GI Hormones: Normal Physiology and Clinical Applications : GI Hormones: Normal Physiology and Clinical Applications Dr. Ajesh Bansal
Gastroenterology INTRODUCTION : INTRODUCTION Chemical Transmission of the gut
Autocrine Endocrine : Endocrine Specialized signaling cells that secrete transmitters into the blood are known as endocrine cells.
Transmitters they produce are known as hormones.
Hormones bind to specific receptors on the surface of target cells at remote sites and regulate metabolic processes
Hormones are mainly peptides. INTRODUCTION : INTRODUCTION Criteria for a transmitter to be defined as hormone
Peptide be released into the circulation in response to a physiologic stimulus.
Target tissue response can be reproduced by infusing the transmitter into the blood, thereby producing the same blood levels that occur physiologically. Introduction : Introduction Paracrine –
Signalling cells of the GI tract that produce transmitters which act on neighbouring cells.
Paracrine transmitters are secreted locally and cannot diffuse far.
They bind to receptors on nearby cells to exert their biological actions
Typical of cells that produce somatostatin Introduction : Introduction Neural transmission-
When neurons of the GI tract are activated, signals in the form of neurotransmitters are released from the nerve terminals.
These synapses deliver neurotransmitters to nerves, muscle cells, epithelial and secretory cells, and other specialized cells of the GI tract. Introduction : Introduction Autocrine-
Some cells release messengers locally and possess cell surface receptors for the same messengers, thus enabling those cells to respond to their own secreted products.
This mode of transmission, known as autocrine signaling, Hormones : Hormones GI Peptides That Function Mainly as Hormones
Glucose-dependent insulinotropic peptide (GIP)
Glucagon and related gene products (GLP-1, GLP-2, glicentin, oxyntomodulin
Peptide tyrosine tyrosine (PYY) Hormones : Hormones Peptides That May Function as Hormones, Neuropeptides, or Paracrine Agents
Corticotropin-releasing factor (CRF)
Neurotensin HORMONES : HORMONES Peptides That Act Principally as Neuropeptides
Calcitonin gene-related peptide (CGRP)
Dynorphin and related gene products
Enkephalin and related gene products
Gastrin-releasing peptide (GRP)
Peptide histidine isoleucine (PHI) or peptide histidine methionine (PHM)
Pituitary adenylate cyclase–activating peptide (PACAP)
Substance P and other tachykinins (neurokinin A, neurokinin B)
Thyrotropin-releasing hormone (TRH)
Vasoactive intestinal peptide (VIP) Peptides That Act on Neurons
Newly Recognized Hormones or Neuropeptides
Guanylin and uroguanylin
Leptin Gastrin : Gastrin Major hormone that stimulates gastric acid secretion.
Product of a single gene located on chromosome 17.
Preprogastrin (101 Amino acids)-Precursor peptide.
The enzymatic processing of preprogastrin produces progastrin and gastrin peptide fragments and all the known physiologically active forms of gastrin.
Amidated tetrapeptide (Try-Met-Asp-Phe-NH2) carboxyl terminus, imparts full biological activity to gastrins. Gastrin : Gastrin G34 and G17,- two major forms of gastrin.
T ½- G34amide is 30 minutes
G17amide is three to seven minutes
Consequently, most gastrin in the circulation during fasting is G34, whereas after a meal it is G17
They are metabolized primarily by the kidney and, in addition, by the intestine and liver
In patients with renal insufficiency as well as massive small bowel resection, fasting blood levels of G17 and G34 are elevated. Slide 14: Modification by sulfation at tyrosine residues produces alternative gastrin forms of equal biological potency.
A nonamidated form of gastrin known as glycine-extended gastrin is produced by colonic mucosa known enhance the development of colorectal cancer in mice but unknown in humans
Pentagastrin is a manufactured analog that contains the biologically active C-terminus sequence Trp-Met-Asp-Phe-NH2. Gastrin : Gastrin Gastrin is produced in
endocrine cells of the gastric antrum.
Smaller amounts of gastrin
the proximal stomach, duodenum, jejunum, ileum, colon and pancreas.
Outside the GI tract
including in the brain, adrenal gland, respiratory tract, and reproductive organs, although its biological role in these sites is unknown. Gastrin : Gastrin Two main classes of gastrin/CCK receptors have been characterized:
CCK1 (formerly CCK-A)
and CCK-2 (formerly CCKB or CCKB/gastrin).
CCK1 receptors are specific for CCK, whereas CCK-2 receptors recognize both CCK and gastrin with high affinity Gastrin : Gastrin Gastrin is released from (G cells) into the circulation in response to
a meal specifically protein, peptides, and amino acids.
high gastric Ph
Inhibit gastrin release
Fasting and increased gastric acidity Slide 19: Gastrin found to have growth-promoting effects on the gastric mucosa and possibly some cancers. Gastrin : Gastrin Hypergastrinemia occurs in pathologic states
associated with decreased acid production, such as atrophic gastritis.
prolonged H2 Blockers and PPI
gastrin-producing tumor, also known as Zollinger-Ellison syndrome. Clinical Application : Clinical Application The gastrin analog, pentagastrin, has been used clinically to stimulate histamine and gastric acid secretion in diagnostic tests of acid secretory capacity. Acid secretory testing : Acid secretory testing Gastric secretory testing assesses the BAO and MAO.
Assist in the diagnosis and management of patients with
Hypergastrinemia (e.g., gastrinoma)
Diagnosis of incomplete vagotomy in patients with postoperative recurrent ulcer. BAO : BAO BAO estimates resting acid secretion in the absence of intentional and avoidable stimulation.
It is expressed as the sum of the measured acid output, expressed as mmol H+ per hour, for four consecutive 15-minute periods.
BAO: 10 mmol H+ per hour (men) 5 mmol H+ per hour (women)
The lowest BAO occurs
between 6 and 11 am
between 2 and 11 pm. MAO & PAO : MAO & PAO Maximal acid output (MAO) and peak acid output (PAO) estimate the acid secretory response to an exogenous secretagogue, usually pentagastrin (6 µg/kg subcutaneous or intramuscular or 6 µg/kg/hr continuous intravenous infusion).
MAO is the sum of acid output of four consecutive 15-minute collection periods.
PAO is calculated by multiplying by two the sum of the two highest outputs recorded in the four test periods. Slide 25: MAO is 5 to 50 mmol H+ per hour
PAO is 10 to 60 mmol H+ per hour.
Possible side effects include flushing, nausea, abdominal pain, dizziness, and palpitations Cholecystokinin : Cholecystokinin CCK is a peptide transmitter produced by I cells of the small intestine
Secreted into the blood following ingestion of a meal.
Originally identified as a 33–amino acid peptide.
Forms of CCK ranging in size from CCK-58 to CCK-8 have similar biological activities
All forms of CCK are produced from a single gene by post-translational processing of a preprohormone. Cholecystokinin : Cholecystokinin Circulating CCK binds to specific CCK-1 receptors on the
Gallbladder- stimulate gallbladder contraction
Pancreas- pancreatic secretion
Smooth muscle of the stomach- regulate gastric emptying
Peripheral nerves- bowel motility
inhibits gastric acid secretion by binding to CCK-1 receptors on somatostatin (D) cells in the antrum and oxyntic mucosa.
These effects serve to coordinate the ingestion, digestion, and absorption of dietary nutrients.
Ingested fat and protein are the major food components that stimulate CCK release. Cholecystokinin : Cholecystokinin In humans, pancreatic CCK-1 receptors are less abundant, CCK appears to stimulate pancreatic secretion indirectly through enteropancreatic neurons that possess CCK-1 receptors.
CCK has trophic effects on the pancreas, although its potential role in human pancreatic neoplasia is speculative. Feedback regulation : Feedback regulation During a meal, when trypsin is occupied by meal proteins, pancreatic secretion is enhanced because trypsin is not available to the surface of the intestinal epithelial cells to cause feedback inhibition.
After the meal, trypsin is free and inhibits intestinal CCK release and pancreatic enzyme secretion via inhibiting monitor peptide and luminal CCK releasing factor (LCRF) Cholecystokinin : Cholecystokinin Clinically, CCK has been used together with secretin to stimulate pancreatic secretion for pancreatic function testing.
It is also used radiographically or scintigraphically to evaluate gallbladder contractility.
Low CCK levels have been reported in individuals with
Celiac disease who have reduced intestinal mucosal surface area
Elevated levels of CCK have been reported in some patients with chronic pancreatitis presumably because of reduced pancreatic enzyme secretion and interruption of negative feedback regulation of CCK release Pancreatic function test : Pancreatic function test Secretory function of the pancreas to diagnose disorders such as
Two general categories:
Direct tests : collection of pancreatic secretions after administration of a secretagogue or a combination of secretagogues.
measurement of pancreatic enzymes in duodenal samples after nutrient ingestion
the measurement of products of digestive enzyme action on ingested substrates
the measurement of pancreatic enzymes in the stool; and
the measurement of the plasma concentration of hormones or other markers that are altered in pancreatic insufficiency states. Direct Tests : Direct Tests Direct tests provide a gold standard for measurement of pancreatic function.
Stimulation of secretion has been described most commonly with secretin, CCK, or the two combined.
The combination provides the complete information about acinar and ductular cell secretions. Direct tests : Direct tests Stomach and duodenum are intubated.
The gastric intubation removes gastric secretions that would interfere with the ability to measure water and bicarbonate secretion from the pancreas.
The duodenal tube is used for infusion of a nonabsorbable marker and collection of pancreatic secretions. Direct tests : Direct tests CCK is best delivered by constant intravenous infusion.
The dose for synthetic CCK-octapeptide is 40 ng/kg/hr.
The dose of synthetic secretin is 0.2 µg/kg injected over 1 minute.
Measurements, are made for fluid and for bicarbonate and protein concentrations, and the activity of digestive enzymes during collections over 15-minute periods for 1 hour.
Amylase, trypsin, chymotrypsin, and lipase are the digestive enzymes most commonly measured. Direct tests : Direct tests In a study of 236 subjects undergoing continuous infusion of CCK-octapeptide (40 ng/kg/hr) and purified natural secretin (0.25 clinical unit [CU]/kg/hr), measurements of chymotrypsin concentration and peak bicarbonate output were used to distinguish subjects with chronic pancreatitis from those without organic disease.
The test was 83% sensitive and 89% specific.
False-positive results may occur in patients with celiac disease and diabetes mellitus. Gall Bladder contractility : Gall Bladder contractility Stimulated Cholescintiography- In acalculous biliary pain
Involves calculation of a gallbladder ejection fraction (GBEF) using cholescintigraphy.
Radiolabeled hepatobiliary agent (e.g., 99mTc-diisopropyl iminodiacetic acid) is administered iv.
Gets concentrated in the gallbladder, and a computer-assisted gamma camera measures activity before and after stimulation of gallbladder contraction with a slow intravenous infusion of CCK over 30 minutes. Stimulated Cholescintiography- : Stimulated Cholescintiography- The GBEF is defined as the change in activity divided by the baseline activity.
Studies in healthy volunteers have shown that normal GBEF averages 75% and virtually always exceeds 35%. Stimulated Cholescintiography- : Stimulated Cholescintiography- Fewer than half of patients with acalculous biliary pain have a depressed GBEF.
If cholecystectomy is performed in these patients, histologic evidence of chronic cholecystitis is found in approximately 90%.
Patients with acalculous biliary pain and a normal GBEF have a variable, although generally benign, course. SECRETIN : SECRETIN Secretin - First hormone to be discovered
Human secretin is a 27–amino acid peptide and, similar to many other GI peptides, is amidated at the carboxyl terminus.
Secretin is selectively expressed in specialized enteroendocrine cells of the small intestine called S cells
The secretin receptor is a member of a large family of G protein–coupled receptors (GPCRs) SECRETIN : SECRETIN Secretin is released by acid in the duodenum
pancreatic fluid and bicarbonate secretion leading to neutralization of acidic chyme in the intestine.
Gastric acid secretion (Enterogastrone)
Intestinal motility SECRETIN : SECRETIN One of the major physiological actions of secretin is stimulation of pancreatic fluid and bicarbonate secretion.
Pancreatic bicarbonate, on reaching the duodenum, neutralizes gastric acid and raises the duodenal pH, thereby “turning off” secretin release (negative feedback).
It has been suggested that acid-stimulated secretin release is regulated by an endogenous intestinal secretin-releasing factor.
This peptide stimulates secretin release from S cells until the flow of pancreatic proteases is sufficient to degrade the releasing factor and terminate secretin release SECRETIN : SECRETIN The most common clinical application of secretin is in the diagnosis of gastrin-secreting tumors. Clinical Application: SecretinFunctional MRCP : Clinical Application: SecretinFunctional MRCP In chronic pancreatitis, MRCP results agree with ERCP results in about 90% of cases.
Agreement between MRCP and ERCP is less common in areas where the pancreatic duct is small (tail of pancreas and side branches) or when the ductal changes are more subtle.
Improved visualization of the pancreatic duct can be achieved by administering secretin. Functional MRCP : Functional MRCP Finally, assessment of fluid output from the pancreas to the duodenum can be made during MRCP after secretin injection.
Just measuring volume after secretin stimulation, instead of bicarbonate concentration, is too inaccurate to be clinically useful. SOMATOSTATIN : SOMATOSTATIN 14–amino acid cyclic peptide.
Found in almost every organ in the body and throughout the GI tract.
In the gut, somatostatin is produced by D cells in the
gastric and intestinal mucosa
islets of the pancreas,
enteric neurons. SOMATOSTATIN : SOMATOSTATIN In the antrum, D cells are open to the lumen, where they are directly exposed to acid.
A low gastric pH stimulates D cells that secrete somatostatin and inhibit gastrin release and ultimately ph rises. SOMATOSTATIN : SOMATOSTATIN Somatostatin release is also influenced by
dietary components of a meal, including protein, fat, and glucose
and other hormones and neurotransmitters.
Muscarinic stimulation appears to be the most important neural stimulus to somatostatin secretion SOMATOSTATIN : SOMATOSTATIN In the gut, somatostatin has broad inhibitory actions.
Reduces gastric acid production,
Somatostatin reduces pepsinogen secretion.
inhibits pancreatic enzyme, fluid, and bicarbonate secretion and reduces bile flow.
Its effects on gut motility are largely inhibitory, with the exception that it stimulates the migrating motor complex, possibly through effects on motilin.
reduces intestinal transport of nutrients and fluid,
reduces splanchnic blood flow
inhibitory effects on tissue growth and proliferation SOMATOSTATIN : SOMATOSTATIN At least five somatostatin receptors have been identified
The inhibitory effects of somatostatin are mediated by
decrease in cAMP,
Ca2+ channel inhibition, or
K+ channel opening. SOMATOSTATIN : SOMATOSTATIN Many endocrine cells possess somatostatin receptors and are sensitive to inhibitory regulation.
Somatostatin analogs are used to treat conditions of hormone excess produced by endocrine tumors, such as
Islet cell tumors (including gastrinomas).
Its ability to reduce splanchnic blood flow and portal venous pressure has led to somatostatin analogs being useful in treating esophageal variceal bleeding SOMATOSTATIN : SOMATOSTATIN The inhibitory effects on secretion have been exploited by using somatostatin analogs to treat some forms of diarrhea and reduce fluid output from pancreatic fistulas.
Many endocrine tumors express abundant somatostatin receptors, making it possible to use radiolabeled somatostatin analogs, such as octreotide, to localize even small tumors throughout the body GLUCAGON : GLUCAGON Glucagon is synthesized and released from pancreatic alpha cells and from intestinal L cells of the ileum and colon.
Pancreatic glucagon is a 29–amino acid peptide that regulates glucose homeostasis via gluconeogenesis, glycogenolysis, and lipolysis and is counter regulatory to insulin. Slide 56: The gene for glucagon encodes not only preproglucagon but also glucagon-like peptides (GLPs).
This precursor peptide consists of a signal peptide, a glucagon-related polypeptide, glucagon, and GLP-1 and GLP-2.
Tissue-specific peptide processing occurs through prohormone convertases that produce glucagon in the pancreas and GLP-1 and GLP-2 in the intestine Glucagon : Glucagon Glucagon and GLP-1 regulate glucose homeostasis.
Glucagon is released from pancreas in response to a meal and binds to G protein–coupled receptors on skeletal muscle and the liver to exert its glucoregulatory effects.
GLP-1 stimulates insulin secretion and augments the insulin-releasing effects of glucose on the pancreatic beta cell (“Enteroinsular Axis”). Glucagon : Glucagon GLP-1 analogs have been developed for the treatment of type II diabetes mellitus.
A long-acting human GLP-1 analog improves beta cell function and can lower body weight in patients with type II diabetes.
GLP-2 is an intestinal growth factor and may have therapeutic implications in the maintenance of the GI mucosal mass and the reversal of villus atrophy. ENTEROINSULAR AXIS : ENTEROINSULAR AXIS In particular, gut peptides control postprandial glucose levels through three different mechanisms:
Stimulation of insulin secretion from pancreatic beta cells
Inhibition of hepatic gluconeogenesis by suppression of glucagon secretion
Delaying the delivery of carbohydrates to the small intestine by inhibiting gastric emptying.
Each of these actions reduces the blood glucose excursions that normally occur after eating. EI Axis : EI Axis Approximately 50% of the insulin released after a meal is the result of GI hormones that potentiate insulin secretion.
This interaction is known as the enteroinsular axis and the gut peptides that stimulate insulin release are known as incretins.
The major incretins are GLP-1 and GIP.
stimulates insulin secretion
increases beta cell mass
Inhibits glucagon secretion
delays gastric emptying. Slide 62: GIP stimulates insulin secretion when glucose levels are elevated and decreases glucagon-stimulated hepatic glucose production.
Thus, on ingestion of a meal, glucose, as it is absorbed, stimulates GLP-1 and GIP secretion. LEPTIN : LEPTIN Leptin is a 167–amino acid protein that is secreted primarily from
the chief cells of the stomach
Blood leptin levels reflect total body fat stores.
Its primary action appears to be to reduce food intake.
At the cellular level, large adipocytes produce more leptin than small adipocytes. Leptin : Leptin Five different forms of leptin receptors.
A short form of the receptor appears to transport leptin from the blood across the blood-brain barrier, where it has access to the hypothalamus.
A long form of the leptin receptor is located in hypothalamic nuclei, where leptin binds and activates the Janis kinase signal transduction and translation system (JAK STAT). LEPTIN : LEPTIN Peripheral administration of leptin reduces food intake.
Leptin “resistance” in obesity occurs at the level of the leptin receptor that transports leptin across the blood-brain barrier. LEPTIN : LEPTIN Leptin's ability to reduce food intake occurs within the brain
Decreasing NPY a potent stimulant of food intake
Increasing (α−MSH), an inhibitor of food intake.
Peripherally, leptin acts synergistically with cholecystokinin to reduce meal size. LEPTIN : LEPTIN Only a very modest effect on weight loss has been demonstrated in clinical trials.
Leptin deficiency has been reported as a cause of obesity in a few families, but this condition is extremely rare.
Mutation of the leptin receptor has been described. GHRELIN : GHRELIN Ghrelin is a 28–amino acid peptide produced by the stomach and is the natural ligand for the growth hormone secretagogue (GHS) receptor.
When administered centrally or peripherally ghrelin
Stimulates growth hormone secretion,
Increases food intake, and
Produces weight gain.
Stimulates gastric contraction and enhances stomach emptying (Motilin like)
Circulating ghrelin levels increase
During fasting or
Conditions associated with negative energy balance, such as starvation or anorexia.
In contrast, ghrelin levels are low
Obesity. GHRELIN : GHRELIN The gastric fundus is the most abundant source of ghrelin, although lower amounts of ghrelin are found in the
Ghrelin is produced by distinctive endocrine cells known as P/D1 cells that are of two types, open and closed.
The open type is exposed to the lumen of the stomach, where it comes into contact with gastric contents,
Closed type lies in close proximity to the capillary network of the lamina propria.
Both cell types secrete hormone into the bloodstream.
Ghrelin appears to play a central role in the neurohormonal regulation of food intake and energy homeostasis. GHRELIN : GHRELIN Ghrelin released from the stomach acts on the vagus nerve to exert its effects on feeding.
At CNS level, ghrelin activates NPY and agouti-related protein-producing neurons in the arcuate nucleus of the hypothalamus, which is involved in the regulation of feeding GHRELIN : GHRELIN Gastric bypass patients do not demonstrate the premeal increase in plasma ghrelin that is seen in normal individuals.
This lack of ghrelin release may be contributing to the overall effectiveness of gastric bypass surgery for inducing weight loss GHRELIN : GHRELIN Prader-Willi syndrome is a congenital obesity syndrome characterized by
Growth hormone deficiency, and
Prader-Willi syndrome have high circulating ghrelin levels that do not decline after a meal responsible for hyperphagia and obesity. VASOACTIVE INTESTINAL POLYPEPTIDE (VIP) : VASOACTIVE INTESTINAL POLYPEPTIDE (VIP) VIP is a neuromodulator.
VIP belongs to a family of GI peptides, including secretin and glucagon, that are structurally related.
Active peptide of 28 amino acids.
VIP, along with NO, is a primary component of nonadrenergic, noncholinergic nerve transmission in the gut.
VIP is expressed primarily in neurons of the peripheral-enteric and central nervous systems.
The VIP receptor is a G protein–coupled receptor that stimulates intracellular cAMP generation. VIP : VIP VIP is a potent vasodilator that
Increases blood flow in the GI tract
Smooth muscle relaxation
Epithelial cell secretion from intestinal epithelium and bile duct cholangiocytes
As a chemical messenger, VIP is released from nerve terminals and acts locally on cells bearing VIP receptors.
Normally, serum VIP levels are low and do not appreciably change with a meal. VIP : VIP VIP is an important neuromodulator of sphincters of the GI tract,
including the lower esophageal sphincter
and sphincter of Oddi.
In certain pathologic conditions, such as achalasia and Hirschsprung's disease, the lack of VIP innervation is believed to play a major role in defective esophageal relaxation and bowel dysmotility, respectively VIP : VIP VIP levels can be extraordinarily high in pancreatic cholera, also known as Verner-Morrison syndrome and manifested by
VIP-secreting tumors usually produce a voluminous diarrhea. SUBSTANCE P AND THE TACHYKININS : SUBSTANCE P AND THE TACHYKININS Substance P belongs to the tachykinin family of peptides, which includes neurokinin A and neurokinin B.
The tachykinins are found throughout the peripheral and central nervous systems, and are important mediators of neuropathic inflammation. SUBSTANCE P AND THE TACHYKININS : SUBSTANCE P AND THE TACHYKININS Three receptors for this family of peptides have been identified—NK-1, NK-2, and NK-3.
Substance P is the primary ligand for the NK-1 receptor,
Neurokinin A for the NK-2 receptor,
Neurokinin B for the NK-3 receptor.
However, all these peptides can bind and signal through all three receptor subtypes SUBSTANCE P AND THE TACHYKININS : SUBSTANCE P AND THE TACHYKININS Substance P has been implicated as a primary mediator of neurogenic inflammation.
In the intestine, Clostridium difficile–initiated experimental colitis results from toxin-induced release of substance P and consequent activation of the NK-1 receptor.
These inflammatory sequelae can be blocked by substance P receptor antagonists.
Substance P receptors are more abundant in the intestine of patients with ulcerative colitis and Crohn's disease MOTILIN : MOTILIN Motilin is a 22–amino acid peptide
Produced by endocrine cells of the duodenal epithelium.
Motilin is secreted into the blood in a periodic and recurrent pattern that is synchronized with the migrating motor complex (MMC) under fasting conditions.
Elevations in blood motilin levels regulate the phase III contractions that initiate in the antroduodenal region and progress toward the distal gut.
Motilin secretion is not stimulated by eating. MOTILIN : MOTILIN Motilin binds to specific receptors on smooth muscle cells of the esophagus, stomach, and small and large intestines through which it exerts propulsive activity.
However, motilin agonists like erythromycin may be useful to treat acute gastroparesis and are being investigated for the treatment of IBS-C. Conclusions : Conclusions Slide 88: THANKS