GIT Hormones

The five established GI hormones include secretin, cholecystokinin (CCK), gastric inhibitory peptide (GIP), and motilin, in addition to gastrin. Several other peptides, though not always granted "full hormone status," play critical physiological roles as paracrines or neurocrines.

I. Secretin

Secretin was the first hormone discovered (by Bayliss and Starling in 1902), conveying the concept of bloodborne chemical messengers.

• Glands of Secretion (Distribution and Release):

    ◦ Secretin is primarily secreted by S cells located in the duodenum and jejunum.

    ◦ These S cells are "open cells," extending from the basal lamina to the apical surface and containing microvilli for sampling luminal contents.

• Composition and Forms:

    ◦ Secretin is a 27-amino acid peptide.

    ◦ It is structurally homologous to glucagon, with 14 of its 27 amino acids being identical. This places it in the secretin family of peptides, which also includes vasoactive intestinal peptide (VIP) and gastric inhibitory peptide (GIP).

    ◦ All of secretin's amino acids are required for its biological activity.

    ◦ Secretin binds to the secretin receptor, a G-protein-coupled receptor (GPCR) primarily linked to Gs signaling pathways, which increase intracellular cyclic adenosine monophosphate (cAMP) in target cells.

• Functions:

    ◦ Primary action: Stimulates pancreatic bicarbonate (HCO3-) and fluid secretion from the duct cells, which neutralizes H+ in the intestinal lumen.

    ◦ Stimulates HCO3- and H2O secretion by the liver, thus increasing bile production.

    ◦ Inhibits H+ secretion by gastric parietal cells.

    ◦ It also counteracts the trophic (growth-stimulating) effects of gastrin on GI tissues.

    ◦ Weakly inhibits gastric motility and emptying, though its physiological significance for these motor effects is considered doubtful in humans.

    ◦ Can increase insulin secretion, but its role in normal GI physiology for this action is uncertain.

• Regulation of Secretion:

    ◦ Stimulants: The most potent releaser of secretin is H+ (acid) in the lumen of the duodenum. Secretin release occurs when the duodenal pH falls below 4.5 and rises almost linearly as the pH is lowered to 3. The amount released depends on the length of gut acidified. Fatty acids in the duodenal lumen also stimulate its release.

    ◦ Inhibition: Somatostatin inhibits the release of all gut hormones, including secretin.

    ◦ Phases: Primarily released during the intestinal phase of digestion.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Secretin's actions are coordinated to reduce the amount of H+ in the lumen of the small intestine.

    ◦ It is considered an "enterogastrone" as it can inhibit gastric acid secretion and gastric emptying.

    ◦ Its effects on pancreatic secretion are potentiated by cholecystokinin (CCK) and acetylcholine (ACh). This potentiation occurs because the potentiating stimuli (secretin, CCK, and ACh) act on different membrane receptors and trigger different cellular mechanisms; secretin primarily increases cAMP, while CCK and ACh increase intracellular Ca2+.

II. Cholecystokinin (CCK)

CCK was initially described in 1928 for its stimulation of gallbladder contraction and later for its pancreatic enzyme stimulating effects, leading to the name "cholecystokinin-pancreozymin" before being shortened to CCK.

• Glands of Secretion (Distribution and Release):

    ◦ CCK is released from I cells predominantly located in the duodenum and jejunum mucosa.

• Composition and Forms:

    ◦ CCK is a 33-amino acid peptide.

    ◦ It is homologous to gastrin, sharing an identical sequence of its five carboxyl-terminal (C-terminal) amino acids. The biological activity of CCK resides in its C-terminal heptapeptide, which can exhibit both CCK and gastrin activity due to this shared sequence.

    ◦ CCK binds with high affinity to the CCK-1 receptor.

    ◦ Its receptors are G-protein-coupled receptors (GPCRs) linked to Gq signaling pathways, which increase intracellular Ca2+ and activate protein kinase C (PKC).

• Functions:

    ◦ Primary actions:

        ▪ Stimulates gallbladder contraction and promotes the expulsion of bile. It is approximately 100 times more effective than the gastrin tetrapeptide in contracting the gallbladder.

        ▪ Causes relaxation of the sphincter of the hepatopancreatic ampulla (sphincter of Oddi), facilitating bile flow into the duodenum.

        ▪ Stimulates pancreatic enzyme secretion (e.g., amylase, lipases, proteases) from pancreatic acinar cells. While it acts on acinar cells in rodents to increase Ca2+, human pancreatic acinar cells are noted to lack functional direct responses to CCK and gastrin, suggesting its effect on enzyme secretion in humans may be largely indirect or potentiated by other mechanisms, such as vagovagal reflexes.

    ◦ Inhibits gastric emptying. This slows the movement of chyme from the stomach to the small intestine, allowing more time for fat digestion and absorption.

    ◦ Tends to stimulate contractions of the small intestine.

    ◦ Increases colonic activity and has been implicated in the mass movements that sometimes occur after eating.

    ◦ Is considered a satiety hormone, eliciting satiety and inhibiting feeding behavior by acting on vagal afferents. Its effects are reduced by vagotomy.

    ◦ Can stimulate glucagon and insulin release.

• Regulation of Secretion:

    ◦ Stimulants: Primarily released by the presence of protein digestion products (small peptides and amino acids) and fatty acids (longer than eight carbon atoms or their monoglycerides) in the lumen of the small intestine. Fat must be broken down into an absorbable form before CCK release occurs.

    ◦ Inhibition: Somatostatin inhibits the release of all gut hormones, including CCK.

    ◦ Phases: Predominantly released during the intestinal phase of digestion.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Its role in inhibiting gastric emptying contributes to the overall satiety response.

    ◦ CCK is considered the most important hormone for the digestion and absorption of dietary fat.

III. Gastric Inhibitory Peptide (GIP)

GIP was purified in 1971 and named for its ability to inhibit gastric secretion, though its insulin-releasing action is now considered more physiologically significant.

• Glands of Secretion (Distribution and Release):

    ◦ GIP is secreted by K cells located in the duodenum and jejunum.

• Composition and Forms:

    ◦ GIP contains 42 amino acids.

    ◦ It is homologous to secretin and glucagon, belonging to the secretin family of peptides.

    ◦ GIP binds to the GIP receptor, a GPCR linked to Gs signaling pathways, which increase intracellular cAMP.

    ◦ Because its inhibitory effects on the stomach are debated as physiological, it has been suggested that its name be changed to glucose-dependent insulinotropic peptide.

• Functions:

    ◦ Primary action (Incretin effect): Stimulates insulin release from pancreatic beta cells, particularly in the presence of an oral glucose load. Oral glucose is more effective than intravenous glucose in causing insulin release, a phenomenon attributed to incretins like GIP.

    ◦ Inhibits H+ secretion by gastric parietal cells.

    ◦ Inhibits gastric emptying, though the physiological significance of this effect is considered doubtful.

• Regulation of Secretion:

    ◦ Stimulants: GIP is the only GI hormone released in response to carbohydrate. It is also released by fat and protein (fatty acids and amino acids).

    ◦ Inhibition: Somatostatin inhibits the release of all gut hormones, including GIP.

• Applied Physiological Aspects (Clinical Significance):

    ◦ GIP's insulinotropic effect is glucose-dependent.

    ◦ It is a key "incretin" responsible for the enteroinsular response, where GI hormones prepare the pancreatic beta cells for an impending rise in blood nutrients.

IV. Motilin

Motilin, purified in the early 1970s, is primarily known for its role in interdigestive motility.

• Glands of Secretion (Distribution and Release):

    ◦ Motilin is purified from the upper small intestine, specifically from M cells in the duodenum and jejunum.

• Composition and Forms:

    ◦ Motilin is a linear 22-amino acid peptide.

    ◦ It belongs to the motilin family of hormones, which also includes ghrelin.

    ◦ Motilin receptors are GPCRs linked to Gq/phospholipase C/IP3 pathways, stimulating protein kinase C- and Ca2+-dependent signaling.

    ◦ Its receptor can also be activated by the antibiotic erythromycin.

• Functions:

    ◦ Primary action: Stimulates upper GI motility during fasting, specifically accounting for the interdigestive migrating myoelectric complex (MMC).

    ◦ Increases contractions of the stomach.

    ◦ Promotes emptying of the stomach and small intestines.

    ◦ Tends to stimulate small intestinal contractions.

• Regulation of Secretion:

    ◦ Stimulants: Released cyclically during fasting (approximately every 90 minutes). Its release is under neural control. Acid and fat in the duodenum can also increase motilin release.

    ◦ Inhibition: Its release is prevented by atropine and by ingestion of a mixed meal.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Erythromycin, by activating motilin receptors, can be used to treat delayed gastric emptying (gastroparesis).

V. Somatostatin (Paracrine)

While also found in the hypothalamus, somatostatin functions physiologically as a paracrine in the GI tract.

• Glands of Secretion (Distribution and Release):

    ◦ Secreted by D cells located throughout the gastric and duodenal mucosa and the pancreas.

• Composition and Forms:

    ◦ It is a known hormone first isolated from the hypothalamus. In the GI tract, it acts as a paracrine, diffusing through the extracellular space to nearby target tissues rather than entering general circulation as a primary messenger.

• Functions:

    ◦ Potent inhibitor of gastrin release.

    ◦ Inhibits gastric acid (H+) secretion by direct action on parietal cells and by inhibiting histamine release from enterochromaffin-like (ECL) cells.

    ◦ It inhibits the release of all gut hormones.

    ◦ Inhibits pancreatic secretions (fluid, bicarbonate, and enzymes).

    ◦ Slows the absorption of nutrients from the GI tract.

    ◦ Inhibits insulin and glucagon release from the pancreatic islets.

• Regulation of Secretion:

    ◦ Stimulants: Primarily released in response to H+ (acid) in the lumen of the stomach and duodenum. This is a crucial negative feedback mechanism, where low pH directly stimulates somatostatin release, which then suppresses gastric acid and gastrin.

    ◦ Inhibition: Vagal stimulation inhibits somatostatin release.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Its mediation of acid-induced inhibition of gastrin is vital for regulating gastric function.

    ◦ Patients with chronic decreased acid-secreting cells (e.g., in pernicious anemia) may have extremely high serum gastrin concentrations because the absence of gastric acid removes this inhibitory feedback on gastrin release.

    ◦ Long-term inhibition of gastric acid production (e.g., with proton pump inhibitors) can lead to an overgrowth of antral G cells, due to reduced somatostatin feedback.

VI. Gastrin-Releasing Peptide (GRP) / Bombesin (Neurocrine)

GRP is the mammalian counterpart of bombesin, a substance first isolated from amphibian skin.

• Glands of Secretion (Distribution and Release):

    ◦ GRP is found in nerves within the gastric mucosa.

    ◦ It is released from vagus nerves that innervate the gastrin-producing G cells.

• Composition and Forms:

    ◦ GRP functions physiologically as a neurocrine.

• Functions:

    ◦ Directly stimulates gastrin release from G cells. This is a key mechanism in the cephalic and gastric phases of acid secretion.

• Regulation of Secretion:

    ◦ Stimulants: Released by vagal stimulation.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Vagally mediated release of gastrin, via GRP, is not blocked by atropine, distinguishing it from acetylcholine's (ACh) direct action on parietal cells.

VII. Histamine (Paracrine)

Histamine, a ubiquitous substance, is a potent stimulant of gastric acid secretion.

• Glands of Secretion (Distribution and Release):

    ◦ Primarily produced in enterochromaffin-like (ECL) cells located within the lamina propria of the gastric glands.

    ◦ Also present in mast cells of the gastric mucosa and basophils.

• Composition and Forms:

    ◦ Histamine is a derivative of the amino acid histidine.

    ◦ It acts physiologically as a paracrine agent, diffusing through the extracellular space to its target cells.

    ◦ Histamine stimulates H+ secretion by activating H2 receptors on the parietal cell membrane. The H2 receptor is coupled to adenylyl cyclase via a Gs protein, increasing cAMP.

• Functions:

    ◦ Primary action: A potent stimulator of gastric acid (H+) secretion from parietal cells.

    ◦ Potentiates the effects of gastrin and acetylcholine (ACh) on acid secretion. This means that in the absence of histamine, the effects of gastrin and ACh on the parietal cell are weak.

    ◦ Gastrin stimulates histamine synthesis and storage in ECL cells by increasing histidine decarboxylase and type 2 vesicular monoamine transporter (VMAT-2).

• Regulation of Secretion:

    ◦ Stimulants: Released from ECL cells primarily by gastrin and indirectly by ACh.

    ◦ Inhibition: Somatostatin inhibits histamine release from ECL cells.

• Applied Physiological Aspects (Clinical Significance):

    ◦ The understanding of histamine's role led to the development of H2 receptor–blocking drugs (e.g., cimetidine, ranitidine), which are highly effective inhibitors of acid secretion because they block both the direct action of histamine and its potentiating effects on gastrin and ACh.

VIII. Pancreatic Polypeptide (PP) (Candidate Hormone)

Pancreatic polypeptide is one of the "candidate hormones" found in GI tract mucosa.

• Glands of Secretion (Distribution and Release):

    ◦ Secreted by F cells (also called PP cells), primarily located in the posterior portion of the head of the pancreas within the pancreatic islets.

• Composition and Forms:

    ◦ It is a peptide that belongs to a separate family, unrelated to gastrin or secretin.

• Functions:

    ◦ Inhibits pancreatic secretions (fluid, bicarbonate, and enzymes).

    ◦ Reduces food intake in mice when administered peripherally.

• Regulation of Secretion:

    ◦ Specific physiological stimuli for its release as a hormone are not detailed in the sources.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Well-defined diseases due to hyposecretion or hypersecretion of pancreatic polypeptide are not yet known.

IX. Ghrelin (Hormone)

Ghrelin is a GI peptide hormone that regulates food intake and was originally identified as a growth hormone secretagogue.

• Glands of Secretion (Distribution and Release):

    ◦ Ghrelin is secreted by P/D1 cells primarily located in the body of the stomach (fundus).

• Composition and Forms:

    ◦ It belongs to the motilin family of hormones.

    ◦ Ghrelin receptors (GHS receptor type 1a) are GPCRs that are linked to Gq/phospholipase C/IP3 pathways, stimulating protein kinase C- and Ca2+-dependent signaling.

• Functions:

    ◦ Primary action: Increases appetite. It does this by stimulating orexigenic neurons and inhibiting anorexigenic neurons.

    ◦ It was originally identified for its ability to stimulate growth hormone secretion (growth hormone secretagogue, GHS).

• Regulation of Secretion:

    ◦ Ghrelin is secreted by gastric cells. Its release is influenced by the integration of signals regulating food intake and metabolism, often discussed in the context of energy homeostasis.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Its primary physiological function is the regulation of food intake.

X. Peptide YY (PYY) (GI Peptide)

PYY is a GI peptide that plays a role in satiety and gut motility regulation.

• Glands of Secretion (Distribution and Release):

    ◦ PYY is released from the distal ileum and colon.

• Composition and Forms:

    ◦ It is listed as a "candidate hormone".

    ◦ PYY belongs to a separate family of peptides and is unrelated to either gastrin or secretin.

• Functions:

    ◦ Reduces food intake.

    ◦ Contributes to the ileal brake, a mechanism that inhibits gastric emptying when nutrients reach the distal ileum.

• Regulation of Secretion:

    ◦ Co-secreted with GLP-1 and GLP-2.

• Applied Physiological Aspects (Clinical Significance):

    ◦ Its role in the ileal brake helps regulate the rate of nutrient transit through the GI tract.

XI. Glucagon-Like Peptide-1 (GLP-1) (GI Hormone/Incretin)

GLP-1 is a key "incretin" and plays a significant role in glucose homeostasis and GI mucosal growth.

• Glands of Secretion (Distribution and Release):

    ◦ GLP-1 is secreted by L cells predominantly found in the ileum and colon.

• Composition and Forms:

    ◦ GLP-1 is a product of the preproglucagon gene.

    ◦ It is homologous to secretin and glucagon, belonging to the secretin family.

    ◦ GLP-1 receptors are GPCRs linked to Gs signaling pathways, which increase intracellular cAMP.

• Functions:

    ◦ Primary action (Incretin effect): Stimulates insulin release from pancreatic beta cells. This action is amplified in the presence of glucose.

    ◦ Inhibits gastric emptying.

    ◦ Promotes GI mucosal growth. It also has a trophic effect on pancreatic islet development and growth, particularly for beta cells.

    ◦ Inhibits appetite.

• Regulation of Secretion:

    ◦ Stimulants: Secretion is stimulated by the presence of free fatty acids and glucose in the lumen of the ileum and colon. Neuronal pathways stimulated by these nutrients in the upper small intestine also increase GLP-1 secretion.

    ◦ It is co-secreted with GLP-2 and PYY.

• Applied Physiological Aspects (Clinical Significance):

    ◦ GLP-1 analogues are being investigated for the treatment of type 2 diabetes mellitus.

    ◦ GLP-1 knockout mice exhibit impaired glucose tolerance.

    ◦ It is a component of the ileal brake mechanism.

    ◦ Its trophic effects on GI mucosa make it relevant for treating patients at risk for mucosal atrophy. In animal models, GLP-1 and related compounds have shown to increase beta-cell mass and neogenesis and inhibit beta-cell apoptosis.

XII. Glucagon-Like Peptide-2 (GLP-2) (GI Peptide)

GLP-2 is another product of the preproglucagon gene with significant trophic effects.

• Glands of Secretion (Distribution and Release):

    ◦ GLP-2 is secreted by L cells in the ileum and colon.

• Composition and Forms:

    ◦ GLP-2 is a product of the preproglucagon gene, like GLP-1.

• Functions:

    ◦ Has a trophic effect on gut mucosa. It promotes GI mucosal growth.

• Regulation of Secretion:

    ◦ Co-secreted with GLP-1 and PYY.

• Applied Physiological Aspects (Clinical Significance):

    ◦ GLP-2 is relevant for treating patients at risk for GI mucosal atrophy due to its enterotropic action.