Integration of Metabolism and

Metabolic Processes in Fed, Fasting 13

Chapter

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and Starvation States

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OBJECTIVES x Describe how carbohydrate, protein, and lipid metabolism are integrated at cellular level

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and at tissue or organ level
After studying this chapter x Describe the metabolic processes and role of specific organs in fed, fasting, and
student should be able to: starvation states

OVERVIEW
We have studied the biochemistry of metabolism of
O The lack of insulin activity in diabetes mellitus results
in failure of transfer of glucose from the blood into cells
and leads to hyperglycemia. The body responds as it was
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carbohydrate, lipid, and protein, one pathway at a time. in the fasting state.
We have seen how useful energy is extracted from fuels
and used to power biosynthetic reactions. Not all the
major metabolic pathways operate in every tissue at any
INTEGRATION OF METABOLISM
given time. However, cells and organs cooperate for the The various anabolic and catabolic pathways by which
common good of the body. Together they control the carbohydrates, lipids, and proteins are processed as
everyday challenges of overeating, fasting, and muscular metabolic fuel for energy supply or as precursors in
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activity. the biosynthesis of compounds required by the cell

The metabolism of carbohydrate, lipids, and proteins for maintenance or growth are closely coordinated.
are interrelated, and occur simultaneously. All products This coordination between three metabolites is
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of digestion are metabolized to a common product, called integration of metabolism. This integration of
acetyl-CoA, which is then oxidized by citric acid cycle to metabolism must be considered at two levels:
yield ATP (Figure 13.1). The best way to understand the 1. Cellular level
inter-relationships of the pathways is to learn the changes 2. Tissue or organ level.
in metabolism during the starvation and fed state. Feed
refers to the intake of meals after which the fuel is stored Significance of Integration of Metabolism
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as glycogen and triacylglycerol to meet metabolic needs

x Integration of metabolism ensures a supply of suitable
of fasting. Cells of the body die without the provision of
continuous supply of energy for ATP synthesis to meet fuel for all tissues, at all times from the fully fed state to
the totally starved state.
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their needs.
This chapter focuses on the integration of the major x Under positive caloric balance, a significant proportion
metabolic processes of carbohydrate, protein, and lipids. of the food energy intake is stored as either glycogen
The chapter begins with the discussion on integration or fat.
of metabolism at cellular level followed by integration x Under negative caloric balance, i.e. in starvation, fatty
of metabolism at tissue or organ level. This chapter also acids are oxidized in preference to glucose to spare
describes metabolic changes that occur in fed, fasting, and glucose for those tissues (e.g. brain and erythrocytes)
starvation states. that require it under all conditions.
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 345

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Figure 13.1: Outline of pathways for the catabolism of three principal nutrients, carbohydrate, protein, and fat.
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x Under conditions of carbohydrate shortage, available tissues having no glycerol kinase. Thus, carbohydrates
fuels are oxidized in the following order of preference: can easily form fat.
– Ketone bodies x Only a fatty acid having an odd number of carbon atoms
– Free fatty acids is glucogenic as it forms a molecule of propionyl-CoA
– Glucose upon E-oxidation. Propionyl-CoA can be converted
to succinyl-CoA, (see Figure 11.11) an intermediate
Integration of Metabolism at Cellular Level of citric acid cycle, which can be converted to glucose
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Integration of metabolism at cellular level includes the by gluconeogenesis. There cannot be a net conversion
flow of key metabolites, e.g. glucose, fatty acids, glycerol, of fatty acids having an even number of carbon atoms
and amino acids, between different metabolic pathways in
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(which form acetyl-CoA) to glucose or glycogen.

the cell (Figure 13.2), which includes: Conversion of acetyl-CoA to glucose is not possible
x Conversion of carbohydrates into fats and fats into because:
carbohydrates.
– The pyruvate dehydrogenase reaction is essentially
x Conversion of carbohydrates into proteins and proteins
nonreversible which prevents the direct conversion
into carbohydrates.
of acetyl-CoA to pyruvate.
x Conversion of proteins to fats.
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– Secondly, there cannot be a net conversion of

Conversion of Carbohydrates into Fats and Fats into acetyl-CoA to oxaloacetate via citric acid cycle,
Carbohydrates since one molecule of oxaloacetate is consumed to
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x Carbohydrates (glucose) are metabolized via glycolytic condense with acetyl-CoA and only one molecule
pathway to pyruvate and then pyruvate to acetyl-CoA of oxaloacetate is regenerated (see Figure 10.19). It
by pyruvate dehydrogenase reaction. Acetyl-CoA is is not formed de nova when acetyl-CoA is oxidized
the precursor for synthesis of fatty acids. Fatty acids, by citric acid cycle.
that are produced, combine with glycerol to form x The glycerol moiety of triacylglycerol will form glucose
triacylglycerol. Glycerol may also be supplied from after activation to glycerol-3-phosphate and this is an
the glycolysis as glycerol-3-phosphate, particularly in important source of glucose in starvation.
 346 Section III: Energy Metabolism and Metabolism of Biomolecules

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Figure 13.2: Integration of three metabolism at cellular level.

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Conversion of Carbohydrates into Proteins and Proteins conversion of amino acids to fat is not a significant
into Carbohydrates process.
x Many carbon skeletons of the nonessential amino x For the same reasons for which it is not possible for a net
acids can be produced from carbohydrate via the conversion of fatty acids to carbohydrate to occur, it is
intermediates of citric acid cycle (see Figure 12.5) and not possible for a net conversion of fatty acids to amino
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transamination. acids to take place.

x By reversal of these processes, glucogenic amino acids
yield carbon skeletons that are either members or Integration of Metabolism at Tissue or Organ Level
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precursors of the citric acid cycle. They are therefore Integration of metabolism at tissue or organ level includes
readily converted by gluconeogenesis to glucose and the inter-relationship of different tissues and organs in
glycogen. maintaining an appropriate metabolic state for the whole
body. All metabolic pathways are not present in all cells
Conversion of Proteins into Fats and Fats into Proteins and tissues, and their distribution varies among the major
x Conversion of carbon skeletons of glucogenic amino tissues.
acids to fatty acids is possible either by formation of The types of fuels that are imported, exported, and
pyruvate or acetyl-CoA. Generally, however, the net stored also vary, depending on the tissues (Figure 13.3).
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 347

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Figure 13.3: Integration of metabolism among major tissues of the body.

The major organs along with their most important metabolic x The protein contained in muscle may be mobilized as
functions are discussed here. a fuel source, if no other fuel is available.
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x Pyruvate, the product of glycolysis in the skeletal

Role of Liver muscle, may be converted to either lactate (by anaerobic
Major roles of the liver include the following: glycolysis) or alanine (by transamination) and exported
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x Liver maintains blood glucose levels. During the fed to the liver (by Cori cycle, see Figure 10.24 and glucose
state, the liver takes up excess glucose and stores it as alanine cycle, see Figure 10.26 respectively) where it is
glycogen or converts it to fatty acids. During the fasting used to regenerate glucose via gluconeogenesis.
state, the glycogenolysis and gluconeogenesis by the
liver are the major sources of glucose for the rest of the Role of Heart Muscle
body. Heart muscle contains essentially no fuel reserves and
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x The liver serves as the major site of fatty acid must be continuously supplied with fuel from liver and
synthesis. adipose tissue (Figure 13.3).
x The liver synthesizes ketone bodies during starvation.
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Role of Adipose Tissue

Role of Skeletal Muscle The primary function of the adipose tissue is the storage of
x Skeletal muscle maintains large stores of glycogen, metabolic fuel in the form of triacylglycerols.
which provide a source of glucose for energy during x During the fed state, the adipose tissues synthesize
exertion. In resting muscle, the preferred fuel is fatty triacylglycerols from glucose and free fatty acids.
acids. During starvation, free fatty acids and ketone x During the fasting state, triacylglycerols are converted
bodies are oxidized in preference to glucose in muscle to glycerol and fatty acids. Fatty acids are exported to
by inhibiting its entry into the cell. the liver and other tissues as a fuel.
 348 Section III: Energy Metabolism and Metabolism of Biomolecules

x In adipose tissue, glycerol liberated cannot be reused x Insulin signals body tissues, especially liver, muscle,
in the synthesis of triacylglycerols because adipocytes and adipose tissue, that blood glucose is higher than
lack glycerol kinase. Therefore, the glycerol which is necessary, as a result, cells take up excess glucose from
released is transported to the liver and kidney, which the blood and convert it to glycogen and triacylglycerols
contain glycerol kinase, which can phosphorylate it. for storage.

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The resulting glycerol phosphate can be used to form x Glucagon signals that blood glucose is too low, and
triacylglycerol in the liver or to be converted to DHAP tissues respond by producing glucose through glycogen
(Figure 13.3). breakdown and gluconeogenesis in the liver and by

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oxidizing fats to reduce the need for glucose.
Role of Brain The changes in metabolism from one stage into the next
Brain tissue normally uses glucose as an exclusive fuel, are not abrupt but gradual.
except during starvation, when it can adapt to use ketone
bodies as an energy source. The brain contains essentially Metabolic Changes in Well Fed State after Meal or
no fuel reserves and must be continuously supplied with Postprandial State

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fuel from the liver (Figure 13.3). After consumption and digestion of an evening meal,
glucose and amino acids are transported from intestine
METABOLIC PROCESSES AND ROLE OF SPECIFIC ORGANS IN to the blood. The dietary lipids are packaged into
FED, FASTING, AND STARVATION STATES chylomicrons and transported to the blood by lymphatic
system. This fed condition leads to the increase in blood
Starvation is the deprivation of the food and thereby glucose level. The high blood glucose concentration leads
deprivation of exogenous supply of calories to meet the
energy demands of the body for basal metabolism and other O
activities. Starvation, in a strict biochemical sense, begins
to secretion of insulin.
Insulin stimulates the glycogen synthesis in both
muscle and liver, and suppresses gluconeogenesis in
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immediately after the absorption of a meal is complete. the liver, and stimulates protein synthesis. Insulin also
Starvation is not always the result of unavailability or accelerates glycolysis in the liver, which in turn increases
scarcity of food. Any medical condition which prevents the synthesis of fatty acids. Figure 13.4 illustrates the
consumption or utilization of available food will effectively role of specific organs in the metabolism in well-fed state.
x The high insulin level in the fed state promotes the entry
lead to starvation, e.g. trauma, surgery, cancer cachexia,
of glucose into muscle and adipose tissue. Insulin
infections, malabsorption, etc.
stimulates the synthesis of glycogen by muscle as well as
We begin with a physiological condition, the starved- by the liver. When there is plenty of glucose in blood, it is
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fed cycle or fast-feed cycle, which occurs after an evening stored as a glycogen, so as to be able to release glucose
meal and through the 12 hours overnight fast. This nightly in times of scarcity (Figure 13.5).
starved fed cycle has three stages: (1) the well fed state after Liver possesses an isoenzyme of hexokinase called
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meal or postprandial state, (2) the early fasting phase glucokinase, which converts glucose into glucose
during night or postabsorptive phase, and (3) the refed 6-phosphate, which cannot be transported out of the
state after breakfast. cell. Glucokinase has high Km value and is thus active
The starved-fed cycle is the physiological response to a only when blood glucose level is high. Moreover,
fast. Here we discuss metabolic changes in the context of glucokinase is not inhibited by glucose 6-phosphate
four normal metabolic states: as hexokinase is. Consequently, the liver forms glucose
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1. The well fed state after meal or postprandial state. 6-phosphate more rapidly, as blood glucose level rises.
2. The early fasting phase during night or postabsorptive The increased level of glucose 6-phosphate leads to the
phase, which covers the 12 hours overnight fast.
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formation of glycogen.
3. The refed state after breakfast. x In the liver, insulin accelerates glycolysis and oxidation
4. Prolonged starvation which lasts longer than 24 hours of pyruvate to acetyl-CoA. Excess acetyl-CoA not needed
and can extend into several days or weeks. for energy production is used for fatty acid synthesis, and
The main purpose of the many biochemical changes in fatty acids are exported from the liver to adipose tissue as
these metabolic phases is to maintain constant blood the triacylglycerol of plasma lipoproteins VLDL. Insulin
glucose level which is maintained by the combined action stimulates the synthesis of triacylglycerol in adipose
of insulin and glucagon. tissue, from fatty acids released from the triacylglycerol
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 349

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Figure 13.4: The metabolic role of specific organs in well-fed state.
(ATP: adenosine triphosphate; VLDL: very low-density lipoprotein; TAG: triacylglycerol)
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Figure 13.5: Effect of insulin on blood glucose.

(GLUT4: glucose transporter-4; PDH: pyruvate dehydrogenase; PFK-1: phosphofructokinase-1)
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of VLDL. These fatty acids are ultimately derived from Metabolic Changes in Early Fasting
the excess glucose taken from blood by the liver. Phase During Night
x The action of insulin also affects protein metabolism.
Insulin promotes the uptake of branched chain amino If we eat another meal within a few hours, we return to the
acids (valine, leucine, and isoleucine) by muscle. Insulin fed state. However, if we continue to fast over a 12 hour pe-
stimulates protein synthesis, which favors building up of riod, we enter the basal state also known as the postab-
muscle protein. In addition, it inhibits the intracellular sorptive state. Figure 13.6 illustrates the main features of
degradation of proteins. the metabolic changes occur during early fasting.
 350 Section III: Energy Metabolism and Metabolism of Biomolecules

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Figure 13.6: The metabolic role of specific organs during early fasting. The circled number indicates the approximate order in which processes
begin to occur.
(FA: fatty acid; TAG: triacylglycerol; ATP: adenosine triphosphate; TCA cycle: tricarboxylic acid cycle).
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Blood glucose level is highest approximately 1 hour released from adipose tissue. The blood glucose level is
after eating and then decrease as tissues oxidize glucose or maintained within normal range (at or above 70 mg/dL)
convert it to storage forms of fuel. Within about 1 hour after by the following ways:
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a meal, blood glucose levels begin to fall and by 2 hours the 1. The decrease in blood glucose causes decrease in
level returns to the fasting range (70–100 mg/dL). insulin secretion and stimulates secretion of glucagon
(Figure 13.7). Just as insulin signals the fed state,
The lack of insulin activity in diabetes mellitus results in failure glucagon signals the starved state. Glucagon is
of transfer of glucose from the blood into cells and leads to
secreted by D- cells of the pancreas in response to low
hyperglycemia. The body responds as it were in the fasting state.
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blood sugar level in the fasting state.

2. The main target organ of glucagon is the liver. Glucagon
For the brain, the erythrocytes, the bone marrow, the
causes an increase in blood glucose concentration
renal medulla and peripheral nerves glucose is the major
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in several ways (Figure 13.8). Glucagon stimulates

fuel and which has to be supplied for their energy needs.
glycogen breakdown and inhibits glycogen synthesis
Most neurons lack enzymes required for oxidation of fatty
acids but they can use ketone bodies to a limited extent. by triggering c-AMP (see Figure 10.36) leading to the
Red blood cells lack mitochondria which contain enzymes phosphorylation and activation of phosphorylase
of fatty acid and ketone body oxidation, and can use only and the inhibition of glycogen synthase. The glucose
glucose as a fuel. Therefore, it is essential to maintain the formed by breakdown of glycogen is then released from
blood glucose level within normal range. However, the the liver into the blood. The liver glycogen is capable of
tissues such as muscle can readily use free fatty acids, maintaining the blood glucose concentration at normal
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 351
resulting accumulation of phosphoenolpyruvate
favors gluconeogenesis. Moreover the rate of
gluconeogenesis is increased by glucagon by
stimulating the synthesis of the gluconeogenic
enzyme PEP carboxylase.

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– Gluconeogenesis initially occurs from lactate
(obtained from glycolysis in red blood cell) and
alanine (coming from muscle). But it should be

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noted that there is no net synthesis or gain of
glucose by this process using lactate and alanine as
the precursors. It simply replaces glucose that had
already been converted into lactate and alanine by
tissues such as muscle and RBC.
– Thus, for the net synthesis of glucose to take

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place, another source of carbon is required. The
Figure 13.7: Release of fuel from the body stores due to changes in glycerol released from adipose tissue by lipolysis
hormone level during the onset of starvation. of triacylglycerol can be converted into glucose,
but only a limited amount is available. The only
values for 8 to 12 hours. Thus, hepatic glycogenolysis potential source of glucose is the carbon skeletons
is a transient response to starvation (Figure 13.7). of amino acids derived from the breakdown of
3. In response to low insulin level, the entry of glucose muscle proteins.
into the muscle and adipose tissue decreases. The
diminished utilization of glucose by muscle and
adipose tissue also contributes to maintain the blood
O – Alanine is a key glucogenic amino acid (see Figure
12.4). The rate of hepatic gluconeogenesis from
alanine is far higher than from all other amino acids.
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glucose level. By stimulating glycogen breakdown,
inhibiting glycolysis, and promoting gluconeogenesis Why does the muscle release alanine?
in liver, glucagon facilitates the liver to provide glucose
for brain (which is exclusively dependent on glucose as ‰ Muscle can absorb and transaminate branch chain amino acids
fuel), and restoring blood glucose to its normal level in order to use the carbon skeleton as fuel, however it cannot
4. As the liver glycogen store begins to be depleted, form urea. Consequently, the amino group is released into the
another mechanism, gluconeogenesis is used to blood as alanine (see Figure 12.13).
‰ Interestingly, the liver cannot remove nitrogen from the
maintain blood glucose levels. In gluconeogenesis,
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branched chain amino acids (leucine, isoleucine, and valine).

lactate, glycerol, and amino acids are used as
Transamination of these amino acids takes place in muscle.
precursors to glucose. Insulin promotes the uptake of branched chain amino acids by
– Glucagon inhibits glycolysis and stimulates muscle.
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gluconeogenesis in the liver and by lowering the

level of fructose 2-6 bisphosphate an allosteric 5. Glucagon like epinephrine affects adipose tissue,
inhibitor of the enzyme fructose 1-6 bisphosphatase. activating triacylglycerol breakdown by triggering
Glucagon also inhibits glycolytic enzyme cAMP-dependent phosphorylation of perilipin and
pyruvate kinase, thus blocking the conversion of hormone sensitive lipase.
phosphoenolpyruvate to pyruvate and preventing – The activated lipase hydrolyses triacylglycerol to free
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oxidation of pyruvate via citric acid cycle. The fatty acids and glycerol. Liberated free fatty acids
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Figure 13.8: Effect of glucagon on blood glucose.

(HSLP: hormone-sensitive lipoprotein lipase; PEP: phosphoenol pyruvate; PFK-1: phosphofructokinase-1).
 352 Section III: Energy Metabolism and Metabolism of Biomolecules

are transported to the liver and other tissues as fuel. (Figure 13.10). The blood glucose levels drop from about
Both muscle and liver use fatty acids as fuel when the 100 mg/dL (5.5 mM) to about 70 mg/dL (4 mM) after 24
blood glucose level drops, sparing glucose for the hours (Figure 13.11). Thereafter, even under starvation
brain. Increased amount of glycerol is transported conditions, the blood glucose level must be maintained
to the liver, which is a substrate for gluconeogenesis. about 70 mg/dL.

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– Glucagon also inhibits fatty acid synthesis by The processes which take place in early fasting cannot
diminishing the production of pyruvate and by go on indefinitely, because, although they provide efficiently
lowering the activity of acetyl-CoA carboxylase, for the body’s energy requirements, they will soon deplete

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(regulatory enzyme in fatty acid synthesis) by the substantial proportion of body protein. However,
maintaining it in the inactive phosphorylated state. proteins are not stored, and so any breakdown will carry
out a loss of function. Adjustments to metabolism are made
The net effect of glucagon is therefore to stimulate glucose after 24–48 hours, which conserve body protein.
synthesis and release by the liver and to mobilize fatty acids from
adipose tissue, to be used instead of glucose by tissues other than
In starvation, energy has to be derived from the body’s own stores.
the brain.

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A typical well-nourished 70 kg man has fuel reserves totaling
about 165,000 kcal (Table 13.1). The energy needed for 24-hour
period ranges from about 1,600 kcal in the basal state to 6,000
The Refed State After Breakfast
kcal depending on the extent of activity. Thus, stored fuels are
Earlier, we considered the metabolic changes occur dur- enough to meet caloric needs in starvation for 1–3 months and
ing overnight or early fasting. After overnight fast when in the case of some obese individuals, much longer. However,
an individual is having breakfast, the body returns to the the carbohydrate reserves are exhausted in only a day. The total
fed state.
x Fat is processed exactly as it is processed in the normal
fed state.
x However, glucose is not processed as it is processed in
O energy, immediately available from the plasma, is very small, and
would only meet the basal metabolic requirements for about 80
minutes.
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the normal fed state. The liver does not initially absorb Metabolic Changes on the First Day of Starvation
glucose from the blood, but instead, spares it for the The metabolic changes on the first day of starvation are
other tissues. like those after overnight fast.
x Furthermore, the liver remains in a gluconeogenic x The low blood sugar level leads to decreased secretion
mode for 2–3 hours after feeding. The newly synthesized of insulin and increased secretion of glucagon.
glucose by gluconeogenesis is used to replenish x The lipolysis, breakdown of triacylglycerol in adipose
the liver’s glycogen stores. As the blood glucose tissue, and gluconeogenesis in liver are the predominant
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concentration continues to rise, the liver completes metabolic processes.

the replenishment of its glycogen stores with end of x The concentration of acetyl-CoA and citrate increase
gluconeogenic mode of the liver and start synthesizing due to increased breakdown of triacylglycerol. Acetyl-
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glycogen from fresh blood glucose. CoA and citrate inhibits glycolysis.
x After complete replenishment of liver glycogen stores,
x The uptake of glucose by muscle is markedly diminished
the remaining excess glucose is processed for fatty acid
because of the low insulin level, whereas fatty acids
synthesis.
enter freely. Now muscle uses no glucose and depends
exclusively on fatty acids for fuel.
Metabolic Changes Occur During
x The E oxidation of fatty acids by muscle stops the
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Prolonged Starvation conversion of pyruvate into acetyl-CoA because acetyl-

When fasting state is prolonged, the condition is called CoA stimulates the phosphorylation of the pyruvate
starvation. Let us now examine what are the adaptations dehydrogenase complex, which makes it inactive.
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if fasting is prolonged to the point of starvation. Figure x Hence, pyruvate, lactate, and alanine are exported to
13.9 illustrates the main features of the prolonged the liver for conversion to glucose by gluconeogenesis.
starvation. Glycerol derived from the degradation of triacylglycerols
The stored quantity of carbohydrate can supply the is also a precursor for the synthesis of glucose by the
energy required for body functions for about 8–12 hours. liver.
Therefore, except for the first few hours of starvation, x Proteolysis also provides carbon skeletons for
there is progressive depletion of tissue fat and protein gluconeogenesis. During starvation, degraded proteins
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 353

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Figure 13.9: The metabolic role of specific organs during prolonged starvation.
(FA: fatty acid; KB: ketone bodies; TAG: triacylglycerol; ATP: adenosine triphosphate; TAC cycle: tricarboxylic acid cycle).
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YPE
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Figure 13.10: Depletion of food stores in the body tissue during Figure 13.11: Changes in the concentration of fuels in the blood
starvation. during starvation (1 mM glucose = 18 mg/dL glucose).
 354 Section III: Energy Metabolism and Metabolism of Biomolecules

TABLE 13.1: Fuel reserved in a well-nourished 70 kg man. the citric acid cycle. Consequently, liver produces
large quantities of ketone bodies and releases into
Weight Caloric equivalent Estimated
Type of fuel (Kg) (thousands of kcal) survival the blood.
Triacylglycerol 15 140
At this time, the brain begins to consume significant
amounts of acetoacetate in place of glucose. After 3 days

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(adipose tissue)
Proteins 6 24 of starvation, about a quarter of the energy needs of the
(mainly muscle) brain are met by ketone bodies. The heart also uses ketone
bodies as fuel.

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Glycogen 0.23 0.90
3 months
(muscle, liver)
Circulating fuels 0.023 0.10
Metabolic Changes after Several Weeks of Starvation
(glucose, fatty acids, x After several weeks of starvation, ketone bodies become
triacylglycerols) the major fuel of the brain. As the supply of ketone
Total 165 bodies increases and the supply of glucose diminish,
the brain reduces its utilization of glucose and begins

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are not replenished and serve as carbon sources for to consume appreciable amounts of ketone bodies in
glucose synthesis. place of glucose.
– Initial sources of protein are those that turn over x The increased use of ketone bodies by the brain is a
rapidly, such as proteins of the intestinal epithelium simple mass action effect of the increased availability
(digestive enzymes) and the secretions of the of the ketone bodies, which like glucose, now can cross
pancreas, as these enzymes are no longer needed. the blood-brain barrier.
These are so-called labile proteins, the loss of which
does not affect the integrity of the tissues.
– Then there is a rapid breakdown of muscle protein,
providing amino acids that are used by the liver
O Up to half the energy requirement of the brain can be met by
ketone bodies. They can cross the blood-brain barrier and diffuse
into brain cells where they are reconverted to acetyl-CoA in the
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mitochondria. The brain does not use amino acids per se but
for gluconeogenesis. The major gluconeogenic
glucose derived from glucogenic amino acids in the liver. It does
amino acids, coming from muscle, are alanine and not use fatty acids as they do not cross the blood-brain barrier in
glutamine. significant amounts to be of use (Figure 13.12).
– Glucagon increases the uptake of alanine by the
liver. The mucosal cells, being rapidly dividing, even x After several weeks of starvation, ketone bodies
the fasting state requires glutamine as a nitrogen become the major fuel of the brain. Although the
donor for the synthesis of the bases of the purine
brain still has a residual glucose requirement, not
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nucleotides.
only for provision of energy, but also for synthesis of
It will soon deplete the substantial proportion of body
neurotransmitters. Only 40 g of glucose is needed per
protein. However, proteins are not stored and so any
day for the brain as compared with about 120 g in the
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breakdown will lead a loss of function. It is known that death

first day of starvation.
ensues when 30–50% of the body protein is lost. Protein
undergoes three phases of depletion, rapid depletion at x Therefore, less muscle is degraded than in the first day of
first then the greatly slowed depletion, and finally rapid starvation. The breakdown of 20 g of muscle compared
depletion again shortly before death. with 75 g early in starvation is most important for
survival. This sequence of events leads to at least partial
Metabolic Changes after Three Days of Starvation preservation of the protein stores of the body.
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x During the conversion of amino acid to glucose by

Now we will see how is the loss of muscle protein
reduced? After about 3 days of starvation, the liver gluconeogenesis, the nitrogen of the amino acid
is converted to urea and so production of urea
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forms large amounts of ketone bodies, acetoacetate,

and E-hydroxybutyrate (Figure 13.11). The synthesis decreases during prolonged starvation, as compared
of ketone bodies from acetyl-CoA increases markedly to its production in short-term starvation. Decrease in
(producing the state of ketosis) because: nitrogen excretion occurs from around 12–15 g/day to
x Citric acid cycle is unable to oxidize all of the acetyl-CoA 3–4 g/day, following 4–6 weeks of starvation (Figure
generated by the degradation of fatty acids. 13.13). Urea nitrogen diminishes markedly, suggesting
x Gluconeogenesis depletes the supply of oxaloacetate, that fewer amino acids undergo gluconeogenesis in
which is essential for the entry of acetyl-CoA into the liver.
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 355
of cellular function, death ordinarily ensues when the
proteins of the body have been depleted to about half
their normal level. The death invariably results from a
loss of heart, liver, or kidney function.

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Strike a Note
‰ Circulating glucose concentrations do not drop below 70 mg/
dL even in prolonged starvation.

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‰ Carbohydrate reserves (glycogen) are depleted after 8 to 12 h
of starvation.
‰ The first priority of metabolism in starvation is to provide
sufficient glucose to the brain and other tissues that are
absolutely dependent on glucose.
‰ Gluconeogenesis plays an essential role in maintaining blood
glucose during both the early fasting phase and prolonged

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starvation.
‰ During starvation, the kidney becomes an important site of
gluconeogenesis and may contribute as much as half of the
blood glucose.
‰ The major substrates for gluconeogenesis are amino acids
derived from skeletal muscle protein breakdown.

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Figure 13.12: Fuel source used by the brain in well-fed and starved
‰

‰
The major glucogenic amino acid coming from muscle to liver
for gluconeogenesis during starvation is alanine.
The second priority of metabolism in starvation is to preserve
protein. This is accomplished by using fatty acids and ketone
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bodies in place of glucose as a fuel.
state.
‰ During starvation, most tissues utilize fatty acids and/or ketone
bodies to spare glucose for the brain.
‰ Glucose utilization by the brain is decreased during prolonged
starvation as the brain utilizes ketone bodies as the major fuel.
‰ Ketosis is a metabolic adaptation to starvation, arises as a result
of deficiency in available carbohydrate.
‰ Protein undergoes three phases of depletion, rapid depletion
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at first then the greatly slowed depletion, and finally rapid

depletion again shortly before death.
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ASSESSMENT QUESTIONS
Long Answer Questions (LAQs)
1. What is integration metabolism? Discuss integration of
metabolism at various levels and its significance.
Figure 13.13: Changes in urea excretion during prolonged fasting. 2. Metabolic changes occur during fed, fasting and starvation
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states with a role of specific organs.

x Because of these adaptive mechanisms, the person’s
Short Notes
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survival time is mainly determined by the size of

the triacylglycerol depot. When the triacylglycerol 1. Integration metabolism at cellular level.
stores are completely exhausted, the only source of 2. Integration metabolism at tissue or organ level.
fuel remains is protein. So degradation of proteins 3. Metabolic changes occur in fed state.
accelerates, and thus, muscle proteins are heavily 4. Metabolic changes occur in fasting state.
drained as a source of energy. At that time, the protein 5. Metabolic changes occur during prolonged starvation.
stores once again enter a stage of rapid depletion. 6. Role of liver in integration metabolism.
Because proteins are also essential for the maintenance 7. Significance of integration metabolism.
 356 Section III: Energy Metabolism and Metabolism of Biomolecules

Solve c. Pyruvate dehydrogenase activity

d. Lactate dehydrogenase activity
Case History 1
10. During starvation, the first reserve nutrient to be depleted
A patient attending an obesity clinic is found to have is:
ketonuria. The patient is on a low-carbohydrate diet in order
to lose weight. There is no glycosuria. Blood glucose level was a. Glycogen b. Proteins

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found 80 mg/100 mL: c. Triglycerides d. Cholesterol
1. Explain the cause of ketonuria. 11. Synthesis of the following enzymes is increased during
starvation.
2. How blood glucose level is maintained in this patient?

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a. Digestive enzymes b. Gluconeogenic enzymes
3. Name the test to confirm ketonuria.
c. Glycolysis enzymes d. Glycogenesis enzymes
4. What is ketosis?
12. In fasting which of the following metabolites will be
elevated in blood after 24 hours?
Multiple Choice Questions (MCQs) a. Triacylglycerol b. Glucose
1. The first priority of metabolism in starvation is to provide c. Free fatty acid d. Glycogen
which of the following substances to the brain and other 13. On prolonged fasting which of the following metabolites

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tissue? will be elevated in blood after 3 days?
a. Fatty acids b. Ketone bodies a. Ketone bodies b. Glycogen
c. Glucose d. Cholesterol c. Triacylglycerol d. Glucose
2. During starvation, blood or tissue levels of all of the 14. After overnight fast one would expect increased activity
following are elevated, except: of what?
a. Free fatty acids b. Ketone bodies a. Hepatic glycogen synthase
c. Glucagon d. Insulin

in maintaining blood glucose during early and prolonged

starvation?
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3. Which of the following processes plays an essential role

15.
b. Pyruvate dehydrogenase
c. Hormone-sensitive lipase
d. Pancreatic lipase
After overnight fast one would expect glucose transporter
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a. Glycolysis b. Gluconeogenesis activity to be what?
c. Ketogenesis d. Glycogenolysis a. Decreased in brain cell
4. In starvation, muscle protein is spared by: b. Enhanced in adipocytes
a. Using fatty acids and ketone bodies c. Decreased in red blood cells
b. By increasing rate of gluconeogenesis d. Decreased in muscle cells
c. By inhibiting glucose utilization 16. Which one of the following statements is correct for
d. By stimulating protein synthesis metabolism during prolonged starvation compared to
5. In prolonged starvation, the main energy source of brain early or short-term starvation?
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is: a. The degradation of proteins is increased

a. Glucose b. Ketone bodies b. The rate of gluconeogenesis in liver is decreased
c. Fructose d. Fatty acids c. The formation of ketone bodies is decreased
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6. The major glucogenic amino acid coming from muscle to d. Heart generates more of its energy from glucose
liver for gluconeogenesis during starvation is: 17. Which of the following statements are correct for amino
a. Threonine b. Methionine acid metabolism during the fasting state compared with
c. Alanine d. Glycine the fed state? except.
7. During early fasting, glucose is derived from: a. Glutamine and alanine are released in increased amounts
a. Glycogen b. Amino acids b. Glucose is preserved for the brain
Y

c. Fatty acids d. Ketone bodies c. Alanine is utilized for glucose synthesis

8. Fatty acid or ketone bodies are used as energy source in: d. Alanine is utilized for protein synthesis
a. Intraprandial phase 18. Which of the following occurs in cardiac muscle but not in
the brain, even in the fasted state?
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b. Postabsorptive phase
c. Prolonged starvation a. Fatty acid oxidation
d. Fully fed state b. Glycolysis
9. During starvation, free fatty acids and ketone bodies are c. TCA cycle
oxidized in preference to glucose in muscle by impairing, d. Glucose uptake via a glucose transporter
except: 19. During starvation, ketone bodies are used as a fuel by:
a. Uptake of glucose by the cell a. Erythrocytes b. Brain
b. Phosphorylation by hexokinase and phosphofructokinase c. Liver d. All of these
 Chapter 13: Integration of Metabolism and Metabolic Processes in Fed, Fasting and Starvation States 357
20. Which type of metabolic fuel is utilized for generating c. Muscle lacks glucose-6-phosphatase
glucose under conditions of severe starvation? d. The liver provides all the glucose necessary for metabolism
a. Glycogen and there is no need for muscle to do the same
b. Fats
c. Starch

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ANSWERS FOR MCQs
d. Amino acids
21. Liver glycogen is used in fasting to provide glucose. 1. c 2. d 3. b 4. a 5. b
Muscle glycogen is not. What is the explanation for this? 6. c 7. a 8. c 9. a 10. a

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a. Muscle does not have a debranching enzyme 11. b 12. c 13. a 14. c 15. d
b. Muscle cannot degrade glycogen further than glucose-1- 16. b 17. d 18. a 19. b 20. d
phosphate 21. c

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E
Y PE
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