Download Lecture Notes - Pitt Honors Human Physiology

NROSCI/BIOSC 1070 and MSNBIO 2070
November 20, 2017
Gastrointestinal 2
Clinical Issues Affecting the Gastrointestinal System
A number of gastrointestinal diseases occur because of damage in the enteric nervous
system, so that motility does not occur properly. For example, 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 Hirshsprung’s disease, where part of the colon loses
motility.
Probably the most common stomach disorder is peptic ulcer, which was discussed previously.
Ulcers often occur in the duodenum of patients with Zollinger-Ellison Syndrome, in which
a tumor begins to excrete gastrin. The end result is that stomach acid secretion becomes so
high that the small intestine is damaged.
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 stones.
The treatment for gallstones is surgical 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.
A number of genetic diseases result in the lack of a transporter for a particular molecule,
impairing the absorption of that molecule. Coincidentally, the same transporter is also missing
from the kidney, so that impaired absorption in the gut is coupled with increased excretion by
the kidney.
Diarrhea is a serious condition affecting the gastrointestinal system, and is a common cause
of death. There are three main causes of diarrhea:
1) Impaired absorption by the intestine (may result from infection or inflammation)
2) Accumulation of nonabsorbable, osmotically-active agents in the gut lumen
3) Infections of the intestinal wall, that result in excessive stimulation of secretory cells
November 20, 2017
Page 1
Gastrointestinal 2
A number of other diseases commonly affect the gastrointestinal system. 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. A closely related
condition is Chrohn’s Disease.
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
An introduction to metabolism
Despite decades of investigation, considerable differences of opinion about how food intake is
controlled still exist. However, 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.
It is important to understand some general principles regarding the metabolism of materials
absorbed via the digestive system before control of food intake is considered. You will hear
considerably more about metabolism in the next lecture.
Because we tend to eat a few large meals per day, 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.
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.
A number of body tissues store nutrients. 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.
November 20, 2017
Page 2
Gastrointestinal 2
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 is converted
to glucose in a process called gluconeogenesis.
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, and glycogenolysis,
ketogenesis, and gluconeogenesis occur during the postabsorptive period.
Overview of Metabolism:
November 20, 2017
Page 3
Gastrointestinal 2
Insulin and its critical role in caloric homeostasis
Insulin is secreted from beta-cells (endocrine cells) of the pancreas. This hormone plays
an important role in the storage of nutrients. 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. The hormone also stimulates enzymes
that produce glycogen, and inhibits glycogenolysis and gluconeogenesis. Finally, the hormone
activates enzymes for protein synthesis and inhibits enzymes that promote protein breakdown.
However, 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.
Many factors govern the secretion of insulin. A major factor is the level of glucose in the blood
to which the beta 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 which was
discussed in the last lecture, also influence insulin release. The beta-cells of the pancreas are
also innervated by sympathetic and parasympathetic postganglionic fibers. Parasympathetic
activity stimulates the secretion of insulin, whereas alpha-adrenergic sympathetic activity
inhibits it.
During the postabsorptive period, insulin secretion drops and secretion of another pancreatic
hormone, glucagon, increases. Glucagon is secreted by alpha-cells of the pancreas, and
acts to stimulate glycogenolysis, gluconeogenesis, and ketogenesis.
November 20, 2017
Page 4
Gastrointestinal 2
Insulin secretion starts even before consumption of
a meal begins. During the cephalic phase of insulin
secretion, the parasympathetic nervous system acts
to stimulate beta-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 beta-cells. The
levels of blood insulin grow even higher during the
substrate phase, when glucose in the blood begins
to directly act on the beta cells.
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. Dr. Sved discussed diabetes insipidus in the renal section of the course.
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 beta cells of the pancreas are destroyed by the immune system. This aberrant
immune response is sometimes triggered by viral infections. There is also some evidence
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: juvenile-onset diabetes. Because patients with this disease are insulin-deficient, the
only treatment is insulin injections. About 10% of all diabetes mellitus patients suffer from
the Type I disease.
November 20, 2017
Page 5
Gastrointestinal 2
The other variant of diabetes mellitus is non-insulin 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.
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. 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 (post-meal) 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. 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
The figure on the next page illustrates the events occurring after the ingestion of carbohydrates
in an insulin-deficient individual. Digestion and absorption of glucose by the small intestine
proceeds normally, but 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 insulindependent, 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.
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 use fatty acids to provide for its
metabolic needs, which results in ketone bodies being dumped into the blood.
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
(we will learn more about this during the renal lectures), 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
November 20, 2017
Page 6
Gastrointestinal 2
November 20, 2017
Page 7
Gastrointestinal 2
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 (high
blood K+ levels due to effects on renal transport mechanisms to be discussed later in the
course). 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.
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 receptor-gamma (PPARg). In humans, PPAR receptors are found in key
target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation
of PPARg nuclear receptors regulates the transcription of insulin-responsive genes involved
in the control of glucose production, transport, and utilization. In addition, PPARg-responsive
genes also participate in the regulation of fatty acid metabolism.
Note: Avandia has been shown to increase the risk for heart attacks. There are very strict
limitations on its use in patients in the United States.
Glucagon and Its Role in Regulating Blood Glucose Levels
Glucagon is released by alpha 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. 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.
November 20, 2017
Page 8
Gastrointestinal 2
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.
Factors that generate satiety signals
All mammals eat periodic meals. It is well-documented
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.
What factors might lead to cessation of eating
at the end of a meal? Obviously, gastric
distension is a possibility. Experiments have
shown that distension of the stomach does
indeed inhibit eating. 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.
It appears that afferents from the liver also play an important role in reducing food intake.
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.
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.
November 20, 2017
Page 9
Gastrointestinal 2
The diagram to the left summarizes the potential
role of leptin and insulin in regulating food intake
and weight gain.
Ghrelin
Another recently-discovered “hunger hormone” is ghrelin, which is produced by stretchsensitive 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 both to increase hunger, and to increase gastric acid
secretion and gastrointestinal motility to prepare the body for food intake. The receptor for
ghrelin is found on the same cells in the brain as the receptor for leptin, the satiety hormone
that has opposite effects from ghrelin.
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.
Central Nervous System Control of Food Intake
Although both blood-borne and afferent signals undoubtedly play an important role in
influencing feeding, it is the central nervous system that controls this complex behavior. Lesions
placed in the hypothalamus can have a great impact on the amount of food consumed, and
thus body weight. 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.
November 20, 2017
Page 10
Gastrointestinal 2
A number of neuropeptides have been shown to
influence feeding, including the following: oxytocin,
insulin, neuropeptide Y, opioids, CCK, galanin,
and the orexins. For example, 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. 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, as shown in the graph
on the next page. 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. As
noted previously, this signal is related to adiposity
and is likely to be integrated with signals conveyed
by the secretion of leptin, although the mechanism
is unknown. Furthermore, insulin has been shown
to sensitize the brain to neural (afferent) signals
from the stomach and liver.
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.
November 20, 2017
Page 11
Gastrointestinal 2
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.
We will not be discussing the roles of other peptides in control of feeding, but compelling data
exist to show that a large number of peptides are involved in regulating this process.
TAKE-HOME MESSAGE
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),
and ghrelin. 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.
November 20, 2017
Page 12
Gastrointestinal 2