Discovery Of Secretin Research Articles

The blurring of the margins of endocrinology and its relevance to the paediatric endocrinologist

The word hormone was coined a century ago by Baylissand Starling when they described the discovery ofsecretin (1, 2). Coupled with the knowledge thathormones were chemical messengers produced at onesite but mediating their actions at a distal site, thespecialty of endocrinology has traditionally focussed ondiseases associated with endocrine glands producingeither excessive or inadequate amounts of hormone.Later, it became apparent that a range of disorders weredue to hormone resistance, characterised by lack ofresponse to a hormone despite normal or usuallyincreased circulating concentrations of the cognatehormone (3). Disorders of the mainstream endocrineglands (pituitary, thyroid and parathyroids, adrenals,gonads and pancreas) still provide the basis for thesyllabus in endocrinology, but now enhanced by theemergence of other organs that also produce hormones.These include the heart, lungs, kidneys, liver, gut andbrain. To this list must be added the skin (the largestorgan in the body), the vascular endothelium, bone andcartilage and fat tissue.Adipose tissue has assumed prime of place inendocrinology with the emergence of obesity as amajor disease affecting a large proportion of thepopulation. The adipocyte is a veritable factory ofhormones producing adipokines such as leptin, resistinand adiponectins. How these relate to appetite controland metabolic balance is now the subject of massiveresearch not only in basic endocrinology, but also in thepharmaceutical industry. How does the paediatricendocrinologist relate to this widening of the boundariesto endocrinology?Paediatric endocrinology as a specialty is a relativenewcomer on the endocrine scene and indeed, nurturedby a non-paediatric physician. The textbook realised byLawson Wilkins etal.on the diagnosis and managementof treatment of endocrine disorders in childhood andadolescence (4) remains a classic of clinical descriptionseven if it is long outdated on the biochemical aspects ofthe subject. The study of growth and puberty hasalways signalled out the paediatrician from the adultendocrinologist. Since growth is generally an indicatorof health and well being in infants and children, theclinical practice of the paediatric endocrinologist islocked in to mainstream paediatrics. Seldom does thepaediatric endocrinologist ‘stray’ into the territory of theadult endocrinologist for clinical practice or vice versa.That must be so inviewof the different skills and trainingneeded to practice at different points of the age span. Theadult physician would not be expected to manage theinfant with ambiguous genitalia of the newborn anymore than the paediatrician would be expected tograpple with a complexcase of acromegaly. Nevertheless,the boundaries of endocrinology are now becoming soblurred that it is incumbent on endocrinologists ofwhatever ilk to at least be aware of the mushroomingbreadth of the subject and consider facets that may berelevant to individual clinical practice.Take, for example, the concept of programmed eventsactivated in foetal life or in early infancy and then onlymanifest in some measurable format in adult life. Thephenomenon now considered under the umbrella titleof ‘developmental origins of adult disease’ (5) trans-cends virtually the whole of clinical medicine. Its originis within the purview of the paediatric endocrinologist,who is knowledgeable about the causes of foetal growthrestraint, its consequences at birth and early infancy,whether it is followed by catch-up growth or not, andhow this may affect puberty thereafter. Yet, it is still notpossible to determine precisely what triggers puberty inhumans at around 10–11 years of age. Each review ofthe subject over the past 20 years has made someheadway in completing the jigsaw, the most recentadding the GPR54 kisspeptin receptor and environ-mental chemicals to the multi-component model of thecontrol of the onset of puberty (6). The paediatricendocrinologist in clinical practice is not party to theadult consequences of foetal growth restraint asmanifested by the metabolic syndrome and subsequentcardiovascular disease. Indeed, the associations withfoetal growth stretch beyond the classic metabolicsyndrome to include reproductive abnormalities, somecancers and certain psychiatric diseases. This broad-ening of the horizon by viewing with a wide-angle lensis the concept developed in the programming for the‘Fourth Ferring Pharmaceuticals Paediatric Endo-crinology Symposium’ and recorded in print in this

Secretin and the exposition of hormonal control.

Secretin and the exposition of hormonal control.

Secretin, 100 years later.

One hundred years have elapsed since the discovery of secretin by Bayliss and Starling in 1902. In the past century, the research of secretin has gone by many milestones including isolation, purification and structural determination, chemical synthesis, establishment of its hormonal status by radioimmunoassay and immunoneutralization, identification of the specific receptor, cloning of secretin and its receptor, and identification of a secretin-releasing peptide. It has become clear that secretin is a hormone-regulating pancreatic exocrine secretion of fluid and bicarbonate, gastric acid secretion, and gastric motility. The release and actions of secretin is regulated by hormone-hormonal and neurohormonal interactions. The vagus nerve, particularly its afferent pathway, plays an essential role in the physiological actions of secretin. Substantial information about the property of the secretin receptor has been accumulated, but a potent secretin receptor-specific antagonist remains to be formulated. The neural regulatory mechanisms of the release and action of secretin await further elucidation. The physiological role of secretin in intestinal secretions and motility and extragastrointestinal organs remains to be defined. The presence of secretin and its receptor in the central nervous system is well documented, but its function as a neuropeptide has been recognized gradually and requires extensive study in the future.

The entero-insular axis in type 2 diabetes--incretins as therapeutic agents.

The search for intestinal factors regulating the endocrine secretion of the pancreas started soon after the discovery of secretin, i.e. nearly 100 years ago. Insulinotropic factors of the gut released by nutrients and stimulating insulin secretion in physiological concentrations in the presence of elevated blood glucose levels have been named incretins. Of the known gut hormones only gastric inhibitory polypeptide (GIP) and glucagon-like polypeptide-1 (GLP-1 [7-36] amide) fulfill this definition.--The incretin effect (i.e. the ratio between the integrated insulin response to an oral glucose load and an isoglycaemic intravenous glucose infusion) is markedly diminished in patients with type 2 diabetes mellitus, while the plasma levels of GIP and GLP-1 and their responses to nutrients are in the normal range. Therefore, a reduced responsiveness of the islet B-cells to incretins has been postulated. This insensitivity of the diabetic B-cells towards incretins can be overcome by supraphysiological (pharmacological) concentrations of GLP-1 [7-36], however not of GIP. Accordingly, fasting and postprandial glucose levels can be normalized in patients with type 2 diabetes by infusions of GLP-1 [7-36]. Further studies revealed that this is partially due to the fact that GLP-1 [7-36]--in addition to its insulinotropic effect--also inhibits glucagon secretion and delays gastric emptying. These three antidiabetic effects qualify GLP-1 [7-36] as an interesting therapeutic tool, mainly for type 2 diabetes. However, because of its short plasma half life time natural GLP-1 [7-36] is not suitable for subcutaneous application. At present methods are being developed to improve the pharmacokinetics of GLP-1 by inhibition of the cleaving enzyme dipeptidyl peptidase IV (DPP-IV) or by synthesis of DPP-IV resistant GLP-1 analogues. Also naturally occurring GLP-1 analogues (for instance exendin-4) with a much longer half life time than GLP-1 [7-36] are being tested.--Thus, after 100 years of speculations and experimentations, incretins and their analogues are emerging as new antidiabetic drugs.

The cholecystokinin--gastrin family of peptides and their receptors.

The two major gastrointestinal hormones, gastrin and cholecystokinin (CCK), were discovered at the beginning of this century. In the immediate wake of Bayliss and Starling’s breakthrough discovery of secretin — the first hormone to be known (1902) — Edkins from the same institute in London suggested that the antral mucosa of the stomach released a specific gastric acid stimulating factor to blood. He named the factor gastrin, an abbreviation of “gastric secretin” (Edkins 1905). Hence, gastrin was the second peptide hormone to be discovered in the history of biology. Twenty three years after Edkins’ discovery, Ivy and Oldberg in Chicago found the third gastrointestinal hormone, CCK, as a new gallbladder emptying factor present in extracts of the small intestinal mucosa (1928). The painstaking efforts to purify and identify the structure of secretin and CCK began in the middle of this century in Stockholm. During this work Jorpes and Mutt (1966) realized that CCK is identical to pancreozymin, the fourth gastrointestinal hormone, which was described by Harper and Raper from Newcastle-upon-Tyne (1943). Pancreozymin regulates the exocrine secretion of enzymes from the pancreas.

Localization of the Gene Encoding the Secretin Receptor, SCTR, on Human Chromosome 2q14.1 by Fluorescencein SituHybridization and Chromosome Morphometry

It has been over 90 years since the discovery of secretin, a duodenal mucosal hormone that stimulates the secretion of bicarbonate, enzymes, and potassium ions by the pancreas. It is now known that secretin is one of the most potent physiological regulators of bicarbonate, water, potassium ion, and enzyme secretion from the pancreas. Other pharmacological actions of secretin have also been reported, with effector tissues throughout the body, including the brain, heart, stomach, intestine, and kidney. The rat secretin is a 27-amino-acid peptide that is synthesized as a precursor protein of 134 amino acids in specific endocrine cells. The nucleotide sequence analysis of the cDNA has revealed that the secretin receptor is a new type of the G protein-coupled receptor with seven transmembrane segments. 9 refs., 1 fig.

Pavlov as a psychophysiological scientist

It is suggested that Pavlov was not only a famous physiologist, but due to his work on the conditional reflex, he could be considered a behavioral scientist. In addition his work on experimental neurosis gives him the distinction of being a pioneer investigator in the area of psychological stress. Pavlov's research is viewed against a background of primitive research tools and unproductive subjective theories. Nineteenth century scientists who influenced Pavlov included Darwin, Botkin, Heidenhain, Gaskell and Bernard. Pavlov's research on the digestive system emphasized the role of the nervous system, launched the field of gastroenterology, and emphasized the concept of the conditional reflex. Pavlov's conditional reflex formulations were based on the theoretical formulations of Sechenov, and possibly the work of David Hartley. The discovery of secretin, by Bayliss and Starling, and its influence on the stomach led Pavlov to diminish his work on the digestive system and to focus his research on the conditional reflex phenomenon. Arguments which suggest that Pavlov worked as a behavioral scientist include his conceptual formulations, his research on traditional psychological topics and his investigation of psychiatric disorders. His conditioning research emphasized the individual differences of his animal subjects which led to his research on typology and experimental neurosis which formed the basis for his work on environmental Stressors and psychopathology.

The Significance of the Discovery of Secretin

The Significance of the Discovery of Secretin

Sir William Bayliss, F.R.S

“UAYLISS'S book is bv far his greatest contribution to science-much more important than any of his individual discoveries is his statement of his point of view.” These were substantially the words used to me by a very competent critic. At the time I wondered whether or not it were so, and I have often wondered since. Bayliss's investigations into the electric phenomena of the heart x and the salivary glands,2 into the conditions which govern the cerebral circulation,3 into the muscular movements of the alimentary canal,4 into the mechanism of vaso-dilatation,5 into the correlation of vaso-motor reflexes;6 his establishment of the existence of antidromic fibres in the mammal,7 his researches on the application of surface phenomena to physiological action,8 and the discovery of secretin these were his principal discoveries.