Gastrointestinal (GI)

Hormones involved in ______ , ______ing and assimilating a meal requires precise coordination

of a huge number of physiologic processes.

Control over GI functions is provided by ______ and _________ systems.

Gastrointestinal (GI)

The hormones most important in

controlling _________ function are synthesized within the ___ tract by cells

scattered in the epithelium of the ____ and __. These endocrine cells and the hormones they secrete are referred to as the _______ endocrine system. Interestingly, most if

not all "GI hormones" are also synthesized in the _______.

Overview of the Digestive SystemConsider for a moment a Big Mac. The purpose of eating a Big

Mac (besides hedonism), is to assimlate the nutrients it represents and make them available to build, repair and maintain your own

tissues, as well as provide energy for studying and occasional other pursuits.

You may have asked yourself - "Exactly what nutrients are present in a Big Mac that I can assimilate?" MacDonald's comes close to full disclosure in this regard- They don't tell you that in order to take advantage of these nutrients, you have to provide the means to carefully break them down into much smaller molecules that

can be imported into _______. Luckily, your digestive system takes care of this very complex

process so ____

Overview of the Digestive System

At its simplest, the digestive system it is a tube running from ____ to ____.

This tube is like an assembly line, or more properly-a disassembly line.

chief goal is to _______ huge macromolecules (proteins, ____ and starch), which cannot be

absorbed into smaller molecules (amino acids, fatty acids and ______ that can be absorbed

across the wall of the tube, and into the circulatory system for dissemination around your

_____.

The breakdown of foodstuffs is accomplished through a

combination of _______ and _______ processes. -the digestive tube requires considerable assistance from

accessory digestive organs such as the ______ glands, liver and p_____, which dump their secretions into the tube.

The name "accessory" should not be taken to mean dispensible-without pancreatic enzymes you would starve

to death in short order.

In many ways, the digestive system can be

thought of as a well-run factory in which a large number of complex tasks are performed. The

three fundamental processes that take place are:

_______: Delivery of enzymes, mucus, ions and the like into the lumen, and hormones into blood _______: Transport of water, ions and nutrients from the lumen, across the epithelium and into

____ _______: Contractions of smooth muscle in the wall of the tube that crush, mix and propel its

contents

Like any well-run factory, proper function of the digestive system requires robust control systems.

Control systems must facilitate communication among different sections of the digestive tract (i.e.

control on the factory floor), and between the digestive tract and the brain (i.e. between workers

and management). Control of digestive function is achieved through

a combination of ______ and ______ messages which originate either within the digestive

system's own nervous and endocrine systems, as well as from the ___ and from _______ organs

such as the adrenal gland.

Finally, a note about differences in digestive anatomy and physiology among animals. The

digestive systems of humans, dogs, mice, horses, kangaroos and great white sharks are, to a first

approximation, ___________.

If you look more carefully however, it becomes apparent that each of these ________has evolved certain digestive specializations that have allowed

it to adapt to a particular _____.

These differences become particularly apparent when you

compare a carnivore like a cat with a herbivore like a goat or a horse. Goats and horses evolved from

ancestors that subsisted on plants and adapted parts of their digestive

tracts into massive fermentation vats which enabled them efficiently

utilize cellulose, the major carbohydrate of plants.

In contrast, cats evolved from animals that lived on the carcasses of other animals, and have digestive systems that reflect this history -

extremely small fermentation vats and essentially no ability to utilize cellulose. Bridging the gap between carnivores and herbivores are omnivores like humans and pigs, whose digestive tracts attest to a

historical diet that included both plants and animals. The image above shows a young omnivore in the company of herbivore and carnivore

friends.

Basic Functional Anatomy of the Digestive System

The digestive system depicted on previous slide-

a carnivore – is the simplest among mammals.

Other species, even humans, have a more or very much more extensive large intestine, and ruminants like cattle

and sheep have a large set of _____stomachs through which food passes before it reaches the stomach.

Each of the organs contributes to the digestive process in several ________ways. If you were to describe their most

important or predominant function, and summarize shamelessly, the list would look something like this:

___: Foodstuffs are broken down mechanically by

chewing and saliva is added as a ____. In some species, saliva contains amylase, an enzyme that digests starch.

_____: A simple conduit between the mouth and stomach - clearly important but only marginally interesting

compared to other regions of the tube. ____: Where the real action begins - _______ digestion of proteins initiated and foodstuffs reduced to liquid form. _____: The center of metabolic activity in the body - its

major role in the digestive process is to provide bile ____ to the ______ intestine, which are critical for

digestion and absorption of _____.

_______: Important roles as both an endocrine and

exocrine organ - provides a potent mixture of digestive enzymes to the small intestine which are critical for

digestion of fats, carbohydrates and _____.

______Intestine: The most exciting place to be in the entire digestive system - this is where the ____ stages of chemical enzymatic digestion occur and where almost

almost all nutrients are ______.

______Intestine: Major differences among ____ in extent and importance - in all animals water is absorbed,

______fermentation takes place and ___ are formed. In carnivores, that's about the extent of it, but in herbivores

like the horse, the large intestine is huge and of critical importance for utilization of cellulose.

______ Life in the Digestive Tract

The GI contains an immensely complex ecology of _____organisms.

A typical person harbors more than ____ distinct species of bacteria, representing dozens of

different lifestyles and capabilities. The composition and distribution of this

menagerie varies with age, state of health and ____.

The number and type of _____ in the GI tract vary dramatically by region.

In healthy individuals the stomach and proximal SI contain few microorganisms, largely a result of the

bacteriocidal activity of __________

In sharp contrast to the stomach and SI, the contents of the _____ literally teem with bacteria, predominantly

strict anaerobes . Between these two extremes is a transitional zone,

usually in the ileum, where moderate numbers of both aerobic and anaerobic bacteria are found.

The GI tract is ____ at birth, but

________typically begins within a few hours of birth, starting in the SI and progressing

caudally over a period of several days. In most circumstances, a "mature" microbial flora is established by _____ weeks of age.

It is also clear that microbial populations exert a profound effect on structure and function of

the _________________tract.

For example:

The morphology of the intestine of ___________ differs considerably from normal animals - villi

of the ___ are remarkably regular and the rate of epithelial cell renew is reduced

The cecum of germ-free rats is roughly ___ times the size of that in a conventional rat.

______ in the intestinal lumen metabolize a variety of sterols and

_______. For example, bacteria convert the bile

salt cholic acid to deoxycholic acid. Small intestinal bacteria also have a

important role in ___________ metabolism

.

Finally, ________ populations in the large intestine digest carbohydrates, proteins and lipids that escape

digestion and absorption in ____ This ________, particularly of cellulose, is of critical

importance to _______ like cattle and horses which make a living by consuming plants.

However, it seems that even species like humans and rodents derive significant benefit from the nutrients

liberated by intestinal microorganisms.

Overview of GI Hormones

If you are like most people, you eat several meals and occasional snacks each day, but rarely think about the immense number of tasks that must be performed by your digestive system to break

down, absorb and assimilate those nutrients. Robust control systems are required to coordinate digestive

processes in man and animals, and are provided by both the _____ and _______ systems.

There are a bunch of hormones, neuropeptides and neurotransmitters that affect GI function.

Interestingly, a number of the classical GI hormones are also synthesized in the brain, and sometimes

referred to as “___________ peptides".

Hormone -Major Activities-Stimuli for Release

Gastrin-Stimulates __________ secretion & proliferation of gastric epithelium Presence of peptides and amino acids in gastric lumen

Cholecystokinin-Stimulates secretion of __________, and contraction and emptying of the gall bladder Presence of ____acids and amino acids in the small intestine

_______-Stimulates secretion of water and bicarbonate from the pancreas and bile ducts Acidic pH in the lumen of the small SI

_________- a strong stimulant for appetite and feeding; also a potent stimulator of GH secretion. Not clear, but secretion peaks prior to feeding and diminishes with gastric filling

Hormone Major Activities Stimuli for Release

______-Apparently involved in stimulating housekeeping patterns of motility in the stomach and small intestine-Not clear, but secretion is associated with fasting

Gastric inhibitory polypeptide-Inhibits gastric secretion and _______and potentiates release of insulin from beta cells in response to elevated blood glucose concentration-Presence of fat and glucose in the small intestine

Gastrin

______is a major physiological regulator of _______acid secretion.

Also has an important _____ or growth-promoting influence on the gastric mucosa.

Gastrin is synthesized in ___ cells, which are located in gastric pits, primarily in the antrum region of the

______and binds receptors found predominantly on ______ and ___________________like cells.

__ major types of secretory epithelial cells cover the surface of the stomach and extend down into

gastric pits and glands:

_____ cells: secrete an alkaline mucus that protects the epithelium

against shear stress and acid

_____ cells: secrete hydrochloric acid!

____ cells: secrete pepsin, a proteolytic enzyme

_ cells: secrete the hormone gastrin

Structure of Gastrin and the Gastrin Receptor

______ is a linear peptide that is synthesized as a preprohormone and is post-translationally cleaved to

form a family of peptides with identical carboxy termini.

The predominant circulating form is ______ ("big gastrin"), but full biologic activity is present in the

smallest peptide (_________ or minigastrin).

Further, full bioactivity is preserved in the 5 C-terminal aa’s of gastrin, which is known as ___________. The five C-terminal amino acids of gastrin and

______are identical, which explains their overlapping biological effects.

The _____receptor is also one of the receptors that bind

cholecystokinin, and is known as the _____ receptor. It is a member of the __ protein-coupled receptor family. Binding of gastrin stimulates an increase in intracellular ____ activation of protein kinase C, and production of

____________.

Control and Physiologic Effects of Gastrin

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

_____, certain amino acids and calcium, in the gastric lumen.

Also, as yet unidentified compounds in coffee, wine and ___ are potent stimulants for gastrin

secretion. Secretion of this hormone is inhibited when the lumenal pH of the stomach becomes very ___

(less than about __).

Control and Physiologic Effects of Gastrin

Gastrin appears to have at least ___ major effects on gastrointestinal function:

Stimulation of __________ secretion: Gastrin receptors are found on parietal cells, and binding of gastrin, along

with ________ and acetylcholine, leads to fully-stimulated acid secretion by those cells.

Canine parietal cells have roughly 44,000 gastrin receptors each, and in that species, it has been

demonstrated that _____________________ of gastrin blocks secretion of acid in response to

intragastric administration of peptides.

Control and Physiologic Effects of Gastrin

Gastrin appears to have at least two major effects on gastrointestinal function:

___________________ also bear gastrin receptors, and recent evidence indicates that this cell may be the most important

target of gastrin with regard to regulating acid secretion. Stimulation of ECL cells by

gastrin leads to histamine release, and histamine binding to ___receptors on

parietal cells is necessary for full-blown ______________

Control and Physiologic Effects of Gastrin

Gastrin appears to have at least two major effects on gastrointestinal function:

_________________________ growth: 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 _______________cells.

Another observation supporting this function is that humans with hypergastrinemia (abnormally high blood

levels of gastrin) consistently show gastric mucosal ____________.

In addition to parietal and ECL cell targets,

gastrin also stimulates pancreatic ______cells via binding to CCK receptors,

and gastrin receptors have been demonstrated on certain populations of gastric smooth muscle cells, supporting

pharmacologic studies that demonstrate a role for gastrin in regulating

_______motility.

Disease States

Excessive secretion of gastrin, or _____gastrinemia, is a well-recognized cause of a severe disease known as

_____________________________syndrome, which is seen at low frequency in _____ and dogs.

The hallmark of this disease is gastric and duodenal _________ due to excessive and unregulated secretion of

gastric acid. Most commonly, hypergastrinemia is the result of

_______secreting tumors (gastrinomas), which develop in the pancreas or duodenum.

Zollinger-Ellison Syndrome (ZES)

-____ disorder that causes tumors in the ________ and duodenum and ulcers in the stomach and duodenum.

-Excesss gastrin cause the stomach to produce too much acid, which in turn causes stomach and duodenal ulcers

(______ ulcers). The ulcers caused by ZES are _____responsive to treatment than ordinary peptic

ulcers.

-What causes people with ZES to develop tumors is unknown, but approximately __ % of ZES cases are

associated with a genetic disorder called MEN 1.

Zollinger-Ellison Syndrome (ZES)

The symptoms of ZES include signs of peptic ____: gnawing, burning pain in the abdomen;

diarrhea; nausea; vomiting; fatigue; weakness; weight loss; and bleeding.

Physicians diagnose ZES through blood tests to measure levels of _______and gastric acid

secretion. They may check for _______ by doing an

endoscopy.

Zollinger-Ellison Syndrome (ZES)

The primary treatment for ZES is medication to

r______the production of ______ acid. ____________ inhibitors that suppress acid production and promote healing are the first line of treatment. H-2 blockers (cimetidine, famotidine, ranitidine) may

also be used, but are l____ effective in reducing stomach acid.

Surgery to treat peptic ulcers or to remove tumors in the pancreas or duodenum are other treatment options.

People who have been treated for ZES should be _____________in case the ulcers or tumors recur.

Cholecystokinin (CCK)

____ plays a key role in facilitating digestion within the ___. It is secreted from mucosal

epithelial cells in the first segment of the small intestine (duodenum), and stimulates delivery

into the small intestine of digestive enzymes for the pancreas and bile from the

_________________. CCK is also produced by _________ in the enteric nervous system and is widely and

abundantly distributed in the ____________.

Structure of Cholecystokinin and Its ReceptorsCCK and gastrin are highly ________ peptides.

Like gastrin, CCK is a ____ peptide that is synthesized as a ________hormone, then

proteolytically cleaved to generate a family of peptides having the same carboxy ends.

Full biologic activity is retained in _____ (8 amino acids), but peptides of 33, 38 and 59 amino acids are

also produced. In all of these CCK peptides, the ______ seven

residues from the end is sulfated, which is _________for activity.

Structure of Cholecystokinin and Its Receptors

_____receptors that bind cholecystokinin have been identified.

CCK__ receptor is found abundantly on pancreatic _____ cells.

CCK__ receptor, which also functions as the gastrin receptor, is the predominant form in

_____and stomach. Both receptors are have 7TMD typical of G protein-

coupled receptors.

Control and Physiologic Effects of Cholecystokinin

Foodstuffs flowing into the SI 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 _________. Digestive enzymes from the _____ and _____ from the

liver (which are stored in the gallbladder) are critical for such digestion.

Control and Physiologic Effects of

Cholecystokinin

_____is the principle stimulus for delivery of _______ and _____ into the ___.

Most potent stimuli for secretion of ____ are the presence of partially-digested ____ and

proteins in the lumen of the duodenum (a

particularly potent stimulus is pictured below).

An elevation in blood concentration of CCK has __ major effects that facilitate digestion:

Release of digestive enzymes from the

______ into the duodenum. Older literature refers to ___ as

pancreozymin, a term coined to describe this effect.

An elevation in blood

concentration of CCK has 2 major effects that facilitate

digestion:

Contraction of the ______ to deliver ___into the

duodenum. The name cholecystokinin (to "move

the gallbladder") was given to describe this effect. ___ is

also known to stimulate secretion of bile salts into

the biliary system

Pancreatic enzymes and bile flow through ducts into the

duodenum, leading to digestion and absorption of the very molecules that stimulate CCK secretion.

Thus, when absorption is completed, CCK secretion ceases.

Injection of CCK into the ventricles of the _____induces

satiety (lack of hunger) in laboratory animals. In view of its pattern of secretion relative to feeding, it would make physiologic sense that this hormone might

participate in control of food intake. However, recent experiments suggest that CCK is at best

a ______player in regulation of food intake.

In addition to its synthesis in small intestinal epithelial

cells, CCK has been clearly demonstrated in _____ within the wall of the intestine and in many areas of the

______.

It seems, in fact, to be the most abundant _______peptide in the ____.

Secretion of CCK from neurons appears to modulate the activity of other hormones and neuropeptides, but it

seems safe to say the understanding its role in function of the brain is rudimentary at best.

Disease States

Diseases resulting from excessive or deficient secretion of CCK are ___.

CCK deficiency has been described in humans as part of autoimmune polyglandular syndrome, and was manifest as a malabsorption syndrome

clinically similar to pancreatic exocrine insufficiency.

Disease States

Diseases resulting from excessive or deficient secretion of CCK are rare.

Additionally, there is mounting evidence that aberrations in expression of ____ or its receptor within the human brain may play a part in the pathogenesis of certain types of a______ and

schizophrenia. Clearly, a much better understanding of the role

of CCK in ______function is required.

Secretin

The __ is periodically assaulted by a flood of _____from the stomach, and it is important to put

out that fire in a hurry to avoid acid ______. Secretin functions as a type of _____: it is released in response to acid in the SI, and

stimulates the pancreas to release a flood of bicarbonate base, which __________ the acid.

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

Structure of Secretin and Its Receptors

Secretin is synthesized as a ______hormone, then proteolytically processed to yield a single ___ aa 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, _________ peptide and ____________ peptide.

The secretin receptor has __ membrane-spanning domains and characteristics typical of a __ protein-

coupled receptor.

Control and Physiologic Effects of Secretin

Secretin is secreted in response to one known stimulus: _______________of the duodenum, which occurs most commonly when liquified ingesta from the stomach are

released into the __. The principal target for secretin is the _____-which responds by secreting a _________e-rich fluid, which flows into the first part of the intestine through the

pancreatic duct.

Control and Physiologic Effects of Secretin

Bicarbonate ion is a base and serves to neutralize the acid, thus preventing acid burns and

establishing a pH conducive to the action of other digestive enzymes.

Control and Physiologic Effects of Secretin

A similar, but quantitatively less important

response to secretin is elicited by bile duct cells, resulting in additional __________

being dumped into the small gut. As acid is ___________ by bicarbonate, the

intestinal pH rises toward neutrality, and secretion of secretin is turned off.

Disease States

Diseases associated with excessive or deficient secretion of

________ have not been identified.

Ghrelin

______ was discovered as the peptide hormone that potently stimulates release of GH from the

________ pituitary. It was subsequently determined that _____, along

with several other hormones, has significant effects on ______ and _______ balance.

The predominant source of ghrelin is epithelial cells in the _________.

Structure of Ghrelin and Its Receptor

Ghrelin is synthesized as a _______hormone, then proteolytically processed to yield a __ aa

peptide. An interesting and unique modification is imposed

on the hormone during synthesis in the form of an ________ acid bound to one of its amino acids; this modification is __________ for

biological activity.

Structure of Ghrelin and Its Receptor

Synthesis of ghrelin occurs predominantly in epithelial cells lining the fundus of the

_________, with smaller amounts produced in the placenta, kidney, pituitary and

hypothalamus.

Structure of Ghrelin and Its Receptor

The ghrelin receptor was known well before ghrelin was discovered. Cells within the _________ bear a receptor that, when activated, potently stimulates secretion of GH - that receptor was named the growth hormone

secretagoue receptor (_____).

The natural ligand for the _______ was announced in 1999 as ghrelin, and ghrelin was named for its ability to provoke growth hormone secretion (the suffix ghre

means "g___").

Ghrelin receptors are present on the cells in the pituitary that secrete growth hormone, and also have been identified in the hypothalamus, heart and adipose

tissue.

Control and Physiologic Effects of Ghrelin

At least 2 major biologic activities have been ascribed to ghrelin:

Stimulation of __ secretion: Ghrelin, as the ligand for the growth hormone secretagogue receptor, potently stimulates secretion of GH. The ghrelin signal is integrated with that of GHRH and SS to

_________________________________________

___________________________.

Control and Physiologic Effects of Ghrelin

At least 2 major biologic activities have been ascribed to ghrelin:

Regulation of ______ balance: In rodents and humans, ghrelin functions to ______ _________ though its action

on hypothalamic feeding centers. This makes sense relative to increasing plasma ghrelin

concentrations observed during _______. Additionally, humans injected with _______ reported sensations of

intense hunger. Ghrelin also appears to suppress ___utilization in adipose tissue, which is somewhat paradoxical considering that GH 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 ______.

Control and Physiologic Effects of Ghrelin

Other effects of ghrelin include stimulating

_______emptying and having a variety of positive effects on cardiovascular function (e.g. increased

cardiac output). It is not totally clear whether the cardiovascular effects are

a direct effect of ghrelin or represent an indirect effect of ghrelin's ability to stimulate ___ secretion.

Blood concentrations of ghrelin are ____

shortly after consumption of a

____, 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 __.

Disease States

Ghrelin concentrations in blood are reduced in ______humans compared to ____ control

subjects, but whether this is cause or effect is not defined.

Patients with _______________________ have higher than normal plasma ghrelin levels, which

decrease if weight gain occurs.

Disease States

______________________syndrome is another disorder relevant to ________ science. Affected

patients develop extreme obesity associated with uncontrollable and voracious ________. The

plasma ghrelin levels are exceptionally high in comparison to patients similarly obese due to

other causes. ___________ syndrome is clearly a complex disease with many defects; it may be

that excessive ghrelin production contributes to the appetite and o______components.

Disease States

___is an uncommon ________disorder characterized by mental retardation, decreased

muscle tone, short stature, emotional lability and an insatiable ______ which can lead to life-threatening _________________.

The syndrome was first described in 1956 by Drs. Prader, Labhart, and Willi.

PWS is caused by the absence of segment 11-13 on

the long arm of the paternally derived chromosome __.

In 70-80% of PWS cases, the region is missing due to a deletion. Certain genes in this region are

normally s_______ on the maternal chromosome, so, for normal development to

occur, they must be expressed on the paternal chromosome. When these paternally derived

genes are absent or disrupted, the PWS phenotype results.

When this same segment is missing from the

maternally derived chromosome 15, a completely different disease,

__________syndrome, arises. This pattern of ___________ — when

expression of a gene depends on whether it is inherited from the mother or the father

— is called _________imprinting. The mechanism of imprinting is uncertain,

but, it appears to involve _______ methylation.

Genes found in the PWS chromosomal region code for the small ribonucleoprotein N (SNRPN).

_______ is involved in mRNA _________.

A mouse model of PWS has been developed with a large deletion which includes the SNRPN region and the

PWS 'imprinting centre' (IC) and shows a phenotype similar to infants with _____.

These and other molecular biology techniques may lead to a better understanding of PWS and the mechanisms of

genomic imprinting.