Secretary Functions DSA- Learning Objectives Flashcards
Types of GI Hormone Peptides
Endocrine, Paracrine, Neurocrine
Endocrine Hormones and candidate hormones
o GI Hormones are released from endocrine cells in the GI mucosa into the portal circulation, enter the general circulation and have physiologic actions on target cells o Specific receptors are found on the target tissue(s) o Five established GI hormones: Secretin Gastrin Cholecystokinin (CCK) Gastric inhibitory peptide (GIP) Motilin o Several candidate hormones Pancreatic polypeptide (PP) Peptide YY Enteroglucagon
Paracrines
o Released from endocrine cells in the GI mucosa
o Diffuse over short distances to act on target cells located in the GI tract
o Effects are limited by short distances necessary for their diffusion
o Have effects in areas where the cells are contained which release them
o Paracrine substances can release or inhibit the release of endocrine substances
o The GI paracrines are:
Somatostatin and
Histamine
o Histamine is a regulatory paracrine substance
Neurocrine peptides
o Synthesized in neurons of the GI tract, moves by axonal transport down the axon, and released by action potentials in the nerves
o GI peptides located in nerves acting as neurotransmitters
o Released near target tissue and diffuses across a short synaptic gap
o May stimulate or inhibit the release of endocrine or paracrine substances
o The GI neurocrines are:
Vasoactive Intestinal peptide (VIP)
Gastrin Releasing Peptide (GRP or Bombesin)
Enkephalins
Neurotensin and Substance P
o Although not a peptide, acetylcholine (Ach) is a neuro-regulator of the GI tract which stimulates acid secretion from gastric parietal cells
General characteristics of GI hormones
• GI tract is largest endocrine organ
• Released from stomach and small intestine mucosa into portal circulation after stimulation from nerves, distention, and chemical stimulation of food intake
• Pass through liver and heart back to the digestive system to regulate movement, secretions,
growth, release of other hormones, and absorption
• Functions may overlap
Endocrine cells
GI endocrine cells have hormone-containing granules at their base, close to capillaries
Granules discharge and release hormone in response to neural, physical, or chemical stimuli associated with eating a meal and presence of food in GI tract
Endocrine cells have microvilli on apical surface that may contain receptors for sampling luminal contents
Secretin
o “Nature’s antacid”
o Released by the S cells of the duodenum in response to:
H+ in the lumen of the duodenum
Fatty acids in the lumen of the duodenum
o Secretin function is to reduce the amount of H+ in the lumen of small intestine by:
Stimulates pancreatic HCO3- secretion and increases growth of the exocrine pancreas. Pancreatic HCO3- neutralizes H+ in the intestinal lumen
Stimulates HCO3- and H2O secretion by the liver, and increases bile production
Inhibits H+ secretion by gastric parietal cells
Inhibits gastrin release
Inhibits gastric emptying
Gastrin (released by what cells? in response to what? Discuss atropine and ach)
o Released from “G” cells in gastric mucosa, duodenum, and pancreas in response to:
Small peptides and amino acids in the lumen of the stomach
• Phenylalanine and Tryptophan are most potent stimuli for gastrin secretion
Distention of the stomach
Vagal stimulation, mediated by Gastrin Releasing peptide (GRP)
• Atropine does not block vagally mediated gastrin secretion because the mediator of the vagal effect is GRP not Acetylcholine (ACh)
Can also be released by calcium, decaffeinated coffee, and wine
Functions of gastrin
o Functions of Gastrin are:
Increases H+ secretion by direct action on gastric parietal cells
Increases H+ secretion indirectly via release of histamine from ECL cells
Aids in gastric motility
Can also stimulate growth of GI mucosal growth
Hyper-secretion may lead to development of carcinoid tumors
Inhibition of Gastrin secretion
o Inhibition of Gastrin secretion:
H+ in the lumen of the stomach inhibits gastrin release. This negative feedback control ensures that gastrin secretion is inhibited if the stomach contents are sufficiently acidified
Somatostatin inhibits gastrin release
Secretin and glucagon also inhibit gastrin release
Conditions leading to decreased acid release lead to high serum gastrin levels
Zollinger-Ellison Syndrome (short story)
(ZES) or Gastrinoma
Occurs when gastrin is secreted by non-beta cells tumors of the pancreas
Cholecystokinin (CCK)
o Released from the mucosal cells (I cells) of the duodenal and jejunal mucosa by:
Small peptides and amino acids
Fatty acids and monoglycerides, triglycerides do not stimulate the release of CCK because they cannot cross intestinal cell membranes
o Actions of CCK are:
Stimulates contraction of gallbladder and simultaneously causes relaxation of the sphincter of Oddi for secretion of bile
Stimulates pancreatic enzyme secretion
Potentiates secretin-induced stimulation of pancreatic HCO3- secretion
Stimulates growth of the exocrine pancreas
Inhibits gastric emptying, thus meals containing fat stimulate the secretion of CCK, which slows gastric emptying to allow more time for intestinal digestion and absorption
Gastric Inhibitory Peptide (Secreted by? in response to? actions?)
o Secreted from by the duodenum and jejunum in response to:
Primarily by glucose and secondarily by fat, protein and carbohydrate
o Actions of GIP:
Stimulates insulin release. In presence of oral glucose, GIP causes the release of insulin from pancreas
Inhibits H+ secretion by gastric parietal cells
Hint: also known as Glucose-dependent Insulinotropic Peptide (GIP!)
Motilin
o Released cyclically (approximately every 90 minutes) from the upper small intestine under neural control during periods of fasting or in presence of acid or fat in duodenum
o Stimulates gastric motility and upper GI motility via the interdigestive migrating myoelectric complex (MMC)
o Motilin is the mediator of these contractions (MMC)
The story of gastrin and CCK
o Gastrin and CCK have five identical amino acids on their C-terminal
o Biologic activity of gastrin is based on the four C-terminal amino acids and is
mediated by gastrin/CCK-B receptors
o Gastrin is synthesized as a larger precursor molecule called progastrin
o Gastrin exists in two main forms: “little gastrin” or G17 and “big gastrin” or G34
o Most gastrin exists in the G34 form in the basal or interdigestive state
o After a meal, the predominant form of gastrin is G17, which stimulates gastric secretion
o Because of its similar structure, desulfated CCK can activate gastrin receptors responsible
for acid secretion (CCK-B receptors)
o Gastrin can also activate CCK receptors responsible for gall bladder contraction (CCK-A
receptors)
• Secretin and similar peptides (Vasoactive intestinal peptide or VIP, GIP, glucagon)
o Glucagon has 14 amino acids identical to secretin
o Entire molecule required for biologic activity
o GIP and VIP have 9 amino acids identical to secretin
o VIP is an inhibitory parasympathetic transmitter
What are candidate endocrine hormones?
Do not meet the classic criteria for consideration as a hormone
However, do exert known physiologic effects
Enteroglucagon
Similar to secretin
Formed by same gene in pancreatic alpha cells which forms glucagon
Intestinal L cells produce 3 forms of glucagon, including glucagon-like peptide-1
(GLP-1)
Release stimulated by fat
Releases insulin, inhibits gastric secretion and delays gastric emptying
Pancreatic polypeptide
Polypeptide isolated from insulin
Release stimulated by protein, fat, and glucose
Inhibits pancreatic bicarbonate and enzyme secretion
Peptide YY
Release stimulated by fat
Inhibits gastric secretion and emptying as well as intestinal motility
Somatostatin
- Found in gastric and duodenal mucosa as well as pancreas
- Secreted by cells throughout the GI tracts in response to H+ in the lumen
- Inhibits gastrin release and gastric acid secretion
- Inhibits the release of all GI hormones
- Its secretion is inhibited by vagal stimulation
Histamine
- Secreted by mast cells of the gastric mucosa and produced in ECL cells
- Released by gastrin and stimulates acid secretion from parietal cells
- Potentiates action of gastrin and acetylcholine on acid secretion
- Basis for histamine (H2) receptor blockers as treatment for hypersecretion of acid
Vasoactive Intestinal Peptide
- Released from neurons in the mucosa and smooth muscle of the GI tract
- Produces relaxation of GI smooth muscle, including the lower esophageal sphincter and vascular smooth muscle (vasodilates) via promoting production of nitric oxide (NO)
- Stimulates pancreatic HCO3- secretion, inhibits gastric H+ secretion, and stimulates intestinal secretion. In these actions, it resembles secretin
Gastrin Releasing Peptide (GRP)
= Bombesin
• Released from vagus nerves that innervates the G cells
• Released by vagal stimulation with resulting release of gastrin
• Stimulates gastrin release from G cells
Enkephalins
- Secreted from nerves in the mucosa and smooth muscle of the GI tract
- Stimulate contraction of GI smooth muscle, particularly the lower esophageal, pyloric, and ileocecal sphincters
- Inhibit intestinal secretion of fluid and electrolytes. Opiates also slow intestinal motility. These actions form the basis for the usefulness of opiates in the treatment of diarrhea
Substance P
• Stimulates intestinal motility and gallbladder contraction
Neurotensin
- Increases blood glucose by stimulation of glycogenolysis and release of glucagon.
- Also inhibits release of insulin
Gastrinoma or ZES (long story)
• Non-beta cell tumor of pancreas or duodenal tumors
• Continually produce and release gastrin into the blood
• Hypergastrinemia results in hypersecretion of gastric acid by parietal cells and increased acid secretory capacity by hyperplastic mucosa
• Results in peptic ulcers, diarrhea, steatorrhea, and hypokalemia
• High gastrin level inhibits absorption of fluid and electrolytes by the intestine, contributing to diarrhea
• Inactivation of pancreatic lipase by gastrin along with precipitation of bile salts at a low luminal pH contributes to steatorrhea
• Treated by drugs which inhibit acid secretion along with gastrectomy if needed
• Elevated serum gastrin level indicates possibility of gastrinoma
• Since gastrin is also elevated in duodenal ulcer disease, definitive diagnosis of gastrinoma requires additional tests which may include:
a) stimulation by protein meal (no measurable change in serum gastrin levels)
b) iv calcium (increased acid and serum gastrin level) or
c) secretin infusion (increased serum gastrin level)
Over Production of GI Peptides Pancreatic Cholera (Watery Diarrhea Syndrome)
• Overproduction of VIP due to pancreatic islet cell tumor
• Results in significant intestinal secretion of fluid and electrolytes with production of
acute watery diarrhea
• Frequently lethal due to large volume of fluid and electrolyte loss
