Download CASE 37

❖
CASE 37
A 46-year-old man presents to his primary care physician with complaints of
confusion, headache, disorientation, and visual difficulties in the morning
upon awakening. He also has episodes of heart palpitations, sweating, and
tremor in the morning. All the symptoms usually resolve after he eats breakfast and do not recur unless he skips a meal. His physical examination is completely normal. A complete blood count is normal, and a basic metabolic panel
reveals a fasting blood sugar < 50 mg/dL. The patient denies any alcohol or
drug use. The patient subsequently is diagnosed with an insulinoma that is
causing hypoglycemia. The physician explains to the patient that the insulin
secreting tumor causes a low blood sugar, and the body increases the hormones epinephrine and cortisol to try to elevate the blood sugar.
◆
What effect does epinephrine have on pancreatic islet cells?
◆
What effect does prolonged fasting have on cortisol secretion?
◆
How many calories per gram does glucose provide?
302
CASE FILES: PHYSIOLOGY
ANSWERS TO CASE 37: HORMONAL REGULATION
OF FUEL METABOLISM
Summary: A 46-year-old man has symptoms of hypoglycemia in the morning
and when meals are skipped secondary to an insulin-secreting insulinoma.
◆
Effect of epinephrine on pancreatic islet cells: Stimulate glucagon
secretion and inhibit insulin secretion.
◆
Cortisol and prolonged fasting: Follow the normal basal diurnal
rhythmic pattern.
◆
Calories provided in glucose: About 4 calories per gram.
CLINICAL CORRELATION
The etiology of hypoglycemia can be broken down into two categories. The
first category is postprandial hypoglycemia, in which symptoms occur 2 to
4 hours after eating, resulting in diaphoresis, anxiety, irritability, palpitations,
and tremor. Epinephrine release is thought to be the cause of these symptoms.
The second category is fasting hypoglycemia. These patients generally have
symptoms of headache, confusion, mental dullness, fatigue, visual changes,
seizures, and, rarely, loss of consciousness. Etiologies for this type of hypoglycemia include excess insulin (self-administered medications, insulinoma),
alcohol abuse and liver disease (decreased gluconeogenesis), and pituitary or
adrenal insufficiency. Insulinomas are endocrine tumors of the pancreas
derived from beta cells that autonomously secrete insulin without normal regulatory control. The diagnosis can be confirmed by finding elevating serum
insulin levels at the time of hypoglycemia. The levels of insulin and glucose
also should be checked during a period of prolonged fasting.
APPROACH TO HORMONAL REGULATION OF FUEL
METABOLISM
Objectives
1.
2.
3.
4.
Know the basic body fuels: glucose, glycogen, fat, protein.
Understand the regulation of blood glucose.
Describe the regulation of metabolism during fasting and after eating.
Know the effects of exercise on glucose metabolism.
Definitions
Body fuel reserves: The body stores metabolic fuels in the form of carbohydrates, fat and protein mainly in the liver, skeletal muscle, and adipose
tissue.
CLINICAL CASES
303
Plasma glucose balance: The primary regulator of insulin and glucagon
secretion is glucose. Elevation of circulating glucose levels stimulates
insulin secretion and inhibits glucagon secretion, in turn stimulating
hepatic glucose uptake and inhibiting glucose production. A fall in circulating glucose has the opposite effect resulting in hepatic glucose production and release into the blood. Thus the circulating levels of glucose
provide a feedback mechanism to control the relative rate of glucose
uptake and glucose production by the liver.
DISCUSSION
The body has three fuel reserves that may be drawn on during a fasting
state: carbohydrate, fat, and protein. In terms of pure energy yield, fat
is the most economical, yielding about 9.4 kcal/g compared with about
4.2 kcal/g for protein and carbohydrate. An examination of the distribution of fuel reserves reveals that about 76% of the caloric content is fat, 23%
is protein, and 1% is carbohydrate, principally as glycogen. The glycogen
reserves are stored in liver and muscle. Fats are stored in adipose tissue
and the liver. The protein reserves are distributed throughout the body, but
are drawn mainly from the muscle mass of the body. An average adult
ingests and expends about 2500 kcal/day. Excess caloric intake provides
nutrients for storage in the fuel reserves of the body. During periods of fasting the body draws on those reserves. The glycogen stores are the smallest
and most rapidly depleted, lasting about a day or two, depending on the
level of activity. Despite this rapid depletion, the plasma glucose concentration remains at a constant level of 80 to 90 mg/dL for the duration of the fast.
The body must maintain this fasting level of glucose to provide a fuel source
for tissues that have an absolute requirement for glucose as an oxidative
substrate.
Shortly after the initiation of the fast, there is an increase in lipolysis in
adipose tissue with a release of free fatty acids (FFA) into the circulation.
The liver oxidizes FFA through β-oxidation, resulting in the production of
ketoacids. The ketoacids are transported into the blood and used as an oxidizable substrate to minimize the demand for glucose. Because the main carbohydrate stores are depleted rapidly, the body draws on the protein mass to
provide glucogenic precursors. The problem that the body faces is that fat can
be used only to provide oxidative energy and cannot serve as a glucogenic
precursor. Protein catabolism releases amino acids that can serve as glucogenic precursors. Drawing on the protein reserves is problematic in that it
necessitates a loss of muscle mass and connective tissue. Return to a normal
feeding cycle permits restoration of the fuel reserves.
304
CASE FILES: PHYSIOLOGY
Control of Plasma Glucose Concentration
Maintaining the plasma glucose concentration and managing the fuel reserves
include a highly choreographed series of events that are directed mainly by
two hormones: insulin and glucagon. In a general sense, insulin may be
viewed as an anabolic hormone and glucagon as a catabolic hormone.
The Role of the Liver in Fuel Metabolism
The major site of action is the liver, which is a target tissue for both hormones;
depending on their relative concentrations, the liver either extracts glucose
from the blood (high insulin/glucagon ratio) or produces and adds glucose to
the blood (low insulin/glucagon ratio). The responses can be divided into
short-term ones such as the changes occurring during a normal daily cycle of
feeding and long-term adaptive responses to prolonged fasting.
In the short term, the effects of insulin and glucagon on several key regulatory reactions in intermediary metabolism are directly opposed to each
other. These key points of regulation have been described as futile cycles
because there is always some basal activity. For example, glycogen synthesis
and glycogenolysis occur simultaneously at a very low rate, with a continuing cycling of glucose between glucose-1-phosphate and glycogen. Net production or breakdown of glycogen is dependent on the relative rates of the two
reactions. Regulation of the process is exerted by activating one reaction and
inhibiting the counterreaction. Often these reactions are controlled by
phosphorylation-dephosphorylation cycles, and in large part these effects can
be attributed to one common factor: cyclic adenosine monophosphate
(cAMP). Glucagon activates adenyl cyclase, causing an increase in cellular cAMP levels and protein kinase A (PKA) activity. This stimulates
glycogenolysis and glucose production. In contrast, insulin binding to its
receptor, a tyrosine kinase, activates a signaling pathway that activates protein kinase B (PKB) and protein phosphatase-1 which inhibits glycogenolysis and activates glycogen synthesis.
Thus, after the ingestion of a carbohydrate-containing meal, the rise in
plasma insulin levels will cause an activation of glycogen synthase and an
inhibition of phosphorylase. A fall in the plasma glucose concentration
reduces pancreatic insulin secretion and stimulates glucagon secretion. The
hepatocyte responds to these changes by initiating a decrease in protein phosphatase activity (as a result of decreased insulin levels) and an increase in PKA
activity (as a result of elevated glucagon levels). The overall effect is an
increase in glycogenolysis with the production of glucose. Similar mechanisms in the glycolytic pathway control the relative rates of glycolysis and gluconeogenesis. With elevated plasma insulin, there is an activation of
glycolysis. Glucagon inhibits the glycolytic pathway and activates gluconeogenesis.
CLINICAL CASES
305
Insulin also promotes hepatic glucose uptake and utilization through
activation of lipogenesis. Insulin activates pyruvate oxidation by the mitochondria, increasing production of acetyl-CoA. The acetyl-CoA is directed
into the lipogenic pathway for fatty acid synthesis. Therefore, in the presence
of insulin, glucose also enters into the glycolytic pathway, providing substrates
for increased fatty acid production. In the absence of insulin, these pathways
are reversed, that is, reduced glycolysis and reduced fatty acid synthesis but
there is an increase in fatty acid oxidation and an increase in the gluconeogenic
enzymes favoring the production of glucose.
The Role of Adipose Tissue in Fuel Metabolism
Adipose tissue is another major site of insulin action. Adipocytes have an
insulin-dependent glucose permeability that is similar to that of muscle cells;
however, its main function is to provide the substrate a-glycerophosphate for
triglyceride formation. The key step in the regulation of triglyceride synthesis
and breakdown is highly regulated. There is a continuous low rate of lipolysis
catalyzed by hormone-sensitive lipase (HSL) in adipose tissue with the production of FFA. The FFA produced by this reaction is reesterified to triglyceride in the presence of insulin and sufficient glucose to supply the
α-glycerophosphate backbone. In the absence of insulin, the FFA produced by
this reaction is released into the blood. This is an important control mechanism
because it couples FFA production to plasma glucose and insulin levels. Other
counterregulatory hormones (eg, cortisol, growth hormone, catecholamines)
stimulate HSL, accelerating lipolysis and the release of FFA. In diabetes mellitus, the failure of insulin-dependent regulation of this reaction permits the
massive production of FFA and leads to diabetic ketoacidosis.
After the ingestion of a carbohydrate-containing meal, plasma insulin
rises as a consequence of elevated plasma glucose levels. Increased insulin
stimulates glucose utilization by the liver through synthesis of glycogen and,
with sufficient glucose levels, FFA. Muscle glucose uptake increases, and glycogen synthesis is stimulated. The glucose permeability of adipose tissue
increases, providing a substrate for triglyceride formation and storage. The combined effect is net glucose utilization and storage as glycogen and fats. The
increase in glucose utilization results in a fall in the plasma glucose concentration and a parallel fall in insulin secretion. The fall in insulin is accompanied by
a fall in glucose tissue utilization. As the glucose concentration approaches
fasting levels, glucagon secretion increases. The increase in plasma glucagon
stimulates hepatic glycogenolysis and gluconeogenesis, and the liver converts
from a glucose-utilizing to a glucose-producing organ. In this case, the patient is
suffering from an increased and uncontrolled level of insulin. As a consequence,
glucose utilization is not limited by factors such as permeability and reduced
enzyme activities; instead, this is because of the availability of glucose itself.
This results in the severe hypoglycemia that accompanies this disorder.
306
CASE FILES: PHYSIOLOGY
The Role of Muscle in Fuel Metabolism
Insulin acts on other tissues to promote glucose utilization. Muscle stores
glucose in the form of glycogen. The glucose is taken up from the plasma and
converted to glycogen in a series of regulated reactions that are analogous to
hepatic glycogen synthesis. Muscle lacks the enzyme glucose-6-phosphatase;
thus, glucose generated by glycogen breakdown cannot be released into the
blood and is destined for oxidation by the muscle. An important difference
between muscle and hepatic glucose utilization is that glucose uptake by resting
muscle is insulin dependent. A specific insulin-dependent glucose transporter,
GLUT-4, is required for glucose uptake by the muscle cell. Therefore, insulin
promotes muscle glucose utilization by activating glycogen synthesis and glucose uptake. In the absence of insulin, the glucose permeability of the resting
muscle cell is low. In exercising muscle, there is an insulin-independent
increase in glucose permeability that is dependent on the level of exercise.
Muscle utilizes FFA as oxidizable substrate preferentially over glucose.
During prolonged exercise, for example, the body’s supply of glycogen can be
exhausted. As described above, there is an increase in fatty acid mobilization
from adipose tissue which is delivered to the muscle tissue on albumin. Muscle
oxidizes FFA as its primary source of energy limiting further glucose utilization.
Adaptive Mechanisms to Stress and Prolonged Food
Deprivation
The central nervous system responds to severe hypoglycemia with an
increase in sympathetic output to the pancreas and the adrenal medulla.
Catecholamine release at the nerve endings directly stimulates alpha cells to
secrete glucagon and inhibits beta-cell secretion of insulin. Catecholamines
released by the adrenals stimulate muscle glycogenolysis and adipose lipolysis and act in synergy with glucagon to stimulate hepatic glucose production.
The central nervous system (CNS) also stimulates hypothalamic ACTH and
growth hormone secretion. Their effects are somewhat delayed, with the major
effect resulting from cortisol secretion. Cortisol alone has a minimal effect, but
in combination with glucagon and epinephrine, it evokes a very pronounced
increase in hepatic glucose production.
The glucocorticoids play a major role in the maintenance of fuel supplies and the mobilization of fats and protein breakdown. Cortisol has a
permissive effect on a number of enzymes that are involved in fuel metabolism. In the experimental setting, fasting adrenalectomized animals fail to generate glucogenic precursors and die shortly after depletion of their carbohydrate
stores. The major deficit is the failure to initiate muscle protein breakdown to
provide the carbohydrate backbone for gluconeogenesis. In the normal animal,
these enzymes are always present because of the secretion of cortisol. During
a prolonged fast, there is a gradual small increase in glucocorticoid secretion
throughout the fast.
CLINICAL CASES
307
During periods of prolonged food deprivation, a series of adaptive
responses result from the lack of insulin. Glucagon secretion is increased to
maintain a fasting level of plasma glucose, however, the body reacts by mobilizing alternative fuel supplies (FFA and ketone bodies) and glucogenic precursor molecules (amino acids derived from protein breakdown). These
changes result from a lack of insulin caused by decreased insulin secretion
during starvation, the failure of the pancreas to produce and secrete insulin, or
insulin resistance. All the short-term changes in enzymatic activities described
above occur, but there are several longer term responses to insulin. For example, glucokinase is a liver-specific enzyme that is required for glucose phosphorylation to glucose-6-phosphate. The synthesis of glucokinase is insulin
dependent. The actual turnover of the protein is such that during a normal
cycle of food intake, there is not a significant enough change in the enzyme
level to interfere with glucose utilization. However, during prolonged food
deprivation, the levels of glucokinase fall to near-zero levels. This is an appropriate adaptive response to starvation because it limits glucose utilization by
the liver. A number of enzymes involved in glucose metabolism and the regulation of energy metabolism in general are insulin dependent in this fashion.
For example, lipoprotein lipase is the committed step in triglyceride accretion
and storage in the adipocyte and is synthesized in an insulin-dependent fashion. This minimizes glucose utilization by the adipocyte by preventing the
uptake and storage of triglycerides during fasting. Finally, insulin has a general effect of increasing protein synthesis.
More than 150 genes have been shown to be insulin dependent. In the
absence of insulin, there is an increase in protein catabolism with an
increase in the rate of amino acid release into the blood. Under normal conditions, with the onset of a fast there is a fall in plasma insulin levels and an
increase in the glucagon concentration. The fall in insulin reduces glucose utilization and, if continued, results in a decrease of several enzymes involved in
glucose utilization. As a consequence, there will be increased mobilization of
FFA from adipose tissue. FFA is transported to the liver, which in the absence
of insulin is in a ketogenic state. FFA b-oxidation results in the production
of ketoacids and their release into the blood. FFA and ketoacids are the preferred oxidative substrates of a number of tissues, further minimizing glucose utilization and conserving the carbohydrate backbone. Muscle protein
catabolism results in a release of amino acids. Glucogenic amino acids are
transported to the liver to serve as a substrate for gluconeogenesis.
Exercise markedly increases the demand for fuels. The glucose stores
are sufficient for short-duration exercise, and these needs are met by the glycogen stores, creatine phosphate, and adenosine triphosphate (ATP)
reserves in the muscle. Exercise of longer duration results in significant alterations of insulin and the counterregulatory hormones, resulting in the breakdown of hepatic glycogen and the mobilization of FFA from adipose tissue.
There is a fall in insulin secretion and an increase in catecholamines,
glucagon, growth hormone, and cortisol. These factors combined result in
308
CASE FILES: PHYSIOLOGY
an overall increase in hepatic glucose production as a consequence of catecholamines and glucagon, and a decrease in glucose utilization by the liver as
a result of the fall in insulin. Decreased insulin levels also minimize glucose
uptake in the adipocyte, resulting in an increase in FFA production. The
increased levels of the counterregulatory hormones will activate hormonesensitive lipase (HSL) in the adipocyte to increase the production of FFA to
serve as an alternative source of oxidizable substrate. During prolonged exercise (> 3 hours), glycogen stores are depleted nearly completely and there
is an increased demand for FFA for oxidizable substrates.
COMPREHENSION QUESTIONS
[37.1]
A 36-year-old female biochemist reflects on the action of insulin as
she is eating toast at breakfast. Insulin action on target cells results in
which of the following?
A.
B.
C.
D.
[37.2]
Activation of a tyrosine kinase
Activation of adenyl cyclase
Increased glucagon secretion
Increased gluconeogenesis
Glucagon action on the liver is mediated by which of the following?
A. A cell surface receptor tyrosine kinase receptor
B. A specific G protein–coupled receptor and activation of adenyl
cyclase
C. Binding to an intracellular receptor
D. Ligand binding to specific enzymes
[37.3]
An 8-year-old child is diagnosed with type I diabetes. Insulin deficiency results in which of the following?
A.
B.
C.
D.
Decreased glycogenolysis
Decreased lipolysis
Increased protein synthesis
Ketogenesis
Answers
[37.1]
A. Insulin does not activate adenyl cyclase. It does bind to a receptor
tyrosine kinase that autophosphorylates upon insulin binding. The
phosphorylation activates the tyrosine kinase to phosphorylate specific insulin receptor substrate molecules. These substrate molecules
then lead to the activation of short- and long-term signaling pathways.
Short-term pathways involve phosphorylation of protein phosphatase-1
by PKB. Protein phosphatase-1 catalyzes the dephosphorylation of
phosphoproteins such as glycogen synthase, leading to their activation.
Although details of the short-term pathway have not been elucidated
CLINICAL CASES
309
completely, the result is enhanced glucose utilization through glycogen synthesis and glycolysis, increased glucose permeability in muscle and adipose tissue, and increased synthesis of triglycerides in
adipose and hepatic tissue. The long-term response is mediated by
activation of the MAP kinase pathway and the activation of specific
transcription factors for the synthesis of key regulatory enzymes in
anabolic pathways and protein synthesis in muscle cells.
[37.2]
B. Glucagon is a peptide hormone that binds to a specific plasma
membrane receptor that is coupled by G proteins to adenyl cyclase.
Activation of the cyclase results in elevated levels of cAMP and activation of PKA. PKA specifically targets enzymes in the hepatocyte
that promote glycogenolysis, gluconeogenesis, and the oxidation of
FFA. The net effect is to increase glucose production and release
from the liver. Secondarily, there is an increase in ketogenesis with
their release into the blood.
[37.3]
D. Insulin deficiency promotes a series of reactions in the body that
are similar to adaptation to food deprivation or starvation. The initial
response is to maintain the plasma glucose concentration through
increased glycogenolysis and hepatic gluconeogenesis. Without the
insulin-dependent control, there will be a decrease in the rate of glucose utilization as a result of decreased permeability in insulindependent tissues such as muscle and adipose tissue. Limiting glucose
permeability to adipose tissue will inhibit triglyceride formation,
resulting in increased release of FFA into the circulation. Hepatic oxidation of FFA will produce ketone bodies that will enter the circulation,
providing alternative energy sources for tissues, and reduce glucose utilization further. Insulin promotes muscle protein synthesis, and in its
absence protein catabolism will prevail, with a release of glucogenic
precursors into the circulation for hepatic gluconeogenesis.
310
CASE FILES: PHYSIOLOGY
PHYSIOLOGY PEARLS
❖
❖
❖
❖
❖
Management of the body’s fuel supplies is dependent on multiple
hormonal interactions and the coordinated activities of several
key organ systems. Both short-term and long-term hormonal
responses are due primarily to changes in the plasma glucose
concentration.
Immediate changes occur in the phosphorylation state and the activities of rate-limiting enzymes in the pathways of carbohydrate,
fat, and protein metabolism. Long-term effects are because of
changes in the rate of protein synthesis and breakdown that alter
the expression of key rate-limiting enzymes in anabolic and catabolic pathways.
The liver can be viewed as a “glucostat” that controls plasma glucose. The liver can either extract glucose from the blood or produce and release glucose into the blood, depending on the
circulating levels of glucagon and insulin. A feedback control
mechanism is built into the system in that the plasma glucose
level controls the rates of insulin and glucagon secretion.
Insulin and glucagon have relatively short half-lives in the circulation. Their circulating levels are dependent on their rates of secretion, which are controlled primarily by the plasma glucose
concentration. Thus, there is a very tight coupling between the
hepatic glucose metabolism and its plasma concentration.
Cortisol has a permissive effect on enzymes that are in the pathways
of protein breakdown for the production of glucogenic precursors
and lipolytic pathways that produce FFA. In its absence, fasting
animals fail to maintain plasma glucose levels and soon die.
REFERENCES
Goodman HM. Hormonal regulation of fuel metabolism. In: Johnson LR, ed.
Essential Medical Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press;
2003:259-276.
Goodman HM. The pancreatic islets. In: Johnson LR, ed. Essential Medical
Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:259-276.