NROSCI-BIOSC-MSNBIO
1070/2070
November 23, 2015
Gastrointestinal 2
Clinical GI Problems
 Damage to the Enteric Nervous System
 Achalasia, or failure of the lower esophageal
sphincter to open, is a result of damage to the
enteric nervous system in the esophagus. As a
result, food becomes trapped in the esophagus,
which becomes ulcerated and infected.
 A similar condition is Hirschsprung’s disease,
where part of the colon loses motility.
 These conditions are often treated surgically, or
by giving a calcium channel blocker.
Clinical GI Problems
 Peptic Ulcer
 Ulcers are erosions in the lining of the stomach or
duodenum (the first part of the small intestines). An
ulcer in the stomach is called a gastric ulcer. An ulcer in
the duodenum is called a duodenal ulcer. Together,
ulcers of the stomach and duodenum are referred to as
peptic ulcers.
 Ulcers are most commonly caused by Helicobactor pylori
breaking down the mucus layer. Consumption of some
substances, including aspirin, excessive alcohol, and
toxins associated with smoking, can also weaken the
mucus layer.
 Ulcers result in pain and discomfort. If a hole goes
through the stomach, allowing acid to get into the
peritoneal cavity, death will occur.
Clinical GI Problems
 Secretory Tumors
 Zollinger-Ellison Syndrome results
from a gastrin-secreting tumor, which
produces excessive stomach acid
secretion
 Any other type of secretory cell in the GI
system can develop into a malignant
tumor, resulting in a clinical condition
Clinical GI Problems
 Gallstones
« Gallstones affect approximately 10% of the
population over 30 years old in the United
States.
« There are two types of gallstones: cholesterol
stones and pigment stones.
Pigment stones are produced when bilirubin precipitates
with calcium to form a stone. Typically, bilirubin is
conjugated with glucuronic acid to make it soluble.
Thus, the presence of beta-glucuronidase de-conjugates
the bilirubin and results in its precipitation into stones.
Beta-glucuronidase is released from a number of
bacteria, and thus infections of the gall bladder can lead
to formation of pigment stones.
« Cholesterol stones occur when bile contains too
much cholesterol, and results in crystal
formation and the growth of crystals into
Clinical GI Problems
The treatment for gallstones is surgical
i.e., removal of the gall bladder
(cholecystectomy).
 After the surgery, bile is no longer stored by
the gall bladder, but is continuously released
into the duodenum.
 Although the total amount of bile released
during a meal is lowered, the patient’s
digestion does not seem to be impaired,
particularly if fat intake is controlled.
 Some species of animals (e.g., horse and rat)
lack a gall bladder, emphasizing that this
organ is not essential if fat consumption is
low.
Clinical GI Problems
 Genetic Diseases
 A genetic problem can result in the
absence of a transporter for a
particular nutrient, so it is not
absorbed from the GI system.
 Because the same transporter is often
present in the kidney, the same
substance is typically excreted.
Clinical GI Problems
Diarrhea
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There are three main causes of diarrhea:
1. Impaired absorption by the intestine (may result
from infection or inflammation)
2. Accumulation of nonabsorbable, osmoticallyactive agents in the gut lumen
3. Infections of the intestinal wall, that result in
excessive stimulation of secretory cells
Clinical GI Problems
 Ulcerative colitis is a chronic inflammatory
condition of the digestive tract.
 It is a form of Inflammatory Bowel Disease that
involves inflammation of the inner lining of the
colon and rectum.
 People with this condition alternate between
flare-ups and periods of remission throughout
their lives.
 The causes of ulcerative colitis are unknown.
Current research suggests that possible causes
may involve, but are not limited to, heredity,
infection, or the immune system.
Clinical GI Problems
 Crohn’s disease
 Crohn's disease is a chronic autoimmune disease
that can affect any part of the gastrointestinal
tract but most commonly occurs in the ileum (the
area where the small and large intestine meet).
 Treatments can include immune suppression and
surgery to remove the affected part of the
intestine.
Clinical GI Problems
 Diverticulosis and Diverticulitis
 Diverticulosis is a condition where small fingerlike
pouches form in the wall of the large intestine.
 It is one of the most common colon problems in
people over 40 years of age.
 The inner layers of the large intestine gradually
weaken, resulting in the outpocketings.
 A complication of diverticulosis results in the
fingerlike pouches breaking and spilling the
contents of the intestine into the peritoneal
cavity. This complication is called diverticulitis.
Control of Food Intake and
Glucose Metabolism
Control of Food Intake
• Theories about food consumption fall into
two general “camps.”
The first group of theories hold that food intake is
triggered by a depletion of energy reserves in one or
more tissues. Thus, eating occurs in response to a
shortage of appropriate nutrients.
The second group of theories suggest that we are
primed to eat unless inhibitory signals associated by
meals are released.
Control of Food Intake
 Two general metabolic states are generally
distinguished:
 The pranial state occurs at the time of meal
consumption, when there is an abundance of
nutrients being absorbed.
 Shortly after a meal, however, the
postabsorptive state begins, when the body
must depend on stored nutrients to support
cellular metabolism.
Types of Nutrients
 Three major types of macronutrients are used
to provide energy for cells: carbohydrates,
lipids, and proteins.
 Most tissues can use either carbohydrates (in
the form of glucose) or lipids (in the form of
free fatty acids) to fuel cellular metabolism.
> An exception includes the nervous system, which
typically requires glucose for normal metabolism.
Unless the brain is provided a constant supply of
glucose, consciousness will be lost. Therefore, a
critical issue for metabolism is to maintain
constant levels of circulating glucose.
Storage of Nutrients During the
Pranial Stage
 Many tissues store glucose in the form a polymer
called glycogen; the largest stores are in the liver and
skeletal muscles.
 Fat is mainly stored in adipose tissue in the form of
triglyceride.
 During the pranial phase, many absorbed nutrients
are stored as triglyceride or glycogen.
 Excess carbohydrate can be converted to lipid for
storage (lipogenesis), as glycogen storage capacity
is limited and triglyceride is a much more efficient
way of storing glucose.
Liberation of Nutrients During the
Postabsorptive Stage
 During the postabsorptive state, liver glycogen is
converted back to glucose in a process called
glycogenolysis.
 The glucose that is formed enters the blood and is
available to all tissues.
 In addition, stored triglycerides are mobilized from
adipose tissue in a process called lipolysis; as a
result, fatty acids and glycerol enter the bloodstream.
 The fatty acids are used by the tissues as needed or
are converted to ketone bodies (ketogenesis).
 Glycerol (the backbone of triglyceride) is converted to
glucose in a process called gluconeogenesis.
Ketone Bodies
 Ketone bodies are products of fatty acid metabolism;
they are produced in the liver and kidney. They
include compounds such as acetone.
 Ketone bodies can be used for energy by the brain
when blood glucose levels are very low (but only as
an emergency back-up).
 Formation of excess ketone bodies occurs when liver
glycogen levels are low. This condition is called
Ketosis.
 Ketone bodies are acidic, and their formation causes
metabolic acidosis.
Overview of Metabolism
Role of the Liver
 The liver plays a
fundamental role in
energy metabolism.
 Lipogenesis (also occurs
in adipose tissue) and
glycogen formation
occur in the liver during
the pranial period
 Glycogenolysis,
ketogenesis, and
gluconeogenesis occur
during the
postabsorptive period.
Insulin and Caloric Homeostasis
 Insulin is secreted from -cells (endocrine cells) of the
pancreas.
 Insulin allows most tissues to take up glucose from the blood
for immediate oxidation. Its major targets are the liver,
adipose tissue, and skeletal muscle.
 The hormone operates by causing GLUT transporters stored in
vesicles in the cytoplasm to be translocated to the cell surface
Insulin and Caloric Homeostasis
 Insulin also stimulates enzymes that produce
glycogen, and inhibits glycogenolysis and
gluconeogenesis.
 The hormone additionally activates enzymes for
protein synthesis and inhibits enzymes that promote
protein breakdown.
 Some tissues do not require the presence of insulin
to transport glucose into cells. These tissues include
the nervous system and transporting epithelia of the
kidney and intestine.
Insulin and Caloric Homeostasis
 Many factors govern the secretion of insulin:
A major factor is the level of glucose in the blood
to which the -cells are exposed.
Other substances in the blood such as amino acids
and ketone bodies can also induce insulin release.
Some hormones, such as GIP, also trigger insulin
release.
The -cells of the pancreas are additionally
innervated by sympathetic and parasympathetic
postganglionic fibers.
 Parasympathetic activity stimulates insulin secretion.
 Sympathetic activity inhibits the secretion of insulin.
Glucagon
 During the postabsorptive period, insulin
secretion drops and secretion of another
pancreatic hormone, glucagon, increases.
 Glucagon is secreted by  -cells of the
pancreas, and acts to stimulate glycogenolysis,
gluconeogenesis, and ketogenesis.
Timing of
Insulin
Release
 During the cephalic phase of
insulin secretion, the
parasympathetic nervous system
acts to stimulate -cells to release
insulin, so that the body prepares
for the storage of glucose.
 Insulin secretion is potentiated
during the gastrointestinal
phase, during which
parasympathetic activity and
hormones such as GIP influence
the -cells.
 The levels of blood insulin grow
even higher during the substrate
phase, when glucose in the blood
begins to directly act on the cells.
Adiposity and Insulin
 Superimposed on the factors that influence
insulin secretion is the amount of body fat
(adiposity).
 People with little body fat have a large number
of insulin receptors on adipose tissue and
skeletal muscle.
 In contrast, obese individuals have a lower
concentration of insulin receptors.
 As a result, obese individuals tend to have a
higher release of insulin after a meal that
corresponds to the lower sensitivity of tissues
to the hormone.
Diabetes Mellitus
 Lack of insulin production results in a collection of
diseases known as diabetes mellitus.
 The word diabetes refers to flow of water through a
siphon (i.e., indicates copious urination), and the
word mellitus comes from the term for honey (i.e.,
indicates large amounts of sugar in the urine). In
ancient times this disease was recognized by voiding
of large volumes of sweet urine.
 It is important to distinguish between diabetes
mellitus and diabetes insipidus, which is characterized
by the urination of large amounts of “flavorless”
urine. Diabetes insipidus results from a deficit in
antidiuretic hormone production or diminished action
of this hormone in the kidney.
Juvenile-Onset Diabetes Mellitus
 The most severe form of diabetes mellitus is insulin dependent
diabetes mellitus (IDDM), which is also known as Type I
diabetes.
 Typically, this condition is an autoimmune disease in which cells of the pancreas are destroyed by the immune system.
 This aberrant immune response is sometimes triggered by
viral infections. Controversial evidence also has suggested
that consumption of cows’ milk before the age of four months
can induce IDDM, although the mechanism is unclear.
 Usually (but not always), Type I diabetes develops in
childhood, providing the condition another name: juvenileonset diabetes. Because patients with this disease are insulindeficient, the only treatment is insulin injections. About 10%
of all diabetes mellitus patients suffer from the Type I disease.
Adult-Onset Diabetes Mellitus
 The other variant of diabetes mellitus is noninsulin dependent diabetes mellitus (NIDDM),
which is sometimes called Type II diabetes or
adult-onset diabetes.
 This label is given to a collection of diseases
that have a variety of causes, but are not
related to a deficiency in insulin production.
 NIDDM patients comprise 90% of the patients
with diabetes mellitus, and typically are over
40 and are obese.
Adult-Onset Diabetes Mellitus
 A common hallmark of NIDDM is a delayed response
to an ingested insulin load.
 This is demonstrated through a procedure known as
a glucose tolerance test.
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First, the patient’s fasting glucose concentration is
determined (time 0).
Then, a specific amount of glucose is ingested.
Plasma glucose levels are then measured periodically for
two or more hours.
Normal subjects show a slight elevation in plasma glucose
concentration in the immediate postprandial period, but
the level quickly falls to normal as insulin is secreted.
In Type II diabetes patients, however, fasting blood
glucose levels are typically a bit above normal, and rise
even higher after glucose is consumed.
Adult-Onset Diabetes Mellitus
☮ The high blood glucose
concentrations in the
presence of normal
insulin levels are related
to the fact that target
tissues do not respond
appropriately to the
insulin. This can result
if the number of insulin
receptors is low, or the
cellular response to the
binding of insulin is
inappropriate.
Physiology of Type I Diabetes
 In individuals with Type I Diabetes, digestion and absorption of
glucose by the small intestine proceeds normally.
 However, once the glucose reaches the liver transport into
hepatic cells is limited because metabolic pathways have not
been stimulated.
 Thus, glucose levels in the blood rise tremendously resulting in
hyperglycemia.
 Tissues where glucose transport is not insulin-dependent, such
as neural tissue, carry on glucose metabolism as normal, but
other tissues such as adipose tissue and muscle are unable to
uptake glucose.
 As a result, muscle and adipose cells go into fasting-state
metabolism. Muscle proteins are broken down to provide a
source of energy, as are fat stores in adipose tissue.
 The lack of insulin also results in the nervous system producing
the sensation of hunger (as will be discussed later during this
lecture), and polyphagia occurs.
Physiology of Type I Diabetes
 Because the liver cannot sense the elevated plasma
glucose concentrations, it initiates glycogenolysis and
gluconeogenesis; these processes further elevate
plasma glucose levels.
 In addition, the liver begins to synthesize ketone
bodies.
 The high levels of glucose in the blood produce an
osmotic load that affects water balance in the body.
The levels of glucose often exceed the reabsorption
capacities of the kidney and thus glucose is released
in the urine.
 As a result, water is “dragged” from the kidney, urine
volume is high, and blood volume is reduced.
 A decrease in blood volume results in a decrease in blood
pressure, and a number of compensatory mechanisms are initiated
(i.e., high vasopressin levels, activation of the renin-angiotensin
system, etc.).
 These compensatory mechanisms induce excessive drinking to
occur.
 However, because of the high vasopressin and angiotensin II
levels, widespread vasoconstriction occurs in the body.
 Thus, most of tissues in the body have an inadequate blood flow,
and receive inadequate oxygen.
 As a result, these tissues must begin anaerobic glycolysis to meet
metabolic needs, which results in lactic acid production.
 The lactic acid secretion into the blood contributes to metabolic
acidosis. However, the primary cause of the metabolic acidosis is
the release of ketone bodies from the liver.
 The high acidity of the blood triggers increased ventilation,
acidification of the urine, and hyperkalemia.
 If untreated, the metabolic acidosis and hypoxia from circulatory
collapse can lead to coma and death.
Physiology of Type II Diabetes
 Symptoms in patients with Type II diabetes
are not nearly as severe as those in individuals
with Type I diabetes.
 Although glucose transport into cells is
impeded, it is usually not absent.
 However, derangements in glucose and fat
metabolism can produce a number of severe
medical problems similar to those in patients
with Type I diabetes.
Treatment of Type 2 Diabetes
 A newly-developed drug, AVANDIA® (rosiglitazone
maleate), has shown promise in treating Type II
diabetes. Rosiglitazone is a highly selective and potent
agonist for peroxisome proliferator-activated receptorgamma (PPARγ).
 In humans, PPAR receptors are found in key target
tissues for insulin action such as adipose tissue, skeletal
muscle, and liver.
 Activation of PPARγ nuclear receptors regulates the
transcription of insulin-responsive genes involved in the
control of glucose production, transport, and utilization.
 In addition, PPARγ-responsive genes also participate in
the regulation of fatty acid metabolism.
Glucagon and its Role in Regulating Blood Glucose
Levels
 Glucagon is released by  -cells in the pancreas; in general its
effects are antagonistic to those of insulin.
 When plasma glucose concentrations decline after a meal,
insulin secretion slows and effects of glucagon on tissue
metabolism take on greater significance. It appears that the
ratio between insulin and glucagon determines the direction of
metabolism rather than an absolute amount of either
hormone.
 The primary stimulus for glucagon release is plasma glucose
concentration. When plasma glucose concentrations fall below
100 mg/dl, glucagon concentration rises dramatically; at
higher blood glucose concentrations (when insulin secretion is
high), glucagon secretion diminishes considerably although a
low basal release is maintained.
Glucagon and its Role in Regulating Blood Glucose
Levels
 The liver is the primary target tissue of
glucagon. Glucagon stimulates glycogenolysis,
conversion of glycogen to glucose.
 In addition, glucagon stimulates the pathways
of gluconeogenesis. These pathways combine
to increase glucose output by the liver.
 During the overnight fast, 75% of the glucose
produced from the liver comes from glycogen
scores and the remaining 25% comes from
gluconeogenesis.
Glucagon and its Role in Regulating Blood Glucose
Levels
 Glucagon secretion is also stimulated by an increase
in plasma amino acid levels.
 This signal serves to prevent hypoglycemia after a
high-protein meal.
 Recall that amino acid absorption is a secondary
stimulus for insulin release. Thus, even if no
carbohydrates are consumed along with the protein,
glucose transport into cells will be enhanced. This
could result in hypoglycemia that threatens the
brain’s glucose supply. However, the co-secretion of
glucagon in this situation prevents hypoglycemia.
Satiety
 All mammals eat periodic
meals. It is welldocumented that one of
the major factors that
governs the period
between meal consumption
is the size of the meals that
are ingested. The graph to
the left shows data for rats
consuming liquid meals,
but a similar graph could
be constructed for humans.
Factors that Lead to Cessation of Eating at
the End of a Meal
 Gastric Distension
[ The stretch receptors in the stomach that detect distension
send their axons to the brainstem via the vagus nerve,
where they terminate in the nucleus of the solitary tract.
[ The activity of these stomach stretch receptors is
potentiated when the hormone CCK is released from the
duodenum. Apparently, the stretch receptors have CCK
receptors located near their terminals so that binding of
hormone to those receptors makes them more sensitive.
[ In neonates, gastric distension may be a major factor that
regulates satiety. This is practical, as newborns consume a
single type of food: milk.
[ As animals mature, and meals become more complex, then
gastric distension in itself is not a good indicator of caloric
consumption. It thus makes sense that many other factors
begin to influence food consumption during development.
Factors that Lead to Cessation of Eating at
the End of a Meal
 Liver Afferents
These afferents respond to nutrients
(predominantly glucose) reaching the liver through
the portal circulation.
 In addition, circulating levels of insulin appear to
influence the activity of the hepatic afferents.
The axons of these afferents, like the axons of the
gastric stretch receptors, project to nucleus tractus
solitarius in the brainstem via the vagus nerve.
Factors that Lead to Cessation of Eating at
the End of a Meal
 Adiposity
Body weight influences the size of meals and the period of
time between meals.
After being deprived of food, both animals and humans eat
more for a period until adiposity returns to levels before the
period of lowered nutrition.
A hormone released by adipose tissue, leptin, may be
important in controlling food intake.
Leptin receptors are located in the hypothalamus, and this
hormone may be an important link between caloric
homeostasis and the central control of food intake.
Low leptin levels have been correlated with increases in
food intake. Plasma levels of insulin are also correlated
with adiposity, as discussed above. Thus, a combination of
insulin and leptin levels may be important in regulating
appetite through their actions in the brain.
Factors that Lead to Cessation of Eating at
the End of a Meal
Ghrelin
 Ghrelin is produced by stretch-sensitive cells,
mainly located in the wall of the stomach but
to some extent in the small intestine.
 When the stomach is empty ghrelin is
secreted, and when it is stretched secretion
stops.
 It acts on hypothalamic brain cells to
increase hunger, and to increase gastric acid
secretion and gastrointestinal motility to
prepare the body for food intake.
Ghrelin
 The receptor for ghrelin is found on the
same cells in the brain as the receptor for
leptin.
 Ghrelin has been linked to inducing appetite
and feeding behaviors.
 Circulating ghrelin levels are the highest right
before a meal and the lowest right after.
 Injections of ghrelin in both humans and rats
have been shown to increase food intake in a
dose-dependent manner.
Control of Appetite
by the Brain
 Lesions of the ventromedial
hypothalamus (VMH) result in
hyperphagia and obesity.
 Conversely, lesions of the
ventrolateral hypothalamus
(VLH) result in a loss of
appetite and starvation.
 The results of lesion
experiments gave rise to a
“dual center” hypothesis of the
control of feeding.
This hypothesis suggests that feeding is determined by the net
balance of activity in the VMH and VLH, the VLH serving as a
hunger center and the VMH serving to inhibit activity of the
hunger center. Not surprisingly, this simplistic hypothesis has
not explained the results of subsequent experiments.
Neurochemistry of Appetite Control
 A number of neuropeptides
have been shown to influence
feeding, including the following:
oxytocin, insulin, neuropeptide
Y, opioids, CCK, galanin, and
the orexins.
 Although neurons do not
require insulin for glucose
transport, insulin receptors are
present on the luminal surface
of brain capillaries.
 Bound insulin is then
transported through the
capillary endothelial cells into
the brain interstitial fluid.
 From there, insulin is free to
bind to specific receptors on
neurons.
Neurochemistry of Appetite Control
 A high density of insulin
receptors exists in the ventral
hypothalamus, where this
peptide undoubtedly influences
neuronal activity.
 Infusion of insulin into the brain
reduces feeding and body
weight. In addition, infusion of
insulin antagonist into the
ventral hypothalamus increases
feeding.
 Thus, insulin appears to act as a
signal of satiety through its
effects on the hypothalamus.
Neurochemistry of Appetite Control
 Neuropeptide Y has been shown
to act in the paraventricular
nucleus of the hypothalamus to
increase food intake.
 Insulin appears to inhibit the
production of NPY, and thus
some of the effects of insulin
may be related to the secretion
of NPY.
 The graph to the left shows
changes in food intake and
body weight produced by the
infusion of NPY into the
paraventricular nucleus of rats
for 6 days.
Neurochemistry of Appetite Control
 Recently, a new group of peptides has been identified
in neurons in the lateral hypothalamus; these
peptides are known as the orexins.
 The orexin-containing neurons are located at the
anatomical site of the feeding center in the lateral
hypothalamus, suggesting a possible role for these
neurons in the control of food intake.
 These neurons project to other hypothalamic regions,
including the paraventricular nucleus, as well as to
various forebrain areas.
 Intraventricular injections of orexins stimulate
feeding, suggesting that this peptide might be
involved in control of satiety.
Summary of Appetite Control
 The control of feeding is not well understood, but
appears to be regulated by neurons in the
hypothalamus, neurons in the brainstem that send
projections to the hypothalamus, and neurons in the
cortex.
 Feeding is influenced by afferent signals from the
stomach and liver and chemical signals such as CCK,
insulin, and leptin (the latter two being linked to
adiposity).
 The integration of these signals by the hypothalamus
involves neurons that contain a number of different
neuropeptides, whose complex role in producing
satiety is yet to be determined.