STARVE FEED CYCLE... Gluconeogenesis

Metabolic
interrelationships
Interdependence of
metabolic processes
• Not all of the metabolic pathways operate

in every tissue at any given time.
• Given the hormonal and nutritional status,
we should be able to predict:
• a) Which of the major metabolic pathways

are functional
Metabolic
interrelationships
• b) How are these pathways related to each
other.
• Important to know:
• a) which tissues are most active in the various
pathways?
• b) when are these processes most or least
active?
• c) how are these processes controlled and
coordinated in different metabolic states ?
Metabolic
interrelationships
• The relationships of major metabolic pathways
to each other are best understood by examining
the metabolism during the starve-feed cycle.
• The starve-feed cycle allows a variable fuel

consumption to meet a variable metabolic
demand
• .
Metabolic
interrelationships
• Feed: intake of meals, after which we
store the fuel (glycogen & fat) to be used
to meet the metabolic demands of fasting.
• Humans are able to use a variable fuel

input to meet a variable metabolic demand.
Metabolic
interrelationships
• We have the capacity to consume food at a rate
of 100 times greater than caloric requirements.
• This allows us to survive from meal to meal

without nibbling continuously between meals.
• Unlimited capacity to store excess energy as

fat.
Starve-feed Cycle
• Diet supplies the energy requirements.
• Glucose and amino acids go directly

into the blood from the intestine and
get to the liver by the portal vein.
Starve-feed Cycle
• Fats as chylomicrons---->lymph----
>thoracic duct----> subclavian vein---->
blood -----> distribution of chylomicrons to
all the tissues.
1. Dietary Glucose (well fed state)
• The Liver is the first tissue to have

the opportunity to use dietary glucose.
Starve-feed Cycle
• In the liver, Glucose can be converted
to:
• a) glycogen by glycogenesis
• b) to pyruvate and lactate by “glycolysis”

Starve-feed Cycle
• c) or used in the pentose PO4
pathway to generate NADPH (minor pathway)
Kreb Cycle
• d) Pyruvate----> Acetyl Co A --------------->
CO2
+ Energy
• e) much of the glucose from the intestine escapes the

liver and circulates to other tissues (brain, testis,
RBCs and medulla depend on glucose only for energy).
Starve-feed Cycle
• Glucose use by tissues other than the
liver (in the fed state)
• Brain: depends on glucose exclusively

(glucose+ O2 ---->ATP)
• Red Blood Cells: glucose -----> lactate only

Starve-feed Cycle
• Adipose tissue: glucose -----> fat (well fed
state)
• Muscle: converts glucose to glycogen, or uses
the glycolytic and the TCA pathway.
• Lactate and pyruvate made by the peripheral

tissues are taken up by the liver and
converted to fat (Lipogenesis) (well fed
state).
Starve-feed Cycle
In the well fed state:
• The liver uses glucose and does not engage in

gluconeogenesis.
• Thus, the “Cori cycle” (conversion of lactate

produced by peripheral cell to glucose in liver)
is Interrupted in the well fed state.
Starve-feed Cycle
• Disposition of glucose, amino acids, and fat
by various tissues in the well fed state
2. Dietary Protein (Well Fed State)
• Dietary protein is hydrolyzed in the intestine,

and some amino acids are used for energy.
Starve-feed Cycle
The Liver:
• Removes amino acids from blood,
and lets most of each amino acid pass
through, unless the concentration of
amino acids is unusually high.
Starve-feed Cycle
• This is important for essential amino acids
needed by all tissues of the body for
protein synthesis.
• The liver can catabolize amino acids, but

the Km value of enzymes for many amino
acids is high, thus amino acids must be in
excess before catabolism can occur (Imp.)
Starve-feed Cycle
Catabolism of Excess Amino Acids in the liver
(Well Fed state)
• (a) Excess amino acids can be oxidized
completely to CO2+ H2O and N goes to urea.
• (b) Or the intermediates generated can be

used as substrate for lipogenesis, while N
goes to urea.
Starve-feed Cycle
• (c) Amino acids that “escape” the
liver can be used for protein
synthesis or for energy in “other
tissues”.
Starve-feed Cycle
• 3. Dietary Fat (Fed State)
• a) Exogenous fat- Delivered to tissues
• b) Endogenous fat-Chylomicron VLDL
a) Exogenous fat:
• Dietary fat is delivered to blood as
chylomicrons.
Starve-feed Cycle
• B). Endogenous fat
• Glucose, lactate, pyruvate and amino acids
can be used for hepatic lipogenesis (excess
energy).
• The fat formed from these substrates is

then released from the liver as VLDL
(mostly contains triglycerides).
Starve-feed Cycle
Early Fasting
• During early fasting, when fuel stops

coming in from the gut: Hepatic
glycogenolysis is very important for the
maintenance of blood glucose.
• Lipogenesis is curtailed and lactate,
pyruvate and amino acids that were
used for lipogenesis are diverted to
glucose formation.
Starve-feed Cycle
• (1) The “Cori Cycle” becomes an important
pathway for blood glucose maintenance.
• Glucose produced by lactate in the liver goes

back to the peripheral tissues as glucose.
• (2) The “Alanine Cycle”, in which C returns

to the liver as alanine is also important.
Starve-feed Cycle
• The catabolism of dietary amino acids
for energy is greatly decreased in the
early fasting (less available from the
gut).
Starve-feed Cycle
Fasting State
• No fuel from the gut and little glycogen left in
the liver.
• Tissues that use glucose are dependent on “hepatic

gluconeogenesis” (from lactate, glycerol and
alanine).
• The Cori and Alanine cycles play an important

role
Starve-feed Cycle
• But these cycles do not provide
carbon for net synthesis of glucose.

Starve-feed Cycle
• “Glucose” formed from alanine or lactate by
the liver replaces that which was converted
to lactate or alanine by the peripheral cells .
• Since glucose is oxidized completely to CO2

and H2O in the brain, “net glucose
synthesis” from some other source is
necessary during fasting.
Starve-feed Cycle
• Fatty acids cannot be used for glucose
synthesis (acetyl Co A cannot be
converted to pyruvate).
• Glycerol (3C), a by product of lipolysis in

adipose tissue (by intracellular lipase), is
an important substrate for glucose
synthesis in the fasting state.
Starve-feed Cycle
Protein Catabolism in Fasting

• Proteins, especially from the skeletal
muscle supply most C needed for net
glucose synthesis.
Starve-feed Cycle
• Proteolysis in muscle cells produces amino acids,
most of which are not released but partially
metabolized within the muscle cells.
• Only two amino acids, alanine and glutamine, are

released in large amounts from the muscle.
• The other amino acids are metabolized in the

muscle to give intermediates (pyruvate and alpha-
ketoglutarate), which yield alanine and glutamine.
Starve-feed Cycle
• Alanine and glutamine are then released
into the blood, and then removed by the
liver or kidney for net glucose synthesis.
Starve-feed Cycle
• Alanine is quantitatively the most

important gluconeogenic substrate
• The synthesis of glucose in the liver
during fasting is closely linked to
urea synthesis.
Starve-feed Cycle
Adipose Tissue during Fasting

• Adipose tissues are also important
during fasting.
Starve-feed Cycle
• Because of a low insulin-glucagon ratio during fasting: lipolysis
increases:
• lipolysis -----> Increases blood fatty acid levels.
• Fatty acids are used in preference to glucose by many tissues (

heart,muscles and kidney).
• In heart and muscle, the oxidation of fatty acids inhibits

glycolysis.
• The brain does not oxidize fatty acids because of the blood
brain barrier.
Starve-feed Cycle
• In the liver fatty acid oxidation
provides most of the ATP needed for
gluconeogenesis.
• In the liver, very little of the acetyl Co

A generated by ß-oxidation of fatty
acids is completely oxidized to CO2
Starve-feed Cycle
• Instead, in the liver, acetyl Co As are converted
to ketone bodies in the mitochondria during
fasting.
• The ketone bodies are released into the blood

and are a source of energy for many tissues.
• Like fatty acids, ketone bodies are preferred by

many tissues over glucose.
Starve-feed Cycle
• In contrast to fatty acids, ketone bodies
“penetrate” the blood-brain barrier.
• Once the blood concentration of ketone bodies

is high enough, they act as an alternative fuel
for the brain.
• Ketone bodies are unable, however, to

completely replace the need for glucose by the
brain.
Starve-feed Cycle
• Ketone bodies also suppress
proteolysis in skeletal muscle and
decrease muscle wasting during
starvation (especially leucine, the
completely ketogenic amino acid,
spares other gluconeogenic
precursors).
Starve-feed Cycle
• As long as ketone levels are maintained

at a high level by hepatic fatty acid
oxidation, there is less need for glucose,
less need for gluconeogenic amino acids,
and less need for using up muscle tissue
by proteolysis.

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Metabolic

• Not all of the metabolic pathways operate

• a) Which of the major metabolic pathways

• The starve-feed cycle allows a variable fuel

• Humans are able to use a variable fuel

• This allows us to survive from meal to meal

• Unlimited capacity to store excess energy as

• Diet supplies the energy requirements.

• Glucose and amino acids go directly

1. Dietary Glucose (well fed state)

• The Liver is the first tissue to have

• b) to pyruvate and lactate by “glycolysis”

• e) much of the glucose from the intestine escapes the

• Brain: depends on glucose exclusively

• Red Blood Cells: glucose -----> lactate only

• Lactate and pyruvate made by the peripheral

• The liver uses glucose and does not engage in

• Thus, the “Cori cycle” (conversion of lactate

2. Dietary Protein (Well Fed State)

• Dietary protein is hydrolyzed in the intestine,

• The liver can catabolize amino acids, but

• (b) Or the intermediates generated can be

• The fat formed from these substrates is

• During early fasting, when fuel stops

• Glucose produced by lactate in the liver goes

• (2) The “Alanine Cycle”, in which C returns

• Tissues that use glucose are dependent on “hepatic

• The Cori and Alanine cycles play an important

• But these cycles do not provide

carbon for net synthesis of glucose.

• Since glucose is oxidized completely to CO2

• Glycerol (3C), a by product of lipolysis in

Protein Catabolism in Fasting

• Only two amino acids, alanine and glutamine, are

• The other amino acids are metabolized in the

• Alanine is quantitatively the most

Adipose Tissue during Fasting

• Fatty acids are used in preference to glucose by many tissues (

• In heart and muscle, the oxidation of fatty acids inhibits

• In the liver, very little of the acetyl Co

• The ketone bodies are released into the blood

• Like fatty acids, ketone bodies are preferred by

• Once the blood concentration of ketone bodies

• Ketone bodies are unable, however, to

• As long as ketone levels are maintained

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