GIT Hormones 2024_updated.pdf

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn GIT hormones Class Year 2 Course GIHEP Title GIT Hormones Lecturer Simon Furney Date 23/09/24 Learning Outcomes Describe the main factors, including hormones, that i...

RCSI Royal College of Surgeons in Ireland Coláiste Ríoga na Máinleá in Éirinn GIT hormones Class Year 2 Course GIHEP Title GIT Hormones Lecturer Simon Furney Date 23/09/24 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 – 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 – some also released in the antrum of the stomach (gastrin) – and also the ileum 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 b. Bile and gall bladder c. 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 by CCK and secretin and slows gastric emptying Gastrin & Cholecystokinin (CCK) Gastrin and CCK are structurally related peptide hormones that act at the CCK receptors Although different length peptides, both share the C-terminal sequence and it is this that is essential for activity – …Gly – Trp – Met – Asp – Phe This homology means they can each act at the other’s receptor – CCK-1 in the gallbladder, predominantly CCK – CCK-2 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 triggered by different stimuli across each of the gastric phases During the cephalic phase and the gastric phase (distension) released by vagovagal stimulation – gastrin releasing peptide (GRP) is the neurotransmitter In gastric and intestinal phase, breakdown of protein to amino acids also stimulates gastrin release Gastrin Actions Gastrin acts on CCK-2 receptors to increase acid secretion from parietal cells – gastrin can also stimulate histamine, which also increases acid secretions but via a different pathway 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 Gastrin Actions (Parietal Cell) Histamine AC cAMP +ve ACh H+ PLC ATPase IP3 Gastrin K+ K+ Oxyntic cell Stomach lumen Interstitial space 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 below The actions on gastric acid secretion are complicated by the overlap with gastrin receptor – some action at CCK-2 increases 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 Parietal Cell – Acid Secretion Somatostatin PGE2 CCK Histamine AC cAMP ACh +ve H+ PLC ATPase IP3 Gastrin K+ K+ Oxyntic cell Stomach lumen Interstitial space Secretin Secretin belongs to a different group of peptides – it shares a number of aa residues with GIP (Gastric inhibitory peptide), VIP (Vasoactive intestinal peptide) 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 secretions from pancreas & gallbladder – will also stimulate insulin from pancreas – decrease acid (via somatostatin) and gastric motility (vagal) – and as with other peptides increase blood flow Other Hormones Somatostatin (delta or D cells in pancreas & stomach) – released in response to H+, 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 Other Hormones 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” 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 peptide 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 b. Bile and gall bladder c. duodenal Brunner’s glands 3) Regulation of food intake a. neurohumoral signals Pancreatic 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 Exocrine secretions can be thought of as an aqueous component and a proteinaceous/enzymatic component These are secreted by the ductal epithelial cells and the acinar cells respectively Pancreatic 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 (CCK) – these are the inactive precursors of the digestive enzymes – trypsinogen, chymotrypsinogen etc This is diluted by a larger volume of aqueous solution by the ductal epithelial cells (Secretin, potentiation by CCK) – mainly Na+ and HCO3- Control of Pancreatic Secretion Cephalic & Gastric phase – vagal ACh stimulates both acinar and ductal secretions – gastrin stimulation of acinar cells? (questionable in humans)  Control of Pancreatic Secretion Intestinal phase – secretin, stimulated by acid, 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 – Via its stimulation of the vagal afferent fibres (ACh) Control of Ductular Secretion Gall bladder - Bile Bile is secreted by 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 bladder and relax the sphincter of Oddi – releasing bile acids The vagus is also involved in gall bladder constriction Gall bladder - Bile 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 b. Bile and gall bladder c. 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 from various neuro- humoral pathways – those involved in digestion but also emotion/behaviour/reward The two efferent pathways from the hypothalamus are: 1. inhibition of food intake and increase of metabolism 2. stimulation of food intake and inhibition of metabolism (orexigenic) Control of Food Intake The inhibitory pathway is the melanocortin pathway Pro-opiomelanocortin (POMC) containing neurons release α-melanocyte-stimulating hormone (α-MSH) – these activate nerves and stimulate metabolism Stimulatory (orexigenic) pathway involves neuropeptide Y (NPY) – this neurotransmitter leads to increased food intake The two pathways are mutually exclusive – stimulation of the POMC pathway inhibits NPY and vice versa Food Intake - Peripheral The vagus nerve contains numerous afferent fibres that relay information back to the brain – see vagovagal reflex from gastric function Vagal stimulation induces satiety 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 Food Intake - Gastric 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 – both by stimulating vagal afferents and insulin release Peptide YY released by enteroendocrine cells by digestion products stimulates satiety – direct inhibition of NPY orexigenic nerves Food Intake - Stimulants Ghrelin is released from oxyntic glands in the stomach – probably from extra-gastric sites too Ghrelin stimulates release of growth hormone and acts directly on orexigenic NPY neurons – 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 both influence the hypothalamus but are also equally affected by ghrelin and leptin etc CCK, Cholecystokinin NPY, neuropeptide Y NTS, nucleus tractus solitarius POMC, pro-opiomelanocortin PYY, peptide YY  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 Enzyme £ £ £ £ Secretion Gastric motility £ £ ¤ ¤ £ Intestinal motility £ £ ¤ £ Insulin release £ £ £ £ Additional Information Gastrointestinal Physiology, Leonard R. Johnson Netter's Essential Physiology Berne & Levy Physiology