Gluconeogenesis

Basically Gluconeogenesis is the reversal of Glycolysis which is the process of breaking

down of glucose to produce energy.

Glycolysis proceeds to another energy cycle called Citric acid cycle by forming a substance
called pyruvate. So, Gluconeogenesis is just the reversal of Glycolysis – starting with
pyruvate. The substrates get converted to pyruvate or other intermediates of the Citric acid
cycle by various chemical reactions from which Gluconeogenesis begins.

Which way does the process go if all the set of enzymes are same for both glucose synthesis
and breakdown? This conflict is overcome by the 3 key steps in Gluconeogenesis which
cannot occur with enzymes of Glycolysis.

So these 3 steps are circumvented by another set of enzymes to form glucose at the end

Substrates of Gluconeogenesis
Glucogenic amino acids like alanine and
glutamine.

Lactate which is produced as a byproduct of

glycolysis in muscles, red blood cells etc

Glycerol, which is a part of triacylglecerol

molecule in adipose tissue Fatty acid

Citric acid cycle intermediates through

oxaloacetic acid

Glucogenic amino acids

Glucogenic amino acid undergoes

transamination which causes change in the
carbon skeleton and directly gets converted to
pyruvate.
Some Glucogenic amino acids form
oxaloacetic acid or other intermediates of
Citric acid cycle.
While alanine is preferred in liver, glutamine is
preferred in kidney.

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 Lactate
Muscular activities and anaerobic glycolysis in red blood
cells produce a large amount of lactate. This lactate is
taken up by the liver and gets converted to pyruvate by the
enzyme lactate dehydrogenase. Pyruvate then gets
converted to glucose by hepatic Gluconeogenesis which is
then sent back to muscles for reuse. This is known as Cori
cycle .

This is the basis of regulation. As Gluconeogenesis is the reversed process of glycolysis, both
are regulated reciprocally. The factors which increase Glycolysis will decrease
Gluconeogenesis and vice versa. This regulation is needed to control the blood glucose level
which will be either too low or too high in an unregulated condition. The regulation of this
process is brought about by availability of substrates and through hormones.

Gluconeogenesis steps:

•Gluconeogenesis starts either in mitochondria or cytoplasm through a series of

enzymatically catalyzed steps. All the steps of Gluconeogenesis are the same
as that of glycolysis with the same enzymes except in 3 steps. They are

•Glucose is converted to glucose 6 phosphate by glucokinase/ hexokinase in

glycolysis which is reversed by glucose 6 phosphatase.

•Fructose 1 phosphate is converted to fructose 6 phosphate in glycolysis by

phosphorfructokinase which is reversed by fructose 1, 6 bisphosphatase.

•Pyruvate is converted to phosphoenol pyruvate by pyruvate kinase in

glycolysis and is reversed by pyruvate carboxylase and Phosphoenol pyruvate
carboxy kinase.

•Rests are steps of Glycolysis in the opposite direction towards glucose using
the same enzymes.

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 Gluconeogenesis Regulation

Unlike the greedy human mind, the human

body is built in such a way that when it senses
the presence of a substance in excess, even
the energy fuel like glucose, it triggers some
mechanism to either utilize it or store it for
future use. When there is a scarcity of a
substance, our body triggers some
mechanisms which will either form the
substance from other available chemicals or
use an alternative source.

There are 3 types of

regulation which takes
Glycerol place at different speed.
They are
Glycerol is formed by breaking down of
triacylglecerol in the fatty tissue. 1. Change in the rate of
It is then carried to the liver where it gets enzyme synthesis –
converted to pyruvate and enters occurs over several
Gluconeogenesis.
hours

 Availability of
substrate – Increased
availability of Glucogenic
amino acid stimulates
Gluconeogenesis. High glucose increases the synthesis of enzymes of Glycolysis so
that the glucose level is brought down. The opposite happens to the enzymes of
Gluconeogenesis. The synthesis of gluconeogenic enzymes are decreased so that there
is less formation of new glucose.

 Through hormones – Gluconeogenesis is increased by the Glucogenic hormones like

glucagon, epinephrine and glucocorticoids. Glucagon stimulates phosphoenolpyruvate
carboxykinase while insulin reduces the synthesis of these enzymes.

2. Covalent modification by reversible phosphorylation – rapid

 Phosphorylation is the process of addition of a phosphate group to an enzyme. On

phosphorylation, some enzymes are activated while some are inactivated. The
gluconeogenic hormones like glucagon and epinephrine leads to the phosphorylation
of a key enzyme of glucose breakdown, pyruvate kinase which gets inactivated.

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  This leads to inhibition of glycolysis and stimulation of Gluconeogenesis. This type of
regulation acts as a rapid response to the presence of low glucose

3. Allosteric modification – instantaneous

 In addition to the enzymes that speeds up a reaction, other substances called allosteric
activators further increase the rate of reaction. Acetyl coA is one such allosteric
activator.

Acetyl coA in Gluconeogenesis:

In starvation, there is excessive breakdown of fatty acids resulting in formation of Acetyl coA
in liver. They ensure the conversion of pyruvate to oxaloacetic acid. It acts as allosteric
activator of the enzyme pyruvate carboxylase and inhibits pyruvate dehydrogenase of
Glycolysis. [1]It is inhibited by ADP and glucose. Thus Acetyl coA is sufficient to divert
pyruvate into Gluconeogenesis from citric acid cycle.

Important Hormones of Gluconeogenesis

The important hormones that regulate the blood sugar level and thus Gluconeogenesis are
glucagon, insulin and glucocorticoids. The hormones which stimulate Gluconeogenesis and
other mechanisms which increase the blood glucose level are called diabetogenic hormones.

Gluconeogenesis and Glucagon:

Glucagon is synthesized by alpha cells of pancreas. They stimulate the Gluconeogenesis by

3 mechanisms. They are

1. When the glucose level is high, the key enzyme of Gluconeogenesis – fructose 1, 6
bisphosphatase is kept under check by its fructose 2, 6 bisphosphate. During fasting,
glucagon inhibits the enzyme catalyzing the synthesis of fructose 2, 6 bisphosphate.
This removes the inhibition on the key enzyme of Gluconeogenesis and stimulates it.
Thus it acts as a counter hormone to insulin.
2. It causes conversion of pyruvate kinase to its inactive form by phosphorylation thus
inhibiting Glycolysis and favoring Gluconeogenesis.
3. It increases the transcription of Phosphoenolpyruvate carboxykinase gene there by
increasing the availability of the enzyme.

Gluconeogenesis and Glucocorticoids

Glucocorticoids are synthesized in the kidney under stressful condition like starvation and
intense exercise. Thus cortisol is stimulated by low blood sugar and increased demand. They
increase Gluconeogenesis by increasing the breakdown of Glucogenic amino acid. They
increase Gluconeogenesis in kidney more than liver through a series of complicated
biochemical steps.

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Gluconeogenesis and Insulin:

It is the anti diabetic hormone synthesized by beta cells of pancreas and its main function is
to lower the blood glucose level. Increased glucose level leads to increased production of
ATP, the energy currency of our cells. This ATP acts on potassium and calcium channel of
the beta cells of pancreas and leads to release of insulin. Insulin inhibits Gluconeogenesis and
causes glucose uptake by cells. Epinephrine inhibits insulin while glucagon stimulates
insulin. [1] It reduces both hepatic and renal Gluconeogenesis to equal extent.

Organs of Gluconeogenesis
The major tissues capable of synthesizing glucose are liver and kidney. Only they have the
sufficient gluconeogenic enzyme activity and glucose 6 phosphatase activity to release
glucose into circulation . It occurs in small intestine to a small extent in fasting state.

Hepatic Gluconeogenesis – Gluconeogenesis in liver

Liver is the major site of Gluconeogenesis. [2, 3] During first 12 hrs of fasting, the glycogen
reserve gets depleted dramatically and Gluconeogenesis increases by its regulatory
mechanism as said above. Liver primarily uses lactate, alanine [10] and glycerol. Lactate gets
converted to pyruvate by Cori cycle and then undergoes Gluconeogenesis in liver. Alanine
gets converted to glucose by Glucose – Alanine cycle. Also acetyl coA is predominantly
produced in liver which further increases Gluconeogenesis . Hepatic Gluconeogenesis
decreases in condition causing acidosis.

Alcohol – Gluconeogenesis

Alcoholics have impaired Gluconeogenesis and are more prone to low blood sugar because
the metabolism of alcohol by alcohol dehydrogenase and aldehyde dehydrogenase, forms
chemical molecules which results in the diversion of the substrates of Gluconeogenesis to
other pathways to lipid accumulation. This results in the fatty liver in the alcoholics and more
chances for hypoglycemic episodes . Thus any disease condition damaging the liver will
affect Gluconeogenesis.

Renal Gluconeogenesis – Gluconeogenesis in kidney

Earlier it was thought that, liver is the major organ of Gluconeogenesis under normal
condition while kidney comes to play only when the body is in distress as in acidosis or
prolonged starvation. But this notion has been challenged by recent studies and is found that
kidney is as important as liver in post absorptive human state. Gluconeogenesis occurs in the
outer tissue of kidney called the cortex .

It mainly uses lactate, glutamine and glycerol. [10 Lactate dehydrogenase, glucose 6
phosphatase and fructose 1, 6 bisphosphatase makes it possible for Gluconeogenesis to occur
in kidney. [6] Renal Gluconeogenesis is greatly stimulated by glucocorticoids. This helps to
maintain the normal blood sugar in people with liver disease and contributes to excess
glucose in diabetes type 1 and 2. It is increased by acidosis in contrast to hepatic
Gluconeogenesis. It is suppressed by insulin as much as in the liver

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Gluconeogenesis Vs Glycogenolysis
Gluconeogenesis Glycogenolysis
Substrates are non carbohydrate substance like lactate and Substrate is glycogen which
amino acids is a complex carbohydrate
Occur in liver and kidney and a small extent in muscle. Occur in liver and muscles
There are 4 key enzymes – Pyruvate carboxylase, Phosphoenol
Key enzyme is glycogen
pyruvate carboxykinase, Fructose 1, 6 bisphosphatase and
phosphorylase
Glucose 6 phosphatase
Glucose 6 phosphate is the
Pyruvate is the first step
first step

Both Glycogenolysis and Gluconeogenesis results in the synthesis of glucose and the
hormone regulation for both the process is the same.