli[37], including duodenal acidification[37], instillation of hypertonic glucose, sucrose, or maltose solutions [16,38], vagal stimulation [39], and mechanical stimulation [40]. 5- HT may increase the discharge of vagal afferent fibers from the stomach and proximal intestine[41,42], which in turn can stimulate pancreatic secretion by way of a vagovagal reflex mediated by a cholinergic afferent pathway[16]. Invivo studies show that vagal responses to luminal osmolarity and the digestion products of carbohydrates depend on the release of endogenous 5-

HT from mucosal enterochromaffin cells, which acts on 5- HT3 receptors on vagal afferent fibers[16] (Fig.7.2).

5- HT and CCK are the principal mediators of postprandial enzyme secretion. A CCK1 receptor antagonist inhibited 54% of postprandial protein secretion in rats. CCK1 receptor and 5- HT3 antagonists combined almost completely abolished exocrine pancreatic secretion[16], suggesting that 5- HT–dependent pancreatic stimulants account for about 50% of postprandial pancreatic secretion. Vagal CCK and 5- HT receptors act synergistically to mediate pancreatic secretion [16], explaining how a small increase in the plasma CCK level is sufficient to produce a robust postprandial pancreatic secretion.

Other Hormones andStimulatory Factors

Insulin plays a significant role in modulating exocrine pancreatic secretion [43]. Animal studies have demonstrated that insulin potentiates the secretory response of secretin plus CCK[44], and that ouabain, an inhibitor of Na+,K+- ATPase activity, abolishes the stimulatory action of insulin. Physiologically, the actions of insulin are important because immunoneutralization experiments in conscious rats showed that pancreatic secretion of water, HCO

–

, and protein stimulated by a meal or by a

combined intravenous infusion of physiological doses of secretin and CCK is markedly reduced when the circulating insulin is neutralized with a rabbit anti- insulin antibody [45]. It is well known that pancreatic enzyme secretion is often reduced in diabetes without overt pancreatic disease[46]. This may be mediated by enhanced

activation of the TRESK K

channel in the nodose ganglia, observed in rats with diabetes[47] or fed a highfat diet, reducing the excitability of the nodose ganglia and contributing to decreased pancreatic secretion mediated by the vagovagal reflex[47].

Bombesin (a gastrin- releasing peptide in mammals), a polypeptide isolated from the skin of frogs and also found in the human digestive tract, stimulates pancreatic secretions that contain small amounts of HCO

–

and

high concentrations of enzymes in humans [48,49]. Bombesin can act directly on the pancreas, or indirectly by promoting CCK release from the small intestinal mucosa [50]. In other systems, bombesin reportedly exerts its effect by way of a cholinergic pathway [51]. Hence, bombesin may act through different pathways to stimulate pancreatic secretion. However, the physiological importance of bombesin in pancreatic secretion is uncertain as bombesin receptor antagonists do not influence postprandial enzyme secretion in mammals[52].

Neurotensin appears to stimulate pancreatic enzyme secretion in humans and dogs. In rats, the stimulation appears to be neurally mediated, involving cholinergic vagal afferent pathways. Neurotensin is released by intestinal fatty acids, suggesting a role in mediating fatstimulated pancreatic secretion. However, exogenous infusion of neurotensin in doses that stimulate pancreatic secretion results in a plasma level much higher than after a normal meal[53,54].

Ghrelin, found in gastric endocrine cells and in neurons of the hypothalamic arcuate nucleus, has been shown to stimulate pancreatic enzyme secretion. It acts as an endogenous ligand for the growth hormone secretagogue receptor, which is found throughout the body, including the hypothalamus and the pancreatic islet and acinar cells. Depending on the animal species, ghrelin acts directly on acinar cells or centrally through the vagal cholinergic pathways[60].

Nitric oxide (NO) is present in pancreatic neurons and vascular endothelium[61], and appears to play a significant role in regulating pancreatic secretion. In humans,

NAME, an inhibitor of NO production, dose depend-

ently reduces enzyme secretion stimulated by secretin and cerulein [62]. In vitro, NO synthase inhibition has no effect on amylase release or intracellular Ca2+ concentration in rat pancreatic acinar cells stimulated by carbachol and CCK- 8[63]. - NAME also reduces CCK- stimulated pancreatic microvascular blood flow and at the same time decreases pancreatic fluid and protein output in rats[64]. This observation may have clinical importance because inadequate blood flow has been associated with clinical pancreatitis. Interestingly, treatment with NO donor - arginine before and after cerulein injection increases pancreatic blood flow and reduces the severity of ceruleininduced hemorrhagic pancreatitis. These observations

Inhibition ofPancreatic Secretion 69

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suggest NO may protect the pancreas from injury, possibly because it increases pancreatic blood flow.

Other peptides with stimulatory effects on enzyme secretion include those with direct effects on acinar cells, including atrial natriuretic factor (ANF), fibroblast growth factor 21 (FGF21), and histamine. Other peptides stimulate pancreatic secretion through neural mechanisms, including C- natriuretic factor (CNP) and melatonin. The effect of amylin on enzyme secretion is unresolved.

Neural Mechanisms

Parasympathetic Nervous System

The pancreas is innervated by parasympathetic and sympathetic nerve fibers. The parasympathetic fibers pass through the pancreas directly through the vagus nerve and indirectly by the celiac ganglion, the splanchnic nerves, and perhaps through the intramural plexus of the duodenum. In humans, the vagus nerve appears to play an important role in mediating pancreatic secretion. Insulin-

induced hypoglycemia, which is presumed to stimulate the vagus nerve centrally, augments secretinstimulated pancreatic protein output [65]. Vagotomy reduces the HCO

–

secretory response to exogenous

hormones. Furthermore, vagotomy also reduces pancreatic enzyme responses to intestinal stimulants and food[31,66]. Exogenous cholinergic stimulation appears to primarily modulate the actions of gut peptides on pancreatic secretion but has no physiologically relevant effect on CCK or secretin release[67].

In humans, stimulation of duodenal volume receptors and osmoreceptors elicits a pancreatic enzyme response mediated by cholinergic neurons[31]. Increased firing in peripheral afferent vagal neurons and in central sites has been recorded after gastric distension and intestinal perfusion with amino acids and HCl[68,69].

Intrapancreatic postganglionic cholinergic neurons regulate enzyme and HCO

–

secretion. These neurons

are activated by central input during the cephalic phase and by vagovagal reflexes initiated by gastric- and intestinal- phase stimulation. Acetylcholine released by pancreatic neurons may act directly on acinar cells or potentiate the action of secretin on HCO

–

secretion

from duct cells invitro. Acetylcholine and CCK interaction is additive. The enteropancreatic reflex may also play a role in mediating postprandial enzyme secretion [31]. This is especially important after chronic vagotomy[70].

Sympathetic Nervous System

Adrenergic innervation of the pancreas occurs mainly through the splanchnic nerves, which are distributed to blood vessels, with a few passing to acini and ducts[28].

Activation of splanchnic nerves usually inhibits exocrine and endocrine pancreatic secretion; splanchnic nerve stimulation decreases and splanchnicectomy increases pancreatic secretion in response to pancreatic stimulants[28,71]. These responses are likely mediated by vasoconstriction caused by stimulation of α- adrenergic receptors on blood vessels. Physiologically, the major role for adrenergic activation appears to be the inhibition of fluid and HCO

–

secretion, which is mainly

mediated by vasoconstriction.

Enteropancreatic Neural Reflex

Functional and anatomic enteropancreatic neural connections have been demonstrated by anterograde and retrograde tracing. Neurons in the ganglia of the myenteric plexus of the stomach and duodenum project directly to the pancreas [72]. Stimulation of duodenal myenteric neurons can influence endocrine and exocrine pancreatic functions in the rat. These enteropancreatic neural pathways have cholinergic and serotonergic components[72,73]. The cholinergic nerves from the duodenum stimulate intrapancreatic neurons through nicotinic synapses. In contrast, stimulation of enteropancreatic serotonergic axons inhibits pancreatic secretion through presynaptic 5-

HT1P receptors on cholinergic nerves[72]. The physiological role of the serotonergic enteropancreatic neural pathways is unclear.

Inhibition ofPancreatic Secretion

The regulation of pancreatic secretion depends on the balance between inhibitory and stimulatory influences exerted through hormones and the autonomic nervous system. The inhibitory phase of pancreatic secretion is mediated by many hormones.

Pancreatic polypeptide (PP) is localized in the islets of Langerhans and between the acinar cells of the exocrine pancreas[74]. PP secretion is regulated mainly by a cholinergic mechanism [75]. Postprandial PP release is mediated by a long vagovagal reflex and short local cholinergic pathways[75].

In humans and dogs, infusion of physiological concentrations of PP inhibits basal and stimulated pancreatic secretion[75,76]. Invivo, PP appears to act preferentially by inhibiting vagal stimulation[77]. Invitro, PP inhibits pancreatic enzyme secretion by way of presynaptic modulation of acetylcholine release [78]. Because its secretion is under cholinergic control and it acts by interfering with cholinergic transmission, PP is an ideal candidate to modulate pancreatic secretion stimulated by the cholinergic enteropancreatic reflex. PP may also act centrally, as suggested by the presence of PP receptors in discrete locations in the hypothalamus, limbic system, brain

Neurohormonal andHormonal Control ofPancreatic Secretion

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stem, and other central locations[79]. Microinjection of PP into the dorsal motor nucleus (DMV) inhibits CCKstimulated pancreatic secretion, suggesting that the DMV is an important site for neural feedback inhibition of pancreatic exocrine secretion[80]. Hence, PP acts at multiple brain stem sites to modulate vagal cholinergic efferent output to the pancreas[81].

Glucagon also inhibits pancreatic exocrine secretion stimulated by secretin and CCK or by ingestion of a test meal in dogs, cats, rats, and humans[82–84]. The inhibitory characteristics are reduced flow volume and decreased HCO

–

and enzyme secretion. Currently, the

sites of action are unclear.

Somatostatin, present in the pancreas as well as the upper gastrointestinal tract and central nervous system, may also play a role in the inhibition of pancreatic secretion. Research indicates that somatostatin does not act on peripheral vagal afferent or efferent pathways nor directly on pancreatic acinar; it exerts its inhibitory action at a central vagal site[85]. Somatostatin injected into the DMV significantly inhibits pancreatic exocrine secretion evoked by intravenous administration of CCK- 8 or 2- deoxy- - glucose, suggesting somatostatin acts through a central cholinergic mechanism[16].

Enteroglucagon is an intestinal hormone believed to mediate the inhibitory action of hypertonic glucose infusion into the jejunum. In animal studies, infusion of oxyntomodulin, a 37- amino acid glucagon- containing peptide isolated from porcine lower intestine, inhibits basal and cerulein- stimulated pancreatic secretion of HCO

–

and enzymes[86]. The inhibitory action of enter-

oglucagon is 10- fold more potent than that of pancreatic glucagon.

Peptide YY (PYY) is a 36- amino acid peptide found in the distal intestine and colon of humans and experimental animals [87]. It is released by fat and, to a lesser degree, protein in the ileum or colon. PYY infusion in dogs significantly inhibits basal and meal- stimulated pancreatic HCO

–

and enzyme secretion [88].

Physiological experiments demonstrate that intra- ileal, but not colonic, carbohydrate increases plasma PYY levels and decreases amylase secretion in dogs [89]. In humans, ileal carbohydrate perfusion inhibits exocrine pancreatic secretion. Therefore, PYY may represent a late postprandial event serving as a physiological signal to reduce exocrine pancreatic secretion after completion of digestion and nutrient absorption.

Glucagon- like peptide 1 (GLP- 1) is another ileal hormone that is elevated in the circulation during ileal carbohydrate infusion. There is conflicting data on whether GLP- 1has inhibitory vs. stimulatory and direct vs. indirect effects on exocrine pancreatic secretion. Recent studies support a direct stimulatory effect on acinar cells through a cyclic AMP- dependent mechanism. Older

studies suggest the opposite. In anesthetized pigs with cut splanchnic nerves, intravenous GLP- 1 infusion inhibits hypoglycemia- induced pancreatic HCO

–

and

protein secretion, effects absent in vagally stimulated, isolated, and perfused porcine pancreas[90], suggesting that GLP- 1 acts through a central mechanism. Studies in rats indicate GLP- 1inhibitory action depends on intact vagal nerves[91].

Other peptides. Although the list of peptides known to inhibit exocrine pancreatic secretion continues to expand, little is known about the mechanisms through which these and other hormones or neurotransmitters inhibit pancreatic enzyme secretion. Most of these peptides lack direct inhibition of pancreatic acinar cells and most suppress pancreatic enzyme secretion in vivo but do not act directly on acinar cells to reduce pancreatic enzyme release. Animal studies suggest that peptides such as PP, somatostatin, calcitonin gene- related peptide (CGRP), enkephalin, and pancreastatin inhibit pancreatic enzyme secretion by modulating cholinergic transmission, and most, if not all, act through a central vagal site [92–98]. Leptin also inhibits pancreatic enzyme secretion through a similar neuro mechanism, but paradoxically increases pancreatic protein output in rats when administered by duodenal perfusion through CCK activation of duodeno- pancreatic reflexes. Less clear are mechanisms of inhibiting pancreatic secretion by adrenomedullin and galanin.

Feedback Regulation ofPancreatic Secretion

A series of observations in rats suggest that intraluminal actions of pancreatic proteases play an important role in regulating pancreatic enzyme secretion [16,99]. It was demonstrated that diversion of pancreatic juice in the duodenum stimulates CCK release and pancreatic enzyme secretion [16]. Conversely, intraduodenal administration of trypsin or chymotrypsin inhibits CCK release and pancreatic enzyme secretion[16]. This phenomenon is specific for activated proteases, not with inactivated trypsin, amylase, lipase, or HCO

Feedback regulation of pancreatic secretion by proteases appears to be mediated by a trypsin- sensitive substance secreted by the proximal small intestine, originally designated CCK–releasing factor (CCK- RF) [16,21]. When trypsin is present, this peptide is cleaved and inactivated. CCK- RF may mediate pancreatic enzyme secretion in response to dietary protein intake in rats. Dietary protein in the intestine competes for the trypsin that would otherwise inactivate CCK- RF[16]. The resulting increase of CCK- RF in the intestinal lumen stimulates CCK release and pancreatic enzyme secretion (Fig.7.1).

–

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Efforts to demonstrate a protease- sensitive feedback mechanism in humans remain controversial because of technical limitations in removing or blocking intraluminal protease activity. Using a different approach, investigators reported that intraluminal administration of trypsin or chymotrypsin in humans suppresses CCK release and partially reduces the CCK response to intestinal administration of amino acids or oral ingestion of a test meal[16,100]. These observations support the existence of feedback regulation of pancreatic enzyme secretion in humans. Liener and colleagues demonstrated that Bowman–Birk soybean trypsin inhibitor, an inhibitor of chymotrypsin and elastase, strongly stimulates pancreatic enzyme secretion in humans[101].

The existence of feedback regulation of pancreatic enzyme secretion in humans may have important clinical implications. In patients with chronic pancreatitis, decreased pancreatic enzyme secretion may result in elevated plasma CCK levels, reflecting a failure in the feedback modulation of CCK release. This may cause hyperstimulation of the pancreas and produce pain. Effective enzyme replacement therapy may reduce pancreatic stimulation, decrease intraductal pressure,

and diminish pain. Large doses of pancreatic extract have reduced pain in some patients with chronic pancreatitis[102,103].

Conclusion

Under physiological conditions, in rodents and humans, cholinergic vagal afferent pathways rather than pancreatic acinar cells represent the primary targets on which CCK may act as a major mediator of postprandial pancreatic secretion. The vagal afferent pathways also transmit sensory information about the mechanical and physiological state of the digestive tract, mediated in part by 5- HT, which in turn influences pancreatic secretion. A synergistic interaction between CCK and 5- HT at the level of the nodose ganglia may explain the robust postprandial pancreatic enzyme secretion despite a modest increase in plasma CCK after a meal. Interestingly, most hormones such as PP, somatostatin, CGRP, and pancreastatin act through a central vagal site. This supports the Pavlovian concept that the neural system is the major regulator of pancreatic secretion.

References

1 Meyer JH, Way LW, Grossman MI. Pancreatic bicarbonate

response to various acids in duodenum of the dog. Am JPhysiol 1970;219:964.

2 Fahrenkrug J, Schaffalitzky de Muckadell OB, Rune SJ. pH

threshold for release of secretin in normal subjects and in patients with duodenal ulcer and patients with chronic pancreatitis. Scand J Gastroenterol 1978;13:177.

3 Chey WY, Chang TM. Secretin: historical perspective and

current status. Pancreas 2014;43(2):162–182.

4 Li P, Lee KY, Chang TM etal. Mechanism of acid- induced

release of secretin in rats. Presence of a secretinpeptide. J Clin Invest 1990;86:1474.

5 Meyer JH, Jones RS. Canine pancreatic responses to

intestinally perfused fat and products of fat digestion. Am JPhysiol 1974;226:1178.

6 Osnes M, Hanssen LE, Flaten O etal. Exocrine pancreatic

secretion and immunoreactive secretin (IRS) release afterintraduodenal instillation of bile in man. Gut 1978;19:180.

7 Ishiguro H, Steward MC, Wilson RW etal. Bicarbonate

secretion in interlobular ducts from guinea- pig pancreas. JPhysiol 1996;495:179.

8 Ishiguro H, Naruse S, Steward MC etal. Fluid secretion in

interlobular ducts isolated from guinea- pig pancreas. JPhysiol 1998;511:407.

9 Wu XY, Zhu JX, Gao J etal. Neurochemical phenotype of

vagal afferent neurons activated to express C- FOS in response to luminal stimulation in the rat. Neuroscience 2005;130:757.

releasing

10 Wang L, Vigna S, Owyang C. Autoradiographic visualization

of secretin receptors on vagal afferent fibers: evidence for receptor coupling to G proteins and modulation by protein kinase C. Gastroenterology 1995;108:A1015.

11 Liddle RA. Cholecystokinin cells. Annu Rev Physiol

1997;59:221.

12 Meyer JH, Kelly GA, Spingola LJ etal. Canine gut

receptors mediating pancreatic responses to luminal L- amino acids. Am J Physiol 1976;231:669.

13 Malagelada JR, DiMagno EP, Summerskill WH etal.

Regulation of pancreatic and gallbladder functions by intraluminal fatty acids and bile acids in man. J Clin Invest 1976;58:493.

14 Jansen JB, Lamers CB. Radioimmunoassay of

cholecystokinin in human tissue and plasma. Clin Chim Acta 1983;131:305.

15 Liddle RA, Goldfine ID, Rosen MS etal. Cholecystokinin

bioactivity in human plasma. Molecular forms, responses to feeding, and relationshipto gallbladder contraction. JClin Invest 1985;75:1144.

16 Owyang C, Logsdon CD. New insights into

neurohormonal regulation of pancreatic secretion. Gastroenterology 2004;127:957.

17 Cantor P, Rehfeld JF. The molecular nature of

cholecystokinin in human plasma. Clin Chim Acta 1987;168:153.

18 Eysselein VE, Eberlein GA, Hesse WH etal.

Cholecystokinin- 58 is the major circulating form of

Neurohormonal andHormonal Control ofPancreatic Secretion

https://t.me/medicina_free

cholecystokinin in canine blood. J Biol Chem 1987;262:214.

19 Glatzle J, Raybould HE, Kueper MA etal.

Cholecystokininintake than cholecystokinin-

58 is more potent in inhibiting food

8in rats. Nutr Neurosci

2008;11:69.

20 Li Y, Owyang C. Peptone stimulates CCK- releasing

peptide secretion by activating intestinal submucosal cholinergic neurons. J Clin Invest 1996;97:1463.

21 Lu L, Louie D, Owyang C. A cholecystokinin releasing

peptide mediates feedback regulation of pancreatic secretion. Am J Physiol 1989;256:G430.

22 Wang Y, Chandra R, Samsa LA etal. Amino acids

stimulate cholecystokinin release through the Ca

sensing receptor. Am J Physiol Gastrointest Liver Physiol 2011;300:G528.

23 Liou AP, Lu X, Sei Y etal. The G- protein- coupled receptor

GPR40 directly mediates long-

chain fatty acid- induced secretion of cholecystokinin. Gastroenterology 2011;140:903.

24 Beglinger C, Fried M, Whitehouse I etal. Pancreatic

enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretin and cholecystokinin levels. J Clin Invest 1985;75:1471.

25 Konturek SJ, Tasler J, Cieszkowski M etal. Hladij M. Effect

of cholecystokinin receptor antagonist on pancreatic responses to exogenous gastrin and cholecystokinin and to meal stimuli. Gastroenterology 1988;94:1014.

26 Cantor P, Mortensen PE, Myhre J etal. The effect of the

cholecystokinin receptor antagonist MK-

329 on mealstimulated pancreaticobiliary output in humans. Gastroenterology 1992;102:1742.

27 Henriksen FW, Worning H. The mutual influence of

gastrin and secretin on the external pancreatic secretion in dogs. Acta Physiol Scand 1969;76:67.

28 Holst J. Neural regulation of pancreatic exocrine function.

In: Go V, Dimagno E, Gardner J etal. (eds). The Pancreas: Biology, Pathobiology, and Disease. 4th edn. NewYork: Raven Press, 1993: 381.

29 You CH, Rominger JM, Chey WY. Potentiation effect of

cholecystokinin-

octapeptide on pancreatic bicarbonate secretion stimulated by a physiologic dose of secretin in humans. Gastroenterology 1983;85:40.

30 Beglinger C, Grossman MI, Solomon TE. Interaction

between stimulants of exocrine pancreatic secretion in dogs. Am J Physiol 1984;246:G173.

31 Owyang C. Physiological mechanisms of cholecystokinin

action on pancreatic secretion. Am J Physiol 1996;271 (1 Pt 1):G1–7.

32 Kato M, Ohkuma S, Kataoka K etal. Characterization of

muscarinic receptor subtypes on rat pancreatic acini: pharmacological identification by secretory responses and binding studies. Digestion 1992;52:194.

33 Gautam D, Han SJ, Heard TS etal. Cholinergic stimulation

of amylase secretion from pancreatic acinar cells studied

with muscarinic acetylcholine receptor mutant mice. JPharmacol Exp Ther 2005;313:995.

34 de Weerth A, Pisegna JR, Huppi K etal. Molecular

cloning, functional expression and chromosomal localization of the human cholecystokinin type A receptor. Biochem Biophys Res Commun 1993;194:811.

35 Murphy JA, Criddle DN, Sherwood M etal. Direct

activation of cytosolic Ca

signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells. Gastroenterology 2008;135:632.

36 Phillips PA, Yang L, Shulkes A etal. Pancreatic stellate

cells produce acetylcholine and may play a role in pancreatic exocrine secretion. Proc Natl Acad Sci U S A 2010;107:17397.

37 Schworer H, Racke K, Kilbinger H. Spontaneous release of

endogenous 55-

hydroxyindoleacetic acid from the isolated vascularly

perfused ileum of the guinea-

hydroxytryptamine and

pig. Neuroscience

1987;21:297.

38 O’Hara RS, Fox RO, Cole JW. Serotonin release mediated

by intraluminal sucrose solutions. Surg Forum 1960;10:214.

39 Larsson I. Studies on the extrinsic neural control of

serotonin release from the small intestine. Acta Physiol Scand Suppl 1981;499:1.

40 Bulbring E, Crema A. The release of 5- hydroxytryptamine

in relation to pressure exerted on the intestinal mucosa. JPhysiol 1959;146:18.

41 Blackshaw LA, Grundy D. Effects of 5- hydroxytryptamine

on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Auton Nerv Syst 1993;45:41.

42 Andrews PL, Davis CJ, Bingham S etal. The abdominal

visceral innervation and the emetic reflex: pathways, pharmacology, and plasticity. Can J Physiol Pharmacol 1990;68:325.

43 Saito A, Williams JA, Kanno T. Potentiation of

cholecystokinin-

induced exocrine secretion by both exogenous and endogenous insulin in isolated and perfused rat pancreata. J Clin Invest 1980;65:777.

44 Matsushita K, Okabayashi Y, Koide M etal. Potentiating

effect of insulin on exocrine secretory function in isolated rat pancreatic acini. Gastroenterology 1994;106:200.

45 Lee KY, Zhou L, Ren XS etal. An important role of

endogenous insulin on exocrine pancreatic secretion in rats. Am J Physiol 1990;258:G268.

46 Chey WY, Shay H, Shuman CR. External pancreatic

secretion in diabetes mellitus. Ann Intern Med 1963;59:812.

47 Grabauskas G, Wu X, Zhou S etal. High- fat diet- induced

vagal afferent dysfunction via upregulation of 2-

pore

domain potassium TRESK channel. JCI Insight 2019;4.

48 Polak JM, Bloom SR, Hobbs S etal. Distribution of a

bombesin- like peptide in human gastrointestinal tract. Lancet 1976;1:1109.

References 73

https://t.me/medicina_free

49 Basso N, Giri S, Improta G etal. External pancreatic

secretion after bombesin infusion in man. Gut 1975;16:994.

50 Erspamer V, Improta G, Melchiorri P etal. Evidence of

cholecystokinin release by bombesin in the dog. Br JPharmacol 1974;52:227.

51 Taylor IL, Walsh JH, Carter D etal. Effects of atropine and

bethanechol on bombesin-

stimulated release of pancreatic polypeptide and gastrin in dog. Gastroenterology 1979;77:714.

52 Varga G, Reidelberger RD, Liehr RM etal. Effects of potent

bombesin antagonist on exocrine pancreatic secretion in rats. Peptides 1991;12:493.

53 Fletcher DR, Blackburn AM, Adrian TE etal. Effect of

neurotensin on pancreatic function in man. Life Sci 1981;29:2157.

54 Konturek SJ, Jaworek J, Cieszkowski M etal. Comparison

of effects of neurotensin and fat on pancreatic stimulation in dogs. Am J Physiol 1983;244:G590.

55 Nagain C, Chariot J, Roze C. Mechanism of neurotensin

stimulation of external pancreatic secretion in the rat. Pancreas 1993;8:346.

56 Kojima M, Hosoda H, Date Y etal. Ghrelin is a growth-

hormone- releasing acylated peptide from stomach. Nature 1999;402:656.

57 169 Date Y, Kojima M, Hosoda H etal. Ghrelin, a novel

growth hormone-

releasing acylated peptide, is synthesized in a distinct endocrine cell type in the gastrointestinal tracts of rats and humans. Endocrinology 2000;141:4255.

58 Cummings DE, Purnell JQ, Frayo RS etal. A preprandial

rise in plasma ghrelin levels suggests a role in meal initiation in humans. Diabetes 2001;50:1714.

59 Lai JK, Cheng CH, Ko WH etal. Ghrelin system in

pancreatic AR42J cells: its ligand stimulation evokes calcium signalling through ghrelin receptors. Int JBiochem Cell Biol 2005;37:887.

60 Li Y, Wu X, Zhao Y etal. Ghrelin acts on the dorsal vagal

complex to stimulate pancreatic protein secretion. Am JPhysiol Gastrointest Liver Physiol 2006;290:G1350.

61 Shimosegawa T, Abe T, Satoh A etal. NADPH- diaphorase

activity in neurons of the mammalian pancreas: coexpression with vasoactive intestinal polypeptide. Gastroenterology 1993;105:999.

62 Konturek JW, Hengst K, Kulesza E etal. Role of

endogenous nitric oxide in the control of exocrine and endocrine pancreatic secretion in humans. Gut 1997;40:86.

63 Yoshida H, Tsunoda Y, Owyang C. Effect of uncoupling

NO/cGMP pathways on carbachol- and CCK- stimulated

entry and amylase secretion from the rat pancreas.

Ca Pflugers Arch 1997;434:25.

64 Patel AG, Toyama MT, Nguyen TN etal. Role of nitric

oxide in the relationship of pancreatic blood flow and exocrine secretion in cats. Gastroenterology 1995;108:1215.

65 Brooks FP, Manfredo H. The control of pancreatic

secretion and its clinical significance. Am J Gastroenterol 1964;42:42.

66 MacGregor I, Parent J, Meyer JH. Gastric emptying of

liquid meals and pancreatic and biliary secretion after subtotal gastrectomy or truncal vagotomy and pyloroplasty in man. Gastroenterology 1977;72:195.

67 Chey WY, Kim MS, Lee KY. Influence of the vagus nerve

on release and action of secretin in dog. J Physiol 1979;293:435.

68 Jeanningros R. Effect of intestinal amino acid infusions on

hypothalamic single unit activity in the anesthetized cat. Brain Res Bull 1983;10:15.

69 Andrews CJ, Andrews WH. Receptors, activated by acid,

in the duodenal wall of rabbits. Q J Exp Physiol Cogn Med Sci 1971;56:221.

70 Lu YX, Tsunoda Y, Li Y etal. Adaptive changes of enteric

cholinergic neurons projecting to the pancreas following chronic vagotomy: upregulation of CCK receptor affinity. Gastroenterology 2001;120(Suppl 1):A24.

71 Larsson LI, Rehfeld JF. Peptidergic and adrenergic

innervation of pancreatic ganglia. Scand J Gastroenterol 1979;14:433.

72 Kirchgessner AL, Gershon MD. Presynaptic inhibition by

serotonin of nerve-

mediated secretion of pancreatic

amylase. Am J Physiol 1995;268:G339.

73 Kirchgessner AL, Gershon MD. Innervation of the

pancreas by neurons in the gut. J Neurosci 1990;10:

1626.

74 Larsson LI, Sundler F, Hakanson R. Pancreatic

polypeptide—

a postulated new hormone: identification of its cellular storage site by light and electron microscopic immunocytochemistry. Diabetologia 1976;12:211.

75 Schwartz TW. Pancreatic polypeptide: a hormone under

vagal control. Gastroenterology 1983;85:1411.

76 Greenberg GR, McCloy RF, Chadwick VS etal. Effect of

bovine pancreatic polypeptide on basal pancreatic and biliary outputs in man. Dig Dis Sci 1979;24:11.

77 Putnam WS, Liddle RA, Williams JA. Inhibitory regulation

of rat exocrine pancreas by peptide YY and pancreatic polypeptide. Am J Physiol 1989;256:G698.

78 Jung G, Louie DS, Owyang C. Pancreatic polypeptide

inhibits pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol 1987;253:G706.

79 Whitcomb DC, Puccio AM, Vigna SR etal. Distribution of

pancreatic polypeptide receptors in the rat brain. Brain Res 1997;760:137.

80 Okumura T, Pappas TN, Taylor IL. Pancreatic polypeptide

microinjection into the dorsal motor nucleus inhibits pancreatic secretion in rats. Gastroenterology 1995;108:1517.

81 Browning KN, Coleman FH, Travagli RA. Effects of

pancreatic polypeptide on pancreas- projecting rat dorsal motor nucleus of the vagus neurons. Am J Physiol Gastrointest Liver Physiol 2005;289:G209.

Neurohormonal andHormonal Control ofPancreatic Secretion

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82 Dyck WP, Rudick J, Hoexter B etal. Influence of glucagon

on pancreatic exocrine secretion. Gastroenterology 1969;56:531.

83 Konturek SJ, Tasler J, Obtulowicz W. Characteristics of

inhibition of pancreatic secretion by glucagon. Digestion 1974;10:138.

84 Singer MV, Tiscornia OM, Mendes de Oliveiro JP etal.

Effect of glucagon on canine exocrine pancreatic secretion stimulated by a test meal. Can J Physiol Pharmacol 1978;56:1.

85 Li Y, Owyang C. Somatostatin inhibits pancreatic enzyme

secretion at a central vagal site. Am J Physiol 1993;265:G251.

86 Inoue K, Fried GM, Wiener I etal. Effect of divalent

cations on gastrointestinal hormone release and exocrine pancreatic secretion in dogs. Am J Physiol 1985;248:G28.

87 Adrian TE, Ferri GL, Bacarese- Hamilton AJ etal. Human

distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 1985;89:1070.

88 Pappas TN, Debas HT, Goto Y etal. Peptide YY inhibits

meal-

stimulated pancreatic and gastric secretion. Am J

Physiol 1985;248:G118.

89 Tohno H, Sarr MG, DiMagno EP. Intraileal carbohydrate

regulates canine postprandial pancreaticobiliary secretion and upper gut motility. Gastroenterology 1995;109:1977.

90 Wettergren A, Wojdemann M, Holst JJ. Glucagon- like

peptide-

1inhibits gastropancreatic function by inhibiting central parasympathetic outflow. Am JPhysiol 1998;275:G984.

91 Li Y, Zhu J, Rillamas E etal. Glucagon- like- peptide- 1 acts

via dorsal vagal complex to inhibit pancreatic enzyme secretion. Gastroenterology 1998;114:A1158.

92 Liao Z, Li ZS, Lu Y etal. Microinjection of exogenous

somatostatin in the dorsal vagal complex inhibits pancreatic secretion via somatostatin receptor- 2in rats. Am J Physiol Gastrointest Liver Physiol 2007;292:G746.

93 Putnam WS, Liddle RA, Williams JA. Inhibitory

regulation of rat exocrine pancreas by peptide YY andpancreatic polypeptide. Am J Physiol 1989;256:G698.

94 Jung G, Louie DS, Owyang C. Pancreatic polypeptide

inhibits pancreatic enzyme secretion via a cholinergic pathway. Am J Physiol 1987;253:G706.

95 Wiley J, Owyang C. Somatostatin inhibits cAMP-

mediated cholinergic transmission in the myenteric plexus. Am J Physiol 1987;253:G607.

96 Li Y, Kolligs F, Owyang C. Mechanism of action of calcitonin

related peptide in inhibiting pancreaticenzyme

genesecretion in rats. Gastroenterology 1993;105:194.

97 Louie DS, Chen HT, Owyang C. Inhibition of exocrine

pancreatic secretion by opiates is mediated by suppression of cholinergic transmission: characterization of receptor subtypes. J Pharmacol Exp Ther 1988;246:132.

98 Herzig KH, Louie DS, Tatemoto K etal. Pancreastatin

inhibits pancreatic enzyme secretion by presynaptic modulation of acetylcholine release. Am J Physiol 1992;262:G113.

99 Lyman RL. The effect of raw soybean meal and trypsin

inhibitor diets on the intestinal and pancreatic nitrogen in the rat. J Nutr 1957;62:285.

100 Slaff J, Jacobson D, Tillman CR etal. Protease- specific

suppression of pancreatic exocrine secretion. Gastroenterology 1984;87:44.

101 Liener IE, Goodale RL, Deshmukh A etal. Effect of a

trypsin inhibitor from soybeans (Bowman-

Birk) on the secretory activity of the human pancreas. Gastroenterology 1988;94:419.

102 Isaksson G, Ihse I. Pain reduction by an oral pancreatic

enzyme preparation in chronic pancreatitis. Dig Dis Sci 1983;28:97.

103 Slaff JI, Wolfe MM, Toskes PP. Elevated fasting

cholecystokinin levels in pancreatic exocrine impairment: evidence to support feedback regulation. JLab Clin Med 1985;105:282.

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Regulation ofPancreatic Protein Synthesis andGrowth

Maria Dolors Sans and John A. Williams

Department of Molecular and Integrative Physiology, University of Michigan Medical School, Ann Arbor, MI, USA

Introduction

Regulation of pancreatic protein synthesis and growth allows the exocrine pancreas to provide an adequate supply of digestive enzymes for nutrient assimilation. In young animals, the pancreas grows along with general body growth and thereby provides an increasing amount of digestive enzymes. In the adult, digestive enzyme synthesis is regulated at both transcriptional and translational levels to match the need for both total and specific digestive enzymes. If the need for digestive enzymes is greater than can be met through these mechanisms, the pancreas can grow or regenerate [1]. This can occur either as a result of increased food intake, or because of decreased pancreatic mass due to disease. Some of the same systemic regulatory signals that regulate enzyme secretion, that is, the vagal nerve and gastrointestinal (GI) hormones, also participate in the regulation of pancreatic protein synthesis and growth, although the intracellular regulatory pathways involved are significantly different. An additional regulatory influence is provided by nutrients, especially amino acids, and islet hormones, particularly insulin, which do not directly affect secretion. The purpose of this chapter is to provide a brief overview of the regulation of pancreatic protein synthesis and growth. Not all areas can be covered in depth owing to page limitations. Areas of recent progress are featured with review articles being cited to cover the older literature.

Regulation ofProtein Synthesis

Protein synthesis plays a central role in the maintenance of the pancreas and provision of digestive enzymes. Both the mRNA profile and autoradiographs of newly

synthesized proteins are dominated by digestive enzymes. Whether the acinar cell can regulate digestive enzyme synthesis independent of the synthesis of cellular structural proteins is unclear. In general, the GI tract, including the exocrine pancreas, atrophies in the absence of food and protein synthesis that occurs in response to food intake helps to maintain normal function. Individual dietary components also regulate protein synthesis. In most cases, as reviewed in the following, this involves transcriptional regulation of digestive enzyme mRNA. By contrast, shorter term meal- stimulated protein synthesis is regulated primarily at the translational level. Finally, increased protein synthesis is necessary for pancreatic growth.

Long- Term Regulation by Diet

Since the original work by Pavlov, the adaptation of the exocrine pancreas to dietary changes has been observed in a variety of species[2,3]. The content and secretion of the major digestive enzymes, proteases, amylase, and lipases change in proportion to the dietary content of their respective substrates, protein, carbohydrate and fat, by stimulation of both, transcriptional and translational mechanisms [4–6]. Various hormones mediate many of these effects and in most cases their release is increased by the nutrients whose digestion they regulate. In some cases the genetic elements regulated in the promoter region have been identified although the full intracellular pathway leading to their regulation is not yet known[2].

Protein

Feeding a high- protein diet to rodents (typically 60–80% casein or other high- quality protein) increases the content of multiple proteases and the mRNA levels of

The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, Fourth Edition. Edited by Hans G. Beger, Markus W. Büchler, RalphH. Hruban, Julia Mayerle, John P. Neoptolemos, Tooru Shimosegawa, Andrew L. Warshaw, David C. Whitcomb, and Yupei Zhao. © 2023 John Wiley & Sons Ltd. Published 2023 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/beger/thepancreas4e

Regulation ofPancreatic Protein Synthesis andGrowth

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trypsinogen, chymotrypsinogen, and proelastase [2,7], with activation of the mTORC1 pathway and can occur independently of cholecystokinin (CCK)[8]. There are, however, differential effects on different isoforms of enzymes such as trypsinogen and this increase is not mimicked by feeding a mixture of amino acids [9–11]. Clinical studies have shown that a severe reduction of protein in the diet causes pancreatic injury, leading to nutrient malabsorption and a state of malnutrition[12,13], which can be especially critical in children and young adults[14]. The pancreas is extremely vulnerable to protein deficiency states, as seen in patients with the kwashiorkor syndrome, where the pancreas is one of the most severely affected organs, with reductions in size and secretory capacity [12,15,16]. In an experimental study, feeding mice a protein- free diet for 4days resulted in a decrease in the relative pancreatic digestive enzyme content and secretion[17]. Other data showed that the stimulation of protease synthesis, by isolated pancreatic lobules following infusion of the CCK analogue caerulein, in vivo, was greatly increased compared with a small increase in translatable mRNA, suggesting a posttranscriptional locus for this regulation.

It has also been shown that a high protein (40%) diet can stimulate pancreas growth in mice, independent of CCK[8]. Individual amino acids can increase pancreatic trypsin levels and stimulate pancreas growth[9,18]. The amino acid leucine, specifically, modulates growth responses of pancreatic progenitors, involving mTORC1 [19], and changing the synthetic rates and messenger RNA (mRNA) levels during several days or weeks.

Carbohydrates

The level of carbohydrate in the diet has long been known to have significant effects on pancreatic amylase content and amylase mRNA[2,3]. This is seen when dietary carbohydrate replaces either dietary fat or protein, provided that dietary protein is adequate. Starch and sugars all similarly affect amylase, as does intravenous glucose. The effects of carbohydrate are believed to be primarily mediated by insulin. When animals are rendered diabetic, the amylase content and synthesis and mRNA levels fall dramatically, whereas lipase increases moderately [3,20]. Insulin restores the amylase synthesis and content and mRNA levels in diabetic rats. Similar decreases in amylase have been seen in obese rat and mouse models with insulin resistance. However, insulin administration to normal rats either decreases or does not change amylase, and other evidence suggests a more direct role for glucose in addition to effects on insulin. Amylase is also regulated by glucocorticoids [21], although this may not mediate dietary effects of carbohydrate. A dietary response sequence in the promoter of the amylase Amy2.2 gene has

been identified that mediates dietary adaptation and the effect of insulin[22].

Fat

In response to a high- fat diet (40–70% of calories as triglycerides), the content and synthesis of pancreatic triglyceride lipase increase [2]. This is accompanied by an increase in its mRNA [23,24]. Adaptation of other pancreatic lipases and colipase have been much less well studied. In neonate mice and rats, bile salt- stimulated lipase and pancreatic lipase- related protein 2 are the two predominant lipases[25]. Secretin has been proposed as a mediator of the effect of dietary lipid [26]. Fatty acids can stimulate secretin release and infusion of secretin in conscious rats led to an increase in the relative synthesis of lipase [2]. Gastric inhibitory peptide (GIP) has also been shown to increase pancreatic lipase and colipase content and mRNA levels[27]. Finally, ketones, metabolites of ingested fat, have also been proposed as a mediator of the increase in pancreatic lipase[2].

Meal- to- Meal Regulation ofTranslation by Hormones andNutrients

Whereas long- term dietary changes in digestive enzymes may be mediated by changes in mRNA expression, shortterm meal- to- meal control needs to be immediate, reversible, and flexible. Such control of protein synthesis is mainly at the translational level[28]. This section reviews the effects of food intake and hormones, especially CCK and insulin, on the exocrine pancreas translational machinery. Translation of mRNA into protein can be divided into three phases: initiation, elongation, and termination. For details on these three mechanisms, the reader is referred to reviews on translation[28–32]. Only a few studies have evaluated the immediate regulation of the pancreatic translational synthetic machinery after food intake. Early studies showed that fasting reduces total protein synthesis in the pancreas and refeeding stimulates it[33,34]. More recent studies showed that feeding a regular meal activates protein synthesis in the mouse pancreas at the translational level without an increase in the mRNA of the digestive enzymes [35]. In humans, feeding increases both the rate of secretion and synthesis of digestive enzymes, although the rate of turnover of zymogens remains fairly constant during feeding and fasting[36]. In rats and mice, feeding stimulates the protein kinase B (PKB/Akt)/mammalian target of rapamycin complex 1 (mTORC1) pathway and the phosphorylation of 4E- BP1 and ribosomal protein S6, downstream of mTORC1, in addition to the formation of the eIF4F complex[35,37] as illustrated in Fig.8.1.

Dietary protein and amino acids have also been shown

to be necessary to stimulate pancreatic protein synthesis

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