Lecture 5-2: Hormonal Regulation of Fuel Metabolism

The fuel hormones (epinephrine, glucocorticoids, glucagon, insulin) are the

major regulators of carbohydrate metabolism. They are the basis of
regulating enzymatic activity of pathways of carbohydrate metabolism and
of some of the tissue specificity of pathways of carbohydrate metabolism.

• Hormones of fuel metabolism

• Sites of synthesis
• Major actions
• Tissue differences in their actions
• Glucose, glucagon & insulin levels following a
carbohydrate meal
• Clinical scenario
• Non-malignant insulinoma and non insulin-
dependent diabetes mellitus

All images are from “Marks et al., 2nd Edition, Copyright © 2005 Lippincott & Williams, A
Wolters Kluwer Co., All rights reserved” unless otherwise noted.
 Fuel Homeostasis
• Fuel availability and tissue needs
must be balanced
• This balance is achieved by three
types of messages
9Blood level of nutrients
9Hormone levels
9Nerve impulse

Glucose is a special fuel

• Tissues that depend upon glycolysis for
energy include red blood cells, the lens
of the eye and the kidney medulla
• Uninterrupted access to glucose is required
to sustain high level of ATP utilization
• Normal homeostatic concentration of
glucose in the blood is 80 – 100 mg/dL
(~ 5 mM)
Taken from Table 43.1: Major Hormones that
Regulate Fuel Metabolism
• Anabolic hormone
• Insulin β cells of pancreas
• Counter-regulatory hormones
Hormones with actions antagonistic to insulin
• Glucagon α cells of pancreas
• Epinephrine Catecholamines - sympathetic
• Norepinephrine neurons, adrenal medula
• Cortisol glucocorticoids – adrenal cortex
• Somatostatin D cells of pancreas
• Growth hormones Anterior pituitary gland
• Thyroid hormone Thyroid acinar cells

Fig 26.9: Major insulin

counter regulatory
hormones

Nervous
system
response

Sites of
hormone
release

Metabolic effects
 Hormones of fuel metabolism

• What are the…

• …major roles of the hormones?
• …tissue differences in their effects?
• Insulin versus glucagon
• These hormones have opposite effects on
metabolism.
• What are the fasting levels of these hormones?
• What are the post absorptive levels of these
hormones?

Table 26.1: Physiological Actions of Insulin and Insulin

Counter-regulatory Hormones

Synthesis versus degradation is carefully regulated for the fuel

glucose and its storage form glycogen as well as for the fuel fatty
acids and its storage form triacylglycerols.
 Figure 26.6:
Major sites of
insulin activity
(anabolic) on
fuel metabolism

pathway inhibited by insulin, pathway stimulated by insulin

Figure 26.7: Major

sites of glucagon
catabolic activity on
fuel metabolism

pathway inhibited by glucagon, pathway stimulated by glucagon

Figure 43.6: Effect
of epinephrine (Epi)
on fuel metabolism
and pancreatic
endocrine function

pathway inhibited,
pathway stimulated
 Glucocorticoids have diverse actions on most tissues that in
aggregate promote survival in times of stress

Figure 43.8: Effects of

glucocorticoids (GC) on fuel
metabolism. GCs stimulate
lipolysis in adipose tissue and
the release of amino acids from
muscle protein. In liver, GCs
stimulate gluconeogenesis and
the synthesis of glycogen. The
breakdown of liver glycogen is
stimulated by epinephrine.

Regulators of insulin and glucagon

release from the pancreatic islets

Table 26.2: Regulators of Table 26.2: Regulators of

Insulin Release Glucagon Release
• Major • Major
Glucose + Glucose −
• Minor Insulin −
Amino Acids +
Amino acids +
Neural Input +
• Minor
Gut hormones +
Cortisol +
Epinephrine − Neural (Stress) +
(-adrenergic) Epinephrine +
Gut hormones +
“+” = stimulates
“−” = inhibits
 Site of insulin secretion and
its pro-hormone structure

Schematic of pancreatic islets

• A cells make glucagon
• B cells make insulin Figure 26.10: Cleavage of proinsulin to insulin.
• D cells make other hormones Proteolytic cleavage occurs at the arrows.

Insulin affects the Glut4

transporter +

Marks Figure 27.13: Stimulation by

insulin of glucose transport into
muscle and adipose cells.

Binding of insulin to its cell

membrane receptor causes vesicles
containing glucose transporter
proteins to move from inside the cell
to the cell membrane.
Does induction change Vmax or Km?
 Signal transduction by glucagon

Principles of hormonal
signaling mechanisms

• The specificity of action is conferred by its receptor

on the cell surface
• The ‘message’ carried by a hormone is amplified
• The metabolic response to a hormone is integrated
• Molecular signals can be augmented or antagonized
• Molecular signals can be rapidly terminated
Figure 26.8:
Changes in blood
glucose, insulin, and
glucagon after a high
carbohydrate meal

Fast Post-absorptive

Outline of the hormonal response to a

high carbohydrate meal

When a platter of pasta is consumed…

• Glucose enters blood and is transported (among
other places) to the pancreas where it enters the
B-cells via the GLUT2 transporter…
• and stimulates insulin secretion
• Insulin enters the blood and binds to receptor on
the surface of muscle plasma membrane
• The insulin receptor initiates a signal cascade
that results in the translocation of GLUT4 to the
muscle cell membrane
• Glucose uptake by muscle cell is increased
• Energy production by glycolysis is increased
What happens when this system doesn’t work?
Clinical scenario: Insulinoma induced hypoglycemia
• The patient is a 46-year old
woman who reports the
following symptoms
• Six months ago, fatigue and
confusion sometimes followed
pre-breakfast jogs - anxiety,
pallor and sweating also
reported
• Blurred vision and an
‘unusually urgent’ hunger
sometimes experienced
• Eating relieved all of the
symptoms within 25 – 30 min
Clinical scenario: Insulinoma induced hypoglycemia
• The episodes now recur
more frequently during the
day with increasing daily
frequency
• The frequency of the episodes
is diminished by snacking
between meals
• The extra calories ingested by
snacking have resulted in a
weight gain of 8 pounds
• The patient’s serum
glucose is 46 mg/dL (80 –
100 is normal) during the
initial late afternoon
consultation
• The patient exercises before
breakfast when glucose and
insulin levels are low and
glucagon is high
• Fatigue suggests a lack of fuel
• Confusion, blurred vision and
‘urgent’ hunger suggest lack of
glucose
• The fact that eating relieves the
symptoms suggests that the
enzymology necessary to
metabolize food is functional
and points to a regulatory
deficiency…
• The problem is progressive
• Again, the relief gained by
eating suggests that the
metabolic pathways are
functional and that the problem
is one of regulation
• The conversion of calories to
weight gain indicates suggests
stimulation of the anabolic
pathways
• The patient is hypoglycemic
(low blood sugar) even
though she has been eating
(presumably) during the day
Clinical scenario: Insulinoma induced hypoglycemia

• The physician ordered • The patient’s fasting serum

• a test of fasting serum
glucose levels and
• requested that the
patient keep a daily
symptoms diary
• The diagnosis is ‘fasting’
hypoglycemia where
glucose stores are not
mobilized in the absence of
available fuel
• What is the source of this
disorder?
glucose level is below
normal
• The symptoms track with
fasting
• The fatigue, confusion and
blurred vision (neuroglycopeic
symptoms) result from the
brain’s lack of glucose
• The anxiety, pallor and sweating
are due to release of
epinephrine in response to the
stress of hypoglycemia

Factors that influence glucose homeostasis

Blood glucose
Low | High

Carbohydrate intake

Exercise (Fuel utilization)

Anabolic metabolism
(Fuel storage)

Catabolic metabolism
(Fuel mobilization)

Insulin Glucagon
Clinical scenario: Insulinoma induced hypoglycemia

• Is the disorder the result • Unregulated hormone

of autonomous secretion disrupts the
(unregulated) hormone homeostatic balance of
secretion? anabolic and catabolic
reactions.
• Why is autonomous
hypersecretion of insulin
suspected?
• Insulin stimulates anabolic
reactions
• Constitutive insulin release will
stimulate glucose uptake from
the blood even when glucose
concentrations are low…

Clinical scenario: Insulinoma induced hypoglycemia

• The test of the proposed • The low blood glucose (45

diagnosis is to mg/dL) measured earlier is
simultaneously measure confirmed
blood glucose and insulin • A high insulin to glucagon
when the patient is ratio was measured
symptomatic • Quantification of the insulin
concentration is accomplished
my measurement of the
concentration of the C-peptide
present in the blood produced
by the conversion of proinsulin
to insulin.
• Note: Epinephrine secretion is
unaffected by insulin hyper-
secretion resulting the patient’s
‘stress response’.
 Clinical scenario: Resolution of the problem
• An ultrasound of the
patient’s abdomen revealed
a mass within the pancreas
• Insulin is secreted by the
pancreas
• New York Times articles - 2006
• A nonmalignant mass
consisting of insulin rich B
cells (an ‘insulinoma’) was
surgically removed
• After recovering from the
surgery, the patient
• no longer experienced the
symptoms of hypoglycemia
• had normal levels of blood
glucose
• lost the weight gained prior
to surgery
• Homeostasis is restored…
 Lecture Summary
• The regulation of glucose metabolism is dominated by the
insulin : glucagon ratio.
• High values of this ratio stimulates glucose uptake and storage
as glycogen and fatty acids and amino acid uptake and protein
synthesis (anabolic reactions)
• Low levels of this ratio stimulate gluconeogenesis and
glycogenolysis to release glucose into the blood (catabolic
reactions)
• Hormones modulate fuel metabolism through multi-step
branching signal transduction pathways. Modulations include
• Allosteric regulation
• Post-translational modification
• Regulation of gene transcription
• Hypoglycemia and hyperglycemia have serious clinical
consequences. Homeostasis is to be maintained…