Gluconeogenesis

is a metabolic process that occurs in the

liver and kidneys to produce glucose,
particularly to meet the body's needs
between meals.
It is stimulated by specific hormones and
utilizes substrates like glycerol, lactate,
and certain amino acids.
Gluconeogenesis supplies the needs for
plasma glucose between meals.
Gluconeogenesis is stimulated by the
diabetogenic hormones (glucagon,
growth hormone, epinephrine, and
cortisol). Gluconeogenic substrates
include glycerol, lactate, propionate, and
certain amino acids. Gluconeogenesis
refers to a group of metabolic reactions
in cytosol and mitochondria to maintain
the blood glucose level constant
throughout the fasting state.
Reactions in the gluconeogenesis
pathway are regulated locally and
globally (by insulin, glucagon, and
cortisol), and some of them are highly
exergonic and irreversible.
The balance between stimulatory and
inhibitory hormones regulates the rate
of gluconeogenesis.
The liver and, secondarily, the kidney
are the organs that supply circulating
blood glucose to various tissues.
Different tissues have multiple
mechanisms to generate glucose during
fasting, maintaining adequate energy
levels for their proper function

Gluconeogenesis is the process that

allows the body to form glucose from non-
hexose precursors, particularly glycerol,
lactate, pyruvate, propionate, and
glucogenic amino acids.
Several tissues require continuous
glucose supply, including the brain,
erythrocytes, renal medulla, the lens
and cornea, testes, and skeletal muscles
during exercise. The brain
uses glucose exclusively in both the fed
and fasting states except for prolonged
fasting, which uses ketones.
Notably, the daily amount of glucose
used by the brain accounts for 70% of
the total glucose produced by the liver
in a normal fasting person.
Initially, during the first hours of fasting, hepatic
glycogenolysis is the primary source of glucose.
Glucose stored as glycogen can cover the energy needs
roughly for one day; the amount of glucose supplied
by glycogen reserves is 190 g, while the daily
requirements for glucose are 160 g. After several
hours of starvation, gluconeogenesis and
glycogenolysis contribute equally to blood glucose.
The amount of glucose supplied by glycogen decreases
rapidly while the increase in the glucose fraction
contributed by gluconeogenesis results in
keeping constant the total amount of glucose
produced. Estimates are that 54% of glucose comes
from gluconeogenesis after 14 hours of starvation, and
this contribution rises to 64% after 22 hours and up to
84% after 42 hours. However, when glycogen stores
deplete, the body uses lactate, glycerol, glucogenic
amino acids, and odd chain fatty acids as glucose
sources. In prolonged fasting, kidney participation in
gluconeogenesis increases and is responsible for about
40% of total gluconeogenesis.
Gluconeogenesis essentially reverses
glycolysis. The brain, eye, and kidney are
some of the organs that have glucose as the sole metabolic
fuel source. Prolonged fasting or vigorous exercise
depletes glycogen stores, making the body switch to de-
novo (De novo synthesis refers to the
production of complex substances from
simple molecules through complex
metabolic pathways) glucose synthesis
to maintain blood levels of this monosaccharide.
Gluconeogenesis is the process that allows the body
to form glucose from non-hexose precursors, particularly
glycerol, lactate, pyruvate, propionate, and glucogenic
amino acidsDefinition

GLUCONEOGENESIS
It is a process transforming non-carbohydrate substrates into
glucose.
It is the synthesis of new glucose from non carbohydrate
precursors providing glucose when dietary intake is lacking or is
insufficient. It is also required in the regulation of acid-base
balance, synthesis of carbohydrate derived structural
constituents.
Gluconeogenesis works in the opposite direction of glycolysis,
which creates glucose from pyruvate, lactate, and glucogenic
amino acids. It’s also known as Neoglucogenesis. It’s a
universal pathway found in humans, animals, plants, fungus, and
other living species.
The definition, occurrence site, importance, and steps involved
in the gluconeogenesis pathway will be discussed in this article.
The substrates that initiate the gluconeogenesis pathway, as well
as the gluconeogenesis regulation, are also discussed.

Table of Contents
 Definition of Gluconeogenesis
 Gluconeogenesis Functions
 Pathway of Gluconeogenesis
 Importance of Gluconeogenesis
 Frequently Asked Questions – FAQs

Definition of Gluconeogenesis
Gluconeogenesis (GNG) is the building of novel glucose
molecules in the body as compared to glucose, which is split
from the prolonged storage molecule glycogen. It primarily
occurs in the liver, but it can also occur in minor levels in the
small intestine and kidney. Gluconeogenesis is the reversal
of glycolysis, which breaks down glucose molecules into their
subcomponents.
Since it requires energy, gluconeogenesis is also known as the
“Endogenous glucose pathway.” When the small precursor
molecules combine, a high-energy product like glucose is
produced. Gluconeogenesis is a necessary cycle that produces
glucose, which is used to carry out all catabolic activities and
support life. What is the main function of gluconeogenesis?
Gluconeogenesis:
Gluconeogenesis is the process by which glucose is produced
from noncarbohydrate sources such as glucogenic amino acids,
glycerol, etc.

What is the main Functions of Gluconeogenesis:

I. It occurs when dietary intake of carbohydrate is
low or at the time of fasting to maintain glucose
level.
II. Non-carbohydrate sources are first converted to
pyruvate or other intermediates of glycolysis.
III. Some cells in our body such as erythrocytes and
brain cells primarily utilise glucose as the
energy source.
IV. Gluconeogenesis mainly occurs in the liver.
 What increases gluconeogenesis?
Solution
Gluconeogenesis:
1. The biochemical process of
preparing glucose from the non-
glucose sources within the cells is
called gluconeogenesis.
 2. Glucose can be formed through
amino acids, fatty acids, lactate as
well as other non-carbohydrate
sources.
3. It occurs when the body is
deficient in glucose. Thus, it is an
energy-saving rather energy-
producing process that occurs
anaerobically.
4. This process is significant since it
leads to the synthesis of glucose
which is the only source of nutrition
for the brain.
5. Pyruvate carboxylase, PEP
carboxykinase, fructose 1,6-
bisphosphatase, and glucose 6-
phosphatase are the enzymes unique
to gluconeogenesis.
6. Gluconeogenesis occurs in the
liver and kidneys.
7. Hormones such as glucagon,
glucocorticoids, etc. stimulate
gluconeogenesis.
Which factors increase the rate of
gluconeogenesis?

Solution
Gluconeogenesis:
1. Gluconeogenesis is a metabolic
process that produces carbohydrates
from several non-carbohydrate carbon-
based materials.
2. It is a procedure that is found in
plants, animals, microorganisms,
bacteria, and other microbes.
3. Gluconeogenesis is the procedure by
which glucose is produced from
lignocellulose sources.
4. When blood sugar levels are low, such
as when abstinence or following a low-
carb diet, the rate of gluconeogenesis
grows.
5. Hormones such as catecholamines,
glucagon, and corticosterone, among
others, promote gluconeogenesis.
6. Hepatic adipose triacylglycerols lipase
activity, intrahepatic lipolysis, hepatic
acetyl-CoA content, and pyruvic acid
carboxylase flux are all increased by
catecholamines, glucagon, and
corticosterone.
Q. Which reaction is unique to
gluconeogenesis?
Solution
Gluconeogenesis:
1. The process of preparing
glucose/sugar from its own byproducts or
those of lipids, fats, or proteins is termed
Gluconeogenesis.
2. Gluconeogenesis occurs mostly within
liver and kidney cells.
3. It regulates acid-base homeostasis
and amino acid metabolism.
Reaction Unique To Gluconeogenesis:
1. The process in which pyruvate is
carboxylated to yield oxaloacetate is
unique to Gluconeogenesis.
2. Pyruvate carboxylase catalyzes the
reaction. It is one of two processes that
are essential for the processing of
pyruvate to phosphoenolpyruvate (PEP).
3. PEP is transformed to pyruvate in
glycolysis by the action of pyruvate
kinase, which is an irreversible event that
necessitates an alternative route in
gluconeogenesis.

Gluconeogenesis is controlled by
I. Cortisol II. Corticosterone. III. Thyroxin
 Stimulation of gluconeogenesis in the liver results
in the synthesis of glucose from non-hexose
substrates, such as amino acids and lipids in
carnivores and certain herbivores.
Enhancing the expression of enzymes involved in
 gluconeogenesis is the metabolic function of
glucocorticoids (cortisol and corticosterone).
Thyroid hormones stimulate carbohydrate
metabolism, including enhancement of insulin
dependent entry of glucose into cells and increased
gluconeogenesis and glycogenolysis to generate
free glucose

Gluconeogenesis Functions
Human systems create glucose to keep blood sugar levels in
check. Because cells use glucose to create the energy component
adenosine triphosphate, blood glucose levels must be maintained
(ATP). When a person hasn’t eaten in a while, such as during a
crisis or starvation, gluconeogenesis takes place.
Since the body does not have enough carbohydrates from the
food to break down into glucose during this time, it must depend
on other molecules for gluconeogenesis, such as amino acids,
lactate, pyruvate, and glycerol. After glucose is produced in the
liver by gluconeogenesis, it is released into the blood, where it
can be used for energy by cells in other regions of the body.
Since it requires energy input, gluconeogenesis is also known as
endogenous glucose production (EGP). Because
gluconeogenesis is the reverse of glycolysis, which releases a lot
of energy, gluconeogenesis would be predicted to require a lot
of energy input. However, because gluconeogenesis happens
when the body is already depleted of energy, it needs
workarounds to conserve energy.
Gluconeogenesis and glycogenolysis serve the same purpose.
However, they are used differently. Glycogenolysis is
commonly used during shorter fasting periods, such as when a
person’s blood sugar decreases between meals or after a good
night’s sleep, but gluconeogenesis is more commonly employed
during longer periods of fasting. Both processes, however, occur
to some degree in the body because glucose is required for
energy production.

Pathway of Gluconeogenesis
1. Gluconeogenesis originates in the liver or kidney’s cytoplasm
or mitochondria. To make oxaloacetate, two pyruvate
molecules are required to carboxylate first. This requires one
ATP (energy) molecule.
2. NADH converts oxaloacetate to malate, which can then be
transported out of the mitochondria.
3. Once malate leaves the mitochondria, it is oxidised back to
oxaloacetate.
4. The enzyme Phosphoenolpyruvate carboxykinase (PEPCK)
converts oxaloacetate to phosphoenolpyruvate.
5. By reversing glycolytic processes, phosphoenolpyruvate is
converted into fructose 1,6-bisphosphate.
6. Fructose-1, 6-bisphosphate is converted to fructose-6-
phosphate in the reaction releasing inorganic phosphate and is
catalysed by fructose-1,6-bisphosphatase.
7. The enzyme phosphoglucoisomerase converts fructose-6-
phosphate to glucose-6-phosphate.
8. Glucose-6-phosphate generates inorganic phosphate that
yields free glucose, which enters the blood. Glucose 6-
phosphatase is the enzyme involved.
In the Mitochondria
Pyruvate + ATP → Oxaloacetate + ADP + Pi
Oxaloacetate + NADH → Malate + NAD+
The conversion to malate enables the molecule to be transferred
out of mitochondria. It is converted back to oxaloacetate in the
cytoplasm.
In the Cytoplasm
Malate + NAD+ → Oxaloacetate + NADH
Oxaloacetate + GTP → PEP + GDP
It then passes through the same intermediates that glycolysis
does. The endoplasmic reticulum is the location of the final
reaction.
In the Endoplasmic Reticulum
G6P → glucose (catalyst: glucose-6-phosphatase)
Glucose is transported out of the cell into the extracellular
environment by a glucose transporter.

Gluconeogenesis of Amino acids

Gluconeogenic amino acids are the amino acids that can be
converted to glucose. Most of these are converted to the
intermediates of the citric acid cycle either by deamination or
transamination. Consequently, about 20 amino acids enter the
TCA cycle, some of which enter the cycle by producing only
one intermediate (Example: Alanine) and some others enter two
intermediates (Example: Phenylalanine). As a result, amino
acids are routed metabolically through phosphoenol pyruvic acid
and oxalo acetic acid leading to the formation of glucose.

Importance of Gluconeogenesis
 During deprivation, the gluconeogenesis cycle is important
for blood glucose regulation.
 Many cells and tissues, including RBCs, neurons, skeletal

muscle, the medulla of the kidney, testes, and embryonic

tissue, rely on glucose to meet their energy needs.
 The Neoglucogenesis cycle removes metabolites such as

lactate (produced by muscles and RBCs) and glycerol from

the bloodstream (produced from adipose tissue).
Related Links:
 Glycogenesis
 What is the main function of gluconeogenesis?
 Is gluconeogenesis glycolysis in reverse?
 What is the difference between glycolysis and
gluconeogenesis?
Frequently Asked Questions – FAQs

Q1. Gluconeogenesis takes place in

Gluconeogenesis takes place in the liver and cortex of kidneys.
It usually takes place when the carbohydrates in the diet are
insufficient to meet the demand of glucose in the body.
Q2. What is the function of ATP in gluconeogenesis?
The energy source for the many steps of this biological reaction
is ATP molecules. In several steps, it promotes the production of
glucose from non-sugar substrates.
Q3. Define Glucagon
Glucagon is a hormone that is secreted by the α-cells of
pancreatic islets when the body’s blood glucose level begins to
drop. By two mechanisms, glucagon regulates the transition of
fructose 1, 6-bisphosphate to fructose 6-phosphate or promotes
the process of gluconeogenesis.

Q4. What enzymes are used in gluconeogenesis?

The gluconeogenesis pathway has four irreversible steps
catalysed by the enzymes phosphoenolpyruvate carboxykinase,
pyruvate carboxylase, glucose 6-phosphatase, and fructose 1,6-
bisphosphatase, which is generally found in the liver, kidney,
intestine, or muscle.
GLYCOGENOLYSIS
Glycogenolysis :-
is the breakdown of glycogen into glucose and occurs
when glucose is needed in the body.
Occurs in the liver and muscle cells.
Pathway is activated by the presence of hormones like
epinephrine(Epinephrine has pleiotropic responses in the
body, which include the activation of glycogenolysis in
the liver and skeletal muscles. Epinephrine also promotes
fat breakdown in adipose tissue, which releases this
energy reserve into the bloodstream for utilization by
muscle tissue.) and glucagon(Glucagon triggers your
liver to convert stored glucose (glycogen) into a usable
form and then release it into your bloodstream. This
process is called glycogenolysis. Glucagon can also
prevent your liver from taking in and storing glucose
so that more glucose stays in your blood)
Epinephrine, similar to
glucagon, stimulates glycogenolysis in
the liver, resulting in the raising of the
level of blood glucose. However, that
process is generally initiated by the
fight-or-flight response, as opposed to
the physiological drop in blood glucose
levels that stimulates glucagon
secretion.
GLYCOGENOLYSIS
Definition
Glycogenolysis,
Is process by which glycogen, the primary carbohydrate stored
in the liver and muscle cells of animals, is broken down
into glucose to provide immediate energy and to maintain blood
glucose levels during fasting.
Glycogenolysis occurs primarily in the liver and is stimulated by
the hormones glucagon and epinephrine (adrenaline).
When blood glucose levels fall, as during fasting,
there is an increase in glucagon secretion from
the pancreas. That increase is accompanied by
a concomitant decrease in insulin secretion, because
the actions of insulin, which are aimed at increasing
the storage of glucose in the form of glycogen in
cells, oppose the actions of glucagon. Following
secretion, glucagon travels to the liver, where it
stimulates glycogenolysis.

The vast majority of glucose that is released from

glycogen comes from glucose-1-phosphate, which is
formed when the enzyme glycogen phosphorylase
catalyzes the breakdown of the glycogen polymer. In
the liver, kidneys, and intestines, glucose-1-phosphate
is converted (reversibly) to glucose-6-phosphate by the
enzyme phosphoglucomutase.
Those tissues also house the enzyme glucose-6-
phosphatase, which converts glucose-6-phosphate into
free glucose that is secreted into the blood, thereby
restoring blood glucose levels to normal. Glucose-6-
phosphate is also taken up by muscle cells, where it
enters glycolysis (the set of reactions that breaks down
glucose to capture and store energy in the form
of adenosine triphosphate, or ATP).
Small amounts of free glucose also are produced
during glycogenolysis through the activity of glycogen
debranching enzyme, which completes the breakdown
of glycogen by accessing branching points in the
polymer.
Glycogenolysis plays a central role in regulating
glucose levels in the blood. In muscle cells,
glycogenolysis delivers an immediate source of
glucose-6-P for glycolysis, which provides
energy for muscle contraction.
Glycogenolysis, process by which
glycogen, the primary carbohydrate
stored in the liver and muscle cells of
animals, is broken down into glucose to
provide immediate energy and to
maintain blood glucose levels during
fasting.
Glycogenesis is the process of storing excess
glucose for use by the body at a later time.
Glycogenolysis occurs when the body, which
prefers glucose as an energy source, needs.
energy. The glycogen previously stored by
the liver is broken down to glucose and
dispersed throughout the body..
Animals store glucose as glycogen, which is broken down in a
process called glycogenolysis. Glycogenolysis is a metabolic
process that converts glycogen from the muscles and liver to its
monosaccharide form, glucose. Glycogen is a glucose
polysaccharide stored in the muscles and liver. The body utilises
this to produce ATP (adenosine triphosphate), an organic
substance that provides energy to drive various activities in
living cells.
Low levels of ATP within live cells trigger the glycogenolysis
process. When the cells detect a low level of ATP, the liver and
muscles liberate glycogen and break it down into glucose or
simple sugars, which are then used to produce ATP.
Thus, glycogen (n) is broken down into glucose-1-phosphate
and glycogen (n-1) during glycogenolysis.

Location
Glycogenolysis occurs in the cytoplasm of cells in the liver,
muscles, and adipose tissue.
The liver breaks down the glycogen to maintain the glucose
level in the blood. The muscle cells break down the glycogen to
conserve the energy required for the contraction of muscles.

Steps or Mechanisms
 Glycogen phosphorylase and phosphorylase kinase,
activated by phosphorylation, are the two main regulating
enzymes of glycogenolysis. These will primarily be
expressed in the brain, muscles, and liver.
 Adenyl cyclase and cAMP activity in the muscle triggers
the beginning of glycogenolysis. After phosphorylase
kinase is bound by cAMP and transformed into its active
state, phosphorylase b is changed into phosphorylase a,
which ultimately catalyses glycogen degradation.
 Glycogenolysis can occur either in the lysosomes or in the
cytosol. The cytosolic enzyme glycogen phosphorylase
uses inorganic phosphate to cleave α-1,4 bonds to catalyse
the production of glucose-1-phosphate from the terminals
of glycogen branches.
  The enzyme phosphoglucomutase converts glucose-1-
phosphate into glucose-6-phosphate, which frequently ends
in glycolysis.
 Acid α-glucosidase, an enzyme in the lysosome, uses an

autophagy-dependent mechanism to break down lysosomal

glycogen. This mechanism acts as an instant source of
energy during the newborn stage.
 When glycogen phosphorylase enzyme reaches a branch

point that is four glucose residues away from it, it transfers

one of the branches to another chain, generating a new α-
1,4 bond and leaving one glucose unit at the branch site
later hydrolysed by α-1,6-glucosidase to produce free
glucose. This occurs because the phosphorylase enzyme
can only cleave until it is four units from the branch point.
 The general reaction for the conversion of glycogen to

Glycogen(n residues) + Pi ⇌ Glycogen(n-1 residues) + Glucose-1-

glucose-1-phosphate is:

phosphate

Enzymes
The important enzymes involved in the process of
glycogenolysis include glycogen phosphorylase, phosphorylase
kinase, and phosphoglucomutase.
In the muscle cells, adenyl cyclase and cAMP bind to and
activate the enzyme phosphorylase kinase and transform
phosphorylase b into phosphorylase a, which catalyses the
glycogen breakdown.
Glycogen is broken down into glucose-1-phosphate and glucose-
6-phosphate in the cytosol by glycogen phosphorylase.
Phosphoglucomutase converts glucose-1-phosphate (reversibly)
into glucose-6-phosphate in the liver, kidney, and intestines.

Functions and Significance

The liver and muscle tissue cells undergo glycogenolysis in
response to neurological and hormonal impulses.
Glycogenolysis, in particular, is crucial for controlling blood
glucose levels and the fight-or-flight response.
Glycogen breakdown in the muscle cells (myocytes) serves as
an instant resource of glucose-6-phosphate for the process of
glycolysis, which produces energy for muscle contraction.
The process of glycogenolysis differs in liver cells or
hepatocytes. The liver does not immediately utilise the glucose
that is created during glycogenolysis in the liver. Instead,
glucose travels via the bloodstream to be utilised by other cells.
Glycogen is a form of energy storage in animals similar to
starch, and a form of energy storage in plants that may be
degraded when a plant requires energy.
Related Links:
 Glycolysis
 TCA Cycle (Tricarboxylic Acid Cycle)

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Frequently Asked Questions – FAQs

Q1
What is the main difference between glycogenolysis and
glycolysis?
The primary energy-producing chemical in our bodies is
glucose. The initial phase of energy synthesis or respiration is
known as glycolysis. Glycogen is produced when there is an
excess of glucose, which is then stored in the tissues of the liver
and muscles. On the other hand, during low energy and low
glucose levels, glycogenolysis is the process of converting
glycogen back to glucose. It is produced and converted into
energy molecules via various metabolic pathways.
Q2
Give an example of glycogenolysis.
Myocytes and hepatocytes undergo glycogenolysis. Glycogen in
hepatocytes or liver cells breaks down to serve as a blood
glucose source, particularly between meals when the glucose
level in the blood is low.