Gastrointestinal Hormones, their uses and functions

It is presentation about different Gastro intestinal hormones, their uses and their functions.

1. GI Hormones

2. History Bayliss & Starling (1902) – Discovered the first GIT hormone Secretin Gregory & Tracy (1964) – Chemical definition of Gastrin Yalow & Benson (1966) – Invented RIA to estimate quantity Jorpes & Mutt (1996) – Chemical nature of secretin and cholecystokinin and a group of other hormones

3. Introduction Hormones secreted from the endocrine cells of the GI tract are collectively known as GI Hormones. Earlier Believed Regulatory mechanisms were controlled by the nervous system Later numerous chemicals in the name of hormones were found Hormones - Play an integral role in most of the regulatory mechanisms in our body

4. Largest endocrine organ Enteric endocrine system Total about 30 GIT hormones These are biologically active polypeptide & act in a paracrine fashion. Endocrine cells are scattered throughout the GI tract especially in stomach and small intestine. Apical surface of epithelial endocrine cells is continously exposed to chemical changes in the luminal content of the gut, which directly stimulates the release of hormone from these cells.

5. Endocrine Cells Enteroendocrine Cells : Endocrine cells that secrete GI Hormones. Enterochromaffin Cells : Cells that secrete serotonin. APUD Cells (Amine Precurssor Uptake and decarboxylation ) : Cells that secrete amines and polypeptide. Neuroendocrine Cells : APUD cells are also found in other organs like lungs. They are also called as neuroendocrine cells.

6. Criteria Meal should alter the concentration of hormones. Persist when lacking neural structure Substance is sufficient to elicit the response in blood (Via Injection). Can be isolated, purified, identified chemically and synthesized.

7. Classification

8. Site of Production

9. Site of Production

10. Factors Influencing Release of Gastrointestinal Hormones

11. Gastrin Peptide hormone that stimulates secretion of gastric acid ( HCl ) by the parietal cells of the stomach and aids in gastric motility. Released by G cells in the antrum of the stomach, duodenum and pancreas. Binds to cholecystokinin B receptors to stimulate the release of histamines in enterochromaffin like cells.

12. It induces the insertion of K + /H + ATPase pumps into the apical membrane of parietal cells (which in turn increases H + release). Release is inhibited by highly acidic pH (< 2.0). A lso found in the pancreatic islets in fetal life A nterior & intermediate lobes of the pituitary gland, in the hypothalamus, medulla oblongata & in the vagus & sciatic nerves G 34, G 17, G 14 (depending on number of AA) G 17- P rincipal gastrin secreted from the stomach

13. Regulation ↑ Gastrin Secretion Luminal : Peptide, amino acids ( Phy , Tryp ), gastric distention Neural : Vagal stimulation via GRP (can’t be blocked by atropine) Blood : Ca, Epinephrine ↓ Gastrin Secretion Luminal : Acid, S omatostatin Blood : S ecretin , GIP, VIP, glucagon, C alcitonin

14. Stimulate gastric a cid and pepsin secretion Trophic action – Growth of gastric mucosa and intestinal mucosa Stimulate Gastric Motility Contraction of muscle at gastro esophageal junction cardiac sphincter prevents reflux oesophagitis Stimulate Exocrine pancreas secretion Stimulate Insulin secretion Function

15. Stimulate mass movement of large intestine Colonic contraction that initiates Gastrocolic reflex – defecation after meal Stimulate Histamine secretion from ECL cells

16. Regulation

17. Feedback Inhibition of G astrin Stimulate Release of S omatostatin by D cell

18. Cholecystokinin Greek – C hole - "bile"; C ysto - "sac"; K inin - "move"; So Move the Bile-sac. Peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein. Source: I cells – Granular mucosal cells of duodenum & jejunum Causes the release of digestive enzymes and bile from the pancreas and gallbladder.

19. Structure Polypeptide hormone. Different forms of CCK depending on the number of AA : CCK 58, 39, 33, 12, 8 and 4. CCK secreted from duodenum and jejunum are usually CCK 12 and CCK 8. In the enteric and pancreatic nerves is CCK 4 and in brain are CCK 58 and 8. Half life is 58 min. Stimuli: Acid, protein, fat Digested products in duodenum

20. Functions of CCK Contraction of gall bladder – increased bile release Stimulate pancreatic secretion rich in enzyme Augments the action of secretin Inhibit gastric acid secretion Inhibit gastric motility Delay gastric emptying Relaxation of sphincter of oddi that allows both pancreatic and bile juice to enter duodenum.

21. Stimulates growth of pancreas. Increases secretion of enterokinase Enhances motility of small intestine Stimulates colonic movement. Augments contraction of pyloric sphincter. Stimulates glucagon secretion Produces analgesia and anxiety.

22. Mechanism of Action Two CCK receptors: CCK A and CCK B. CCK A receptors are mainly located in the peripheral structure like gall bladder, GI tract etc. CCK B receptors are present in central structure like brain. Both receptors activates membrane phospholipase C and stimulates production of intracellular IP 3 and DAG.

23. Regulation of Secretions Increased by: Acid in duodenum Products of carbohydrates, fats, & proteins digestion. Mainly peptides & amino acids Also secreted in response to CCK-releasing factor Positive feedback : CCK → enzyme release → more digestive products → more CCK (stop when digestive products move to next part)

24. Secretin Bayliss & Starling (1902) discovered the first gastro intestinal hormone Secretin Source : S cells – Upper Small Intestine ( Argentaffin cells) Structure : 27 AA Stimuli : Acid in duodenum

25. Function of S ecretin Stimulate secretion of pancreatic juice rich in HCO 3 - Stimulate bile secretion Augment action of CCK to produce pancreatic secretion rich in enzymes Reduces the gastric acid secretion and motility Contraction of pyloric sphincter

26. Control Secretin is secreted in response to protein digestive products, bile acid, fatty food and increased acidity in duodenal content (pH< 4.5-5) Inhibited by somatostatin and Metenkephalin Secretin release may be mediated by secretin -releasing peptide

27. Gastric Inhibitory Peptide( GIP) Also known as Glucose dependent insulinotropic polypeptide 42 AA Source : K cells – Duodenum & Jejunum Initially called Enterogastrone Discovered as a factor in extracts of intestine that inhibited gastric motility and secretion of acid.

28. Another activity of GIP is its ability to Enhance the release of insulin in response to infusions of glucose. Glucose-dependent insulinotropic peptide. Regulation – Increases by fat in duodenum

29. Function Inhibits gastric secretion and motility. Stimulates insulin secretion. Considered as an important physiological regulator of insulin secretion.

30. Vasoactive Intestinal Polypeptide (VIP) Source – Mucosal cells in jejunum Stimuli – Fatty meal Structure - Polypeptide 28 amino acids Other Sites — Nerves in GIT, Blood, Brain (cerebral cortex), Autonomic nerves.

31. Actions Stimulate Intestinal secretion of electrolytes & water. Induce smooth muscle relaxation (lower esophageal sphincter, stomach, gallbladder) Stimulate secretion of water into pancreatic juice and bile.

32. Inhibition of gastric acid secretion and absorption from the intestinal lumen. Decreases the GI motility. VIP a crucial component of the mammalian circadian timekeeping machinery. It is also found in the heart and has significant effects on the cardiovascular system. It causes coronary vasodilation .

33. Enteroglucagon & GLP Source : Terminal SI and LI - L cells. In the L cells, processed to form glucagon, glicentin and GLP. Given the name " Enteroglucagon ", " Proglucagon -derived Peptides". In both pancreas and gut, 3 types of products are generated: Glucagon-like Peptide-1 (GLP-1) Glucagon-like Peptide-2 (GLP-2) Glucagon-like Peptide-3 (GLP-3)

34. GLP-1 Inhibit gastric emptying Inhibit gastric secretion Inhibit pancreatic secretion Decreases food intake. Glucagon-like peptide-2 It stimulates proliferation of intestinal epithelial cells.

35. Somatostatin Source - S Cells or δ cells GIT MUCOSA. Structure – SS14, SS28 (more active) Presented in 2 forms Somatostatin 14 : Prominent in hypothalamus Somatostatin 28 : Prominent in GI tract Also secreted by the Hypothalamus & pancreas. Stimuli – Acid in stomach, stimuli which increases insulin secretion Acts through G-protein couple receptor (inhibit adenylate cyclase )

36. Actions S ecretions of Gastrin , S ecretin , Motilin , Pancreatic – Exocrine & Endocrine secretions G astric acid secretions & motility (Dyspepsia & slow gastric emptying) Inhibits gall bladder contractions (Precipitate gall stone) A bsorption of glucose, amino acid & triglyceride.

37. Motilin Source - Endocrinocytes (Mo Cells) in the mucosa of the proximal Small Intestine. Based on 22 AA sequence. Motilin participates in controlling the pattern of smooth muscle contractions in the upper GI tract that increases the Migrating Motor Complex ("Housekeeping contractions“). It sweep the stomach and SI clear of undigested material and stimulates the production of Pepsin.

38. Ghrelin Ghre – Growth - Europian Name . Source - P redominantly produced in the stomach and its plasma concentrations are increased by fasting and reduced by feeding. Action - I mportant mediator of signaling between the intestine and hypothalamus to increase metabolic efficiency at times when nutrient supplies are limited. This action counteracts the inhibition of feeding by L eptin and PYY 3-36.

39. Guanylin 15 amino acid residues Source : Cells of the intestinal mucosa ( Paneth cells) Stimulant : Stimulation of Guanylin Function : It increase Cl - movement to intestine and thus regulates fluid movement across intestinal tract.

40. P eptide YY S ynthesized and released by enteroendocrine cells in the distal small intestine and colon in response to the presence of fat in the ileal lumen. Its actions are largely inhibitory, reducing gastrointestinal motility as well as gastric acid secretion and secretion of chloride by the intestinal epithelium. Some have proposed that peptide YY can be considered an Ileal Brake i.e . S ubstance that acts to slow propulsive motility and reduce luminal fluidity if nutrients remain unabsorbed by the time the meal reaches the ileum, thereby maximizing contact time and ability to absorb nutrients.

41. Other Hormones

42. Applied Aspect Gastrinoma : Neuroendoincrine tumor that produces gastrin . Gastrin secreting tumor causes severe and chronic hypergastrenemia that causes peptic ulcer disease. This is called as Zollinger Ellison Syndrome. VIPoma : Tumor of VIP secreting cells. Causes profuse diarrhoea and hypotension. Hypokalemia , hypercalcemia and hyperglycemia. This is known as Verner Morrison Syndrome

43. Carcinoid Tumors (APUDOMAS) Carcinoid tumors originate from the diffuse neuroendocrine system, specifically the enterochromaffin (EC) cells ( submucosa of the intestine). Gastrointestinal Peptides and Amines Secreted by Carcinoid Tumors: ACTH, Gastrin , Pancreatic polypeptide, Insulin, Vasoactive intestinal polypeptide (VIP), Serotonin, 5-hydroxyindoleacetic acid

44. Digestion & Absorption of Carbohydrates Dietary intake of carbohydrates is 250–850 g/day, which represents 50– 60% of the diet. Major carbohydrates in the human diet are present in the following forms: Polysaccharides Oligosaccharides Monosaccharides

45. Digestion of Carbohydrates Digestion of Carbohydrates Mouth α-Amylase present in the saliva acts on the 1-4 linkages (but not on 1-6 linkages). It digests cooked starch to maltose. Digestion of Carbohydrates Stomach In the stomach, there occurs minimal carbohydrates digestive activity. α- Amylase activity continues in the stomach for 20–30 min till the highly acidic gastric juice mixes with the food and makes it inactive. The HCl of the gastric juice may hydrolyse some sucrose.

46. Digestion of Carbohydrates Small Intestine In the small intestine, carbohydrates are digested by the amylolytic enzymes present in the pancreatic juice and brush border enzymes of small intestine. Brush Border Enzymes of Small Intestine The carbohydrate-splitting brush border enzymes of small intestine include dextrinase , maltase, sucrase and lactase . These brush border enzymes digest the oligosaccharides into monosaccharides on the surface of epithelial cells of villi .

47. Absorption of Carbohydrates Carbohydrates are absorbed from the GIT in the form of monosaccharides . The monosaccharides include those formed at the brush border and also those ingested as such (e.g. glucose and fructose in fruits).

48. Site of Absorption Most of the monosaccharides are absorbed from the mucosal surface of jejunum and upper ileum. The absorption is almost completed before the remains of a meal reach the terminal ileum. Negligible absorption also occurs in stomach and colon. Glucose and G alactose are absorbed by a common Na + -dependent active transport system.

49. Fructose is absorbed by facilitated diffusion. Fructose absorption occurs readily, because most of the fructose is rapidly converted into glucose and lactic acid within the epithelial cells, thus maintaining a high concentration gradient for diffusion. Pentoses are absorbed by simple diffusion.

50. Fate of Glucose in Body Storage as glycogen Catabolism to produce energy Conversion into fat

51. Digestion & Absorption of Proteins Sources of Proteins The proteins that are digested and absorbed in the GIT come from two sources: exogenous and endogenous. Exogenous (dietary) Proteins Daily requirement of dietary proteins for adults is 0.5–0.7 g/kg body weight and for children (1–3 years), it is 4 g/kg.

52. Quantity of dietary proteins varies with the socioeconomic status of the individuals; a balanced diet contains about 95–100 g/day. Sources of dietary proteins with high biological value are meat, fish, eggs, cheese and other milk products. Soyabeans , wheat and various types of pulses are also rich source of proteins. Endogenous Proteins Endogenous proteins, totaling 30–50 g/day are the proteins which reach the intestine through various gastrointestinal secretions and those which are present in the desquamated epithelial cells of the gut.

53. Digestion of Proteins Proteins are digested by the proteolytic enzymes to amino acids and small polypeptides, before they are absorbed. Digestion of proteins does not occur in the mouth, as there are no proteolytic enzymes in the saliva. Digestion of proteins thus begins in the stomach and is completed in the small intestine.

54. Digestion of proteins in the stomach Pepsin, secreted by chief cells of the main gastric glands in an inactive form ( pepsinogen ), is responsible for digesting about 10–15% proteins entering the gastrointestinal tract.

55. Digestion of Protein

56. Absorption of Proteins E nd products of protein digestion (amino acids, dipeptides and tripeptides ) are absorbed through the luminal membrane of the epithelial cells of small intestine. Absorption of amino acids is faster in duodenum and jejunum and slower in ileum. Following mechanisms of absorption are known: Transport Systems Simple Diffusion Endocytosis

57. Digestion & Absorption of Fats Types of Fats : Fats are of three types: Simple fats or neutral fats e.g. Triglycerides and Cholesterol . Compound fats e.g. Phospholipids . Associated fats e.g. Steroids and Fat-Soluble V itamins

58. Dietary fat is of both vegetable and animal origin. Mostly, it is in the form of neutral fat (triglycerides). It also includes small amounts of phospholipids, cholesterol, some free fatty acids, lecithin and cholesterol esters. Daily intake of fats in the diet varies widely, from about 25 to 160 g.

59. Digestion of Fats Site of Digestion Lipolytic enzymes are secreted in the mouth (lingual lipase) and stomach (gastric lipase) Their action is so insignificant that practically digestion of all the dietary fats occurs in the small intestine. Gastric lipase which initiates fat digestion acts only on butter. Under normal conditions, gastric lipase is soon inactivated by gastric juice (pH 1–2), as it is inactivated at pH 2.5 and acts at an optimum pH of 4.5.

60. Mechanism of Digestion of Fats Digestion of fat includes three steps: Emulsification of fat by bile salts Hydrolysis of fat by pancreatic and intestinal lipolytic enzymes Acceleration of fat digestion by micelle formation.

61. Mediators of Intestinal Lipolysis

62. Absorption of Fats Most of the fat absorption occurs in the duodenum. Almost all the digested lipids are totally absorbed by the time the chyme reaches the mid-jejunum.

63. Absorption of Water

64. Absorption o f Fat Soluble Vitamins S uch vitamins are reesterified in the enterocyte and incorporated into the developing chylomicron. Presumably this is the form in which they are trafficked to sites of need . S everal cell types may act as reservoirs for specific fat-soluble vitamins (e.g., resting hepatic stellate cells for vitamin A).

65. A failure to form micelles in the intestinal lumen will almost inevitably be followed by deficiencies in fat-soluble vitamins in the body as a whole, which may manifest clinically as rickets, night blindness, or an inability to effectively clot the blood, among others. Many fat-soluble vitamins are now available in more water-soluble forms that can be used to treat such problems such as prior to elective surgery.

66. Water S oluble Vitamin Assimilation Most vitamins are absorbed in the upper part of small intestine (jejunum) except vitamins B12, which is absorbed in the ileum.