GIT Function II Hormones PDF

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn GIT hormones Class Year 1 Course Gastrointestinal Biology Module Code GB8 Title GIT Hormones Lecturer Prof. Christopher Torrens...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn GIT hormones Class Year 1 Course Gastrointestinal Biology Module Code GB8 Title GIT Hormones Lecturer Prof. Christopher Torrens Presented by Dr Ebrahim Rajab Date 22/09/24 Learning Outcomes Describe the main factors, including hormones, that inhibit gastric acid secretion Describe secretin and cholecystokinin (CCK), including origin, function and factors influencing secretion Outline the main hormonal and neuronal control mechanisms that regulate exocrine pancreatic and biliary secretions, and secretions of Brunner’s glands Outline the role additional gastrointestinal hormones (motilin, serotonin, GIP, VIP, somatostatin) play in gastrointestinal function Describe how GIT hormones are involved in the control of food intake Hormones & Communication Autocrine – communication with the same cell Paracrine – communication with neighbouring cells Endocrine – communication with distance cells The term hormone can refer to all of these  Hormones & Communication In the GI tract there are lots of GI peptides/amines that have functions – only five currently considered to be hormones [i.e. they enter the systemic circulation; gastrin, cholecystokinin (CCK ), secretin, glucose- dependent insulinotropic peptide (GIP), and motilin) – some are endocrine, some paracrine and some neural These peptides are released from enteroendocrine cells that are distributed throughout the mucosa – not arranged in glands The duodenum and jejunum are sites for all hormones FIG. 1.4 Distribution of the – some also released in the antrum of the stomach gastrointestinal hormones. (gastrin) Shaded areas indicate where – and also the ileum the most release occurs under normal conditions. Gastrointestinal Physiology. L. R. Johnson Outline of Lecture 1) Major gastrointestinal hormones (there is some revision in this section!) a. gastrin and cholecystokinin (CCK) b. secretin c. various others 2) Non-gastric actions a. pancreatic acinar cells and bile b. duodenal Brunner’s glands 3) Regulation of food intake a. neurohumoral signals Gastric Phases Cephalic phase – initiated by sight, smell or thoughts of food – release of gastrin into blood – secretion of mucous, HCl and pepsinogen Gastric phase – stretching of stomach activates stretch receptors – stimulation of peristalsis (mixing) and gastric emptying Intestinal phase – begins with activation of receptors in the small intestines – Inhibition of gastric secretion by CCK and secretin – slows gastric emptying The basal gastric acid secretion during the inter-digestive period increases when food is anticipated or consumed. This is driven by mechanisms having their origin in the head (cephalic phase), stomach (gastric phase) and intestine (intestinal phase) Gastrin & Cholecystokinin (CCK) Gastrin and CCK are structural related peptide hormones that act at the CCK receptors Although longer peptides, both share the C-terminal sequence, and it is this that is essential for activity – Gastrin is 17 amino acids and CCK 33 – …Gly – Trp – Met – Asp – Phe This homology means they can each act at the other’s receptor – CCK-1 receptor in the gallbladder, predominantly CCK – CCK-2 (or gastrin) receptor in the stomach, predominantly gastrin  Gastrin Release The densest collection of gastrin containing cells (G cells) are in the antrum of the stomach – some in the duodenum but not really extending beyond that Gastrin release is trigger by different stimuli across each of the gastric phases – During the cephalic phase and the gastric phase Fig. 8.7 cephalic phase. (distension) released by vagovagal stimulation gastrin releasing hormone (GRP) is the neurotransmitter – In gastric and intestinal phase, breakdown of protein to amino acids also stimulates gastrin release Fig. 8.8 Gastric phase.  Gastrin Actions Gastrin acts on CCK-2 (gastrin) receptors in stomach to increase acid secretion from oxyntic/parietal cells – gastrin can also stimulate histamine, which also increases acid secretions but via a different pathway involving ECL cells Gastrin is a trophic agent and can stimulate the growth of stomach mucosa – also possibly involving histamine Overlap with CCK actions – can also stimulate the CCK-1 receptor Can increase splanchnic blood flow FIG. 15.16 Physiological mechanisms in the control of gastric acid secretion by the parietal cell. (From: Medical Sciences, Naish)  Cholecystokinin (CCK) Release CCK is released from I cells in upper small intestine – duodenum and jejunum although may well descend into iluem As with gastrin it is stimulated by proteins and fats – peptides and single amino acids for the protein – fatty acids or monoglycerides for the fats This involves the activation of sensory afferents although the I cells may be able to sense directly – as substrates are absorbed Cholecystokinin (CCK) Actions Most CCK actions are on the gallbladder and pancreas – hence the name (chole-cysto-kinin = bile-sac- move) – see later in this lecture The actions on gastric acid secretion are complicated by the overlap with gastrin /CCK-2 receptor – some action at CCK-2 increases/stimulates acid secretion – however, direct action via CCK-1 receptors is inhibition of acid secretion via release of somatostatin from D cells Also increases splanchnic blood flow Secretin Secretin shares a number of AA residues with GIP*, VIP** and glucagon It is released by S cells, mostly in the duodenum – stimulated by pH and, to a lesser extent, fatty acids triggered by secretin releasing peptide following activation of sensory afferent S cells may also have direct sensing of pH / fatty acids Main action is (stimulation of) secretions from pancreas & gallbladder – will also stimulate insulin from pancreas – decrease acid secretion (via somatostatin) and gastric motility (vagal) – and as with other peptides increase blood flow *GIP=gastric inhibitory polypeptide; **VIP=Vasoactive intestinal peptide FIG. 15.15 Neurohumoral mechanisms stimulating gastric, pancreatic and biliary secretions during the cephalic (A), gastric (B) and intestinal (C) phases of control (From: Medical Sciences, Naish) Other Hormones Somatostatin (released from delta or D cells in pancreas & stomach) – released in response to CCK and ACh that are stimulated by the increased blood glucose and amino acids after eating – actions are generally inhibitory, decreasing motility and acid secretions as well as blood flow Motilin is a peptide released from the mucosa* of the upper GI tract – released in ~90 min cycles, inhibited by ingestion of a meal – cause of migrating motor complex (rumbling), which may help clear foreign bodies (bones, fibre etc) – “this is the only known function for this hormone” *specifically, motilin is released from entero-endocrine or “Mo” cells Other Hormones Gastric inhibitory peptide (GIP) is stimulated by presence of food in upper small intestine – released from K cells in duodenum and jejunum – GIP inhibits gastric secretions and motility (hence name) but major action is stimulating insulin secretion – it’s now called glucose-dependent insulinotropic polypeptide – See later for actions of Tirzepatide/Mounjaro on this hormone Serotonin (5-HT) from the enterochromaffin cells appears to be involved in vomiting – some anti-emetics work by blocking 5-HT3 receptor on sensory afferent fibres (ondansetron) Outline of Lecture 1) Major gastrointestinal hormones a. gastrin and cholecystokinin (CCK) b. secretin c. various others 2) Non-gastric actions a. pancreatic acinar cells and bile b. duodenal Brunner’s glands 3) Regulation of food intake a. neurohumoral signals Pacreatic Secretions Pancreas has both endocrine and exocrine secretions – endocrine in the blood, exocrine into ducts Endocrine secretions are glucagon and insulin – not really the focus of this lecture The Exocrine secretions can be thought of as, – an aqueous component (mainly Na+ and HCO3-secreted by ductal epithelial cells) – a proteinaceous/enzymatic component (inactive precursors of the digestive enzymes secreted by acinar cells) PANCREAS http://www.nature.com/nrc/journal/v2/n12/fig_tab/ Pacreatic Secretions Exocrine secretory units are the lobules supplied by branches of the pancreatic duct – resemble a bunch of grapes The acinar cells secrete a small volume of protein-rich “juice” into the ducts – these are the inactive precursors of the digestive enzymes – trypsinogen, chymotrypsinogen etc This is diluted by a larger volume of aqueous solution from the ductal epithelial cells – mainly Na+ and HCO3- Control of pancreatic secretion The pancreas produces a basal secretion of enzymes and fluid during the interdigestive period. The parasympathetic nervous system is responsible for coordinating this secretory activity, aided by the hormone CCK. Pancreatic juice secretion during a meal increases up to 20 times that of the basal secretion. It is determined by stimulatory and inhibitory mechanisms. As with gastric juice, this occurs in three overlapping phases: cephalic, gastric and intestinal  Control of Pancreatic Secretion Cephalic phase Stimuli for this phase are the conditioned reflexes, smell, taste, chewing and swallowing. Afferent impulses travel to the vagal nucleus. Vagal ACh stimulates both acinar and ductal secretions Also, gastrin (released by the vagus) stimulates acinar cells; this mechanism occurs in dogs but whether it happens in humans is unclear FIG. 9.4 Mechanisms involved in the stimulation of pancreatic secretion during the cephalic phase. Dashed lines represent minor effects. ACh, Acetylcholine; HCO3–, bicarbonate; H2O, water. Gastrointestinal Physiology. L. R. Johnson. Control of Pancreatic Secretion Gastric phase Stimulation of pancreatic secretion originating from food in the stomach is mediated by the same mechanisms as the cephalic phase. Distension of the stomach wall initiates vagovagal reflexes to the pancreas. Gastrin is released by protein digestion products and distension (see gastric function lecture) but plays little/no role in the stimulation of the pancreas.  Control of Pancreatic Secretion Intestinal phase Presence of digestion products and H+ in small intestine accounts for 70-80% of the stimulation of pancreatic secretion. Secretin and CCK account for almost all the hormonal stimulation of pancreatic secretion. Secretin release, stimulated by acid and high concentrations of long chain fatty acids, stimulates the ductal cells to increase the aqueous solution – increases the volume and, because of the HCO3-, the pH CCK, stimulated by fat and protein digestion, stimulates the acinar cells to increase enzyme secretion FIG. 9.7 Mechanisms involved in the stimulation of pancreatic secretion during the intestinal phase in – does not appear to do this directly the human. Dashed lines indicate potentiative but via CCK stimulation of the vagal interactions. AAs, Amino acids; ACh, acetylcholine; CCK, cholecystokinin; FAs, fatty acids; H+, afferent fibres and initiation of hydrogen ion; HCO3–, bicarbonate; H2O, water. vagovagal reflexes Gastrointestinal Physiology. L. R. Johnson.  Bile Bile is secreted by liver cells called hepatocytes, stored in the gall bladder and released into duodenum – crucial for fat digestion, it consists of water, bilirubin, cholesterol, bile salts* and other fats ** Secretin stimulates water and bicarbonate secretion from bile ducts CCK acts on CCK-1 receptors to constrict the gall FIG. 10.1 Overview of the biliary system and bladder and relax the sphincter of Oddi** the enterohepatic circulation of bile acids. – releasing bile acids (into small intestine) *Bile salts are made of bile acids that are The vagus (via ACh) is also involved in gall conjugated with glycine or taurine. Solid arrows indicate active transport processes. bladder constriction ACh, Acetylcholine; Ca2+, calcium; CCK, cholecystokinin; Cl−, chloride; H+, hydrogen ion; HCO3–, bicarbonate; H2O, water; K+, potassium; Na+, sodium. From Johnson LR: Essential Medical Physiology, 3rd ed. Brunner’s Glands These are mucous secreting glands in the early part of the duodenum They secrete mucous and HCO3- that protects the duodenum from the acidic contents of the stomach Secretion is increased by presence of food in the duodenum (distention/irritation) and vagal stimulation – also secretin & CCK, themselves released by presence of food Secretion is decreased by sympathetic stimulation Outline of Lecture 1) Major gastrointestinal hormones a. gastrin and cholecystokinin (CCK) b. secretin c. various others 2) Non-gastric actions a. pancreatic acinar cells and bile b. duodenal Brunner’s glands 3) Regulation of food intake a. neurohumoral signals Control of Food Intake Central regulation of food intake occurs in the hypothalamus The hypothalamus receives signals (afferent pathways) from various neuro-humoral pathways – those involved in digestion but also emotion/behaviour/reward The two efferent pathways from the hypothalamus are: 1. Anorexigenic pathway - inhibition of food intake and increase of metabolism 2. Orexigenic - stimulation of food intake and inhibition of metabolism Central Control of Food Intake The inhibitory (anorexigenic) pathway is the melanocortin pathway – Pro-opiomelancortin (POMC) containing neurons in the hypothalamus release α-melanocyte-stimulating hormone (α-MSH) which binds to melanocortin receptors (MC4) present on 2nd order neurons to inhibit food intake and stimulate metabolism Stimulatory (orexigenic) pathway involves neuropeptide Y (NPY) – Hunger signals stimulate the release of NPY, which binds to Y1 receptors to increase feeding behaviour and the storage of calories. this neurotransmitter leads to increased food intake and inhibits metabolism FIG. 8.66 Central pathways involved in feeding. CCK, cholecystokinin. From: Medical Sciences, Naish  Central Control of Food Intake The inhibitory and stimulatory pathways are mutually exclusive; it would make little sense for both pathways to be operating at the same time. Stimulation of the POMC pathway inhibits NPY and vice versa. – The NPY system also releases agouti- related peptide (AgRP) which is an antagonist of the MC4 receptor. – Peptides that stimulate the melanocortin system inhibit the NPY system. FIG. 13.1 Integration of signals regulating food intake and metabolism by the components of the arcuate nucleus of the hypothalamus. AgRP, Agouti-related peptide; MC4R, melanocortin receptor; αMSH, α-melanocyte- stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin. Gastrointestinal Physiology. Leonard R. Johnson. Food Intake – Peripheral regulation The vagus nerve contains numerous afferent fibres that rely information back to vagal nuclei in the nucleus tractus solitarius of the brain – In some cases, this input causes an efferent signal also relayed by vagal nerves that result in a change in gut function: “vagovagal reflex” (see gastric function lecture) – Vagal stimulation induces satiety (a feeling of fullness) and inhibits feeding – blocking of the vagal afferent eliminates satiety Insulin from pancreatic β-cells following a meal, acts directly on the hypothalamus to induce satiety Leptin released from adipocytes, stimulates the POMC pathway and inhibits the NPY pathway; overall it induces satiety Food Intake – Gastric (inhibitors) Local gastric stimuli pass information back to the hypothalamus Distension of the stomach stimulates vagal afferents and inhibition of feeding CCK released due to presence of food in the small intestine stimulates satiety and inhibition of feeding – both by stimulating vagal afferents and insulin release Peptide YY released by enteroendocrine cells of the ileum and colon by fat digestion products ; it stimulates satiety – direct inhibition of NPY orexigenic nerves Food Intake - Stimulants Ghrelin is released from oxyntic glands* in the stomach – probably also released from extra-gastric sites too – stimulates release of growth hormone and directly stimulates orexigenic NPY neurons (increased food intake!) – ghrelin release is not affected by protein intake or distention Dopaminergic neurons from the ventral tegmental area (VTA) of the midbrain (reward pathways) – sight, smell taste of food etc – These can influence the hypothalamus but are also equally affected by ghrelin and leptin etc (*P/D1 cells release ghrelin)  Additional Peptides (not examinable) Other peptides from the GI tract have been shown to inhibit food intake and may have anorectic (=appetite loss) functions. Glucagon-like peptide 1 (GLP-1): effects on brainstem; inhibits food intake, stimulates insulin release and inhibits gastric function. – Semaglutide/Ozempic is a GLP-1 agonist – Tirzepatide/Mounjaro is a GIP and GLP- 1 agonist Oxyntomodulin (OXM): effects on arcuate nucleus; inhibits food intake Pancreatic polypeptide (PP): inhibits food intake. Mechanisms of action of GIP, GLP-1 and their agonists. Bass et al. (2023). Control of Food Intake Fasted State Fed State Hypothalamus NPY POMC Food intake Food intake  Ghrelin  Ghrelin  Insulin  Insulin  leptin  leptin Summary Trigger Hormones Gastrin CCK Secretin GIP Motilin Acid      Carbohydrate      Fats      Protein      Distension      Nervous      Summary Action Hormones Gastrin CCK Secretin GIP Motilin Acid Secretion     Gastric emptying     Pancreatic Secretion     Gastric motility      Intestinal motility     Insulin release     Is it a GI Hormone? Step 1: Does a meal or other physiological event provide a stimulus for one part of the GI tract to affect another? Step 2: Does this affect persist after nervous communication between those parts is removed? Step 3: Can you isolated a substance from the site of the stimulus that when injected mimics the effect of the stimulus? Step 4: Can you identify the substance chemically and synthesise it? If yes to all of these, you’ve found a new GI hormone – currently only gastrin, CCK, secretin, GIP and motilin fit this but many other candidates exist that don’t yet answer all four Qs Try summarising this information in a table Hormone/ source Stimulus Target Action peptide organ Gastrin CCK Secretin Somatostati n Motilin GIP Serotonin Additional Information Ganong’s Review of Medical Physiology Dr Ebrahim Rajab [email protected] Additional Information that you may find useful but is not examinable…