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The mechanism of pancreatic secretion

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... Lancet" in 1905 (1) -three years after his and William Bayliss' breakthrough discovery of the first hormone in history, secretin (2). "Hormone" was rapidly accepted as a general designation for blood-borne chemical messengers of which secretin was the first and gastrin the second example (2,3). ...
... Lancet" in 1905 (1) -three years after his and William Bayliss' breakthrough discovery of the first hormone in history, secretin (2). "Hormone" was rapidly accepted as a general designation for blood-borne chemical messengers of which secretin was the first and gastrin the second example (2,3). Accordingly, hormones and blood-borne regulation became coreconcepts in endocrinology as complementary to neuronal regulation, which until then had been considered the only way for regulation and coordination of bodily functions (4,5). ...
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The birth certificate for endocrinology was Bayliss’ and Starling’s demonstration in 1902 that regulation of bodily functions is not only neuronal, but due also to blood-borne messengers. Starling named these messengers hormones. Since then, transport via blood has defined hormones. This definition, however, may be too narrow. Thus, today we know that several peptide hormones not only are produced and released to blood from endocrine cells. They are released also from neurons, myocytes, immune cells, endothelial cells, spermatogenic cells, fat cells, etc. And they are often secreted in cell-specific molecular forms with more or less different spectra of activity. The present review depicts this development with the story about cholecystokinin, which was discovered in 1928 as a hormone and still in 1976 was conceived as a single blood-borne peptide. Todays’ multifaceted picture of cholecystokinin suggests that time may be ripe for expansion of the hormone concept to all messenger molecules, which activate their target cells – irrespective of their road to the target (endocrine, neurocrine, neuronal, paracrine, autocrine, etc.) and irrespective of their kind of activity as classical hormone; growth factor; neurotransmitter; adipokine; cytokine; myokine; or fertility factor.
... Peptide hormones have been comprehensively studied and marked important in animal biology for over 100 years (Bayliss & Starling, 1902). In the plant kingdom, the first peptide hormone was identified 30 years ago (Pearce et al., 1991). ...
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Endogenous peptide hormones represent an essential class of biomolecules, which regulate cell–cell communications in diverse physiological processes of organisms. Mass spectrometry (MS) has been developed to be a powerful technology for identifying and quantifying peptides in a highly efficient manner. However, it is difficult to directly identify these peptide hormones due to their diverse characteristics, dynamic regulations, low abundance, and existence in a complicated biological matrix. Here, we summarize and discuss the roles of targeted and untargeted MS in discovering peptide hormones using bioassay‐guided purification, bioinformatics screening, or the peptidomics‐based approach. Although the peptidomics approach is expected to discover novel peptide hormones unbiasedly, only a limited number of successful cases have been reported. The critical challenges and corresponding measures for peptidomics from the steps of sample preparation, peptide extraction, and separation to the MS data acquisition and analysis are also discussed. We also identify emerging technologies and methods that can be integrated into the discovery platform toward the comprehensive study of endogenous peptide hormones.
... McDougall was at the epicenter of British psychology and physiology at a time when the physiology of the brain was a hot topic. It was in 1902 that Bayliss and Starling isolated the first hormone from the stomach of dogs which they called secretin (Bayliss and Starling, 1902;Modlin and Kidd, 2001). At Cambridge, Elliot was examining the functions of adrenaline (Elliott, 1904) and Langley was proposing the existence of receptors for chemical drugs such as nicotine, curare, and atropine (Langley, 1905). ...
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Since the work of Semon was rediscovered by Schacter in 1978, there has been a renewed interest is searching for the “engram” as the locus of memory in the brain and Hebb’s cell assembly has been equated with Semon’s engram. There have been many theories of memory involving some concept of synaptic change, culminating in the “Hebb Synapse” theory in 1949. However, Hebb said that the idea that any two cells or systems of cells that are repeatedly active at the same time will tend to become “associated,” was not his idea, but an old one. In this manuscript we give an overview of some of the theories of the neural basis of learning and memory before Hebb and describe the synaptic theory of William McDougall, which appears to have been an idea ahead of its time; so far ahead of its time that it was completely ignored by his contemporaries. We conclude by examining some critiques of McDougall’s theory of inhibition and with a short discussion on the fate of neuroscientists whose ideas were neglected when first presented but were accepted as important many decades later.
... The secretin receptor (SCTR), which was the first to be discovered in duodenal mucosa, is a G protein-coupled receptor and a member of the glucagon-VIP-secretin receptor. 19 The SCTR gene is located on chromosome 2q14.2, which contains 3 hypermethylation genes (EN1, SCTR, and INHBB) in correlation with LRES in CRC. ...
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Diagnostic markers for both colorectal cancer (CRC) and its precursor lesions are lacking. Although aberrant methylation of SCTR gene was observed in CRC, the diagnostic performance has not been evaluated. Therefore, this study aimed to assess and verify the diagnostic value of SCTR methylation of CRC and its precursor lesions through integrating the largest methylation data. The diagnostic performance of SCTR methylation was analyzed in the discovery set from The Cancer Genome Atlas (TCGA) CRC methylation data (N = 440), and verified in a large-scale test set (N = 938) from the Gene Expression Omnibus (GEO). Targeted bisulfite sequencing analysis was developed and applied to detect methylation status of SCTR in our independent validation set (N = 374). Our findings revealed that SCTR gene was frequently hypermethylated at its CpG islands in CRC. In the TCGA discovery set, the diagnostic score was constructed using 4 CpG sites (cg01013590, cg20505223, cg07176264, cg26009192) and achieved high diagnostic performance (AUC = 0.964). In the GEO test set, the diagnostic score had robust diagnostic ability to distinguish CRC (AUC = 0.948) and its precursor lesions (AUC = 0.954) from normal samples. Moreover, hypermethylation of SCTR gene was also found in cell-free DNA samples collected from CRC patients, but not in those from healthy controls. In the validation set, consistent results were observed using the targeted bisulfite sequencing array. Our study highlights that hypermethylation at CpG islands of SCTR gene is a potential diagnostic biomarker in CRCs and its precursor lesions.
... E ndocrine peptides have been studied for over 100 yr (1). Analytical methods were developed that could sequence linear peptides purified from bioassays that quickly led to the determination of the sequences of insulin, secretin, gastrin, and cholecystokinin (CCK) (2). ...
... In 1923 the diabetes pathophysiology was explained taking into account only two elements, glucose and insulin; no other scientific findings were considered to support or to discredit this pathophysiological model. At that time, this model was considered the only valid point of view, although the gut was already identified as an organ able to produce hormones affecting glucose homeostasis, such as secretin [3], and glucagon was discovered as another Langerhans islet hormone. This latter hormone, even if capable of counter-regulating insulin's excessive action, was considered only as an antidote for insulin action. ...
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Glycemic homeostasis is an essential mechanism for the proper working of an organism. However, balance in blood lipid and protein levels also plays an important role. The discovery of the hormone insulin and the description of its function for glycemic control made fundamental scientific progress in this field. However, since then our view of the problem has been deeply influenced only in terms of glucose and insulin (in an insulin-centric and glucose-centric way). Based on recent scientific discoveries, a fine and sophisticated network of hormonal and metabolic interactions, involving almost every apparatus and tissue of the human body, has been theorized. Efficient metabolic homeostasis is founded on these intricate interactions. Although it is still not fully defined, this complex network can undergo alterations that lead to metabolic disorders such as diabetes mellitus (DM). The endocrine pancreas plays a crucial role in the metabolic balance of an organism, but insulin is just one of the elements involved and each single pancreatic islet hormone is worthy of our concern. Moreover, pancreatic hormones need to be considered in a general view, concerning both their systemic function as direct mediators and as hormones, which, in turn, are regulated by other hormones or other substances. This more complex scenario should be taken into account for a better understanding of the pathophysiology and the therapeutic algorithms of DM. As a consequence, improvements in modern medicine could help to contemplate this new perspective. This review is focused on some aspects of gut-pancreas interaction, aiming to integrate this synergy into a wider context involving other organs and tissues.
... The origin of the word "hormone" comes from work published in 1902, when Bayliss and Starling used this word to describe a "secretin" that they identified in the duodenum and jejunum and that stimulated pancreatic secretion [6]. This was the first of a large number of peptide products produced by the gut that were characterized in the twentieth century. ...
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Well differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal and pancreaticobiliary system are the most common neuroendocrine neoplasms. Studies of the molecular basis of these lesions have identified genetic mutations that predispose to familial endocrine neoplasia syndromes and occur both as germline events and in sporadic tumors. The mutations often involve epigenetic regulators rather than the oncogenes and tumor suppressors that are affected in other malignancies. Somatic copy number alterations and miRNAs have also been implicated in the development and progression of some of these tumors. The molecular profiles differ by location, but many are shared by tumors in other sites, including those outside the gastroenteropancreatic system. The approach to therapy relies on both the neuroendocrine nature of these tumors and the identification of specific alterations that can serve as targets for precision oncologic approaches.
... This powerful idea gained support from independent observations that diabetes was sometimes associated with pancreatic damage. In addition, the concept of internal endocrine secretions was beginning to develop, with the discovery of the first hormone, secretin, by Bayliss and Starling at University College London in 1902 [2]. As a result, the hypothesis that the pancreas produced an internal secretion that controlled carbohydrate metabolism became increasingly discussed. ...
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Background: The 100th anniversary of the discovery of insulin in Toronto in 1921 is an important moment in medical and scientific history. The demonstration that an extract of dog pancreas reproducibly lowered blood glucose, initially in diabetic dogs and then in humans with type 1 diabetes, was a medical breakthrough that changed the course of what was until then a largely fatal disease. The discovery of the "activity", soon named "insulin", was widely celebrated, garnering a Nobel Prize for Banting and McLeod in 1923. Over the ensuing 100 years, research on insulin has advanced on many fronts, producing insights that have transformed our understanding of diabetes and our approach to its treatment. Scope of review: This paper will review research on insulin that had another consequence of far broader scientific significance, by serving as a pacesetter and catalyst to bioscience research across many fields. Some of this was directly insulin-related and was also recognized by the Nobel Prize. Equally important, however, was research stimulated by the discovery of insulin that has profoundly influenced biomedical research, sometimes also recognized by the Nobel Prize and sometimes without this recognition. Major conclusions: By reviewing some of the most notable examples of both insulin-related and insulin-stimulated research, it becomes apparent that insulin had an enormous and frequently under-appreciated impact on the course of modern bioscience.
... It has long been long known that specialised cells lining the gut epithelium can sense changes in luminal content and respond by releasing chemicals. Bayliss and Starling [1] described the first gut hormone secretin, and demonstrated its release following delivery of acidic solutions into the small intestine. Similarly, nutrients ingested or liberated following digestion can stimulate hormone secretion from enteroendocrine cells (EECs), which are specialised gut epithelial cells that reside within the polarized absorptive epithelial layer. ...
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The gastrointestinal tract can assess the nutrient composition of ingested food. The nutrient-sensing mechanisms in specialised epithelial cells lining the gastrointestinal tract, the enteroendocrine cells, trigger the release of gut hormones that provide important local and central feedback signals to regulate nutrient utilisation and feeding behaviour. The evidence for nutrient-stimulated secretion of two of the most studied gut hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), along with the known cellular mechanisms in enteroendocrine cells recruited by nutrients, will be the focus of this review. The mechanisms involved range from electrogenic transporters, ion channel modulation and nutrient-activated G-protein coupled receptors that converge on the release machinery controlling hormone secretion. Elucidation of these mechanisms will provide much needed insight into postprandial physiology and identify tractable dietary approaches to potentially manage nutrition and satiety by altering the secreted gut hormone profile.
... Investigations of the function of this organ have also resulted in major discoveries of general importance. Bayliss and Starling (1,2) discovered that pancreatic fluid secretion could be stimulated by a substance they called secretin, and Starling later introduced the name ...
Article
This review deals with the roles of calcium and ATP in the control of the normal functions of the different cell types in the exocrine pancreas as well as the roles of these molecules in the pathophysiology of Acute Pancreatitis. Repetitive rises in the local cytosolic calcium ion concentration in the apical part of the acinar cells do not only activate exocytosis but also, via an increase in the intra-mitochondrial calcium ion concentration, stimulate the ATP formation that is needed to fuel the energy-requiring secretion process. However, intracellular calcium overload, resulting in a global sustained elevation of the cytosolic calcium ion concentration, has the opposite effect of decreasing mitochondrial ATP production and this initiates processes that lead to the necrotic destruction of the cells. In the last few years it has become possible to image calcium signalling events simultaneously in acinar, stellate and immune cells in intact lobules of the exocrine pancreas. This has disclosed processes by which these cells interact with each other, particularly in relation to the initiation and development of Acute Pancreatitis. By unravelling the molecular mechanisms underlying this disease, several promising therapeutic intervention sites have been identified. This provides hope that we may soon be able to effectively treat this often fatal disease.
... While the gut hormones secretin and gastrin were discovered almost two decades earlier (1,2), it was the extraction, isolation and purification of insulin from canine pancreatic extracts in Toronto in 1921, that truly signifies the advent of peptide-based therapeutics (3). Indeed, the first clinical use of animal-derived insulin began the following year. ...
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Initially discovered as an impurity in insulin preparations, our understanding of the hyperglycaemic hormone glucagon has evolved markedly over subsequent decades. With description of the precursor proglucagon, we now appreciate that glucagon was just the first proglucagon-derived peptide (PGDP) to be characterised. Other bioactive members of the PGDP family include glucagon-like peptides -1 and -2 (GLP-1 and GLP-2), oxyntomodulin (OXM), glicentin and glicentin-related pancreatic peptide (GRPP), with these being produced via tissue-specific processing of proglucagon by the prohormone convertase (PC) enzymes, PC1/3 and PC2. PGDP peptides exert unique physiological effects that influence metabolism and energy regulation, which has witnessed several of them exploited in the form of long-acting, enzymatically resistant analogues for treatment of various pathologies. As such, intramuscular glucagon is well established in rescue of hypoglycaemia, while GLP-2 analogues are indicated in the management of short bowel syndrome. Furthermore, since approval of the first GLP-1 mimetic for the management of Type 2 diabetes mellitus (T2DM) in 2005, GLP-1 therapeutics have become a mainstay of T2DM management due to multifaceted and sustainable improvements in glycaemia, appetite control and weight loss. More recently, longer-acting PGDP therapeutics have been developed, while newfound benefits on cardioprotection, bone health, renal and liver function and cognition have been uncovered. In the present article, we discuss the physiology of PGDP peptides and their therapeutic applications, with a focus on successful design of analogues including dual and triple PGDP receptor agonists currently in clinical development.
... In recent years, protein hydrolysates have attracted many researchers' interests due to their multiple functions. It has been more than 100 years since the peptide was first found by Bayliss and Starling, two physiologists at the London Medical College, who found secretin in animal gastrointestinal [12]. Based on the difference in function, these peptides can be roughly divided into two categories, one is nutritive peptides, and the other is bioactive peptides (BAP). ...
Article
Evidences suggest that the homeostasis of gut microbiota is among the most important factors for maintaining the physical and mental health of the host. Among the multiple factors affecting the homeostasis of gut microbiota, diet is one of the decisive factors. Bioactive peptides derived from protein hydrolyzed by protease or fermented by microorganism have many physiological activities that their parent proteins do not have. Currently, bioactive peptides attract more and more attention due to their bidirectional interaction with gut microbes. It has been reported that some bioactive peptides could alter the composition of gut microbiota by influencing the intestinal microenvironment. Meanwhile, quite a few bioactive peptides that are released by gut microbes or intestinal cells could resist the pathogenic bacteria to sustain the homeostasis of gut microbiota. In this review, some exogenous bioactive peptides derived from food and some endogenous bioactive peptides released from intestinal cells or microbes were discussed to summary their effects on the modulation of gut microbiota. This review is expected to provide new ideas for related research, and as well to promote the application of bioactive peptides in the fields of food and medicine.
... Secretin, SCT, is a 27 amino acid peptide secreted by the duodenum and the brain (Bayliss & Starling, 1902;Charlton et al., 1981). Its receptor (SCTR) is widely distributed throughout the CNS including the hippocampus, hypothalamus and medulla (O'Donohue et al., 1981). ...
Article
The number of people living with obesity has tripled worldwide since 1975 with serious implications for public health, as obesity is linked to a significantly higher chance of early death from associated comorbidities (metabolic syndrome, type 2 diabetes, cardiovascular disease and cancer). As obesity is a consequence of food intake exceeding the demands of energy expenditure, efforts are being made to better understand the homeostatic and hedonic mechanisms governing food intake. Gastrointestinal peptides are secreted from enteroendocrine cells in response to nutrient and energy intake, and modulate food intake either via afferent nerves, including the vagus nerve, or directly within the central nervous system, predominantly gaining access at circumventricular organs. Enteroendocrine hormones modulate homeostatic control centres at hypothalamic nuclei and the dorso-vagal complex. Additional roles of these peptides in modulating hedonic food intake and/or preference via the neural systems of reward are starting to be elucidated, with both peripheral and central peptide sources potentially contributing to central receptor activation. Pharmacological interventions and gastric bypass surgery for the treatment of type 2 diabetes and obesity elevate enteroendocrine hormone levels and also alter food preference. Hence, understanding of the hedonic mechanisms mediated by gut peptide action could advance development of potential therapeutic strategies for the treatment of obesity and its comorbidities.
... Secretin, gastrin, and cholecystokinin were the rst gastrointestinal hormones (Bayliss & Starling, 1902;Edkins, 1905;Ivy & Oldberg, 1928) and also the rst structurally identi ed and are the largest endocrine organ in the body. Knowledge about the physiology and anatomy of the gut endocrine system is most helpful for the clinician to understand the pathophysiology of certain diseases (excess hormone production from gut endocrine tumours) (Rindi et al., 1999). ...
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Based on the classification of human hormones, there is no solid idea in most books. In this view, this article could exemplify a concrete solution, especially for medical and university students. Hormones have many life-saving roles in the human body. With the deficiency of hormones, our body might fall into lots of problems. Data analyses of much information from books, articles, online supplements gave different ideas on total hormones. The result suggested that some hormones were secret from the same glands. Out of 110 hormones (when the same hormone came from different sources), exact different types of hormones were 88. Analyzed hormones consisted of four major groups- amine (4 hormones), eicosanoid (4), steroid (15), and peptide were (65) out of 88 endocrine chemicals. The endocrine and reproductive system (56) jointly secreted most of the hormones, and secondly gastrointestinal tract (26 hormones). Besides the organ system or glands, some are come out from the cell, tissue, tissue system, and placenta. This paper also mentions, phenotypically males and females exhibit many differences, hence hormonal analyses; they are more or less the same. For instance, many sex hormones are also present both in males and females. In the future, it needs to enhance more research on the classification of the hormones in the human body.
... Secretin, gastrin, and cholecystokinin were the rst gastrointestinal hormones (Bayliss & Starling, 1902;Edkins, 1905;Ivy & Oldberg, 1928) and also the rst structurally identi ed and are the largest endocrine organ in the body. Knowledge about the physiology and anatomy of the gut endocrine system is most helpful for the clinician to understand the pathophysiology of certain diseases (excess hormone production from gut endocrine tumours) (Rindi et al., 1999). ...
Preprint
Full-text available
Based on the classification of human hormones, there is no solid idea in most books. In this view, this article could exemplify a concrete solution, especially for medical and university students. Hormones have many life-saving roles in the human body. With the deficiency of hormones, our body might fall into lots of problems. Data analyses of much information from books, articles, online supplements gave different ideas on total hormones. The result suggested that some hormones were secret from the same glands. Out of 110 hormones (when the same hormone came from different sources), exact different types of hormones were 88. Analyzed hormones consisted of four major groups- amine (4 hormones), eicosanoid (4), steroid (15), and peptide were (65) out of 88 endocrine chemicals. The endocrine and reproductive system (56) jointly secreted most of the hormones, and secondly gastrointestinal tract (26 hormones). Besides the organ system or glands, some are come out from the cell, tissue, tissue system, and placenta. This paper also mentions, phenotypically males and females exhibit many differences, hence hormonal analyses; they are more or less the same. For instance, many sex hormones are also present both in males and females. In the future, it needs to enhance more research on the classification of the hormones in the human body.
... We did not assess the effects of mechanical stimulation in this study, but neither cholinergic nor adrenergic activation evoked motilin release. In addition to motilin, secretion of other duodenal hormones by acidification has also been described including secretin [55], somatostatin [56,57], and the neuronal vasoactive intestinal peptide [58]. This is generally downstream of increased gastric emptying but, to our knowledge, no molecular mechanisms have yet been proposed and future studies should therefore investigate whether ASICs also play a role in acid-sensing in other enteroendocrine populations. ...
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Objective Motilin is a proximal small intestinal hormone with roles in gastrointestinal motility, gallbladder emptying and hunger initiation. In vivo motilin release is stimulated by fats, bile and duodenal acidification but the underlying molecular mechanisms of motilin secretion are poorly understood. This study aimed to establish the key signalling pathways involved in the regulation of secretion from human motilin-expressing M-cells. Methods Human duodenal organoids were CRISPR-Cas9 modified to express the fluorescent protein Venus or the Ca²⁺ sensor GCaMP7s under control of the endogenous motilin promoter. This enabled identification and purification of M-cells for bulk RNA sequencing, peptidomics, calcium imaging and electrophysiology. Motilin secretion from 2D organoid-derived cultures was measured by liquid chromatography tandem mass spectrometry (LC-MS/MS), in parallel with other gut hormones. Results Human duodenal M-cells synthesise active forms of motilin and acyl-ghrelin in organoid culture, and also co-express cholecystokinin (CCK). Activation of the bile acid receptor GPBAR1 stimulated a 3.4-fold increase in motilin secretion and increased action potential firing. Agonists of the long chain fatty acid receptor FFA1 and monoacylglycerol receptor GPR119 stimulated secretion by 2.4-fold and 1.5-fold, respectively. Acidification (pH 5.0) was a potent stimulus of M-cell calcium elevation and electrical activity, an effect attributable to acid-sensing ion channels, and a modest inducer of motilin release. Conclusions This study presents the first in-depth transcriptomic and functional characterisation of human duodenal motilin-expressing cells. We identify several receptors important for the postprandial and interdigestive regulation of motilin release.
... Gut physiological functions such as secretion, digestion, absorption, and motility are regulated by these luminal substances, in addition to neural regulation by the central nervous system via vagal nerves activated during the cephalic phase of food intake. The first discovery of gut hormone release in response to a luminal substance was secretin, released in response to luminal acid (H þ ) [3]. To date, $20 gut hormones, principally localized in enteroendocrine cells (EECs) or myenteric neurons of the submucosal and myenteric plexus in the gastrointestinal tract have been identified. ...
Article
Purpose of review: The gut barrier serves as the primary interface between the environment and host in terms of surface area and complexity. Luminal chemosensing is a term used to describe how small molecules in the gut lumen interact with the host through surface receptors or via transport into the subepithelial space. In this review, we have summarized recent advances in the understanding of the luminal chemosensory system in the gastroduodenal epithelium consisting of enterocytes, enteroendocrine, and tuft cells, with particular emphasis on how chemosensing affects mucosal protective responses and the metabolic syndrome. Recent findings: Recent single-cell RNA sequencing provides detailed cell type-specific expression of chemosensory receptors and other bioactive molecules as well as cell lineages; some are similar to lingual taste cells whereas some are gut specific. Gut luminal chemosensing is not only important for the local or remote regulation of gut function, but also contributes to the systemic regulation of metabolism, energy balance, and food intake. We will discuss the chemosensory mechanisms of the proximal intestine, in particular to gastric acid, with a focus on the cell types and receptors involved in chemosensing, with emphasis on the rare chemosensory cells termed tuft cells. We will also discuss the chemosensory functions of intestinal ectoenzymes and bacterial components (e.g., lipopolysaccharide) as well as how they affect mucosal function through altering the gut-hormonal-neural axis. Summary: Recent updates in luminal chemosensing by different chemosensory cells have provided new possibilities for identifying novel molecular targets for the treatment of mucosal injury, metabolic disorders, and abnormal visceral sensation.
... Hormones are a large class of chemical messengers with diverse compositions, functions, and origins. The term "hormone" was coined by Ernest Starling in a series of lectures to the Royal College of Physicians in 1905(Starling, 1905apud Hirst 2004 following his discovery of secretin in 1902 (Bayliss and Starling 1902). Per the original definition, hormones are messengers that "have to be carried from the organ they are produced to the organ which they affect by means of the bloodstream" (Starling, 1905apud Hirst 2004, drawing from the concept of a chemical reflex, happening independent of the nervous system. ...
... The Work of the Digestive Glands [1] . In direct opposition to Pavlov's assertion of a local nerve-centric mechanism in regulating the digestive response, Bayliss and Starling presented clear evidence of a circulating hormonal messenger (i.e., secretin) that stimulated pancreatic secretory activity [2] . Shortly thereafter, a series of seminal studies led by John Edkins elucidated an analogous mechanism in the stomach and contributed to the pivotal discovery of the acid-stimulating hormone known as gastrin. ...
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Abetted by widespread usage of acid-suppressing proton pump inhibitors, the mitogenic actions of the peptide hormone gastrin are being revisited as a recurring theme in various gastrointestinal malignancies. While pathological gastrin levels are intricately linked to hyperplasia of enterochromaffin-like cells leading to carcinoid development, the signaling effects exerted by gastrin on distinct cell types of the gastric mucosa are more nuanced. Indeed, mounting evidence suggests dichotomous roles for gastrin in both promoting and suppressing tumorigenesis. Here we review the major upstream mediators of gastrin gene regulation, including inflammation secondary to H. pylori infection and the use of proton pump inhibitors. We further explore the molecular biology of gastrin in gastrointestinal malignancies, with particular emphasis on the regulation of gastrin in neuroendocrine neoplasms. Finally, we highlight tissue-specific transcriptional targets as an avenue for targetable therapeutics.
... Since the discovery of secretin over a hundred years ago (W. M. Bayliss, 1902), about 100 mammalian hormones have been identified (Takei et al., 2015). Over the decades, these hormones have been purified, sequenced, and synthesized, their receptors have been identified, and the intracellular signaling pathways they regulate have been explored (Tata, 2005). ...
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Hormones coordinate long-range cell-cell communication in multicellular organisms and play vital roles in normal physiology, metabolism, and health. Using the newly-completed organism-wide single cell transcriptional atlas of a non-human primate, the mouse lemur (Microcebus murinus), we have systematically identified hormone-producing and -target cells for 87 classes of hormones, and have created a browsable atlas for hormone signaling that reveals previously unreported sites of hormone regulation and species-specific rewiring. Hormone ligands and receptors exhibited cell-type-dependent, stereotypical expression patterns, and their transcriptional profiles faithfully classified the discrete cell types defined by the full transcriptome, despite their comprising less than 1% of the transcriptome. Although individual cell types generally exhibited the same characteristic patterns of hormonal gene expression, a number of examples of similar or seemingly-identical cell types (e.g., endothelial cells of the lung versus of other organs) displayed different hormonal gene expression patterns. By linking ligand-expressing cells to the cells expressing the corresponding receptor, we constructed an organism-wide map of the hormonal cell-cell communication network. The hormonal cell-cell network was remarkably densely and robustly connected, and included classical hierarchical circuits (e.g. pituitary → peripheral endocrine gland → diverse cell types) as well as examples of highly distributed control. The network also included both well-known examples of feedback loops and a long list of potential novel feedback circuits. This primate hormone atlas provides a powerful resource to facilitate discovery of regulation on an organism-wide scale and at single-cell resolution, complementing the single-site-focused strategy of classical endocrine studies. The network nature of hormone regulation and the principles discovered here further emphasize the importance of a systems approach to understanding hormone regulation.
... The discovery of the incretin dates to 1929 due to the work of La Barre [1], but the true pioneers of the incretin concept were Bayliss and Moore 20 years earlier, when they hypothesized that the endocrine pancreas secretion was regulated by hormones contained in the gut extracts [2,3]. Incretin was forgotten for three decades until the discovery by McIntyre [4] that stated that intestines released some humoral substances, after glucose ingestion, that helped to promote β-cellular secretion of insulin, followed by the introduction by Unger and Eisentrout of the concept of "entero-insular axis" [5]. ...
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Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are two gut hormones, defined incretins, responsible for the amplification of insulin secretion after oral glucose intake. Unlike GLP-1, GIP has little acute effect on insulin secretion and no effect on food intake; instead it seems that the GIP may be an obesity-promoting hormone. In patients with type2 diabetes mellitus (T2DM) some studies found a downregulation of GIP receptors on pancreatic β cells caused by hyperglycemic state, but the glucagonotropic effect persisted. Agonists of the receptor for the GLP-1 have proven successful for the treatment of diabetes, since they reduce the risk for cardiovascular and renal events, but the possible application of GIP as therapy for T2DM is discussed. Moreover, the latest evidence showed a synergetic effect when GIP was combined with GLP-1 in monomolecular co-agonists. In fact, compared with the separate infusion of each hormone, the combination increased both insulin response and glucagonostatic response. In accordance with theseconsiderations, a dual GIP/GLP-1receptor agonist, i.e., Tirzepatide, known as a “twincretin” had been developed. In the pre-clinical trials, as well as Phase 1–3 clinical trials, Tirzepatideshowedpotent glucose lowering and weight loss effects within an acceptable safety.
... It contains 27 amino acids residues.It was identified by Bayliss and Starling in 1902. [27] It is secreted by the duodenal mucosa in response to the presence of chyme from stomach [ Fig.2.]. The prime function of seretin is the regulation of the secretion of pancreatic juice [ Fig.2.]. ...
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The Gastrointestinal hormones (GIH) are a group of hormone secreted by the endocrine cells distributed in the various organs of the digestive system. These GIH are known to control various functions of the digestive organs which includes gastric an intestinal movements and secretions of various digestive juices.[1] Some of these GIH such as secretin, gastrin and cholecystokinin are reported to act as neurotransmitters and neuromodulators in the central and peripheral nervous system.[2,3,4] These GIH have some extra-GI functions , many of which are not yet clearly known. Some of these can regulate the brain to regulate the food intake while others are known to regulate proliferation of certain cells. Receptors of these GIH are reported to be expressed also in various tissues other than in the GI system.GIH have valuable diagnostic and therapeutic uses.[5]
... SCTR, encoding the protein named G protein-coupled receptor, belongs to the glucagon-VIP-secretin receptor family (Bayliss and Starling, 1902). It has been reported that in colorectal cancer, hypermethylation of SCTR had a diagnostic value (Li et al., 2020). ...
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Hepatocellular carcinoma (HCC) is a malignant tumor with high morbidity and mortality worldwide. Many studies have shown that dedicator of cytokinesis 2 (DOCK2) has a crucial role as a prognostic factor in various cancers. However, the potentiality of DOCK2 in the diagnosis of HCC has not been fully elucidated. In this work, we aimed to investigate the prognostic role of DOCK2 mutation in HCC. The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) cohorts were utilized to identify the mutation frequency of DOCK2. Then, univariate Cox proportional hazard regression analysis, random forest (RF), and multivariate Cox regression analysis were performed to develop the risk score that was significantly related to DOCK2 mutation. Moreover, Gene Set Enrichment Analysis (GSEA), Gene Set Variation Analysis (GSVA), and immune correlation analysis were conducted for an in-depth study of the biological process of DOCK2 mutation involved in HCC. The results revealed that the mutation frequency of DOCK2 was relatively higher than that in non-cancer control subjects, and patients with DOCK2 mutations had a low survival rate and a poor prognosis compared with the DOCK2-wild group. In addition, the secretin receptor (SCTR), tetratricopeptide repeat, ankyrin repeat and coiled-coil domain-containing 1 (TANC1), Alkb homolog 7 (ALKBH7), FRAS1-related extracellular matrix 2 (FREM2), and G protein subunit gamma 4 (GNG4) were found to be the most relevant prognostic genes of DOCK2 mutation, and the risk score based on the five genes played an excellent role in predicting the status of survival, tumor mutation burden (TMB), and microsatellite instability (MSI) in DOCK2 mutant patients. In addition, DOCK2 mutation and the risk score were closely related to immune responses. In conclusion, the present study identifies a novel prognostic signature in light of DOCK2 mutation-related genes that shows great prognostic value in HCC patients; and this gene mutation might promote tumor progression by influencing immune responses. These data may provide valuable insights for future investigations into personalized forecasting methods and also shed light on stratified precision oncology treatment.
... Secretin is a peptide hormone produced in the S cells of the small intestinal mucosa [1]. It was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from the pancreas [2] and liver [3] and delays gastric emptying [4]. More recently, it has been implicated in the regulation of food intake [5], drinking behavior and water homeostasis [6][7][8], as well as motor behavior, learning and memory [9]. ...
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Secretin was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from the pancreas and liver and delays gastric emptying. In disease, a secretin receptor (SCTR) was found to occur as a splice variant in gastrinoma and pancreatic adenocarcinoma. Overexpression of SCTR has been described for gastrinomas, carcinoid tumors of the lung and cholangiocarcinoma. SCTR therefore is considered a candidate target for molecular tumor imaging as well as for peptide receptor radioligand therapy (PRRT) in a number of oncological indications. The aim of this study was to characterize SCTR expression in esophageal and pancreatic cancer, demonstrating for the first time high SCTR overexpression in these tumor types. In total, 65 of 70 pancreatic ductal adenocarcinoma tissues stained strongly positive for SCTR in immunohistochemistry, as did most of the 151 esophageal cancer samples, with minor influence of grading in both entities. In addition, the aim of this study was to further delineate residues in human secretin that are critical for binding to and activation of human SCTR. For a potential development of short and metabolically stable analogs for clinical use, it was intended to probe the peptide for its capacity to incorporate deletions and substitutions without losing its affinity to SCTR. In a systematic approach, a library of 146 secretin variants containing single amino acid substitutions as well as truncations on either end was tested in β-arrestin2-GFP translocation and fluorescent ligand internalization assays employing high-content analysis, in cAMP assays which run in agonist and antagonist mode, and in radioligand binding. The main structural determinants of SCTR binding and activation were localized to the N-terminus, with His1, Asp3 being among the most sensitive positions, followed by Phe6, Thr7 and Leu10. Aminoterminal truncation caused a rapid decline in receptor activity and most of these variants proved to be partial agonists showing antagonistic properties. In this study, the most potent novel antagonist showed an IC50 of 309 ± 74 nM in the β-arrestin2-GFP translocation assay on human SCTR while remaining a weak partial agonist. Future studies will have to demonstrate the utility of further enhanced secretin analogues as tracers for in vivo imaging and therapy.
... The identification of syndromes of uncontrolled hormone secretion from neuroendocrine neoplasms (NENs) significantly advanced our understanding of the physiology of several blood-borne substances such as peptide hormones and biogenic amines [1][2][3]. NENs are associated with secretory properties and specific syndromes of uncontrolled hormone hypersecretion, including Cushing, Verner-Morrison, Zollinger-Ellison, and other eponymic syndromes. The identification by Oberndorfer in 1907 of an intestinal "carcinoma-like" lesion, which he called "carcinoid," [4] was soon associated with symptoms of flushing and diarrhea [5] previously described for a case of "primary carcinoma of the ileum" [6]. ...
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... In mammals, an important mechanism namely, peristalsis is observed by medical doctors Bayliss and Starling [1]. Since this phenomenon is necessary for life of humans and animals, several investigators are carried out by engineers and mathematicians all over the world [2][3][4][5][6][7][8][9][10][11][12][13][14]. ...
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The study of gut hormones provides a unique microcosm as to how trends in drug discovery and development have evolved over the last century. With the elucidation of secretin in 1902, discovery of this first gut hormone led to a paradigm shift in how scientists viewed anatomical function. The emphasis was taken away from nerve-based theories and implicated these new chemical messengers in such processes. These chemical messenger proteins were termed “hormones,” and with over a century of hindsight, we now appreciate their huge importance. In the early days of hormone discovery, substances were administered to various animal models and secretions collected and purified to identify potential hormone content. However, nowadays the rapid refinement of scientific techniques, combined with exponential advancements in available technology have led to more elegant research technologies for discovery of other gut hormones. Furthermore, we now understand the full structure of these hormones, their processing from precursors, the enzymes by which they are degraded, their target receptors and the downstream signaling events elicited by receptor activation. Such advancements have been accompanied by synthesis of structurally modified gut hormone mimetics with improved half-life and/or potency over the native hormone, to be used as viable therapeutics for the management of an array of chronic conditions. This review considers many important gut hormones, providing an overview of their function, metabolism, and consideration of how modern peptide chemistry techniques have been employed to modify their structures to provide stable, long-acting and biologically effective peptide mimetics with therapeutic utility especially in diabetes and obesity.
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Diabetes mellitus (DM) is a worldwide ailment which leads to chronic complications like cardiac disorders, renal perturbations, limb amputation and blindness. Type one diabetes (T1DM), Type two diabetes (T2DM), Another types of diabetes, such as genetic errors in function of β-cell and action of insulin, cystic fibrosis, chemical-instigated diabetes or following tissue transplantation), and pregnancy DM (GDM). In response to nutritional ingestion, the gut may release a pancreatic stimulant that affects carbohydrate metabolism. The duodenum produces a ‘chemical excitant’ that stimulates pancreatic output, and researchers have sought to cure diabetes using gut extract injections, coining the word ‘incretin’ to describe the phenomena. Incretins include GIP and GLP-1. The ‘enteroinsular axis’ is the link between pancreas and intestine. Nutrient, neuronal and hormonal impulses from intestine to cells secreting insulin were thought to be part of this axis. In addition, the hormonal component, incretin, must meet two requirements: (1) it secreted by foods, mainly carbohydrates, and (2) it must induce an insulinotropic effect which is glucose-dependent. In this review, we clarify the ability of using incretin-dependent treatments for treating DM.
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Based on the classification of human hormones, there is no solid idea in most books. In this view, this article could exemplify a concrete solution, especially for medical and university students. Hormones have many life-saving roles in the human body. With the deficiency of hormones, our body might fall into lots of severe problems. Data analyses of much information from books, articles, as well as online supplements provided different ideas on the total hormones. The result suggested that some hormones were secreted from the same glands. Out of 110 hormones (when the same hormone produced from different sources), different types of hormones were 88. Analyzed hormones consisted of four major groups-amine (4 hormones), eicosanoid (4), steroid (15), and peptide (65) out of 88 endocrine chemicals. The endocrine and reproductive system (56) jointly secreted most of the hormones, and secondly gastrointestinal tract (26 hormones). Besides the organ system or glands, some were secreted from the cell, tissue, tissue system, and placenta. This paper also mentioned that many sex hormones were found both in males and females. In future, it is needed to enhance more research on the classification of the hormones in human body. MOTIVATION
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Peptide hormones are first produced as larger precursor prohormones that require endoproteolytic cleavage to liberate the mature hormones. A structurally conserved but functionally distinct family of nine prohormone convertase enzymes (PCs) are responsible for cleavage of protein precursors of which PC1/3 and PC2 are known to be exclusive to neuroendocrine cells and responsible for prohormone cleavage. Differential expression of PCs within tissues define prohormone processing; whereas glucagon is the major product liberated from proglucagon via PC2 in pancreatic α-cells, proglucagon is preferentially processed by PC1/3 in intestinal L cells to produce glucagon-like peptides 1 and 2 (GLP-1, GLP-2). Beyond our understanding of processing of islet prohormones in healthy islets, there is convincing evidence that proinsulin, proIAPP, and proglucagon processing is altered during prediabetes and diabetes. There is predictive value of elevated circulating proinsulin or proinsulin : C-peptide ratio for progression to type 2 diabetes and elevated proinsulin or proinsulin : C-peptide is predictive for development of type 1 diabetes in at risk groups. After onset of diabetes, patients have elevated circulating proinsulin and proIAPP and proinsulin may be an autoantigen in type 1 diabetes. Further, preclinical studies reveal that α-cells have altered proglucagon processing during diabetes leading to increased GLP-1 production. We conclude that despite strong associative data, current evidence is inconclusive on the potential causal role of impaired prohormone processing in diabetes, and suggest that future work should focus on resolving the question of whether altered prohormone processing is a causal driver or merely a consequence of diabetes pathology.
Chapter
This chapter provides an introduction to the importance of hormones to the healthy functioning of the human body and an overview of the varied types and sources of environmental chemicals that can interfere in their action. Such compounds, termed endocrine-disrupting chemicals (EDCs), may occur naturally, but the majority are man-made compounds that have been released into the environment without prior knowledge of their impact on animal welfare or human health. The chapter begins with some historical background, especially related to the endocrine-disrupting effects of EDCs in wildlife, and then outlines general mechanisms by which EDCs may disrupt hormone activity. Descriptions are then given of the range of compounds that are EDCs, their chemical structures, and the sources of exposure for the human population.
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The COVID‐19 pandemic has highlighted the vulnerability of people with diabetes mellitus (DM) to respiratory viral infections. Despite the short history of COVID‐19, various studies have shown that patients with DM are more likely to have increased hospitalization and mortality rates as compared to patients without. At present, the mechanisms underlying this susceptibility are unclear. However, prior studies show that the course of COVID‐19 disease is linked to the efficacy of the host’s T cell responses. Healthy individuals that can elicit a robust T cell response are more likely to limit the severity of COVID‐19. Here, we investigate the hypothesis that an impaired T cell response in patients with type 2 diabetes mellitus (T2DM) drives the severity of COVID‐19 in this patient population. Whilst there is currently a limited amount of information that specifically addresses T cell responses in COVID‐19 patients with T2DM, there is a wealth of evidence from other infectious diseases that T cell immunity is impaired in patients with T2DM. The reasons for this are likely multifactorial, including the presence of hyperglycaemia, glycaemic variability as well as metformin use. This review emphasises the need for further research into T cell responses of COVID‐19 patients with T2DM in order to better inform our response to COVID‐19 and future disease outbreaks.
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