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CASE 36
A 12-year-old boy presents to the emergency department with complaints of
weight loss, fatigue, polydipsia (excess thirst), polyphagia (excess hunger),
and polyuria (excess urination). The patient has no medical problems but there
are many family members with diabetes and hypertension. On examination,
the patient is a thin ill-appearing male in no acute distress with normal vital
signs. His examination is unremarkable. A urinalysis reveals glucosuria and a
markedly elevated serum fasting blood sugar. The patient is diagnosed with
type I diabetes mellitus (insulin-dependent), and is advised by the physician to
start insulin therapy. The patient’s parents ask whether oral agents such as sulfonylurea tablets can be used instead of insulin.
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What is the major factor that regulates insulin secretion?
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What hormones do the delta cells of the pancreas produce?
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How do sulfonylurea drugs increase insulin secretion?
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ANSWERS TO CASE 36: PANCREATIC ISLET CELLS
Summary: A 12-year-old boy with weight loss, fatigue, polydipsia, polyphagia, polyuria, and elevated fasting blood sugar is diagnosed with type I diabetes mellitus.
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Major regulating factor: Serum sugar levels.
Delta cells produce: Somatostatin and gastrin.
Sulfonylurea medications: Close the KATP potassium channels in the
beta cells allowing activation of voltage dependent Ca2+ channels
resulting in insulin secretion.
CLINICAL CORRELATION
Type I diabetes (juvenile) is caused by destruction of pancreatic islet cells, leading
to insulin deficiency. The destruction of the pancreatic islet cells may have multifactorial causes, such as genetic predisposition, viral, or autoimmune. Patients usually present in childhood or early adulthood and account for about 10% of all cases
of diabetes. These patients’ symptoms include polydipsia, polyphagia, weight loss,
and recurrent infections. Severe derangements may induce diabetic ketoacidosis,
characterized by markedly elevated blood sugar levels, elevated serum ketone levels, metabolic anion gap acidosis, and a variety of metabolic derangements such
as hypokalemia. A fasting blood sugar will help make the diagnosis of diabetes.
Because the primary deficit is lack of insulin, patients will need insulin replacement to improve their symptoms. Oral agents usually cannot be used as primary
therapy in type I diabetes because of the basic defect caused by insulin deficiency.
Type II diabetes occurs because of peripheral tissue resistance to insulin.
APPROACH TO PANCREATIC PHYSIOLOGY
Objectives
1.
2.
3.
Understand glucagon secretion, action, and regulation.
Understand insulin secretion, action, and regulation.
Understand somatostatin secretion, action, and regulation.
Definitions
Islets of Langerhans: Highly vascularized and innervated structures in the
pancreas containing three major cell types that secrete insulin (beta cells),
glucagon ( alpha cells) and somatostatin (delta cells).
Insulin: A small polypeptide anabolic hormone that promotes the sequestration of carbohydrate, fat and protein mainly in liver, adipose tissue
and skeletal muscle. In the absence of insulin these substances are mobilized from tissues to meet the fuel demands of the body.
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295
Glucagon: A small polypeptide hormone that targets mainly the liver to
promote glucose production through gluconeogenesis and glycogenolysis, and fatty acid oxidation with the production and release of keto acids
to meet the energy demands of the body during periods of fasting.
Sulfonyl ureas: A class of small therapeutic molecules that are potent stimulants of insulin secretion by pancreatic beta cells.
DISCUSSION
The cells of the islets of Langerhans in the endocrine pancreas are the site
of synthesis and secretion of the peptide hormones glucagon, insulin, and
somatostatin. The islets are highly vascularized, with a blood flow pattern
that drains directly into the portal vein, delivering the hormones directly to
the liver. The islets are innervated in the areas of the secretory cells with both
sympathetic (middle splanchnic nerve) and parasympathetic (vagus nerve)
input.
Mechanism of Secretion
A general model applies to the mechanism of secretion for each of the three
hormones, but the specific stimuli vary. The hormones are synthesized on
the rough endoplasmic reticulum (ER) as propeptide hormones. They are
processed in the ER and transported to the Golgi apparatus for sorting and
packaging into secretory vesicles. Secretory vesicles bud off of the transGolgi network and are directed toward the plasma membrane. The vesicles
containing the prohormone and the hormone-converting enzyme accumulate
in proximity to and just below the plasma membrane. After the appropriate
stimulus, the vesicles are recruited to the cell surface, where they fuse with the
plasma membrane, and their contents are ejected from the cell. During this
process of degranulation, there is a conversion to the hormone by specific
enzymatic cleavage of the prohormone.
The specifics of the activation of the secretory process are more fully characterized for insulin than for the other hormones. The mechanism is clinically relevant because it is the site of therapeutic intervention to increase insulin secretion
from the beta cells. Insulin secretion is dependent on a rise in the intracellular calcium concentration according to the following sequence of events:
1.
2.
3.
4.
The main stimulus is an increase in the plasma glucose concentration
that causes an increase in intracellular glucose.
Increased glucose in the cell promotes an increase in adenosine
triphosphate (ATP) levels.
ATP inhibits a potassium channel in the plasma membrane, with a
resultant depolarization of the membrane potential.
Depolarization of the membrane activates a voltage-dependent calcium
channel, permitting calcium influx and the initiation of secretory
vesicle fusion.
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The importance of this sequence of events is underscored by the finding
that the potassium channel is blocked by sulfonylureas. Thus, therapeutic
use of these agents can enhance insulin secretion in patients with an insulindeficient or resistant disease.
Regulation of Secretion
There is a complex physiologic interaction between insulin and glucagon
that is reflected in their regulation and mechanism of action. Generally, factors
that result from stresses to the individual, such as starvation and low plasma
glucose and elevated levels of epinephrine, norepinephrine, cortisol, or
growth hormone all stimulate glucagon secretion and suppress insulin
secretion. During unstressful periods with adequate food, metabolic factors
such as carbohydrates, fatty acids, and amino acids stimulate insulin secretion.
Insulin
Insulin is an anabolic hormone that promotes the utilization and storage of glucose, fatty acids, and amino acids. Insulin is secreted by the beta
cells of the islet in response to numerous stimuli, including metabolites, hormones, and neural mediators. The most important regulator of insulin secretion is the plasma glucose concentration. Increasing plasma glucose causes
a stimulation of insulin secretion, whereas a fall in glucose is accompanied by
a decline in insulin secretion. Regulation of insulin secretion by other factors
such as amino acids, fatty acids, and ketone bodies for the most part is a complex interaction and is dependent on the circulating level of glucose and not
relevant to the present case.
Insulin secretion is stimulated by several hormones. There is a class of
hormones called incretins that are mainly enteric hormones that stimulate
insulin secretion. Interestingly, these hormones are secreted in response to the
ingestion and absorption of carbohydrate, protein, or lipid and are secreted in
advance of an increase in the circulating levels of the metabolites. The insulin
response is thus anticipatory of the increase. The ultimate effect is to enhance
insulin secretion by the beta cells. In the experimental setting, there are several hormones that exhibit this response; however, the physiologically relevant
agents are glucose-dependent insulinotropic peptide (GIP) and glucagonlike peptide-1 (GLP-1). A paracrine effect of glucagon is to stimulate
insulin secretion, presumably to potentiate the effect of glucagon on the elevation of plasma glucose levels. Secretion of insulin also is enhanced by cortisol and growth hormone. Somatostatin inhibits insulin secretion through
a paracrine effect.
The islets are innervated with both sympathetic and parasympathetic
neurons. The beta cells are stimulated by the parasympathetic release of
acetylcholine or vasoactive intestinal peptide (VIP). The sympathetic hormones, epinephrine and norepinephrine, are potent inhibitors of insulin
secretion. A strong sympathetic response can shut down insulin secretion
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297
completely, thereby minimizing glucose utilization as part of the flight or
fight response.
The role of insulin is to promote the storage of metabolic fuels in the
form of glycogen, triglyceride, and protein. The main targets of insulin
action are the liver, muscle, and adipose tissue. The mechanism of action of
insulin is complex, eliciting both rapid responses and longer term effects on
cell metabolism. Insulin action is mediated by a plasma membrane insulin
receptor that is one of the tyrosine kinase receptors that can activate multiple intracellular signaling pathways (see Case 2). In the short term, the effects
of insulin on the cell are increased glucose transport (adipose and muscle),
glycogen synthesis, and fatty acid synthesis. In the long term, a parallel
pathway involving MAP kinase activation leads to the activation of transcription factors that regulate specific protein synthesis.
Glucagon
Glucagon is produced and secreted by the alpha cells of the islets,
although the regulation and mechanism of secretion are not clearly understood
(see above). As is the case with insulin secretion, the most important determinant in the secretion of glucagon is the blood glucose concentration.
However, the rate of glucagon secretion decreases with increasing blood
glucose. Glucagon secretion is maximal at plasma glucose concentrations
less than 50 mg/dL and completely blocked at concentrations above 200
mg/dL. A comparison of several effectors on glucagon secretion by the alpha
cell shows that the response is the opposite of the effect on beta-cell secretion
of insulin. In addition to glucose, ketone bodies and free fatty acids inhibit
glucagon secretion. The enteric hormones GIP and GLP-1 that stimulate
insulin secretion inhibit glucagon secretion. Finally, insulin itself and somatostatin inhibit glucagon secretion.
Alpha cells also secrete glucagon in response to neural stimulation from
both sympathetic and parasympathetic neurons. In contrast to the beta cell,
epinephrine and norepinephrine are potent stimuli for glucagon secretion, as
are acetylcholine and VIP from parasympathetic neurons.
The major target tissue for glucagon is the liver, and in most regards
glucagon is counterregulatory to insulin action. The mechanism of glucagon
action is very well defined and well described. Although glucagon receptors
are found on other tissues, the concentration of the hormone necessary to elicit
a response is well above the physiologic range. The hepatic glucagon receptor is a G protein–coupled receptor. Binding of glucagon leads to activation
of adenyl cyclase and synthesis of cyclic adenosine monophosphate
(cAMP). Elevated cAMP activates protein kinase A, resulting in the phosphorylation of a number of key regulatory enzymes. The result is a stimulation of glycogen breakdown and gluconeogenesis with a net production and
release of glucose into the blood. During periods of fasting (low circulating
levels of insulin) glucagon will also limit fatty acid synthesis and promote its
breakdown and production of ketone bodies.
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Control of the Plasma Glucose Concentration
The opposing actions of insulin and glucagon on hepatic function are the basis of
a simple but elegant feedback mechanism to control net glucose production. The
key regulator of pancreatic secretion of insulin and glucagon is the plasma glucose
concentration, which is controlled by the action of these two hormones on the liver.
As plasma glucose concentrations approach fasting levels below 90 mg/dL,
glucagon secretion increases and insulin secretion decreases. These changes promote the production of glucose in the liver and its release into the blood.
Somatostatin
Pancreatic somatostatin is secreted by the delta cells of the islets. The
role of pancreatic somatostatin is poorly understood. From a number of experimental studies, somatostatin has been shown to inhibit both alpha-cell and
beta-cell secretion of glucagon and insulin, respectively, suggesting a possible paracrine role for the hormone.
COMPREHENSION QUESTIONS
[36.1]
Insulin secretion is inhibited by which of the following?
A.
B.
C.
D.
[36.2]
An experimental animal is instrumented to monitor plasma glucose
and insulin levels. After a control fasting period to establish a steady
state, a test substance is administered to the animal. Shortly after the
administration of the substance, there is an increase in the plasma
insulin concentration and a fall in the plasma glucose concentration.
The substance is most likely which of the following?
A.
B.
C.
D.
E.
[36.3]
Glucagon
Epinephrine
Amino acids
Glucose
Glucagon
Epinephrine
A sulfonylurea compound
Somatostatin
Glucose
In a normal individual, the liver is the main regulator of the plasma
glucose concentration. When there is an increase in the plasma glucose concentration, the liver extracts glucose from the blood and converts it into glycogen and, to a lesser extent, triglycerides. When the
plasma glucose concentration falls, the liver will begin to produce
glucose and release it into the blood to maintain its concentration. In
an untreated type I diabetic patient, the liver fails to extract glucose
and continues to produce glucose regardless of its plasma concentration. Which of the following most likely contributes to this failure?
CLINICAL CASES
A.
B.
C.
D.
E.
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Increased glucokinase activity
Decreased phosphorylase activity
Increased gluconeogenesis
Diminished muscle protein catabolism
Insulin-dependent glucose transport in the liver
Answers
[36.1]
B. Insulin secretion is stimulated by amino acids and glucose and
inhibited by somatostatin and epinephrine and sympathetic stimulation. Epinephrine is a potent blocker of insulin secretion and stimulates glucagon secretion. This is the so-called flight or fight response
to provide a burst of glucose for rapid and immediate utilization.
[36.2]
C. The correct answer is a sulfonylurea compound. These compounds
block the ATP-inhabitable K+ channel in the beta cells, which causes
a depolarization and activation of a Ca2+ channel. The influx of
Ca2+stimulates insulin secretion. As insulin levels rise, there is
increased glucose utilization by liver, muscle, and adipose tissues,
causing a fall in the plasma glucose concentration. Glucagon or glucose would stimulate insulin secretion; however, there would be a
transient increase in the plasma glucose concentration. Epinephrine
and somatostatin would inhibit insulin secretion.
[36.3]
C. The liver has no insulin-dependent glucose transport system.
Glucose transport is insulin-independent, and glucose rapidly equilibrates across the hepatocyte membrane. One of the most important
factors in the failure of the liver to extract glucose in a chronically
insulin-deficient state is reduced glucokinase activity. Glucokinase is
liver-specific and has several important features that distinguish it
from the analogous hexokinase in other cell types. It also has a higher
Km and is not feedback-inhibited by its product glucose-6-phosphate. Therefore, even at high glucose concentrations, glucokinase
does not saturate and continues to produce glucose-6-phosphate,
which can accumulate in the cell. Insulin has a permissive effect on
glucokinase, and in its absence, glucokinase levels can fall to very
low levels. As a consequence, glucose entry into the glycolytic or
glycogen synthetic pathway is limited. The lack of insulin also
reduces the activities of key regulatory enzymes (eg, glycogen synthase, phosphofructokinase, and pyruvate kinase) involved in directing glucose toward glycogen synthesis or glycolysis, further limiting
glucose utilization. Insulin also promotes protein synthesis in muscle
tissue, and in its absence, there is an increased protein catabolism
with a release of glucogenic precursors into the blood. These precursors are taken up by the liver and used to produce glucose through the
gluconeogenic pathway.
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PHYSIOLOGY PEARLS
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The major hormones regulating energy metabolism are glucagon
and insulin. They are produced and secreted by the alpha and beta
cells of the pancreatic islets of Langerhans.
Insulin is an anabolic hormone that targets the liver, adipose tissue,
and muscle tissue and promotes glycogen synthesis, fatty acid
synthesis and triglyceride formation, and protein synthesis.
Glucagon targets the liver and is counterregulatory to insulin, promoting glycogenolysis, fatty acid oxidation, and gluconeogenesis.
Glucagon action is mediated by G protein–coupled plasma membrane receptor activation of adenyl cyclase and protein kinase A
activation.
Insulin targets mainly the liver, muscle, and adipose tissues, and its
action is mediated by a plasma membrane tyrosine kinase receptor and has short-term and long-term effects on the target cell. The
immediate effects are the activation of protein kinase B and phosphoprotein phosphatase-1, which antagonize cAMP-dependent
reactions and promote glycogen synthesis, fatty acid synthesis,
and triglyceride formation.
Longer term insulin effects are mediated by the MAP kinase signaling pathway, with activation of specific transcription factors that
leads to increased protein synthesis.
During starvation, there is a dramatic fall in insulin levels, leading to
a decrease in insulin-dependent processes and allowing
glucagon-dependent processes to prevail. The fall in plasma glucose stimulates glucagon secretion, which promotes hepatic fatty
acid oxidation, glycogen breakdown, and gluconeogenesis. The
lack of insulin allows protein breakdown to occur, with a release
of glucogenic precursors from muscle into the circulation.
Glucagon-dependent gluconeogenesis from these precursors in
the liver is driven by energy derived from fatty acid oxidation.
REFERENCE
Goodman HM. The pancreatic islets. In: Johnson LR, ed. Essential Medical
Physiology. 3rd ed. San Diego, CA: Elsevier Academic Press; 2003:259-276.