INTESTINAL HORMONES & THEIR CONTROL

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HORMONE A chemical substance produced in the body that controls

and regulates the activity of certain cells or organs.

Many hormones are secreted by special glands, such as thyroid hormone produced by the thyroid gland.

Hormones are essential for every activity of life, including the processes of digestion, metabolism, growth, reproduction, and mood control.

Many hormones, such as neurotransmitters, are active in more than one physical process.

OR a product of living cells that circulates in body fluids (as blood) or sap and produces a specific often stimulatory effect on the activity of cells usually remote from its point of origin; also : a synthetic substance that acts like a hormone

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GUT HORMONES Over two dozen hormones have been identified in various parts

of the gastrointestinal system.

Most of them are peptides. (a compound consisting of two or more amino acids linked in a chain, the carboxyl group of each acid being joined to the amino group of the next by a bond of the type -OC-NH-.)

Many of them are also found in other tissues, especially the brain.

Many act in a paracrine* manner as well as being carried in the blood as true hormones.

THEIR IMPORTANCE TO HEALTH IS UNCERTAIN AS NO KNOWN DEFICIENCY DISORDERS HAVE BEEN FOUND FOR ANY OF THEM.

*( relating to or denoting a hormone which has effect only in the vicinity of the gland secreting it.)

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IMPORTANT GUT HORMONES GASTRIN

SOMATOSTATIN

SECRETIN

CHOLECYSTOKININ(CCK)

FIBROBLAST GROWTH FACTOR (FGF19 )

INCRETINS

GHERLINS

NEUROPEPTIDE

PEPTIDE (PYY)

SEROTININ

SUBSTANCE P

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1) GASTRINa) Gastrin is a major physiological regulator of GASTRIC ACID secretion.

b) It also has an important trophic* or growth-promoting influence on the gastric mucosa.

G cells ….. located in gastric pits

primarily in the antrum region of the stomach

Binds RECEPTORS found on parietal and enterochromaffin-like cells.

Trophic … of or relating to nutrition

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GASTRIN Gastrin is a peptide hormone that :

stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach

aids in gastric motility.

It is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.

Gastrin binds to cholecystokinin B receptors to stimulate the release of histamines in enterochromaffin-like cells,

It induces the insertion of K+/H+ ATPase pumps into the apical membrane of parietal cells (which in turn increases H+ release into the stomach cavity).

Its release is stimulated by peptides in the lumen of the stomach

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Structure of Gastrin and the Gastrin Receptor

Gastrin is a LINEAR PEPTIDE . It is synthesized as a pre pro hormone and is post-translationally

cleaved to form a family of peptides with identical CARBOXYTERMINI( is the end of an amino acid chain (protein orpolypeptide), terminated by a free carboxyl group (-COOH).

The predominant circulating form is GASTRIN-34 ("big gastrin.Gastrin is found primarily in three forms:

gastrin-34 ("big gastrin") gastrin-17 ("little gastrin") gastrin-14 ("mini gastrin")

Full bioactivity is preserved in the five C-terminal amino acidsof gastrin, which is known as penta gastrin.

The five C-terminal amino acids of gastrinand cholecystokinin are identical, which explains theiroverlapping biological effects.

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The gastrin receptor is also one of the receptors that bind cholecystokinin, and is known as the CCK-B receptor.

It is a member of the G protein-coupled receptor family.

Binding of gastrin stimulates an increase in intracellular Ca++, activation of protein kinase C, and production of inositol phosphate.

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Control and Physiologic Effects of Gastrin

The primary stimulus for secretion of gastrin is the presence of certain foodstuffs:

ESPECIALLY PEPTIDES

CERTAIN AMINO ACIDS

CALCIUM ….. in the gastric lumen.

UNIDENTIFIED COMPOUNDS IN

COFFEE

WINE

AND BEER …. are potent stimulants for gastrin secretion.

Secretion of this hormone is inhibited when the lumenalpH of the stomach becomes very low (less than about 3).

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MAJOR FUNCTIONS OF GASTRINA. STIMULATION OF GASTRIC ACID

SECRETION: Gastrin receptors are found on parietal cells, and binding

of gastrin, along with histamine and acetylcholine, leads tofully-stimulated acid secretion by those cells.

Enterochromaffin-like (ECL) cells also bear gastrinreceptors, and recent evidence indicates that this cell maybe the most important target of gastrin with regard toregulating acid secretion. Stimulation of ECL cellsby gastrin leads to histamine release, andhistamine binding to H2 receptors on parietalcells is necessary for full-blown acid secretion.

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B. PROMOTION OF GASTRIC MUCOSAL ROWTH:

Gastrin clearly has the ability to stimulate many aspects of mucosal development and growth in the stomach.

Treatment with gastrin stimulates DNA, RNA and protein synthesis in gastric mucosa and increases the number of parietal cells

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In addition to parietal and ECL cell targets,gastrin also stimulates pancreatic acinar cellsvia binding to cholecystokinin receptors.

Gastrin receptors have been demonstrated oncertain populations of gastric smooth musclecells

Supporting pharmacologic studies thatdemonstrate a role for gastrin in regulatinggastric motility.

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DISEASE STATES Excessive secretion of gastrin, or hyper

gastrinemia, is a well-recognized cause of a severedisease known as ZOLLINGER-ELLISONSYNDROME, which is seen at low frequency inman and dogs.

The hallmark of this disease is gastric andduodenal ulceration due to excessive andunregulated secretion of gastric acid.

Most commonly, hyper gastrinemia is the result ofgastrin-secreting tumours (gastrinomas), whichdevelop in the pancreas or duodenum.

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2 ) CHOLECYSTOKININ Cholecystokinin plays a key role in facilitating

digestion within the small intestine.

It is secreted from mucosal epithelial cells in the first segment of the small intestine (duodenum).

It stimulates delivery of digestive enzymes from :

the pancreas

bile from the gallbladder

into the small intestine

Cholecystokinin is also produced by neurons in the enteric nervous system, and is widely and abundantly distributed in the brain.

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Structure of Cholecystokinin and Its Receptors Cholecystokinin and gastrin are highly similar peptides.

Like gastrin, cholecystokinin is a linear peptide that is synthesized as a preprohormone, then proteolytically cleaved to generate a family of peptides having the same carboxy ends.

Full biologic activity is retained in CCK-8 (8 amino acids), but peptides of 33, 38 and 59 amino acids are also produced.

In all of these CCK peptides, the tyrosine seven residues from the end is sulfated, which is necessary for activity.

TWO RECEPTORS THAT BIND CHOLECYSTOKININ HAVE BEEN IDENTIFIED.

The CCKA receptor is found abundantly on pancreatic acinar cells.

The CCKB receptor, which also functions as the gastrin receptor, is the predominant form in brain and stomach.

Both receptors are have seven transmembrane domains typical of G protein-coupled receptors.

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Summary of CCK Cholecystokinin (CCK) is secreted from endocrine cells that are concentrated in the

duodenum, but found throughout the length of the small intestine.

The postprandial release of CCK is key in the activation of intestinal feedback control of gastrointestinal function:

comprising short term inhibition of gastric emptying and acid secretion

stimulation of the exocrine pancreas and gall bladder

inhibition of food intake.

CCK plays a key role in coordinating the entry of nutrients into the small intestine with its digestive and absorptive capacity .

CCK-mediated intestinal feedback is mediated by activation of extrinsic neuralpathways, the VAGAL AFFERENT PATHWAY. VAGAL AFFERENTS EXPRESS CCK1RS;THE PERIPHERAL TERMINALS OF THESE AFFERENT NEURONS LIE IN THEWALL OF THE GI TRACT, BOTH IN THE MUCOSAL AND MUSCLE LAYERS.WITHIN THE MUCOSA, VAGAL AFFERENTS TERMINATE WITHIN THE LAMINAPROPRIA IN CLOSE APPOSITION TO THE BASO LATERAL MEMBRANE OFENTERO-ENDOCRINE (EC) CELLS .

Exogenous administration of CCK initiates action potentials in vagal afferent nerve fibers via CCK1 receptors.

Importantly, a number of studies have shown that CCK and the CCK1R mediate inhibition of gastric function, food intake and satiation in response to intestinal nutrients in humans 17

Control and Physiologic Effects of Cholecystokinin

Foodstuffs flowing into the small intestine consist mostly of large macromolecules (proteins, polysaccharides and triglyceride) that must be digested into small molecules (amino acids, monosaccharides, fatty acids) in order to be absorbed.

Digestive enzymes from the pancreas and bile salts from the liver (which are stored in the gallbladder) are critical for such digestion. Cholecystokinin is the principle stimulus for delivery of pancreatic enzymes and bile into the small intestine.

The most potent stimuli for secretion of cholecystokinin are the presence of partially-digested fats and proteins in the lumen of the duodenum.

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An elevation in blood concentration of cholecystokinin has two major effects that facilitate digestion:

Release of digestive enzymes from the pancreas into the duodenum.

Contraction of the gallbladder to deliver bile into the duodenum. The name cholecystokinin (to "move the gallbladder") was given to describe this effect.

Cholecystokinin is also known to stimulate secretion of bile salts into the biliary system.

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Pancreatic enzymes and bile flow through ducts into theduodenum, leading to digestion and absorption of the verymolecules that stimulate cholecystokinin secretion. Thus,when absorption is completed, cholecystokinin secretionceases.

Injection of cholecystokinin into the ventricles of the braininduces satiety (lack of hunger) in laboratory animals. Inview of its pattern of secretion relative to feeding, it wouldmake physiologic sense that this hormone mightparticipate in control of food intake. .

In addition to its synthesis in small intestinalepithelial cells, cholecystokinin has been clearlydemonstrated in neurons within the wall of theintestine and in many areas of the brain. It seems, to bethe most abundant neuropeptide in the central nervoussystem.

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Disease States Diseases resulting from excessive or deficient secretion

of cholecystokinin are rare.

Cholecystokinin deficiency has been described inhumans as part of autoimmune poly glandularsyndrome, and was manifest as a mal absorptionsyndrome clinically similar to pancreatic exocrineinsufficiency.

Additionally, there is mounting evidence thataberrations in expression of cholesystokinin or itsreceptor within the human brain may play a part in thepathogenesis of certain types of anxiety andschizophrenia. Clearly, a much better understandingof the role of cholecystokinin in brain function isrequired.

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3) SECRETIN The small intestine is periodically assaulted by a flood

of acid from the stomach, and it is important to put out that fire in a hurry to avoid acid burns.

Secretin functions as a type of fireman: it is released in response to acid in the small intestine, and stimulates the pancreas and bile ducts to release a flood of bicarbonate base, which neutralizes the acid.

Secretin is also of some historical interest, as it was the first hormone to be discovered.

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Structure of Secretin and Its Receptors

Secretin is synthesized as a pre pro hormone, then proteolytically processed to yield a single 27-amino acid peptide by removal of the signal peptide plus amino and carboxy-terminal extensions.

The sequence of the mature peptide is related to that of glucagon, vasoactive intestinal peptide and gastric inhibitory peptide.

The secretin receptor has seven membrane-spanning domains and characteristics typical of a G protein-coupled receptor.

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Control and Physiologic Effects of Secretin Secretin is secreted in response to one known

stimulus: acidification of the duodenum, which occursmost commonly when liquefied ingesta from the stomachare released into the small intestine.

The principal target for secretin is the pancreas, whichresponds by secreting a bicarbonate-rich fluid, whichflows into the first part of the intestine through thepancreatic duct.

Bicarbonate ion is a base and serves to neutralize the acid,thus preventing acid burns and establishing a pHconducive to the action of other digestive enzymes.

A similar, but quantitatively less important response tosecretin is elicited by bile duct cells, resulting in additionalbicarbonate being dumped into the small gut.

As acid is neutralized by bicarbonate, the intestinal pHrises toward neutrality, and secretion of secretin is turnedoff.

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Disease States

Diseases associated with excessive or deficient secretion of secretin are not recognized.

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4) GHRELINSTRUCTURE OF GHRELIN AND ITS RECEPTOR

Ghrelin is synthesized as a preprohormone, then proteolytically processed toyield a 28-amino acid peptide.

The predominant source of circulating ghrelin is the the stomach, but also insmaller amounts from the intestine.

The hypothalamus in the brain is another significant source of ghrelin; smalleramounts are produced in the placenta, kidney, and pituitary gland.

The GHRELIN RECEPTOR was known well before ghrelin was discovered.Cells within the anterior pituitary bear a receptor , when activated, stimulatessecretion of growth hormone - that receptor was named the growth hormonesecretagoue receptor(GHS-R). The natural ligand for the GHS-R wasannounced in 1999 as ghrelin, and ghrelin was named for its ability to provokegrowth hormone secretion (the suffix ghre means "grow").

Ghrelin's activity in modulating feeding behaviour and energy balance are bestexplained by the presence of ghrelin receptors in areas of the hypothalamuslong known to be involved in appetite regulation.

Receptors are also found concentrated in other areas of the brain, including thehippocampus and regions known to be involved in reward systems (e.g.tegmental area); indeed, ghrelin appears to activate some of the same circuitsthat are involved in drug reward, which may also be related to this hormone'seffects on appetite.

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Physiologic Effects of Ghrelin and Control of SecretionAt least two major biologic activities have been ascribed to ghrelin:

Stimulation of growth hormone secretion: Ghrelin, as the ligand for the growth hormone secretagogue receptor, potently stimulates secretion of growth hormone. The ghrelin signal is integrated with that of growth hormone releasing hormone and somatostatin to control the timing and magnitude of growth hormone secretion.

Regulation of energy balance: ghrelin functions to increase hunger though its action on hypothalamic feeding centres. This makes sense relative to increasing plasma ghrelin concentrations observed during fasting .

Ghrelin also appears to suppress fat utilization in adipose tissue, which is somewhat paradoxical considering that growth hormone has the opposite effect. Overall, ghrelin seems to be one of several hormonal signals that communicates the state of energy balance in the body to the brain.

Other effects of ghrelin include stimulating gastric emptying and having a variety of positive effects on cardiovascular function (e.g. increased cardiac output).

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Blood concentrations of ghrelin are lowest shortly after consumption of a meal, then rise during the fast just prior to the next meal. The figure to the right shows this pattern based on assays of plasma ghrelin in 10 humans during the course of a day.

Given the effects of ghrelin on energy metabolism and hunger, itis a prominent target for development of anti-obesity treatments.Control of ghrelin secretion remains poorly understood. Otherhormones that influence it's secretion include estrogen andleptin, but a comprehensive understanding of, for example, shortterm control of secretion from the stomach, is lacking.

DISEASE STATES Ghrelin concentrations in blood are reduced in obese humans

compared to lean control subjects, but whether this is cause oreffect is not defined. Patients with anorexia nervosa have higherthan normal plasma ghrelin levels, which decrease if weight gainoccurs.

Prader-Willi syndrome is another disorder relevant to ghrelinscience. Affected patients develop extreme obesity associatedwith uncontrollable and voracious appetite. The plasma ghrelinlevels are exceptionally high in comparison to patients similarlyobese due to other causes. Prader-Willi syndrome is clearly acomplex disease with many defects; it may be that excessiveghrelin production contributes to the appetite and obesitycomponents.

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5) MOTILIN Motilin is a 22 amino acid peptide secreted by endo crinocytes in the

mucosa of the proximal small intestine. Based on amino acid sequence, motilin is unrelated to other hormones.

Motilin participates in controlling the pattern of smooth muscle contractions in the upper gastrointestinal tract. There are two basic states of motility of the stomach and small intestine: the fed state, when foodstuffs are present, and the inter digestive state between meals.

Motilin is secreted into the circulation during the fasted state at intervals of roughly 100 minutes. These bursts of motilin secretion are temporily related to the onset of "housekeeping contractions", which sweep the stomach and small intestine clear of undigested material (also called the migrating motor complex).

Control of motilin secretion is largely unknown, although some studies suggest that an alkaline pH in the duodenum stimulates its release. 31

6) GASTRIC INHIBITORY PEPTIDE Gastric inhibitory peptide (GIP) is a member of the

secretin family of hormones.

It was discovered as a factor in extracts of intestine that inhibited gastric motility and secretion of acid, and initially called enterogastrone.

Like secretin, it is secreted from mucosal epithelial cells in the first part of the small intestine.

Another activity of GIP is its ability to enhance the release of insulin in response to infusions of glucose. For this action, it has also been referred to as glucose-dependent insulinotropic peptide.

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7) VASOACTIVE INTESTINAL PEPTIDE VIP is a 28-amino acid peptide structurally related to secretin.

It has shown to be a potent vasodilator.

Subsequent work demonstrated that VIP is very widelydistributed in the peripheral and central nervous systems, andprobably should not be considered a true GI hormone.

A huge number of biological effects have been attributed to VIP.

With respect to the digestive system, VIP seems to induce: smooth muscle relaxation (lower oesophageal sphincter, stomach,

gallbladder)

stimulate secretion of water into pancreatic juice and bile

cause inhibition of gastric acid secretion and absorption from theintestinal lumen.

Certain tumours arising from the pancreatic islets or nervoustissue (called VIPomas) secrete excessive quantities of VIP, andare associated with chronic, watery diarrhoea.

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