Gastrointestinal Hormones

Introduction

• Gastrointestinal hormones act both locally and systemically to regulate digestive function. Beyond controlling secretion and motility, they influence appetite, metabolism, pancreatic hormone release, cardiovascular activity, and neural processes, highlighting their essential role in maintaining overall physiological balance.
• Gastrointestinal hormones are secreted by endocrine cells distributed within the epithelial lining of the tract. These cells are especially abundant in the stomach and small intestine. Their apical surfaces detect chemical changes in luminal contents and trigger hormone release.
• Hormone-secreting cells are termed enteroendocrine cells.
• Enterochromaffin cells specifically release serotonin and regulate local functions.
• Neuroendocrine cells, also called amine precursor uptake and decarboxylation cells, secrete amines and peptide hormones. These cells are present in other organs and may give rise to carcinoid tumors.
• Gastrointestinal hormones are classified into major families.
• The gastrin family includes gastrin and cholecystokinin, which regulate secretion and motility.
• The secretin family includes secretin, gastric inhibitory peptide, glucagon, and vasoactive intestinal peptide.
• Additional peptides form a third group with diverse regulatory roles. These hormones coordinate digestion by integrating luminal signals with secretory and motor responses.

GI Hormones Of Gastrin Family

Gastrin

Gastrin is a key hormone of the gastrin family that regulates gastric function.

Source

• Gastrin is secreted by G cells located mainly in the antral region of the stomach. These cells are conical, with apical microvilli exposed to the gastric lumen.
• The microvilli contain receptors that detect chemical stimuli and trigger hormone release.
• Smaller amounts of gastrin-producing cells are present in the brain and fetal pancreas.
• Gastrin-like peptides may also act as neurotransmitters in certain neural pathways.

Structure

• Gastrin is a polypeptide hormone with multiple molecular forms. It shows structural diversity in both chain length and molecular configuration.
• The major physiologically active forms include G-34, G-17, and G-14. Among these, G-17 is the predominant form secreted by the stomach. G-17 plays a major role in stimulating gastric acid secretion.
• Shorter peptide fragments, such as the carboxyl-terminal tetrapeptide, retain biological activity. However, these smaller forms have lower potency compared to full-length gastrin.
• Overall, gastrin structure and source enable precise regulation of gastric secretion in response to luminal signals.

Metabolism

• Gastrin enters systemic circulation after secretion from G cells. It has a short half-life, about 2–5 minutes for G-14 and G-17, and about 15 minutes for G-34. It is inactivated in the intestine and degraded in the kidneys.

Functions

• Gastrin stimulates secretion of gastric acid and pepsin from the stomach. It is the most potent physiological stimulus for hydrochloric acid release. Excess secretion may contribute to peptic ulcer development.
• It exerts a trophic effect by promoting growth of gastric and intestinal mucosa.
• It enhances gastric motility, improving mixing and emptying of contents.
• It increases tone of the lower esophageal sphincter, reducing reflux.
• It stimulates pancreatic exocrine secretion and insulin release.
• It promotes colonic mass movements and initiates the gastrocolic reflex after meals.
• It also stimulates histamine release, which further enhances acid secretion.

Mechanism of Action

• Gastrin stimulates gastric acid secretion by acting on specific receptors on parietal cells. It activates intracellular signaling through inositol trisphosphate, increasing cytosolic calcium levels.
• Elevated calcium activates protein kinases that stimulate the hydrogen–potassium adenosine triphosphatase pump. This enhances secretion of hydrochloric acid into the gastric lumen.

Control of Gastrin Secretion

• Control of gastrin secretion depends on multiple physiological stimuli.
• Gastric distension and the presence of peptides and amino acids increase its release.
• Vagal stimulation through gastrin-releasing peptide also enhances secretion.
• Circulating factors such as epinephrine and calcium further promote release.
• Increased levels may occur in conditions with reduced acid secretion due to feedback mechanisms.
• Several factors inhibit gastrin secretion.
• High acidity in the stomach suppresses further release through negative feedback. This effect is partly direct and partly mediated by somatostatin.
• Other inhibitory hormones include secretin, gastric inhibitory peptide, vasoactive intestinal peptide, calcitonin, and glucagon. These regulatory mechanisms maintain appropriate acid levels and protect the mucosa.

Cholecystokinin

• Cholecystokinin is a peptide hormone involved in digestive regulation.

Source

• It is secreted by I cells located in the mucosa of the duodenum and jejunum. It is also present as a neurotransmitter in the cerebral cortex, somatic nerves, and enteric nerves of the distal intestine.

Structure

• It exists in multiple molecular forms such as CCK-58, CCK-39, CCK-33, CCK-12, CCK-8, and CCK-4.
• CCK-8 and CCK-12 are the main circulating forms.
• CCK-4 is commonly found in enteric and pancreatic nerves.
• The half-life of cholecystokinin is approximately five minutes.

Functions

• It causes contraction of the gallbladder, promoting bile release into the intestine.
• It stimulates pancreatic secretion rich in digestive enzymes.
• It enhances the action of secretin to produce alkaline pancreatic juice.
• It reduces gastric acid secretion and slows gastric emptying.
• It relaxes the sphincter of Oddi, allowing bile and pancreatic juice to enter the duodenum.
• It promotes growth of the pancreas and increases enterokinase secretion.
• It enhances motility of the small intestine and stimulates colonic movements.
• It increases pyloric sphincter tone, preventing duodenal reflux.
• It stimulates glucagon secretion and reduces food intake by acting on the brain.

Mechanism of Action

• It acts through CCK-A receptors in peripheral organs and CCK-B receptors in the brain.
• Receptor activation stimulates phospholipase C, producing inositol trisphosphate and diacylglycerol. This increases intracellular calcium and mediates physiological responses.

Regulation of Secretion

Factors that increase CCK secretion:

• Fatty acids, peptides, and amino acids in the intestine stimulate its release.
• Bile and pancreatic secretions enhance digestion and provide positive feedback for further secretion.

GI Hormones Of Secretin Family

Secretin

Secretin is a key hormone of the secretin family that regulates digestive secretions.

Source

It is released from S cells located in the mucosa of the duodenum and proximal jejunum.

Structure

It is a polypeptide hormone composed of 27 amino acids.

Functions

• It stimulates secretion of bicarbonate-rich pancreatic juice, which is alkaline and watery.
• It enhances alkaline bile secretion from the liver.
• It works synergistically with cholecystokinin to support pancreatic enzyme secretion.
• It reduces gastric acid secretion and slows gastric motility.
• It increases tone of the pyloric sphincter, regulating gastric emptying.

Mechanism of Action

• It activates adenylate cyclase, leading to increased cyclic adenosine monophosphate formation. This signaling pathway mediates its secretory effects.

Regulation of Secretion

• Acidic chyme and protein digestion products stimulate its release.
• Neutralization of intestinal acidity decreases secretion through negative feedback.

GIP

Structure

• Glucose-dependent insulinotropic polypeptide is a peptide hormone consisting of 42 amino acids. It is also referred to as gastric inhibitory peptide.

Source

• It is secreted by K cells located in the mucosa of the duodenum and jejunum.

Functions

• It reduces gastric acid secretion and slows gastric motility.
• It strongly stimulates insulin secretion in response to nutrient intake.
• Its insulinotropic effect is prominent after oral glucose administration.
• It acts as an incretin hormone and supports glucose homeostasis.
• Along with glucagon-like peptide-1, it plays a major role in pancreatic beta cell function.

Regulation of Secretion

• Its release is stimulated by glucose and lipids present in the intestinal lumen.
• This ensures insulin release is matched to nutrient absorption.

VIP

Structure

• Vasoactive intestinal peptide is a polypeptide hormone consisting of 28 amino acids.
• It is derived from a precursor molecule that also forms related peptides.

Source

• It is secreted from mucosal cells and widely distributed in enteric and autonomic nerves.
• It is present throughout the gastrointestinal tract, with higher levels in the colon. It is also found in blood and the brain, with a short half-life of about two minutes.H4: Functions
• It increases intestinal secretion of water and electrolytes, which may cause diarrhea in excess.
• It produces vasodilation, reducing blood pressure.
• It relaxes gastrointestinal smooth muscle and decreases motility.
• It inhibits gastric acid secretion and enhances salivary gland activity.

Clinical Significance

• VIPoma is a tumor causing excessive vasoactive intestinal peptide secretion. It leads to profuse watery diarrhea and hypotension.

Glucagon

• Glucagon in the gastrointestinal tract is structurally similar to pancreatic glucagon.
• It is secreted by cells in the stomach and intestinal mucosa, where it is termed enteroglucagon. It contributes to increased blood glucose levels.

Glucagon-like Polypeptides

• Glucagon-like peptides are derived from a common precursor, preproglucagon.
• In pancreatic cells, it is processed to form glucagon and related fragments.
• In intestinal cells, it forms glucagon, glicentin, and glucagon-like peptides.
• Two major forms are GLP-1 and GLP-2, which are also produced in the brain.
• GLP-1 strongly stimulates insulin secretion and supports glucose regulation.
• GLP-2 has limited direct metabolic action but influences intestinal growth and function.
• Other peptides include oxyntomodulin, which inhibits gastric acid secretion.
• These peptides collectively regulate metabolism, digestion, and appetite.

Miscellaneous Family

Motilin

Structure and Source

• Motilin is a polypeptide hormone composed of 22 amino acids. It is secreted by enterochromaffin and specialized cells in most parts of the gastrointestinal mucosa.
• It acts through G protein-coupled receptors on enteric neurons.

Functions

• It stimulates contraction of intestinal smooth muscle and increases motility.
• It plays a key role in the migrating motor complex, which occurs during fasting.
• This complex clears residual contents and prepares the intestine for the next meal.
• Motilin levels decrease after food intake and remain low during digestion.
• Levels rise again after digestion, initiating cyclic motor activity.

Applied Physiology

• Certain drugs, such as erythromycin, activate motilin receptors.
• These agents are useful in conditions with reduced gastrointestinal motility.

Other Hormones

Neurotensin

• Neurotensin is a peptide hormone consisting of 13 amino acids.
• It is produced by neurons and intestinal mucosal cells, mainly in the ileum.
• It reduces gastrointestinal motility and increases ileal blood flow.

GRP

• Gastrin-releasing polypeptide is a peptide of 27 amino acids.
• It is released from non-cholinergic vagal nerve fibers.
• It stimulates gastrin secretion through neural pathways.
• Its terminal structure resembles certain bioactive peptides found in other species.

Somatostatin

• Somatostatin exists in two forms containing 14 and 28 amino acids.
• It is secreted from the gastrointestinal tract, pancreas, and hypothalamus.
• It inhibits secretion of gastrin and several other gastrointestinal hormones.
• It also functions as an inhibitory neurotransmitter in the central nervous system.

Guanylin

Structure and Source

• Guanylin is a peptide hormone composed of 15 amino acids.
• It is secreted by intestinal mucosal cells, especially Paneth cells in the small intestine.

Mechanism of Action

• It activates guanylyl cyclase receptors on intestinal epithelial cells.
• This increases intracellular cyclic guanosine monophosphate levels.
• Elevated cyclic guanosine monophosphate enhances chloride channel activity.
• This leads to increased chloride secretion into the intestinal lumen.

Functions

• It regulates fluid and electrolyte movement across the intestinal epithelium.
• It helps maintain luminal hydration and supports normal digestive processes.
• Receptors are also present in the kidney, liver, and reproductive tract.
• It contributes to coordinated fluid balance between the intestine and other organs.

Applied Physiology

• Certain bacterial enterotoxins mimic guanylin action.
• This results in excessive fluid secretion and leads to diarrhea.

TRH

• Thyrotropin-releasing hormone in the intestine resembles hypothalamic hormone structurally.
• It acts locally and does not significantly influence thyroid function.
• It contributes to regulation of intestinal immune responses.

ACTH

• Adrenocorticotropic hormone-like peptides are present in the intestine.
• Their exact physiological role in gastrointestinal function remains unclear.

Ghrelin

• Ghrelin is a 28 amino acid peptide mainly secreted by the stomach.
• It is a strong orexigenic hormone that increases appetite. It stimulates growth hormone release and influences energy balance.

Peptide YY

• Peptide YY is secreted from the small intestine and colon.
• It inhibits gastric secretion and motility, slowing digestion. It reduces appetite despite structural similarity to appetite-stimulating peptides.

Substance P

• Substance P is released from enteric neurons and endocrine cells. ·  It enhances intestinal motility and participates in pain transmission.