Gastrointestinal Hormones by Pandian M, Dept of Physiology DYPMCKOP, for MBBS, BPTH,Nursing, BDS other paramedical students

Classify GIT hormones
List the source and functions of different GI hormones
Explain the mechanism of action and regulation of secretion of different GI Hormones
Describe the role of GI hormones in regulation of GI functions
Explain the dysfunctions produced by alteration in secretion of GIT hormones

1. Gastrointestinal Hormones Pandian M Dept of Physiology DYPMCKOP

2. Describe the source of GIT hormones, their regulation and functions Classify GIT hormones List the source and functions of different GI hormones Explain the mechanism of action and regulation of secretion of different GI Hormones Describe the role of GI hormones in regulation of GI functions Explain the dysfunctions produced by alteration in secretion of GIT hormones

3. Learning Objectives The student will be able to: ( MUST KNOW ) 1. Classify GI hormones. 2. Name the source and functions of GI hormones. 3. Appreciate the role of GI hormones in the regulation of GI functions. 4. Understand the dysfunctions produced by alteration in secretion of GI hormones .

4. INTRODUCTION The hormones secreted from the endocrine cells of the GI tract are collectively known as gastrointestinal hormones ( GI hormones ). Endocrine cells that secrete GI hormones are called enteroendocrine cells . Cells that secrete serotonin are called enterochromaffin cells , and cells that secrete amines and polypeptides are called APUD cells (amine precursor uptake and decarboxylation). APUD cells are also found in other organs like lungs. They are also called neuroendocrine cells . Carcinoid tumors originate from these neuroendocrine cells.

5. TYPES OF GI HORMONES: 1.  Gastrin family that includes cholecystokinin and gastrin. 2.  Secretin family that includes GIP, glucagon, secretin, and VIP. 3.  Other polypeptides .

6. GI HORMONES OF GASTRIN FAMILY Gastrin Source Gastrin is produced by G cells in the stomach that are located mainly in the antral region. G cells are conical cells with apex projecting towards the lumen. Apical surface of G cells contains numerous microvilli. Microvilli of G cells contain receptors for chemicals that mediate gastrin release. Gastrin producing cells are also present in hypothalamus, anterior pituitary, medulla and fetal pancreas. Gastrin as a neurotransmitter is also secreted from vagus and sciatic nerve .

7. Structure Gastrin is a polypeptide hormone . Gastrin exhibits both macroheterogeneity and microheterogeneity . TYPES OF GASTRIN: Depending on the number of amino acids they possess, they are named as G 34, G 17 and G 14. Other types of gastrins are C- tetrapeptide (carboxyl terminal tetrapeptide , which is also called minigastrin ), and gastrin containing 45 amino acids ( megagastrin ). However, G 17 is the principal gastrin secreted from the stomach and is the major stimulator of gastric acid secretion. Though C- tetrapeptide executes all the actions of G-17, it has only 10% of its physiological strength.

8. Metabolism Gastrin secreted from G cells enters general circulation. In blood, half-life of gastrin is less. Half-life of G 14 and G 17 is 2–5 min and of G 34 is about 15 min. Gastrin is inactivated in the intestine and degraded in the kidney. Functions 1. Stimulation of gastric acid and pepsin secretion . 2. Gastrin stimulates growth of gastric mucosa and mucosa of intestine. This is called trophic action of gastrin. 3. It stimulates gastric motility . 4. It causes contraction of muscles at the gastro-esophageal junction 5. It stimulates exocrine pancreatic secretion. 6. It also stimulates insulin secretion . 7. It stimulates mass movement of large intestine. 8. It causes colonic contraction that initiates gastrocolic reflex after a meal. Therefore, usually defecation is activated after a meal. 9. It stimulates histamine secretion from ECL ( enterochromaffin like cells) in GI mucosa.

9. Mechanism of Action Gastrin acting on gastrin or CCK receptors on parietal cells increases intracellular calcium concentration via second messenger, IP3. Increased cytosolic calcium activates protein kinase that stimulates H+–K+ ATPase to promote acid secretion. Control of Gastrin Secretion   1. Stimuli that increase gastrin secretion: Gastric distention, products of protein digestion in the stomach, increased vagal discharge via GRP ( non-cholinergic ), epinephrine and calcium. Hypergastrinemia occurs in Zollinger -Ellison syndrome . Gastrin secretion is also elevated in pernicious anemia , in which acid secretion in the stomach is less as parietal cells are damaged. This causes feedback release of gastrin from G cells.

10. 2. Stimuli that decrease gastrin release: Acid in the stomach, somatostatin , secretin, GIP, VIP, calcitonin and glucagon. Acid in the antrum inhibits gastric secretion by negative feedback mechanism , which is partly by direct action of acid on G cells and partly by release of somatostatin .

11. Cholecystokinin Source Secreted from I cells in the mucosa of upper small intestine . CCK is present as neurotransmitter in cerebral cortex, in somatic nerves and in nerves of distal ileum and colon. Structure Cholecystokinin (CCK) is a polypeptide hormone. There are different forms of CCK depending on the number of amino acids present, like CCK 58, CCK 39, CCK 33, CCK 12, CCK 8, and CCK 4 (carboxyl terminal tetrapeptide ). CCK secreted from duodenum and jejunum are usually CCK 12 and CCK 8. CCK in the enteric and pancreatic nerves is mainly CCK 4. The forms of CCK in brain are primarily CCK 58 and 8. Half-life of CCK is about 5 minutes .

12. Functions 1. CCK causes contraction of gall bladder and increases bile release . 2. It stimulates pancreatic secretion rich in enzymes . Therefore, CCK is also called cholecystokinin- pancreozymin (CCK-PZ). 3. It also augments the action of secretin to produce alkaline pancreatic secretion. 4. It inhibits gastric acid secretion . 5. It inhibits gastric motility , thereby delays gastric emptying . 6. Causes relaxation of sphincter of Oddi that allows both bile and pancreatic juice to enter duodenum. 7. Stimulates growth of pancreas.

13. 8. Increases secretion of enterokinase . 9. Enhances motility of small intestine. 10. Stimulates colonic movements . This action mediates gastrocolic reflex. 11. Augments contraction of pyloric sphincter. Therefore, prevents reflux of duodenal contents into the stomach. 12. Stimulates glucagon secretion. 13. In brain, it acts as an anorexigenic neurotransmitter. It inhibits food intake . 14. It also produces analgesia and anxiety.

14. Mechanism of Action There are two CCK receptors : CCK A and CCK B. CCK A receptors are mainly located in the peripheral structures like gall bladder, pancreas, GI tract etc. CCK B receptors are present in central structures like brain areas. CCK acting on both receptors activates membrane phospholipase–C and stimulates production of intracellular IP3 and DAG. Regulation of Secretion Factors that increase CCK secretion 1. Contact of intestinal mucosa with products of digestion especially fatty acids, peptides and amino acids . 2. Bile and pancreatic juice: Bile and pancreatic juice facilitate digestion of protein and fat. Therefore, they provide positive feedback for CCK secretion .

15. GI HORMONES OF SECRETIN FAMILY Secretin   Source - S cells located in the mucosa of upper part of small intestine. Structure - Polypeptide hormone containing 27 amino acids. Functions 1. Secretin increases secretion of pancreatic juice rich in bicarbonate (watery and alkaline pancreatic secretion). 2. It also increases alkaline bile secretion . 3. Augments the action of CCK to produce pancreatic secretion rich in enzymes. 4. Decreases gastric acid secretion and motility. 5. Causes contraction of pyloric sphincter.

16. Mechanism of Action Secretin acts on adenylate cyclase on the cell membrane and increases cytosolic formation of cAMP . Regulation of Secretion Secretion of secretin is increased by acidic chyme and products of protein digestion entering the upper part of intestine. Secretin stimulates watery and alkaline pancreatic secretion. When watery and alkaline pancreatic juice enters intestine, the acidic content of upper small intestine is neutralized. The increased pH of duodenal and upper jejunal content decreases secretin secretion by feedback mechanism

17. GIP Structure Glucose-dependent insulinotropic polypeptide (GIP) is a polypeptide hormone containing 42 amino acids. This is also called gastric inhibitory peptide (GIP). Source GIP is produced by K cells present in the mucosa of duodenum and jejunum. Functions 1. It inhibits gastric secretion and motility . 2. It stimulates insulin secretion . For this function, GIP is considered as an important physiological regulator of insulin secretion .

18. Though other hormones like gastrin, CCK, secretin and glucagon also stimulate insulin secretion, plasma insulin level of insulin in response to GIP resembles the concentration of insulin attained following oral glucose ingestion. Therefore, GIP is called glucose-like insulinotropic polypeptide . However, GLP-1, derived from glucagon appears to be more potent than GIP in promoting insulin secretion. Hence, both GIP and GLP-1 are among the important physiological regulator of insulin secretion from beta cells of pancreas. Regulation of Secretion Secretion of GIP is increased by glucose and fat in the duodenum

19. VIP Structure : Polypeptide containing 28 amino acids. It is formed from prepro -VIP that contains both VIP and PHM-27, a closely related peptide. Source VIP is secreted from mucosal cells of entire GIT, starting from stomach to colon. It is found in the nerves of GIT, other autonomic nerves, blood and also in brain. Its half-life is 2 minutes. Functions 1. VIP markedly increases intestinal secretion rich in electrolytes and water . Therefore, in excess it produces watery diarrhea . 2. It causes vasodilation . Therefore, it decreases blood pressure .

20. 3. It decreases GI motility . It causes relaxation of intestinal smooth muscle including sphincters. 4. It potentiates the action of acetylcholine on salivary glands. 5. It inhibits gastric acid secretion . Clinical Significance The tumor of VIP secreting cells is called VIPoma . Profuse watery diarrhea and hypotension are major features of VIPoma .

21. Glucagon This is structurally similar with glucagon secreted from A (α) cells of pancreas. In GIT, it is secreted from A cells in the stomach and L cells in intestine, where it is known as enteroglucagon . This produces hyperglycemia. SOURCE : Glucagon is mainly produced from A (α) cells in pancreas and L cells in intestine . A cells: In A cells, preproglucagon is processed to form glucagon and major proglucagon fragments (MPGF). L cells: In L cells, it is processed to form glucagon, glicentin and glucagon-like peptides (GLP). Both A and L cells also produce oxyntomodulin and glicentin related polypeptide (GRPP)

22. Glucagon-Like Polypeptides: GLP 1 and GLP 2 and both are also produced in brain. GLP 1 is a potent stimulator of insulin secretion. GLP 2 does not have definitive biological activity. However , GLP 2 produced in the brain inhibits food intake and acts as a neurotransmitter in the neurons that project from NTS to dorsomedial nucleus of hypothalamus. Oxyntomodulin & GRPP Both A and L cells also produce oxyntomodulin and glicentin -related polypeptide (GRPP). Oxyntomodulin inhibits gastric acid secretion.

23. OTHER GI HORMONES Motilin Structure & Source This is a polypeptide hormone containing 22 amino acids. It is secreted from enterochromaffin cells and Mo cells present in the mucosa of all parts of GIT, except esophagus and rectum. It acts on G-protein coupled receptors on enteric neurons. Functions It causes contraction of intestinal smooth muscle and therefore, increases GI motility , especially in the interdigestive phase. It is a major regulator of migrating motor complex (MMC), that regulates GI motility between meals.

24. Secretion of motilin is decreased following ingestion of a meal and its concentration remains low until the digestion and absorption of that meal is complete. Then the concentration increases and activates MMC that sweeps and cleans the intestine. Thus, it prepares the intestine for next meal. Applied Physiology Erythromycin can be used in patients having hypomotility of GI tract, as this antibiotic and its derivative bind to motilin receptors and facilitate intestinal motility.

25. Other Peptides Neurotensin This is a polypeptide hormone containing 13 amino acids. It is produced by neurons and mucosal cells of intestinal epithelium, mainly in ileum. It inhibits GI motility but increases ileal blood flow. GRP Gastrin releasing polypeptide (GRP) is a polypeptide containing 27 amino acids. It is secreted from non-cholinergic vagal fibers. It mediates gastrin release via non-cholinergic vagal stimulation . The 10 amino acid residues at the carboxyl terminal of GRP is almost similar to the bombesin of amphibians.

26. Somatostatin This is a polypeptide containing either 14 ( SS 14 ) or 28 ( SS 28 ) amino acids. Somatostatin is secreted from GIT, hypothalamus and D cells of pancreas. It inhibits gastrin secretion. It also inhibits secretion of VIP, GIP, secretin, and motilin . It is an inhibitory neurotransmitter in many parts of brain, especially in hypothalamus and pituitary. Guanylin Structure and Source This is a polypeptide hormone containing 15 amino acids. It is secreted from the cells of intestinal mucosa. In human, it is produced by Paneth cells (endocrine cells located in the crypts of Lieberkuhn of small intestine).

27. Mechanism of Action It acts by stimulating the activity of guanylyl cyclase which increases the concentration of cGMP . The cGMP in turn increases activity of chloride channels and increases chloride secretion into the intestine. Functions Guanylin increases secretion of chloride ions into the intestinal lumen and therefore regulates fluid movement across intestinal tract. Guanylin receptors are present in kidney, liver and female reproductive tract. In these organs, guanylin appears to control fluid movement and particularly integrates the actions of intestine and kidneys. Applied Physiology Enterotoxins of some strains of E. coli that cause diarrhea have structural similarity with guanylin . They activate guanylin receptors in intestine and produce fluid secretion into the intestinal lumen.

28. TRH This is structurally similar to the hypothalamic TRH. But, as it does not enter circulation, it does not produce any effect on thyroid. However, it is involved in the regulation of secretory immunity of intestine. ACTH Structurally, it is similar to the ACTH of anterior-pituitary. The function of intestinal ACTH is not clearly known. Ghrelin It is a 28 amino acid polypeptide secreted mainly from stomach. It has more systemic effects than local actions. It is a strong orexigenic agent that increases food intake by acting on arcuate nucleus of hypothalamus . It stimulates secretion of growth hormone from anterior pituitary.

29. Peptide YY It is a polypeptide hormone secreted from small intestine and colon. It inhibits gastric secretion and motility . Hence, it is proposed to be an effective gastric inhibitory peptide . Its secretion is stimulated by presence of fat in jejunum. Though, structurally it resembles neuropeptide Y that stimulates food intake, peptide YY inhibits feeding. Substance P Substance P is secreted from endocrine cells and neurons of entire GIT starting from stomach to colon. It increases intestinal motility

30. Referred :- Text book of Medical Physiology Guyton, 12 th edition, Text book of Medical Physiology Indu khurana , & Sembulingam Fundamental Physiology L.P.Reddy Net source

31. THANK YOU . . .