INTRODUCTION — The field of endocrinology and the study of "hormones" began at the turn of the 20th century when Bayliss and Starling described a chemical substance in intestinal extracts that, when injected intravenously, stimulated pancreatic secretion [1]. They named this substance secretin because it caused the pancreas to secrete fluid when acid was present in the gut. This discovery led to a search for other chemical substances that when released from one tissue could excite or stimulate organ function in a different location. The Greek word "hormone," meaning "arise to activity," was used to designate these chemical messengers. It is now known that secretin stimulates pancreatic fluid and bicarbonate secretion leading to neutralization of acidic chyme in the intestine. Secretin also inhibits gastric acid release and intestinal motility.
MOLECULAR FORMS — Despite knowledge of physiological activity, it took more than 50 years for the chemical nature of the hormone secretin to be identified. The amino acid sequence was not determined until the 1960s [2]. Human secretin is a 27 amino-acid peptide, with a molecular weight of 3055 D. Its sequence is conserved across many mammalian species (figure 1).
Similar to other gastrointestinal peptides, secretin is amidated at the C-terminus. It is the founding member of the secretin/glucagon/vasoactive intestinal polypeptide family of gastrointestinal hormones. The gene structure of preprosecretin contains an N-terminal signal peptide, a short peptide sequence, secretin, and a C-terminal extension peptide [3]. The gene encoding secretin is selectively expressed in specialized enteroendocrine cells of the small intestine, called S cells. The details of secretin gene transcriptional control have been studied in secretin-producing islet cells [4].
TISSUE DISTRIBUTION — Immunocytochemistry has demonstrated that secretin-producing cells are found along the small intestine (figure 2) [5]. With the exception of L cells that produce peptide YY and glucagon-like peptides, historically, it was believed that an individual enteroendocrine cell produced only one hormone. However, a number of studies using single-cell molecular profiling have demonstrated that although one hormone may predominate, an enteroendocrine cell often produces multiple different peptides. Notably, secretin appears to be expressed in virtually all enteroendocrine cells [6] and is prominently expressed in cells that express 5-hydorxytryptamine (serotonin) [7].
Secretin is also produced by cholangiocytes which express secretin receptors on their basolateral surfaces. Thus, through a paracrine action, secretin can stimulate ductal secretion of fluid and electrolytes [8]. Under conditions of bile duct obstruction, secretin contributes to cholangiocyte proliferation [9].
Other sites shown to produce secretin mRNA are the pancreas, heart, lung, kidney, testis and brain including the hypothalamus, cortex, cerebellum, and brainstem [3,10,11].
RECEPTORS — The secretin receptor is a member of the family of G protein-coupled receptors (GPCRs), within which the secretin/glucagon family is structurally unique. This group consists of receptors for secretin, glucagon, calcitonin, parathyroid hormone, pituitary adenylyl cyclase-activating peptide (PACAP), vasoactive intestinal polypeptide, and others. These receptors lack structural signature sequences present in the rhodopsin/beta-adrenergic receptor family (such as a DRY motif — Asp-Arg-Tyr — at the end of the third transmembrane spanning domain), which appear to be important in receptor coupling to G proteins. Secretin binds to its specific heptahelical membrane receptor and activates the heterotrimeric G protein, Gs, leading to elevation of cellular cAMP levels. This second messenger begins the signaling cascade that initiates appropriate cell physiological responses. (See "Peptide hormone signal transduction and regulation".)
The mechanisms for secretin receptor signal termination involve receptor phosphorylation [12], mediated by GPCR kinases [13]. The mechanism for secretin receptor internalization is distinct from that used by prototypical Class I GPCRs [14]. The specific mechanism for receptor internalization suggests that novel proteins may be involved in its regulation.
Secretin receptors are abundant on duct and acinar cells of the pancreas, where they mediate secretin-stimulated fluid and bicarbonate secretion and may potentiate cholecystokinin and acetylcholine-stimulated enzyme secretion. Secretin receptors are also present in cholangiocytes, kidney, brain cells, sensory neurons in the vagus nerve, and endocrine and other cells of the gastrointestinal tract [15,16]. It is possible the secretin and cholecystokinin receptors on vagal sensory neurons synergistically enhance postprandial pancreatic enzyme secretion [17].
Secretin receptors are also found on some tumors of the gastrointestinal tract. Alternative splicing of secreting receptor pre-mRNA in such tumors may be biologically important for understanding the function of the receptor and in developing potential chemotherapeutic targets [18].
SECRETIN RELEASE — The major physiological actions of secretin are stimulation of pancreatic fluid and bicarbonate secretion. Bicarbonate, upon reaching the duodenum, neutralizes gastric acid and raises the duodenal pH, thereby "turning off" secretin release via a negative feedback mechanism [19]. It has been suggested that acid-stimulated secretin release is regulated by an endogenous intestinal secretin-releasing factor (SRF) (figure 3) [20]. This peptide stimulates secretin until the flow of pancreatic proteases is sufficient to degrade the releasing factor and terminate secretin release. Confirmation of this negative feedback pathway awaits identification of the putative SRF.
PHYSIOLOGY — Although the primary action of secretin is to produce pancreatic fluid and bicarbonate secretion [21], it is also an enterogastrone (a substance that is released by ingested fat and inhibits gastric acid secretion). In physiological concentrations, secretin inhibits gastric acid release, gastric motility, and gastrin release [22]. Similar to other hormones released from the upper small intestine, like cholecystokinin, secretin slows the rate of gastric emptying [23]. When studied using pharmacologic doses, secretin also increases bile flow, gastrointestinal motility, and lower esophageal sphincter pressure, and stimulates insulin release following the ingestion of glucose When studied using pharmacologic doses, secretin also increases bile flow, gastrointestinal motility, and lower esophageal sphincter pressure, and stimulates insulin release following the ingestion of glucose [15,24-26].
Many studies suggest that secretin can promote growth of the pancreas [27]. This latter finding has raised speculation that secretin may contribute to pancreatic cancer [28]. However, direct evidence for secretin in the pathogenesis of pancreatic cancer is currently lacking. Interestingly, targeted ablation (knockout) of secretin-producing cells in transgenic mice resulted in an animal devoid of many enteroendocrine cells, suggesting that secretin expression may be necessary at an early step in the development of gut endocrine cells [29].
Like several other gut peptides, secretin has anorectic properties when administered centrally or peripherally [30]. The central effects of secretin on satiety are mediated by the melanocortin system. The satiety-inducing effects of peripherally administered secretin are blocked by vagotomy or ablating sensory nerves with capsaicin, indicating that secretin signals through the sensory fibers of the vagus nerve [31]. Following Roux-en-Y gastric bypass surgery (RYGB), secretin levels more than double [32]. Although the satiety effects of secretin are relatively weak compared with other gut peptides such as cholecystokinin or peptide YY, its action on the vagus nerve may contribute to the reductions in food intake following RYGB.
The physiologic role of secretin in the brain is incompletely understood, although it may act as a neuropeptide. Impaired synaptic plasticity and antisocial behavior has been observed in secretin-receptor-deficient mice [33]. During development, secretin has neurotrophic effects on serotoninergic mesencephalic neurons, and these effects are lost in neurodegenerative diseases [34].
CLINICAL USES — The most common clinical application of secretin is in the diagnosis of gastrin-secreting tumors. Under normal conditions, secretin administration inhibits gastrin release (see 'Physiology' above). However, in gastrinomas, injection of secretin causes a paradoxical increase in gastrin release. This pathophysiological phenomenon is the basis for the secretin stimulation test. This test is a safe, effective, and reliable method for determining the presence of a gastrin-producing tumor (table 1) [35,36]. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
Due to its effect on pancreatic exocrine secretion, secretin has been used clinically to diagnose pancreatic insufficiency [37,38] (see "Approach to the adult patient with suspected malabsorption"). Acute administration of secretin causes temporary dilation of pancreatic ducts by increasing pancreatic secretions. This pharmacologic effect is the basis for administration of secretin during endoscopic retrograde cholangiopancreatography to aid in ductal cannulation (primarily the minor duct) (see "Pancreas divisum: Clinical manifestations and diagnosis"). In addition, secretin has been used in magnetic resonance imaging of the pancreas during functional testing to evaluate pancreatic secretion and ductal obstruction [39,40]. Secretin-enhanced magnetic resonance cholangiopancreatography is particularly useful to detect and diagnose congenital, inflammatory, and neoplastic conditions of the pancreas and may be more useful than standard magnetic resonance imaging to evaluate subtle changes in chronic pancreatitis [41,42]. In addition, secretin administration appears to accentuate regions of pancreatic vascular hypoperfusion [43].
Anecdotal reports suggest that secretin administration might be an effective treatment for autism spectrum disorders. However, these early reports have not been validated in randomized controlled trials and secretin is not recommended for treatment of autism [44].
SUMMARY AND RECOMMENDATIONS
●Secretin is a 27 amino-acid peptide produced by cells in the small intestine, hypothalamus, cortex, cerebellum, and brainstem. (See 'Introduction' above and 'Molecular forms' above.)
●Secretin receptors are abundant on duct and acinar cells of the pancreas, where they mediate secretin-stimulated fluid and bicarbonate secretion leading to neutralization of acidic chyme in the intestine and may potentiate cholecystokinin and acetylcholine-stimulated enzyme secretion. (See 'Tissue distribution' above and 'Receptors' above.)
●The most common clinical application of secretin is in the diagnosis of gastrin-secreting tumors. Under normal conditions, secretin administration inhibits gastrin release. However, in gastrinomas, injection of secretin causes a paradoxical increase in gastrin release. This pathophysiological phenomenon is the basis for the secretin stimulation test. (See 'Physiology' above and 'Clinical uses' above.)
1 : The mechanism of pancreatic secretion.
2 : Structure of porcine secretin. The amino acid sequence.
3 : Secretin: structure of the precursor and tissue distribution of the mRNA.
4 : Transcriptional regulation of secretin gene expression.
5 : Transcriptional regulation of secretin gene expression.
6 : A single-cell survey of the small intestinal epithelium.
7 : Quantitation and chemical coding of enteroendocrine cell populations in the human jejunum.
8 : Secretin promotes osmotic water transport in rat cholangiocytes by increasing aquaporin-1 water channels in plasma membrane. Evidence for a secretin-induced vesicular translocation of aquaporin-1.
9 : Secretin stimulates biliary cell proliferation by regulating expression of microRNA 125b and microRNA let7a in mice.
10 : Expression and spatial distribution of secretin and secretin receptor in human cerebellum.
11 : Tissue-specific expression of the rat secretin precursor gene.
12 : Agonist-stimulated phosphorylation of the carboxyl-terminal tail of the secretin receptor.
13 : A role for receptor kinases in the regulation of class II G protein-coupled receptors. Phosphorylation and desensitization of the secretin receptor.
14 : Properties of secretin receptor internalization differ from those of the beta(2)-adrenergic receptor.
15 : The physiological roles of secretin and its receptor.
16 : Secretin, at the hub of water-salt homeostasis.
17 : Sensory signal transduction in the vagal primary afferent neurons.
18 : Alternative splicing of pre-mRNA in cancer: focus on G protein-coupled peptide hormone receptors.
19 : Secretion pattern of secretin in man: regulation by gastric acid.
20 : Mechanism of acid-induced release of secretin in rats. Presence of a secretin-releasing peptide.
21 : Effects of atropine on the action and release of secretin in humans.
22 : Secretin is an enterogastrone in humans.
23 : Secretin effects on gastric functions, hormones and symptoms in functional dyspepsia and health: randomized crossover trial.
24 : Canalicular bile secretion in man. Studies utilizing the biliary clearance of (14C)mannitol.
25 : Motor responses of the sigmoid colon and rectum to exogenous cholecystokinin and secretin.
26 : Hormonal regulation of human lower esophageal sphincter competence: interaction of gastrin and secretin.
27 : Cell site and time course of DNA synthesis in pancreas after caerulein and secretin.
28 : Duodenal acidity may increase the risk of pancreatic cancer in the course of chronic pancreatitis: an etiopathogenetic hypothesis.
29 : Targeted ablation of secretin-producing cells in transgenic mice reveals a common differentiation pathway with multiple enteroendocrine cell lineages in the small intestine.
30 : Central and peripheral administration of secretin inhibits food intake in mice through the activation of the melanocortin system.
31 : Vagal afferent mediates the anorectic effect of peripheral secretin.
32 : Secretin release after Roux-en-Y gastric bypass reveals a population of glucose-sensitive S cells in distal small intestine.
33 : Secretin receptor-deficient mice exhibit impaired synaptic plasticity and social behavior.
34 : Transient expression of secretin in serotoninergic neurons of mouse brain during development.
35 : Secretin injection test in the diagnosis of gastrinoma.
36 : Secretin provocation test in the diagnosis of Zollinger-Ellison syndrome.
37 : Prospective evaluation of endoscopic ultrasonography, endoscopic retrograde pancreatography, and secretin test in the diagnosis of chronic pancreatitis.
38 : Rapid endoscopic secretin stimulation test and discrimination of chronic pancreatitis and pancreatic cancer from disease controls.
39 : Secretin-stimulated magnetic resonance pancreaticogram to assess pancreatic duct outflow obstruction in evaluation of idiopathic acute recurrent pancreatitis: a pilot study.
40 : Pancreatic duct after pancreatoduodenectomy: morphologic and functional evaluation with secretin-stimulated MR pancreatography.
41 : Dynamic secretin-enhanced MR cholangiopancreatography.
42 : Suspected chronic pancreatitis with normal MRCP: findings on MRI in correlation with secretin MRCP.
43 : Pancreatic perfusion: noninvasive quantitative assessment with dynamic contrast-enhanced MR imaging without and with secretin stimulation in healthy volunteers--initial results.
44 : Intravenous secretin for autism spectrum disorders (ASD).