476

Chapter 75

Starvation (The Intermediate Phase)

Overview

• The intermediate phase of starvation is best characterized by the carbohydrate- and

nitrogen-sparing effect of fat.
• During starvation KB–s help to restrain glucose utilization by a number of tissues,
and they also help to restrain muscle proteolysis, and adipose tissue lipolysis.
• KB–s can provide up to 70% of the brain’s energy supply during starvation.
• As AcAc is removed by muscle tissue during starvation, it is sometimes returned to
the circulation in a more reduced state as b-OH-butyrate.
• During starvation b-OH-butyrate stimulates modest pancreatic insulin release, and it
increases sensitivity of adipose tissue to insulin.
• Insulin helps to restrain proteolysis in muscle tissue, and lipolysis in adipose tissue
during starvation.
• The basal metabolic rate (BMR) normally decreases during starvation due to a
decrease in the active forms of thyroid hormones.

The basic chemistry of carbohydrate and
lipid metabolism has been described in
previous chapters. With starvation progressing
into the intermediate phase, it now becomes
possible to discuss the integration of metabolic
pathways between several different tissues;
specifically the integration of carbohydrate
and lipid metabolism in brain, muscle, adipose
tissue, and liver. A more complete descrip-
tion of metabolic integration must necessarily
include consideration of protein and amino
acid metabolism, and extend the discussion to
other tissues as well, including the kidneys.
The intermediate phase of starvation is best
characterized by the carbohydrate- and nitro-
gen-sparing effect of fat. Explanations for
these effects lie in unique interrelationships
between glucose, free fatty acid (FFA), ketone
body (KB–), and muscle protein metabolism
(Fig. 75-1).
Copyright © 2015 Elsevier Inc. All rights reserved.
As mentioned in the previous chapter, early
in starvation KB–s serve as muscle fuel, but
with more prolonged starvation they are
less well utilized. As acetoacetate (AcAc) is
removed by muscle, it is sometimes returned
back into blood as b-OH-butyrate, signifying
a more reduced state of muscle mitochondria
secondary to FFA utilization (see Chapter 71).
Thus, FFAs appear to take preference over
KB–s as muscle fuel during the intermediate
stages of starvation (Fig. 75-2). This effect
spares KB–s for utilization by nervous tissue, a
superb overall survival process.
The reduced state of muscle mitochondria
due to FFA oxidation also results in a lower rate
of amino acid release from proteolysis. A direct
inhibitory effect of KB–s on muscle proteolysis
has also been demonstrated. Thus, fat, in the
form of both FFAs and KB–s, spares oxidation of
amino acids in muscle tissue, which appears

to play a central role in maintaining muscle
protein reserves during starvation. The blood
urea nitrogen (BUN) concentration is typically
lower during the intermediate than during
the early gluconeogenic phase of starvation,
and total urinary nitrogen excretion decreases
(Fig. 75-3). Feeding only a small amount of
energy as protein can sometimes replace the
nitrogen depletion of otherwise total starva-
tion, a concept emphasized by investigators
who propose that endogenous fat, if allowed
to be mobilized by not giving carbohydrate,
may be efficient in sparing nitrogen in patients
receiving parenteral alimentation.
64 Chapter 75 477
Figure 75-1
Ketone bodies and FFAs also help to restrain
the uptake and utilization of glucose by muscle,
the renal cortex, lactating mammary gland,
small intestine, and nerve tissue. Through this
reduction in glucose utilization, gluconeogenic
organs like the liver and kidneys are under
less pressure to convert gluconeogenic (and
proteogenic) amino acids to glucose. Under
normal circumstances the kidneys provide less
than 10% of glucose production. However, in
prolonged starvation, as overall gluconeogen-
esis decreases (see Chapter 74), the component
provided by liver decreases dramatically while
that of the kidneys increases (Figs. 75-4 &
478 Starvation (The Intermediate Phase)
Figure 75-2
75-5). The explanation for this shift involves
ketoacidosis, an increase in hepatic nitrogen
production as glutamine (Gln) rather than urea
(see Chapter 10), and renal utilization of Gln for
gluconeogenesis and urinary NH4+ disposal (see
Chapter 11).
The combination of increased blood KB– levels
and the derepression of enzymes required
for their utilization as fuel (b-hydroxybutyrate
dehydrogenase, b-ketoacid-CoA transferase,
and acetyl-CoA acetyltransferase; see Chapter
71) enables the brain in starvation to use KB–s
instead of (and in addition to) glucose. Studies
indicate that KB–s (particularly b-OH-bu-
tyrate) can provide up to 70% of the energy
requirements of the brain during prolonged
starvation, with a substantial reduction in
simultaneous glucose utilization (Fig. 75-6).
Figure 75-5
Early vs. Intermediate - Late Starvation
Starvation Phase Glucose Production Urinary Nitrogen Excretion Fuel for Brain
Rate Liver Kidney
Early (Postabsorptive) High > 90% < 10% Urea > NH4+ Glucose > KB–s
Intermediate - Late Lower 55% 45% NH4+ > Urea KB–s > Glucose
Because of this reduced dependency upon
glucose catabolism, the threshold concentra-
tion at which hypoglycemic shock will ensue
is also reduced. However, a diabetic, hyperg-
lycemic and ketotic animal may not experience
this reduced threshold concentration since the
brain continues to oxidize glucose over KB–s
in hyperglycemia. Thus, the enzymes required
for KB– oxidation are less active. If hypogly-
cemia is induced through insulin injection in
diabetic, ketotic, hyperglycemic animals, the
brain cannot convert to KB– utilization rapidly
enough to prevent hypoglycemic shock from
occurring at slightly higher plasma glucose
levels.
During starvation it is important that the
rate of FFA mobilization from adipose tissue
be precisely related to the ability of aerobic
tissues to remove and metabolize these
substrates (particularly muscle and liver
tissue). Undoubtedly, changes in the concen-
trations of several hormones play an important
role in the regulation of FFA mobilization, but
it is unlikely that they alone can provide the
precision necessary to meet rapid changes in
energy demand. The rate of glyceroneogenesis
from pyruvate in adipocytes is thought to play
an important role in the re-esterification of
FFAs generated in lipolysis, thus modulating
their release when cAMP levels are high. Up to
60% of the FFAs generated during lipolysis may
enter into re-esterification via this pathway
(see Chapter 70).
Investigators have determined that KB–s,
particularly b-OH-butyrate, also play an

Figure 75-3
important role in preventing excessive lipolysis
during starvation. As NADH:NAD+ ratios
in liver and muscle mitochondria begin to
increase because of excessive FFA b-oxida-
tion, increased quantities of b-OH-butyrate
are generated from acetoacetate. b-OH-Bu-
tyrate has been shown to exert three important
metabolic effects which tend to modulate blood
levels of FFAs:
• Reduce the rate of adipose tissue lipolysis.
• Stimulate modest pancreatic insulin release.
• Increase sensitivity of adipose tissue to
insulin.
Although all three effects could simultane-
ously reduce the rate of lipolysis, arguments
have been forwarded to suggest that the
increase in insulin sensitivity may be quantita-
tively the most important.
As shown over 50 years ago, in addition to
facilitating glucose uptake into muscle and
adipose tissue, and inhibiting lipolysis, insulin
also initiates uptake of certain amino acids into
muscle, and facilitates their incorporation into
protein. A more recently described effect of
insulin is to decrease muscle proteolysis. Thus
insulin, like KB–s, appears to help control the
rate of net muscle proteolysis during starvation.
64 Chapter 75 479
A decrease in the basal metabolic rate
(BMR) also occurs with starvation. Part of this
reduction is explained by the progressively
decreasing body mass. However, selective
use of fat as fuel, everything else being equal,
would be expected to increase O2 consumption,
since fat, unlike glycogen, is a strictly "aerobic"
fuel. However, total O2 consumption normally
decreases about 10-15% during the interme-
diate phase of starvation. The explanation for
this decrease is found in circulating thyroid
hormone levels, most notably triiodothyronine
(T3, the most active form), and reverse T3 (rT3,
the inactive form). Circulating T3 levels progres-
sively decrease during starvation, while rT3
levels increase. When starved animals are
appropriately refed with carbohydrate, these
triiodothyronine levels reverse, and the active
Figure 75-4
form returns within the euthyroid range.
An additional parameter that may change
during starvation is the plasma unconju-
gated bilirubin (UCB) concentration. The liver
exhibits a reduced capacity to remove UCB
from plasma during starvation, particularly in
equine species, thus promoting an unconju-
gated hyperbilirubinemia (see Chapter 33).
480 Starvation (The Intermediate Phase)
Figure 75-6
In summary, starvation entails a progressive
selection of fat as body fuel. KB–s become
elevated during the early-intermediate
phases of starvation, and tissues preferen-
tially use these fuels for energy purposes,
thus reducing their dependency upon glucose.
Additionally, KB–s also inhibit muscle proteol-
ysis. Nevertheless, starvation is usually asso-
ciated with a negative nitrogen balance that
can be partially nullified by amino acid or
protein supplementation. Insulin appears to be
an important regulatory hormone in starvation.
Its release is promoted by increased circu-
lating levels of b-hydroxybutyrate, and it helps
to spare both fat and protein from excessive
breakdown. Studies indicate that decreased
circulating levels of active T3 (and increased
levels of the inactive rT3) may play a role in
sparing otherwise obligatory caloric depletion
through decreasing the BMR. Once the supply
of FFAs from depot fat has been consumed,
the basal energy requirement of the organism
must be met from body protein. It is at this time
that the muscle mass, the largest single source
of protein, can be heavily depleted. This third
and final phase of starvation will have a most
unfortunate, inevitable end unless nutritional
intervention occurs.
OBJECTIVES
• Discuss the integration of carbohydrate, protein
and lipid metabolism during the intermediate
phase of starvation.
• Explain what is meant by the "carbohydrate- and
nitrogen-sparing effect of fat."
• Understand the relationship between the
AcAc:b-OH-butyrate ratio and FFA utilization.
• Identify the effects of KB–s on muscle proteol-
ysis and glucose utilization, insulin release and
adipose tissue lipolysis.
• Know how and why the BUN concentration
changes throughout starvation.
• Explain why the proportion of glucose produced
by the kidneys increases during the intermedi-
ate stage of starvation (see Chapter 11).
• Understand why the hypothalamic hypoglycemic
threshold of a non-diabetic animal is reduced
during the intermediate stage of starvation.
• Describe factors involved in the rate of FFA
mobilization from adipocytes during starvation
(see Chapter 70).
• Discuss the control of insulin release and the
effects of this hormone on different tissues
throughout starvation.
• Show how and why the BMR changes through-
out starvation.
• Explain how and why urinary nitrogen excretion
changes throughout starvation (see Chapter 11).
• Explain what an a-keto acid is (see Chapter 9).
• Understand how and why lipid fuels feedback
negatively on muscle protein catabolism during
starvation.
• Explain how the "rate" of lipolysis is controlled
during starvation (see Chapters 70 & 71).
• Recognize why the rate of renal gluconeogene-
sis increases during the intermediate stages of
starvation (see Chapter 11).
• Understand how and why the b-OH-butyrate
concentration influences fat mobilization and
muscle protein catabolism.
• Identify the tissues that experience reduced
uptake and utilization of glucose when the plas-
ma KB- and FFA concentrations are elevated.
 64 Chapter 75 481

QUESTIONS 5. b-OH-Butyrate has been shown to exert

1. During the intermediate phase of
starvation, FFAs:
a. Become preferred fuel over KB–s in
muscle tissue.
b. Restrain muscle proteolysis.
c. Restrain the uptake of utilization of
glucose by muscle tissue.
d. Restrain the uptake of utilization of
glucose by the renal cortex.
e. All of the above
2. The threshold concentration at which
hypoglycemic shock will occur is reduced
during the intermediate phase of starva-
tion, because:
a. Starvation reduces pancreatic insulin
output.
b. The brain is deriving most of its metabolic
fuel from circulating FFAs.
c. The brain has an increased dependency
upon glucose.
d. The enzymes required for KB– oxidation
in the brain are inactive.
e. Glucose utilization by the brain is
normally reduced during this phase.
3. During starvation the reduced state of
muscle mitochondria secondary to FFA
utilization is exemplified by:
a. Conversion of acetoacetate to
b-OH-butyrate.
b. Increased aerobic oxidation of glucose.
c. Increased ketone body oxidation.
d. Reduced oxygen utilization.
e. The breakdown of muscle protein.
4. Approximately what percentage of the
all of the following metabolic effects,
EXCEPT:
a. Stimulate hepatic and renal gluconeogen-
esis.
b. Reduce the rate of adipose tissue lipolysis.
c. Stimulate modest pancreatic insulin
release, and increase sensitivity of adipose
tissue to insulin.
d. Reduce glucose utilization by muscle,
nerve, and renal tissue.
e. Reduce muscle proteolysis.
6. Select the FALSE statement below
regarding the intermediate stages of
starvation:
a. Reverse T3 levels in plasma typically
increase.
b. Derepression of enzymes required
for ketone body oxidation in the
brain occurs.
c. Oxygen consumption normally decreases
(during resting stages).
d. Amino acids are not used by the liver for
gluconeogenic purposes.
e. T3 levels in plasma typically decrease.
7. During the intermediate stages of
starvation, ketone bodies and free
fatty acids help to restrain the uptake
and utilization of glucose by all of the
following, EXCEPT:
a. Erythrocytes.
b. Renal cortex.
c. Small intestine.
d. Nerve tissue.
e. Lactating mammary gland.
8. c

brain’s energy requirement can be met 8. Compared to the early postabsorptive

7. a
through ketone body oxidation during the phase, the intermediate-late phase of 6. d
intermediate stages of starvation? starvation shows: 5. a
a. 2% a. Greater glucose utilization by
b. 20% the brain. 4. d
b. Greater urinary urea excretion.
c. 45%
3. a
c. A lower rate of hepatic glucose
d. 70% production.
2. e
e. 95% d. A lower rate of hepatic KB– 1. e
production.
e. A higher BMR. ANSWERS