Secretin

by John A. Williams

Bookmark/Search this post

John A. Williams

University of Michigan, Ann Arbor MI
jawillms@umich.edu

Entry Version: 

Version 1.0, July 2, 2013

Citation: 

Williams JA. (2013). Secretin.
Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2013.5
AttachmentSize
PDF icon Secretin 390.22 KB

Gene Symbol:  Sct

Abstract

Secretin is one of the “classical” gastrointestinal hormones and in fact was the first peptide hormone identified.  The mature hormone is a 27 amino acid peptide produced and secreted by a specific type of enteroendocrine cell, the S cell which is of the open type with its apical surface exposed to luminal content.  Secretin is packaged into granules and released across the basolateral membrane into the blood in response to acid in the duodenum when the pH falls below 4.5; it is also released in response to fatty acids but without a response to glucose or amino acids.  Basal and stimulated concentrations are low normally in the 1-10 pM range.  The principal action of secretin is to stimulate bicarbonate secretion by pancreatic and biliary ducts and duodenal Brunner’s glands into the lumen such that acid in the duodenum will be neutralized.  Secretin also acts to potentiate CCK action on acinar cells, to inhibit gastric acid secretion and to inhibit gastric emptying.  Secretin also has actions in the brain. At the cellular level the action of secretin is primarily mediated by cAMP which is increased in response to activation of secretin receptors.

1. General

Secretin has the distinction of being the first peptide hormone identified.  Bayliss and Starling in 1902 showed that an acid extract of the proximal small intestine mucosa, when injected intravenously into dogs, brought about pancreatic secretion similar to that induced by acid perfusion of the duodenum (4).  They named the messenger, “Secretin” and a few years latter Starling coined the word “hormone” for a substance released into the blood which acts on targets at a distance.  Thus was born the field of Endocrinology.  For a personal view of more recent secretin research from a leading investigator see (15).

After multiple attempts and improvements, secretin was isolated in purified form through the work of Jorpes and Mutt (50) and later its amino acid sequence was determined (11,77).  It is a linear peptide of 27 amino acids and is structurally similar to glucagon and VIP (111).  Its cDNA (56) and gene sequences (57,116) have been determined and the gene consists of four exons with the mature peptide in a single exon.  A precursor for secretin was isolated from porcine and rat intestine which has additional N-terminal and C- terminal peptides that are cleaved to result in the mature peptide which is then amidated at the C-terminal (36,56). The  domain structure of the precursor and the amino acid sequence of secretin is shown in Fig. 1.  It’s amino acid sequence is highly conserved except for the three amino acids in the middle of the molecule. At present there are no known functions for the N or C-terminal peptides.  Secretin gene expression is regulated by a 5’ flanking sequence (115). The entire 27 amino acid sequence is required for maximal potency but the 5-27 amino acid C-terminal fragment has partial activity (71).

Secretin producing cells have been identified as a specific type of enteroendocrine cell by immunohistochemistry and are located in the duodenal and jejunal mucosa (18,63,83,86).  Chey et al  also reported the presence of secretin containing cells in the gastric antral mucosa but this has not been confirmed (17). These cells are of the open type with apical surface exposed to the intestinal luminal contents.  Ultrastructurally, they possess small dense granules of diameter 150-250 nm located in the basal pole of the cell which have been identified as containing secretin by immunogold staining (106,107).  The cell type is termed S-cells, originally for small granules but “S” can also stand for secretin. Their differentiation as part of the secretory lineage and the importance of the transcription factors NeuroD in the endocrine lineage has been reviewed (93). The distribution of secretin in the GI tract has also been studied by radioimmunoassay (RIA) and by identification of mRNA.  These studies have shown decreasing concentration of secretin from the duodenum to ileum (76,101). One early report identified immunoreactive secretin mRNA in the brain (82) and this has subsequently been confirmed and studied in detail by quantitative PCR and in-situ hybridization.  Both secretin and its receptor have been found in the cerebellum, amygdala, hippocampus and other areas (66,104).  Thus secretin clearly belongs to the general family of brain – gut peptides.

Figure 1. The domain structure and amino acid sequence of secretin. Individual amino acids serving to localize processing sites are shown in the domain structure.

Regulation of secretin secretion

The primary physiological stimulus for release of secretin is acidification of the duodenal lumen which brings about an increase in plasma secretion and thereby pancreatic bicarbonate secretion (7,32,52).  In dogs, both a normal meal and infusion of acid into the duodenum brings about  secretion with a duodenal pH threshold of about 4.5 (16,41,97).  Increased gastric acid secretion or experimental infusion of acid brings about more secretin release both by being a stronger stimulus to individual S-cells and by extending acidification further down the small intestine thereby stimulating more S-cells (73). Inhibition of acid secretion as brought about by H2 blocker cimetidine inhibits the plasma secretin increase. The plasma half life is about 2-3 minutes (27).  In humans, either feeding a normal meal or infusing acid into the duodenum increased plasma secretin with a similar pH threshold of 4.5 (20,32).  No significant changes occurred after intraduodenal infusion of glucose, amino acids, fat emulsion or ethanol (32).  The secretin response was also reported similar in normal subjects, patients with duodenal ulcers and after vagotomy (113). The half life of secretin in human plasma was reported to be 4 minutes (55). Studies in other species include the showing that luminal acid stimulates secretin release in anesthetized pigs (88), in the perfused pig intestine (44) and in fasting rats (67). The mechanism by which acid brings about secretin release is not fully understood but probably involves acid sensing ion channels of the Trp family present in the brush border of S-cells.  An alternative mechanism presented by Chey and colleagues based on studies in rats was for the existence of a intestinal derived secretin releasing peptide, analogous to the CCK releasing peptide concept, that was released in response to acid (67).  A secretin releasing peptide was also reported in dog pancreatic juice (68).  The existence of such a mechanism has not been further confirmed.  What is currently needed is the development of a mechanism to sort and study S-cells similar to methods being used for CCK release from I-cells. For more detailed coverage of the older literature on secretin secretion see Walsh (111).

In addition to acid, there is a considerable amount of evidence that fatty acids can stimulate secretin release in dogs (31,79,114), humans (92) and rats (95) although the plasma secretin levels are usually lower than the response to acid.  Oleic acid is the most common form of fat used and some studies show no response although this could be due to limits on the RIAs used.  One report indicated that intraduodenal oligopeptides could also increase plasma secretin and stimulate pancreatic bicarbonate output  in rats (94). Multiple studies have shown the lack of neural involvement in secretin release using both atropine administration and vagotomy in dogs, humans and rats (19,42,95,113).

Both basal and stimulated levels of plasma secretin are low (1 to 10 pM) and there are issues with preparing samples as well as the need for sensitivity that make it hard to perform in small animals. Description and validation of secretin RIAs used in studies reviewed here have been presented (10,12,89). Antibodies have usually been raised against the C- terminal of the secretin molecule.  Studies have indicated that the kidney is the major organ metabolizing secretin (33).

Actions of Secretin

All known actions of secretin are mediated by the secretin receptor, a G-protein coupled, 7 transmembrane domain protein whose primary signal transduction mechanism is to activate adenylate cyclase and stimulate formation of cAMP (75).  The receptor is structurally similar to receptors for VIP, glucagon, parathyroid hormone and other Class II G-protein linked receptors.  Secretin receptors have been identified by ligand binding and recognition of its mRNA in pancreas, biliary system, stomach, brain and kidney (47,48,58,59). For more information see the Secretin receptor Molecule Page.

The principle action of secretin is to stimulate bicarbonate secretion to neutralize gastric acid in the duodenum (37,62,111).  Actions on the pancreas to stimulate duct cells to secrete bicarbonate is considered in the next section.  Secretin also stimulates bicarbonate secretion by cholangiocytes, the cells lining the bile ducts with most studies having been carried out in dogs, humans and rats (39,43,51).  The cellular mechanism appears identical to pancreatic secretion by pancreatic duct cells  although the final concentration in bile is not as high.  Secretin does not appear to affect canalicular bile formation where the driving force is secretion of bile salts (8).  In addition to stimulating bicarbonate secretion from the pancreas and liver, secretin also stimulates Brunners glands in the duodenal submucosa to secrete bicarbonate rich fluid (53,70).

In a second protective action against duodenal acid, secretin acts as an enterogastrone and both reduces acid secretion and inhibits gastric emptying thereby reducing entry of acid into the duodenum (23,54,108,122).  Some of the antisecretory effects are mediated by release of somatostatin and involve inhibition of gastrin secretion (119).  Somewhat paradoxically secretin stimulates pepsinogen release both in intact animals (6,99) and from isolated gastric chief cells (84,102).

Considerable recent interest has focused on a role for secretin in the brain (62) after the claim based on anectdotal evidence that secretin was an effective treatment for autism spectrum disorders (ASD) (45). Both secretin protein and secretin receptors are present in brain in various regions including the hippocampus, cerebellum and mortor cortex (60,66,80,82,104).  Secretin administration intravenously affects the firing rate of hypothalamic neurons including oxytocin and vasopressin neurons (13,109). Secretin administration suppressed feeding in wild type but not secretin receptor KO mice through an action on the melanocortin Mc4 receptor (14). Using brain slices, secretin was shown to affect transmission from Purkinje neurons to basket cells (124). Both secretin and secretin receptor KO mice have been studied as to brain function and showed impaired hippocampal neurotransmission in brain slices (80,121) and some impaired social behavior (80).  A mouse equivalent to ASD, however, has not been reported and systematic reviews of randomized trials have not confirmed an effect of secretin on children with ASD (61,118).

Other effects of secretin have been reported in the kidney and heart and are reviewed elsewhere (24,62).  A recent report has shown effects on preadipocye differentiation and mature adipocyte function (74).

2. Effects of Secretin on the Pancreas

In vivo studies of secretin action

The primary action of secretin on the pancreas is to stimulate the flow of bicarbonate rich pancreatic juice from the duct cells.  Proof of this required the advent of purified and then recombinant secretin to avoid possible effects of contaminants along with sensitive secretin RIAs. A number of studies have addressed the question of whether secretin in amounts released after a meal when duplicated by exogenous infusion can stimulate normal pancreatic bicarbonate.  This has been especially difficult to establish in humans because the normal postprandial rise in secretin is only a doubling from a baseline of a few pM. In one complete study with multiple doses, Schaffalitzky de Muckadell et al (90) infused 0.25 and 0.5 pmol/kg which increased plasma secretin by 3 and 6 pM and stimulated normal amounts of bicarbonate secretion when collected by ERCP or intraduodenally. In another study the same group showed that the secretion of bicarbonate was linearly related to the rise in plasma secretin (91).  Studies by others infusing 1-2.8 pmol/kg also showed pancreatic bicarbonate secretion but less than meal stimulated (5,38,123).  Several of these studies also showed that adding physiological amounts of CCK or caerulein would potentiate the submaximal bicarbonate secretion.  In all studies secretin infusion had no effect on trypsin secretion.  Similar studies in dogs and pigs where plasma secretin levels are higher have led to the same conclusion, that infusion of secretin to reproduce physiological levels induces pancreatic bicarbonate secretion but to a submaximal amount which can be potentiated by CCK or by endogenous cholinergic tone (16,21,40,96). Secretin infusion could also stimulate bicarbonate secretion from the perfused pig pancreas confirming its ability to work in the absence of other stimulants (49).  A different approach to evaluating the physiological role of a hormone is to block its action with a antagonist, antibody administration, or by gene knockout.  In an important study in dogs, Chey and colleagues (22) showed that administration of secretin antibody sufficient to bind all plasma secretin essentially blocked the bicarbonate response to a meal as well as the response to exogenous secretion thus showing that secretin plays an essential role.  Interestingly, cervical vagotomy or administration of atropine also reduced bicarbonate secretion.   At present there are no usable secretin antagonists and deletion of secretin or its receptor in mice has not been studied on pancreatic bicarbonate secretion.  In total these studies indicate that secretin is the primary driver of pancreatic bicarbonate secretion but requires potentiation by CCK, cholinergic tone and possibly insulin (64) to exert its physiological action.

Other in vivo actions of secretin on the exocrine pancreas have been described but have not yet been convincingly been shown to be physiological actions.  Pancreatic acinar cells have secretin/VIP responding receptors and in vitro, secretin has actions on pancreatic acini to increase cAMP and potentiate amylase secretion (117).  However, in vivo, studies designed to evaluate the interaction of secretin and CCK have not shown an effect of physiological levels of secretin to potentiate digestive enzyme secretion (21,123). A potentiating action of secretin on pancreatic growth in response to CCK has also been proposed based on studies in rats where caerulein, secretin or both were injected multiple times daily (78,98).  Secretin also increased the content of polyamines in the pancreas which accompanies and is required for growth (28).  However, studies in mice with genetically deleted secretin or secretin receptor showed a normal sized pancreas which grew normally in response to elevated endogenous CCK (87). Another proposed action of secretin not fully evaluated is to stimulate the synthesis of pancreatic lipase.  Infusion of secretin in supraphysiological doses for up to 24 hours in rats was shown to increase the synthesis of lipase and proelastase 2 (85). It was suggested that secretin might mediate the effect of high fat diets to increase pancreatic lipase.  Pancreatic lipase, however, is normally present in mice lacking secretin receptors (Williams, JA, unpublished data).

In vitro studies of secretin action on pancreatic ducts

The in vitro studies of secretin action have primarily involved the use of microdisected duct fragments from rat, mouse and guinea pig pancreas.  The Secretin receptor is known to couple through Galpha s to adenylyl cyclase and secretin increases cyclic AMP accumulation in isolated ducts (2,29,35). The first successful isolated ducts were dissected from rat pancreas in which acini were caused to atrophy on a copper deficient diet (2).  Latter studies isolated ducts by microdissection  from pancreas of rats, guinea pigs, and mice partially digested with collagenase. Secretin has been shown to stimulate bicarbonate fluid in the isolated duct fragments by microperfusion and by letting the ends of the ducts seal in culture after which the volume increase can be monitored by video microscopy and the ion content sampled by micropuncture (3,34,46).  Guinea pig ducts have been especially useful because they secrete a high concentration of bicarbonate similar to humans while rats and mice secrete lower amounts (100).  Using such preparations, secretin and other hormones that increase cyclic AMP have been shown to stimulate a cellular mechanism involving bicarbonate influx across the basolateral membrane primarily by a Na+-HCO3- symporter and efflux of bicarbonate across the apical membrane through the anion channel, CFTR, and a Slc26a6 anion exchanger that is reviewed elsewhere (1,65).  Cyclic AMP appears to act through protein kinase A (PKA) and a key step involves phosphorylation of CFTR. In the pig an alternate mechanism involves secretin stimulation of insertion of vesicles containing vacuolar type H+-ATPase into the basolateral membrane of duct cells leading to export of H+ which thereby increases the intracellular HCO3- (9,110).

Secretin action has also been studied in monolayer cultures of canine and bovine pancreatic ducts (26,125) and in Capan-1 cells which are derived from a human tumor but which form a tight monolayer and possess secretin receptors (103,112). Only basic studies have been carried out to date but secretin will increase cAMP and ion transport in these monolayers.

3. Tools for the Study of Secretin

3a. Peptide.

Secretin was originally purified from pig or other large animal intestine and standardized in biological units termed clinical units (C.U.) based on pancreatic secretion in dogs or other animals.  Today a number of chemical companies sell synthetic, HPLC purified (>98% pure) most commonly human and it is measured by weight.

3b. Antibodies. 

Antibodies to secretin are available from a number of commercial sources.  See Linscott’s Directory or other directories.

3c. Assay. 

A number of RIA’s capable of measuring secretin in human or canine plasma have been described in the past but are not routinely available today.  Phoenix Pharmaceutical sells both ELISA and RIA kits and Antibodies.online.com and Elabscience sell similar ELISA kits said to have a sensitivity as low as 10pg/ml.  Whether this will measure fasting levels is unclear but it would probably work if several ml of plasma could be absorbed onto resin and eluted.  Measurement in mice and rats may be problematic.

3d. Mouse Models. 

Mice with genetic deletion of secretin and secretin receptor have been described (25,80,121).

3e. Clinical Testing. 

Synthetic human secretin in sterile single use vials can be obtained from ChiRhoStim.  As a pancreatic function test it is usually given intravenously at 0.2 ug/kg over 1 min after injecting a test dose of 0.2 ug to check for an allergic reaction with collection of duodenal fluid (69,120).  It is also given iv to test for gastrinoma (Zollinger-Ellison syndrome) by measurement of plasma gastrin.  In control subjects secretin reduces or has no effect on plasma gastrin but stimulates gastrin release from gastrinomas (30,72).  Secretin is also given to enhance contrast in some pancreatic imaging techniques (81,105)

4. References

  1. Argent BE, Gray MA, Steward MC, and Case RM. Cell Physiology of Pancreatic Ducts. In Physiology of the Gastrointestinal Tract 5th ed. Ed. by Johnson RL et al, Elsevier, 2012. Pp 1399-1423.
  2. Arkle S, Lee CM, Cullen MJ, and Argent BE. Isolation of ducts from the pancreas of copper-deficient rats. Q J Exp Physiol 71; 249-265, 1986. PMID: 3012621
  3. Ashton N, Argent BE, and Green R. Characteristics of fluid secretion from isolated rat pancreatic ducts stimulated with secretin and bombesin. J Physiol 435: 533-546, 1991. PMID: 1770448
  4. Bayliss WM, Starling EH. The mechanism of pancreatic secretion. J Physiol 28: 325-53, 1902. PMID: 16992627
  5. Beglinger C, Fried M, Whitehouse I, Jansen JB, Lamers CB, and Gyr K. Pancreatic enzyme response to a liquid meal and to hormonal stimulation. Correlation with plasma secretion and cholecystokinin levels. J Clin Invest 75: 1471-1476, 1985. PMID: 3998145
  6. Berstad A and Petersen H. Dose-response relationship of the effect of secretin on acid and pepsin secretion in man. Scand J Gastroenterol 5: 647-654, 1970. PMID: 4922127
  7. Boden G, Essa N, and Owen OE. Effects of intraduodenal amino acids, fatty acids, and sugars of secretin concentrations. Gastroenterology 68: 722-727, 1975. PMID: 1123139
  8. Boyer JL and Bloomer JR. Canalicular bile secretion in man. Studies utilizing the biliary clearance of (14C)mannitol. J Clin Invest 54: 773-781, 1974. PMID: 4610005
  9. Buanes T, Grotmol T, Landsverk T, and Æder MG. Ultrastructure of pancreatic duct cells at secretory rest and during secretin-dependent NaHCO3 secretion. Acta Physiol Scand 131: 55-62, 1987. PMID: 3673612
  10. Byrnes DJ and Marjason JP. Radioimmunoassay of secretin in plasma. Horm Metab Res 8: 361-365, 1976. PMID: 1086282
  11. Carlquist M, Jörnvall H, and Mutt V. Isolation and amino acid sequence of bovine secretin. FEBS Lett 127: 71-74, 1981. PMID: 7250377
  12. Chang TM and Chey WY. Radioimmunoassay of secretin. A critical review and current status. Dig Dis Sci 25: 529-552, 1980. PMID: 6104568
  13.  Chen XY, Wang H, Xue Y, and Chen L. Modulation of paraventricular firing rate by secretin in vivo. Neurosci Lett 532: 29-32, 2013. PMID: 23149133
  14.  Cheng CY, Chu JY, and Chow BK. Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system. Neuropsychopharmacology 36: 459-471, 2011. PMID: 20927047
  15. Chey WY and Chang TM. Secretin, 100 years later. J Gastroenterol 38: 1025-1035, 2003. PMID: 6347663
  16. Chey WY and Konturek SJ. Plasma secretion and pancreatic secretion in response to liver extract meal with varied pH and exogenous secretion in the dog.  J Physiol 324: 263-272, 1982. PMID: 7097601
  17. Chey WY, Chang TM, Park HJ, Lee KY, and Escoffery R. Secretin-like immunoreactivity and biological activity in the antral mucosa. Endocrinology 113: 651-656, 1983. PMID: 6347663
  18. Chey WY, Escoffery R. Secretin cells in the gastrointestinal tract. Endocrinology 98: 1390-1395, 1976. PMID: 1278107
  19. Chey WY, Kim MS, and Lee KY. Influence of the vagus nerve on release and action of secretin in dog.  J Physiol 293: 435-446, 1979. PMID: 501615
  20. Chey WY, Lee YH, Hendricks JG, Rhodes RA, and Tai HH. Plasma secretin concentration in fasting and postprandial state in man. Am J Dig Dis 23: 981-988, 1978. PMID: 31087
  21. Chey WY, Lee YL, Chang TM, Chen YF, and Millikan L. Potentiating effect of secretin on cholecystokinin-stimulated pancreatic secretion in dogs. Am J Physiol 246: G248-G252, 1984. PMID: 6322594
  22. Chey WY, Myung SK, Lee KY, and Chang TM. Effect of rabbit antisecretin serum on postprandial pancreatic secretion in dogs. Gastroenterology 77: 1268-1275, 1979. PMID: 499714
  23. Chey, WY, Kim MS, Lee KY, and Chang TM. Secretin is an enterogastrone in the dog. Am J Physiol 240: G239-244, 1981. PMID: 6782895
  24. Chu JY, Cheng CY, Lee VH, Chan YS, and Chow BK. Secretin and body fluid homeostasis. Kidney Int 79: 280-287, 2011. PMID: 20944548
  25. Chu JYS, Chung SCK, Lam AKM, Tam S, Chung SK, and Chow BKC. Phenotypes developed in secretin receptor-null mice indicated a role for secretin in regulating renal water reabsorption. Mol Cell Biol 27: 2499-2511. 2007. PMID: 17283064
  26. Cotton CU and Al-Nakkash L. Isolation and culture of bovine pancreatic duct epithelial cells. Am J Physiol272: G1328-G1337, 1997.PMID: 9227467
  27. Curtis PJ, Fender HR, Rayford PL, and Thompson JC. Disappearance half-time of endogenous and exogenous secretin in dogs. Gut 17: 595-599, 1976. PMID: 976797
  28. Danzin C, Bolkenius RN, Claverie N. Wagner J, and Grove J. Secretin-induced accumulation of N1-acetylspermidine and putrescine in the rat pancreas. Biochem Biophys Res Commun 109: 1234-1239, 1982. PMID: 7168763
  29. de Ondarza J and Hootman SR. Regulating of cyclic AMP levels in guinea pig pancreatic duts and cultured duct epithelial monolayers. Pancreas 11: 261-270, 1995. PMID: 8577680
  30. Deveney CW, Deveney KS, Jaffe BM, Jones RS, and Way LW. Use of calcium and secretin in the diagnosis of gastrinoma (Zollinger-Ellison syndrome). Ann Intern Med 87: 680-686, 1977. PMID: 931203
  31. Draviam EJ, Gomez G, Hashimoto T, Miyashita T, Hill FL, Uchida T, Singh P, Greeley GR Jr, and Thompson JC. Characterization of secretin release in response to food and intraduodenal administration of fat and hydrochloric acid. Dig Dis Sci 36: 513-519, 1991. PMID: 2007369
  32. Fahrenkrug J and Schaffalitzky de Muckadell OB. Plasma secretin concentration in man: effect of intraduodenal glucose, fat, amino acids, ethanol, HCl, or ingestion of a meal. Eur J Clin Invest 7: 201-203, 1977. PMID: 408145
  33. Fahrenkrug J, Schaffalitzky de Muckadell OB, and Holst JJ. Elimination of procine secretin in pigs. Clin Sci Mol Med 54: 61-68, 1978. PMID: 620494
  34. Fernández-Salazar MP, Pascua P, Calvo JJ, López MA, Case RM, Steward MC, and San Román JI. Basolateral anion transport mechanisms underlying fluid secretion by mouse, rat guinea-pug pancreatic ducts.  J Physiol 556: 415-428, 2004. PMID: 14978209
  35. Fölsch UR, Fischer H, Söling HD, and Creutzfeldt W. Effects of gastrointestinal hormones and carbamylcholine on cAMP accumulation in isolated pancreatic duct fragments from the rat. Digestion 20: 277-292, 1980. PMID: 6248407
  36. Gafvelin G, Jornvall H, and Mutt V. Processing of prosecretin: Isolation of a secretin precursor from porcine intestine.  Proc Natl Acad Sci USA 87: 6781-6785, 1990. PMID: 2395872
  37. Gomez GA, Englander EW, and Greeley GH Jr. Postpyloric Gastrointestinal Peptides. In Physiology of the Gastrointestinal Tract 5th ed. Ed. by Johnson RL et al, Elsevier, 2012. Pp 155-198.
  38. Greenberg GR, Domschke S, Domschke W, Rösch W, and Bloom SR. Effect of low dose secretin and caerulein on pure pancreatic bicarbonate secretion and plasma secretin in man. Acta Hepatogastroenterol (Stuttg) 26: 478-481, 1979. PMID: 549430
  39. Grossman MI, Janowitz HD, et al. The effect of secretin on bile formation in man. Gastroenterology 12: 133-138, 1949. PMID: 18109101
  40. Grundy D, Hutson D, and Scratcherd T. The response of the pancreas of the anaesthetized cat to secretin before, during and after reversible vagal blockade. J Physiol 341: 517-526, 1983. PMID: 6631748
  41. Gyr K, Beglinger C, Fried M, Grötzinger U, Kayasseh L, Stadkler GA, and Girard J. Plasma secretin and pancreatic response to various stimulants including a meal. Am J Physiol 246: G535-G542, 1984. PMID: 6720952
  42. Hanssen LE. The effect of atropine on secretin release and aspirated bicarbonate secretion after duodenal acidification in man. Scand J Gastroenterol 15: 465-469, 1980. PMID: 7433911
  43. Hirata K and Nathanson MH. Bile duct epithelia regulate biliary bicarbonate excretion in normal rat liver. Gastroenterology 121: 396-406, 2001. PMID: 11487549
  44. Holst JJ, Lauritsen K, Jensen SL, Nielsen OV, and Schaffalitzky de Muckadell OB. Secretin release from the isolate, vascularly perfused pig duodenum. J Physiol 318: 327-337, 1981. PMID: 7320893
  45. Horvath K, Stefanatos G, Sokolski KN, Wachtel R, Nabors L, and Tildon JT. Improved social and language skills after secretin administration in patienets with autistic spectrum disorders.  J Assoc Acad Minor Phys 9: 9-15, 1998. PMID: 9585670
  46. Ishiguro H, Naruse N, Steward MC, Kitagawa M, Ko SBH, Hayakawa T, and Case RM. Fluid secretion in interlobular ducts isolated from guinea-pig pancreas.  J Physiol 511: 407-422, 1998. PMID: 9706019
  47. Ishihara T, Nakamura S, Kaziro Y, Takahashi T, Takahashi K, and Nagata S. Molecular cloning and expression of a cDNA encoding the secretin receptor. EMBO J 10: 1635-1641, 1991. PMID: 1646711
  48. Jensen RT, Charlton CG, Jones SW, O’Donohue TL, and Gardner JD. Use of 125I-secretin to identify and characterize high-affinity secretin receptors on pancreatic acini. Am J Physiol 245L G186-G195, 1983. PMID: 6309017
  49. Jensen SL, Fahrenkrug J, Holst JJ, Kühl C, Nielsen OV, and Schaffalitzky de Muckadell OB. Secretory effects of secretin on isolated perfused porcine pancreas. Am J Physiol 235: E381-E386, 1978.
  50. Jorpes JE and Mutt V. The preparation of secretin. Biochem J 52: 328-330, 1952. PMID: 696858
  51. Jorpes JE, Mutt V, Jonson G, Thul, and Sundmanlin L. The effect of secretin on bile flow.  Gastroenterology 45: 786-788, 1963. PMID: 14134013
  52. Kim MS, Lee KY, and Chey WY. Plasma secretin concentrations in fasting and postprandial states in dog. Am J Physiol 236: E539-544, 1979. PMID: 35981
  53. Kirkegaard P, Olsen PS, Poulsen SS, Holst JJ, Schaffalitzky de Muckadell OB, and Christiansen J. Effect of secretin and glucagon on Brunner’s gland secretion in the rat. Gut 25: 264-268, 1984. PMID: 6698442
  54. Kleibeuker JH, Beekhuis H, Piers DA, Schaffalitzky de Muckadell OB. Retardation of gastric emptying of solid food by secretin. Gastroenterology 94: 1220126, 1988. PMID: 3335284
  55. Kolts BE and McGuigan JE. Radioimmunoassay measurement of secretin half-life in man. Gastroenterology 72: 55-60, 1977. PMID: 830238
  56.  Kopin AS, Wheeler MB, Leiter AB. Secretin: Structure of the precursor and tissue distribution of the mRNA. Proc Natl Acad Sci USA 87: 2299-2303, 1990. PMID: 2315322
  57. Kopin AS, Wheeler MB, Nishitani J, McBride EW, Chang TM, Chey WY, and Leiter AB. The secretin gene: Evolutionary history, alternative splicing, and developmental regulation. Proc Natl Acad Sci USA 88: 5335-5339, 1991. PMID: 1711228
  58. Körner M, Hayes GM, Rehmann R, Zimmermann A, Friess H, Miller LJ, and Reubi JC. Secretin receptors in normal and diseased human pancreas: marked reduction of receptor binding in ductal neoplasia. Am J Pathol 167: 959-968, 2005. PMID: 16192632
  59. Körner M, Hayes M, Rehmann R, Zimmermann A, Scholz A, Wiedenmann B, Miller LJ, and Reubi JC. Secretin receptors in the human liver: expression in biliary tract and cholangiocarcinoma, but not in hepatocytes or hepatocellular carcinoma. J Hepatol 45: 825-835, 2006. PMID: 16935383
  60. Köves K, Kausz M, Reser D, Illyés G, Takács J, Heinzlmann A, Gyenge E, and Horváth K. Secretin and autism: a basic morphological study about the distribution of secretin in the nervous system. Regul Pept 123: 209-216, 2004. PMID: 15518914
  61. Krishnaswami S, McPheeters ML, Veenstra-Vanderweele J. A systematic review of secretin for children with autism spectrum disorders.  Pediatrics 127: 1322-1325, 2011. PMID: 21464196
  62. Lam IPY, Siu FKY, Chu JYS, and Chow BKC. Multiple actions of secretin in the human body. Int Rev Cytol 256: 159-190, 2008. PMID: 18275888
  63. Larsson LI, Sundler F, Alumets J, Hakanson R, Schaffalitzky de Muckadell OB, and Fahrenkrug J. Distribution, ontogeny and ultrastructure of the mammalian secretin cell. Cell Tissue Res 181: 361-368, 1977. PMID: 328159
  64. Lee KY, Zhou L, Ren XS, Chang TM, and Chey WY. An important role of endogenous insulin on exocrine pancreatic secretion in rats. Am J Physiol 258: G268-G274, 1990. PMID: 1689549
  65. Lee MG and Muallem S. Physiology of duct cell secretion. In The Pancreas: An Integrated Textbook of Basic Science, Medicine, and Surgery, 2nd ed. Ed. by Beger HG, Warshaw AL, Büchler, Kozarek RA, Lerch MM, and Neoptolemos JP, Blackwell Publishing Limited: NJ, 2008. Pp 78-90.
  66. Lee SMY, Yung WH, Chen L, and Chow BKC. Expression and spatial distribution of secretin and secretin receptor in human cerebellum. Neuroreport 16: 219-222, 2005. PMID: 15706223
  67. Li P, Lee KY, Chang TM, and Chey WY. Mechanism of acid-induced release of secretin in rats. Presences of a secretin-releasing peptide. J Clin Invest 86: 1474-1479, 1990. PMID: 2243126
  68. Li P, Song Y, Lee KY, Chang TM, and Chey WY. A secretin releasing peptide exists in dog pancreatic juice. Life Sci 66: 1307-1316, 2000. PMID: 10755466
  69. Lieb JG 2nd, Brensinger CM, and Toskes PP. The significance of the volume of pancreatic juice measured at secretin stimulation testing: a single-center evaluation of 224 classical secretin stimulation tests. Pancreas 41: 1073-1079, 2012. PMID: 22481285
  70. Love JW, Walder AI, and Bingham C. Effect of pure natural and synthetic secretin on Brunner’s gland secretion in dogs. Nature 219: 731-732, 1968. PMID: 5667063
  71. Makhlouf GM, Bodanszky M, Fink ML, and Schebalin M. Pancreatic secretory activity of secretin5-27 and substituted analogues. Gastroenterology 75: 244-248, 1978. PMID: 669210
  72. McGuigan JE and Wolfe MM. Secretin injection test in the diagnosis of gastrinoma. Gastroenterology 79: 1324-1331, 1980. PMID: 7439637
  73. Meyer JH, Way LW, and Grossman MI. Pancreatic response to acidification of various lengths of proximal intestine in the dog. Am J Physiol 219: 971-977, 1970. PMID: 5459499
  74. Miegueu P, Cianflone K, Richard D, and St-Pierre DH. Effect of secretin on preadipocyte, differentiating and mature adipocyte function. Int J Obes (London) 37: 366-374, 2013. PMID: 22565418
  75. Miller LJ and Dong M. (2011). Secretin Receptor. The Pancreapedia: Exocrine Pancreas Knowledge Base, DOI: 10.3998/panc.2011.12.
  76. Miller TA, Llanos OL, Swierczek JS, Rayford PL, and Thompson JC. Concentrations of gastrin and secretin in the alimentary tract of the cat. Surgery 83: 90-93, 1978. PMID: 619477
  77. Mutt V, Jorpes JE, and Magnusson S. Structure of porcine secretion. The amino acid sequence.  Eur J Biochem 15: 513-519, 1970. PMID: 5465996
  78. Nagy I, Takács T, and Mahácsi G. One-year treatment with cholecystokinin-octapeptide and secretin: effects on pancreatic trophism in the rat. Pharmacol Res 36: 77-85, 1997. PMID: 9368919
  79. Niebel W, Singer MV, Hanssen LE, and Goebell H. Effect of atropine on pancreatic bicarbonate output and plasma concentrations of immunoreactive secretin in response to intraduodenal stimulants. Scand J Gastroenterol 18: 803-808, 1983. PMID: 6669945
  80. Nishijima I, Yamagata T, Spencer CM, Weeber EJ, Alekseyenko O, Sweatt JD, Momoi MY, Ito M, Armstrong DL, Nelson DL, Paylor R, and Bradley A. Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior. Hum Mol Genet 15: 3241-3250, 2006. PMID: 17008357
  81. O’Connell AM, Lyon SM, O’Sullivan P, Given MF, Morrin M, and Lee MJ. Secretin-assisted CT of the pancreas: improved pancreatic enhancement and tumour conspicuity. Clin Radiol 63: 401-406, 2008. PMID: 18325360
  82. O’Donohue TL, Charlton CG, Miller RL, Boden G, and Jacobowitz DM. Identification, characterization, and distribution of secretin immunoreactivity in rat and pig brain. Proc Natl Acad Sci USA 78: 5221-5224, 1981. PMID: 6946469
  83. Polak JM, Bloom S, Coulling I, and Pearse AGE. Immunofluorescent localization of secretin in the canine duodenum. Gut 12: 605-610, 1971. PMID: 18668825
  84. Raufman JP. Gastric chief cells: receptors and signal-transduction mechanisms. Gastroenterology 102: 699-710, 1992. PMID: 1310085
  85. Rausch Y, Rudiger K, Vasiloudes P, Kern H, and Scheele G. Lipase synthesis in the rat pancreas is regulated by secretin. Pancreas 1: 522-528. 1986. PMID: 3645660
  86. Roth KA and Gordon JI. Spatial differentiation of the intestinal epithelium: Analysis of enteroendocrine cells containing immunoreactive serotonin, secretin, and substance P in normal and transgenic mice.  Proc Natl Acad Sci USA 87: 6408-6412, 1990. PMID: 1696730
  87. Sans MD, Sabbatini ME, Ernst SA, D’Alecy LG, Nishijima I, and Williams JA. Secretin is not necessary for exocrine pancreatic development and growth in mice. Am J Physiol Gastrointest Liver Physiol 301: G791-G798, 2011. PMID: 21852360
  88. Schaffalitzky de Mucadell OB, Fahrenkrug J, and Holst JJ. Plasma secretin concentration and pancreatic exocrine secretion after intravenous secretin or intraduodenal HC1 in anaesthetized pigs.  Scand J Gastroenterol 12: 267-272, 1977. PMID: 866988
  89. Schaffalitzky de Muckadell OB and Fahrenkrug J. Radioimmunoassay of secretin in plasma. Scand J Clin Lab Invest 37: 155-162, 1977. PMID: 616043
  90. Schaffalitzky de Muckadell OB, Fahrenkrug J, Matzen P, Rune SJ, and Worning H. Physiological significance of secretin in the pancreatic bicarbonate secretion. II. Pancreatic bicarbonate response to a physiological increase in plasma secretin concentration.  Scand J Gastroenterol 14: 85-90, 1979. PMID: 424692
  91. Schaffalitzky de Muckadell OB, Fahrenkrug J, Watt-Boolsen S, and Worning H. Pancreatic response and plasma secretin concentration during infusion of low dose secretin in man.  Scand J Gastroenterol 13: 305-311, 1978. PMID: 755275
  92. Schaffalitzky de Muckadell OB, Olsen O, Cantor P, and Magid E. Concentrations of secretin and CCK in plasma and pancreatico-biliary secretion in response to intraduodenal acid and fat. Pancreas 1: 536-543, 1986. PMID: 3562445
  93. Schonhoff SE, Giel-Moloney M, and Leiter AB. Minireview: Development and differentiation of gut endocrine cells. Endocrinology 145: 2639-2644, 2004. PMID: 15044355
  94. Shimizu K, Shiratori K, Watanae S, Takeuchi T, Chang TM, and Chey WY. Effect of protein derivative on pancreatic secretion and release of secretin and CCK in rats. Am J Physiol 267: G508-G514, 1994. PMID: 7943315
  95. Shiratori K, Watanabe S, and Takeuchi T. Effect of fatty acid on secretin release and cholinergic dependence of pancreatic secretion in rats. Pancreas 4: 452-458, 1989. PMID: 2762274
  96. Singer MV, Niebel W, Elashoff J, and Grossman MI. Does basal cholinergic activity potentiate exogenous secretin for stimulation of pancreatic bicarbonate output in dogs. Digestion 24: 209-214, 1982. PMID: 7152146
  97. Soloman TE, Grossman MI, and Meyer JH. Pancreatic response to intestinal perfusion with lactic acid or acidified albumin. Am J Physiol 235: E560-E564, 1978. PMID: 31795
  98. Soloman TE, Petersen H, Elashoff J, and Grossman MI. Interaction of caerulein and secretin on pancreatic size and composition in rat. Am J Physiol 235: E714-E719, 1978. PMID: 736132
  99. Stening GF, Johnson LR, and Grossman MI. Effect of secretin on acid and pepsin secretion in cat and dog. Gastroenterology 56: 468-475, 1969. PMID: 4886027Steward MC, Ishiguro H, and Case RM. Mechanisms of bicarbonate secretion in the pancreatic duct. Annu Rev Physiol 67: 377-409, 2005. PMID: 15709963
  100. Steward MC, Ishiguro H, and Case RM. Mechanisms of bicarbonate secretion in the pancreatic duct. Annu Rev Physiol 67: 377-409, 2005. PMID: 15709963
  101. Straus E and Yalow RS. Immunoreactive secretin in gastrointestinal mucosa of several mammalian species. Gastroenterology 75: 401-404, 1978. PMID: 98389
  102. Sutliff VE, Raufman JP, Jensen RT, and Gardner JD. Actions of vasoactive intestinal peptide and secretin on chief cells prepared from guinea pig stomach. Am J Physiol 251: G96-G102, 1986. PMID: 3014896
  103. Szucs A, Demeter I, Burghardt B, Ovári G, Case RM, Steward MC, and Varga G. Vectorial bicarbonate transport by Capan-1 cells: a model for human pancreatic ductal secretion. Cell Physiol Biochem 18: 253-264, 2006. PMID: 17167230
  104. Tay J, Goulet M, Rusche J, and Boismenu R. Age-related and regional differences in secretin and secretin receptor mRNA levels in the rat brain. Neurosci Lett 366: 176-181, 2004. PMID: 15276242
  105. Tirkes T, Akisik F, Tann M, and Balci NC. Imaging of the pancreas with secretin enhancement. Top Magn Reson Imaging 20: 19-24, 2009. PMID: 19687722
  106. Usellini L, Capella C, Frigerio B, Rindi G, and Solcia E. Ultrastructural localization of secretin in endocrine cells of the dog duodenum by the immunogold technique. Histochemistry 80: 435-441, 1984. PMID: 6480411
  107. Usellini L, Finzi G, Riva C, Capella C, Mochizuki T, Yanaihara C, Yanaihara N, and Solcia E. Ultrastructural idenitification of human secretin cells by the immunogold technique. Their costorage of chrommogranin A and serotonin. Histochemistry 94: 113-120, 1990. PMID: 1972699
  108. Valenzuela JE, Defilippi C. Inhibition of gastric emptying in humans by secretion, the octapeptide of cholecystokinin, and intraduodenal fat. Gastroenterology 81: 898-902, 1981. PMID: 6269946
  109. Velmurugan S, Brunton PJ, Leng G, and Russell JA. Circulating secretin activates supraoptic nucleus oxytocin and vasopressin neurons via noradrenergic pathways in the rat. Endocrinology 151: 2681-2688, 2010. PMID: 20332196
  110. Villanger O, Veel T, and Ræder MG. Secretin causes H+/HCO3- secretin from pig pancreatic ductules by vacuolar-type H+-adenosine triphosphates. Gastroenterology 108: 850-859, 1995. PMID: 7875488
  111. Walsh JH. Gastrointestinal Hormones. In Physiology of the Gastrointestinal Tract 3rd ed. Ed. by Johnson LR, Raven Press: NY, 1994. Pp 1-128.
  112. Wang K and Novak I. Ion transport in human pancreatic duct epithelium, Capan-1 cells, is regulated by secretin, VIP, acetylcholine, and purinergic receptors. Pancreas 42: 452-460, 1013. PMID: 22982819
  113. Ward AS and Bloom SR. Effect of vagotomy on secretin release in man. Gut 16: 951-956, 1975. PMID: 1218818
  114. Watanabe S, Chey WY, Lee KY, and Chang TM. Secretin is released by digestive products of fat in dogs. Gastroenterology 90: 1008-1017, 1986. PMID: 3949103
  115. Wheeler MB, Nishitani J, Buchan AMJ, Kopin AS, Chey WY, Chang TM, and Leiter AB. Identification of a transcriptional enhancer important for enterendocrine and pancreatic islet cell-specific expression of the secretin gene. Mol Cell Biol 12: 3531-3539, 1992. PMID: 1378528
  116. Whitmore TE, Holloway JL, Lofton-Day CE, Maurer MF, Chen L, Quinton TJ, Vincent JB, Scherer SW, and Lok S. Human secretin (SCT): gene structure, chromosome location, and distribution of mRNA. Cytogenet Cell Genet 90: 47-52, 2000. PMID: 11060443
  117. Williams JA and Yule DI. Stimulus-secretion coupling in pancreatic acinar cells. In Physiology of the Gastrointestinal Tract 5th ed. Ed. by Johnson RL et al, Elsevier, 2012. Pp 1361-1398.
  118. Williams K, Wray JA, and Wheeler DM. Intravenous secretin for autism spectrum disorders (ASD). Cochrane Database Syst Rev 4: CD003495, 2012. PMID: 22513913
  119. Wolfe MM, Reel GM, and McGuigan JE. Inhibition of gastrin release by secretin is mediated by somatostatin in cultured rat antral mucosa. J Clin Invest 72: 1586-1593, 1983. PMID: 6138366
  120. Wu B and Conwell DL. The endoscopic pancreatic function test. Am J Gastroenterol 104: 2381-2383, 2009. PMID: 19806083
  121. Yamagata T, Urano H, Weeber EJ, Nelson DL, and Nishijima I. Impaired hippocampal synaptic function in secretin deficient mice.  Neuroscience 154: 1417-1422, 2008. PMID: 18534766
  122. You CH and Chey WY. Secretin is an enterogastrone in humans. Dig Dis Sci 32: 466-471, 1987. PMID: 2952476
  123. You CH, Rominger JM, and Chey WY. Potentiation effect of cholecystokinin-octapeptide on pancreatic bicarbonate secretion stimulated by a physiologic dose of secretin in humans. Gastroenterolgy 85:40-45, 1983. PMID: 6303892
  124. Yung WH, Leung PS, Ng SSM, Zhang J, Chan SCY, and Chow BKC. Secretin facilitates GABA transmission in the cerebellum.  J Neurosci 21: 7063-7068, 2001. PMID: 11549716
  125. Zhang M, Schleicher RL, Fink AS, Gunter-Smith P, Savard C, Nguyen T, and Lee SP. Growth and function of isolated canine pancreatic ductal cells. Pancreas 20: 67-76, 2000. PMID: 10630386