Gastrointestinal Hormones and Digestive Secretions

Cellular

The GI hormones classify as endocrines, paracrine, or neurocrine based on the method by which the
molecule gets delivered to its target cell(s). Endocrine hormones are secreted from enteroendocrine
cells directly into the bloodstream, passing from the portal circulation to the systemic circulation,
before being delivered to target cells with receptor-specificity for the hormone. The five GI
hormones that qualify as endocrines are gastrin, cholecystokinin (CCK), secretin, glucose-dependent
insulinotropic peptide (GIP), and motilin. Enteroendocrine cells also secrete paracrine hormones, but
they diffuse through the extracellular space to act locally on target tissues and do not enter the
systemic circulation. Two examples of paracrine hormones are somatostatin and histamine.
Additionally, some hormones may operate via a combination of endocrine and paracrine
mechanisms. These “candidate” hormones are glucagon-like peptide-1 (GLP-1), pancreatic
polypeptide, and peptide YY. Lastly, neurocrine hormones get secreted by postganglionic non-
cholinergic neurons of the enteric nervous system. Three neurocrine hormones with significant
physiologic functions in the gut are vasoactive intestinal peptide (VIP), gastrin release peptide (GRP),
and enkephalins.[1]

Gastrointestinal hormones undergo synthesis in specialized cells of the GI tract mucosa known as
enteroendocrine cells. Enteroendocrine cells are specialized endoderm-derived epithelial cells that
originate from stem cells located at the base of intestinal crypts. These cells are dispersed
throughout the GI mucosa, sprinkled in between epithelial cells from the stomach all the way
through to the colon. Also, these enteroendocrine cells possess hormone-containing granules
concentrated at the basolateral membrane, adjacent to capillaries, that secrete their hormones via
exocytosis in response to a wide range of stimuli related to food intake. These stimuli include small
peptides, amino acids, fatty acids, oral glucose, distension of an organ, and vagal stimulation.[2]

G cells secrete gastrin in the antrum of the stomach and the duodenum in response to the presence
of breakdown products of protein digestion (such as amino acids and small peptides), distention by
food, and vagal nerve stimulation via GRP. More specifically, phenylalanine and tryptophan are the
most potent stimulators of gastrin secretion among the protein digestion products. The vagal nerve
stimulation of gastrin secretion is unique because gastrin and motilin are the only hormones
released directly by neural stimulation.

CCK is secreted from I cells in the duodenum and jejunum in response to acids and monoglycerides
(but not triglycerides), as well as the presence of protein digestion products.

Secretin is secreted from S cells in the duodenum in response to H+ and fatty acids in the lumen.
Specifically, a pH less than 4.5 signals arrival of gastric contents, which initiates the release of
secretin.

GIP is secreted by K cells in the duodenum and jejunum in response to glucose, amino acids, and
fatty acids. GIP is the only GI hormone with a response to all three macronutrient types, and newer
studies suggest that changes in intraluminal osmolarity may be what stimulates GIP secretion.[3]
GLP-1 is also produced in the small intestine and secreted from L cells. The presence of hexose and
fat stimulate its release. Pancreatic polypeptide and peptide YY are secreted by protein and fat,
respectively, although their functions are still relatively unknown.

Development

The enteroendocrine cells responsible for synthesizing and secreting GI hormones derive from
pluripotent intestinal stem cells in the intestinal crypts. As these stem cells move up the crypt-villus
axis, they express specific transcription factors that give rise to absorptive enterocytes or cells of
secretory lineages (Paneth cells, goblet cells, and enteroendocrine cells). The sequential expression
of three basic loop helix loop (bHLH) transcription factors (Math1, Neurogenin3, and NeuroD1) is
involved in specifying the enteroendocrine cell lineage. Math1 expression specifies cells that are
fated for the secretory progenitor lineage and segregates them from the absorptive enterocyte
lineage. Subsequent expression of Neurogenin3 represents a secretory progenitor cell that has
initiated differentiation into the endocrine cell lineage. Lastly, NeuroD1 expression induces cell cycle
arrest and commits a cell to an enteroendocrine fate.[4][5]

In addition to the bHLH transcription factors, numerous paired and homeodomain genes, including
Isl-1, Pdx1, Nkx6.1, Nkx2.2, Pax4, and Pax6, are involved in differentiation of enteroendocrine cells
into the distinct subtypes of hormone-secreting cells scattered throughout the GI tract. These
subpopulations include G cells, I cells, S cells, K cells, Mo cells, L cells, and D cells, which are primarily
responsible for secreting gastrin, CCK, secretin, GIP, motilin, GLP-1, and somatostatin, respectively.
Interestingly, many subtypes of enteroendocrine cells are able to secrete multiple hormones, but the
expression of hormonal genes is controlled by location in the GI tract.[6]

Gastrointestinal hormones are composed of polypeptides that can divide into two structurally
homologous families that include the hormones responsible for a majority of regulation of GI
function. The first hormone family consists of gastrin and CCK because both hormones share an
identical 5 C-terminal amino acid sequence, also known as “pentagastrin.” This sequence includes
the tetrapeptide that is minimally required for gastrin activity but is only about one-sixth as potent
as the entire 17-amino acid gastrin peptide. Gastrin also exists in a 34-amino acid form called “big”
gastrin which gets secreted during the inter-digestive period. During meal ingestion, the 17-amino
acid form of gastrin, also called “little” gastrin, is secreted. Although each form of gastrin has its own
distinct biosynthetic pathway, the mediation of the action of both gastrin peptides is via binding of
cholecystokinin (CCK-2) receptors. The other member of the gastrin family, CCK, is a 33-amino acid
peptide that includes the pentagastrin sequence and the C-terminal tetrapeptide sequence
necessary for minimal gastrin activity; this enables CCK to demonstrate activity on gastrin (CCK-2)
receptors, although it mediates a very weak stimulation of gastric acid secretion. Furthermore, the
minimally active fragment for CCK activity is its C-terminal heptapeptide, which acts on CCK-1
receptors to mediate gallbladder contraction. Gastrin can also act on the CCK-1 receptor, but each
hormone is more potent at its own receptor than those of its homolog.

The second hormone family consists of secretin, glucagon, GLP-1, and GIP. Secretin has 27 amino
acids and is structurally similar to glucagon, which has 29 amino acids. However, in contrast with the
gastrin-CCK family, all amino acids in the polypeptide are necessary for biological activity, and these
two polypeptides only share 14 common amino acids. Glucagon derives from a 180-amino acid
precursor peptide called proglucagon, which undergoes tissue-specific post-translation processing to
produce different peptides in different cell types. Proglucagon is cleaved to form glucagon in the
pancreas, while in the intestines, proglucagon undergoes processing to produce a 30-amino acid
peptide called GLP-1. GIP is 42 amino acids long but only shares nine amino acids with secretin and
16 amino acids with glucagon.[7]

Organ Systems Involved

The digestive system is the primary site of action for most GI hormones and related polypeptides.
The stomach is the primary site of gastrin production with some D-cells also populating the
duodenum. Somatostatin and histamine are also produced in the stomach by enterochromaffin-like
(ECL) cells, which is an enteroendocrine cell subtype. The small intestines, namely the duodenum
and jejunum handle secretion of CCK, secretin, GIP, and motilin.

Function

The two gastrointestinal hormone families discussed above are responsible for most of the
regulation of gastrointestinal function. The main actions of the gastrin-CCK family and the secretin
family of hormones are listed below.

Gastrin

 Stimulates H+ (acid) secretion by parietal cells in the stomach

 Trophic (growth) effects on the mucosa of the small intestine, colon, and stomach

 Inhibits the actions of Secretin and GIP

 Inhibited by H+

CCK

 Contraction of the gallbladder with simultaneous relaxation of the sphincter of Oddi

 Inhibits gastric emptying

 Stimulates secretion of pancreatic enzymes: lipases, amylase, and proteases

 Secretion of bicarbonate from the pancreas

 Trophic effects on the exocrine pancreas and gallbladder

Secretin

 Inhibits gastrin, H+ secretion, and growth of stomach mucosa

 Stimulates biliary secretion of bicarbonate and fluid

 Secretion of bicarbonate from the pancreas

 Trophic effect on the exocrine pancreas

GIP
  Stimulation of insulin secretion

 Induces satiety

 In large doses, decreases gastric acid secretion

 In large doses, decreases the motor activity of the stomach and therefore slows gastric
emptying when the upper small intestine is already full of food products.

 Stimulates the activity of lipoprotein lipase in adipocytes

 Protects beta-cells of the pancreas from destruction by apoptosis

GLP-1

 Decreases gastric emptying

 Induces satiety

 Increases sensitivity of pancreatic beta-cells to glucose.

Motilin

 Increases gastrointestinal motility by stimulating the “migrating motility” or “myoelectric

complex” that moves through the fasting stomach and small intestines every 90 minutes.
This cyclical release and action get inhibited by the ingestion of food. Not much is known
about this peptide, except for this essential function.

Mechanism

The release of GI hormones is in response to input from G-protein-coupled receptors that detect
changes in luminal contents. Some of these receptors only respond to selective luminal substances
and subsequently release GI hormones from their respective enteroendocrine cells through
unknown mechanisms. Overall, gastrointestinal hormones manage a diverse set of actions in the
body including:

 Contraction and relaxation of smooth muscle wall and sphincters

 Secretion of enzymes for digestion

 Secretion of fluid and electrolytes

 Trophic (growth) effects on tissues of GI tract

 Regulating secretion of other GI peptides (i.e., somatostatin inhibits secretion of all GI

hormones)

To better understand how these actions are carried out by GI hormones, it is best to use gastrin’s
functions as an example. Gastrin is an interesting hormone because it acts through two mechanisms
that ultimately increase the secretion of gastric acid (hydrogen ions) into the stomach. The first
mechanism involves gastrin binding to CCK-2 receptors on parietal cells, causing increased
expression of K/H ATPase enzymes that are directly responsible for increased hydrogen ion secretion
into the stomach. The second mechanism is mediated by enterochromaffin-like cells, which secrete
histamine in response to activation by gastrin. Histamine then binds H2 receptors on nearby parietal
cells, which further stimulates secretion of hydrogen ions. In addition to stimulating ECL cells to
produce acid, gastrin also stimulates these parietal cells and ECL cells to proliferate.

The following points highlight the ten important gastrointestinal hormones that regulates digestive
secretion. The hormones are: 1. Gastrin 2. Enterogastrone 3. Secretin 4. Cholecystokinin pancre-
ozymin 5. Duocrmin 6. Enterocrinin 7. Vasoactive Intestinal Peptide 8. Villikinin 9. Somatostatin 10.
Pancreatic Polypeptide.

Hormone # 1. Gastrin:

This hormone is secreted by gastrin cells (= G-cells) in the pyloric region of the stomach. It stimulates
gastric glands to secrete and release the gastric juice. It also stimulates gastric mobility.

Hormone # 2. Enterogastrone:

(= Gastric Inhibitory Peptide— GIP). It is secreted by the duodenal epithelium. It inhibits gastric
secretion and motality. It slows gastric contraction, hence it is also called gastric inhibitory peptide.

Hormone # 3. Secretin:

It was the first hormone to be discovered by scientists. It is secreted by the epithelium of duodenum.
It releases bicarbonates in the pancreatic juice. It increases secretion of bile. It decreases gastric
secretion and motality.

Hormone # 4. Cholecystokinin pancreozymin (CCK-PZ):

The word cholecystokinin is derived from three roots: Chol meaning bile, cyst meaning bladder and
kinin meaning to remove. The word pancreozymin is derived from pancreas and zymin, which means
enzyme producer. This hormone is secreted by the epithelium of entire small intestine. It stimulates
the gall bladder to release bile and pancreas to secrete and release digestive enzymes in the
pancreatic juice.

Hormone # 5. Duocrmin:

It is secreted by the duodenal epithelium and stimulates the Brunner’s glands to release mucus and
enzymes into the intestinal juice.

Hormone # 6. Enterocrinin:

It is secreted by the epithelium of entire small intestine. It stimulates the crypts of Lieberkuhn to
release enzymes into the intestinal juice.

Hormone # 7. Vasoactive Intestinal Peptide (VIP):

It is secreted by the epithelium of entire small intestine. It dilates peripheral blood vessels of the gut.
It also inhibits gastric acid secretion.
Hormone # 8. Villikinin:

It is secreted by the epithelium of entire small intestine. It accelerates movement of villi.

Hormone # 9. Somatostatin (SS):

Somatostatin secreted by the Delta cells of islets of Langerhans of the pancreas inhibits the secretion
of glucagon by aplha cells and insulin by beta cells Somatostatin produced by argentaffin cells of
gastric and intestinal glands suppresses the release of hormones from the digestive tract.

Hormone # 10. Pancreatic Polypeptide (PP):

It is secreted by the pancreatic polypeptide cells (also ailed PP cells or F-cells) of islets of Langerhans.
It inhibits the release of pancreatic juice from the pancreas.