Secretary Functions DSA- Learning Objectives

Question 1

Types of GI Hormone Peptides

Answer 1

Endocrine, Paracrine, Neurocrine

Question 2

Endocrine Hormones and candidate hormones

Answer 2

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

Question 3

Paracrines

Answer 3

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

Question 4

Neurocrine peptides

Answer 4

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

Question 5

General characteristics of GI hormones

Answer 5

• 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

Question 6

Endocrine cells

Answer 6

 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

Question 7

Secretin

Answer 7

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

Question 8

Gastrin (released by what cells? in response to what? Discuss atropine and ach)

Answer 8

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

Question 9

Functions of gastrin

Answer 9

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

Question 10

Inhibition of Gastrin secretion

Answer 10

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

Question 11

Zollinger-Ellison Syndrome (short story)

Answer 11

(ZES) or Gastrinoma

Occurs when gastrin is secreted by non-beta cells tumors of the pancreas

Question 12

Cholecystokinin (CCK)

Answer 12

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

Question 13

Gastric Inhibitory Peptide (Secreted by? in response to? actions?)

Answer 13

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!)

Question 14

Motilin

Answer 14

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)

Question 15

The story of gastrin and CCK

Answer 15

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)

Question 16

• Secretin and similar peptides (Vasoactive intestinal peptide or VIP, GIP, glucagon)

Answer 16

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

Question 17

What are candidate endocrine hormones?

Answer 17

 Do not meet the classic criteria for consideration as a hormone
 However, do exert known physiologic effects

Question 18

Enteroglucagon

Answer 18

 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

Question 19

Pancreatic polypeptide

Answer 19

 Polypeptide isolated from insulin
 Release stimulated by protein, fat, and glucose
 Inhibits pancreatic bicarbonate and enzyme secretion

Question 20

Peptide YY

Answer 20

 Release stimulated by fat

 Inhibits gastric secretion and emptying as well as intestinal motility

Question 21

Somatostatin

Answer 21

• 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

Question 22

Histamine

Answer 22

• 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

Question 23

Vasoactive Intestinal Peptide

Answer 23

• 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

Question 24

Gastrin Releasing Peptide (GRP)

Answer 24

= 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

Question 25

Enkephalins

Answer 25

• 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

Question 26

Substance P

Answer 26

• Stimulates intestinal motility and gallbladder contraction

Question 27

Neurotensin

Answer 27

• Increases blood glucose by stimulation of glycogenolysis and release of glucagon.
• Also inhibits release of insulin

Question 28

Gastrinoma or ZES (long story)

Answer 28

• 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)

Question 29

Over Production of GI Peptides
Pancreatic Cholera (Watery Diarrhea Syndrome)

Answer 29

• 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