Emerick

Gluconeogenesis – “When gluconeogenesis is activated, where do the substrates come

from?”
By : Natalie Emerick
NUTR633 – Written Report
Gluconeogenesis is the synthesis of glucose from non-carbohydrate sources.

This allows for the sustainability of blood glucose levels without ingesting carbohydrates.

This process occurs after liver glycogen is completely consumed to sustain blood

glucose levels, usually after about 10-12 hours without consuming a meal with

carbohydrates. It is also activated after all muscle glycogen is consumed during physical

activity, and there has not been a carbohydrate meal to replenish the glycogen.

Gluconeogenesis is the reversal of glycolysis; the pathways are very similar and use

some of the same enzymes, and similar enzymes. The pathway showed in Figure 1

display the similarities and key differences between glycolysis and gluconeogenesis.

We need glucose in our blood in order to sustain activity. Blood glucose is

especially important in terms of having a constant supply of glucose for our brains and

red blood cells. The brain needs about 100 grams of glucose each day (Edwards, 2017).

The human brain can also use ketone bodies as a source of energy, but this process is a

lot harder on the body, and can cause acidosis if used for too long. The brain prefers to

have a constant source of glucose; however, neurons are not good at storing glucose as

glycogen (Edwards, 2017). Gluconeogenesis allows for the brain to have glucose to

consume even in times without carbohydrates present in meal or in starvation. Also our

red blood cells exclusively use glucose as a source of energy. So gluconeogenesis is

important for our red blood cells to have adequate energy to do their jobs in the body.

Gluconeogenesis takes place in two organs within the body. The major site is in

the liver and to the lesser extent kidneys, which activate in times of starvation.
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Figure 1: This figure displays glycolysis and gluconeogenesis side by side. It shows how

similar the two pathways are the key differences between the two processes

(AVBERSEK-LUZNIK and nishanth, 2017).

These two organs are special, because they have a specific enzyme that allows them to

undergo gluconeogenesis. These two organs are the only organs with Glucose-6-

Phosphatase in them, this enzyme allow the removal of phosphate off of the enzyme

Glucose-6-Phosphate, thus allowing the glucose to be exported from the cell.

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There are several routes of regulation for gluconeogenesis. There are two

different types of regulation: acute and chronic. Acute controls are rapid, reversible and

usually allosteric. There are also chronic controls that are just the opposite of acute,

slow, permanent and mainly transcriptional. There are also hormones and enzymes that

activate and inhibit the process. One of the hormones is cortisol. Cortisol promotes

glucose production, allows glucose to be made available for the rest of the body in times

of heightened stress and prolonged starvation. Cortisol accomplishes this by

synthesizing the enzymes needed to go through the process of gluconeogenesis,

Phosphoenolpyruvate carboxykinase (PEPCK), Glucose-6-phosphatase (G6Pase) and

Pyruvate carboxylase (PC) (King, 2017). This is a case of chronic regulation; this

hormone will be activated several days into starvation mode. Another hormone that

activates gluconeogenesis is glucagon, but it is considered to be an acute regulator. The

alpha cells of the pancreas in response to low blood glucose levels release glucagon.

Glucagon activates gluconeogenesis in the liver, and will deactivate glycolysis, this is

displayed in figure 2, where glucagon inhibits Fructose 2,6 - Bisphosphate (F26BP)

(Berg, Tymoczko and Stryer, 2002). Glucagon inactivates (F26BP) and thus inactivates

Phosphofructokinase 1 (PFK1) this tells the liver that the blood glucose levels are low

(Berg, Tymoczko and Stryer, 2002). This tells the liver to begin use alternative energy

sources, like glycerol, amino acids or lactate. The F26BP is an allosteric regulator of

gluconeogenesis that reflects the cellular blood glucose levels for the liver

(Gluconeogenesis, 2007). The main hormonal inhibitor of gluconeogenesis is insulin,

which is an acute regulator. Insulin tells the muscle and fat that there is adequate energy

in the blood, and deactivates gluconeogenesis in the liver and kidneys. Insulin will

stimulate glycolysis to allow blood glucose clearing.

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Figure 2: This figure displays where two of the substrates (lactate and glycerol) enter

gluconeogenesis and also some of the key regulatory steps of the process (Chhabra,

2017).

There are several substrates used in gluconeogenesis to allow blood glucose

sustainability without any carbohydrates being consumed. The three major substrates

utilized are glycerol, lactate and amino acids, specifically alanine. Each substrate comes
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from a different source and undergoes different processing before entering

gluconeogenesis.

Muscles breakdown into its primary structure of amino acids, and these can to be

converted into glucose in the liver. This occurs during high exertion states after muscle

glycogen storage has been depleted. All amino acids except leucine and lysine can be

turned into TCA Cycle intermediates to be used as energy when energy needs are high

and there is not enough glucose to sustain energy. There are two types of amino acids,

one of them is called glucogenic, and will be broken down into oxaloacetate and then

into pyruvate, this pyruvate will then enter gluconeogenesis (King, 2017). The other type

of amino acids cannot undergo this process are ketogenic amino acids. The list of the

different glucogenic and ketogenic amino acids can be found in the Table 1. The

glucogenic amino acids all have different routes of catabolism to form glucose, but the

most important amino acid is alanine. Alanine supplies the muscle with glucose through

the glucose – alanine cycle.

The glucose – alanine cycle, is a process that indirectly removes nitrogen from

the muscle and replenishes its energy supply. This cycle oxidizes glucose to produce

pyruvate, which then undergoes a transamination to allow the amino acids to be

degraded for energy. The transamination of pyruvate creates alanine, which is

transported through the blood to the liver to be reconverted to pyruvate to synthesize

glucose. The amino group containing nitrogen is then excreted as urea (King, 2017).

Due to the excretion of nitrogen as urea, this cycle consumes the most energy of any

substrate. The urea excretion consumes 4 ATP molecules and alanine’s role in

gluconeogenesis consumes 7 ATP molecules, for a total of 11 ATP molecules consumed

(King, 2017).
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Table 1:

This table displays the different types of amino acids; glucogenic amino acids undergo

gluconeogenesis (Biology LibreTexts, 2017).

Glutamine is the amino acid that supplies a carbon molecule that the kidneys

utilize for gluconeogenesis. Glutamate is utilized by deamination into glutamine, and is

then converted into 2-oxoglutarate via glutamate dehydrogenase. 2-Oxoglurate is able to

enter the TCA cycle to be converted to malate. This malate is then transported out of the

mitochondria and is oxidized into oxaloacetate via cytoplasmic malate dehydrogenase.

The oxaloacetate can then be converted into Phosphoenolpyruvate (PEP) through the

action of phosphoenolpyruvate carboxylase that is in the cytosol (PEPCK-c). This PEP

can then undergo gluconeogenesis in the kidneys to provide fuel for itself (King, 2017)

There has been recent debate amount when the kidneys begin to undergo

gluconeogenesis. It has been recently hypothesized that the kidneys only begin to

undergo gluconeogenesis during acidotic conditions, especially if the person is diabetic,

and during a prolonged fasting period (Gerich et al., 2017).

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Another substrate used in gluconeogenesis is glycerol. Adipocyte triglyceride

breakdown release glycerol and free fatty acids. Even though the free fatty acids are not

directly turned into glucose like glycerol, they still help the process by regulating

Pyruvate Carboxylase (via acetyl-CoA). Fatty acids cannot be used in gluconeogenesis,

because its carbons cannot be harnessed for glucose. After the fatty acids undergo beta-

oxidation, and enter the TCA two carbon molecules are lost as carbon dioxide, thus

preventing the carbon backbone from becoming glucose (King, 2017). Lipolysis

increases the amount of glycerol available for gluconeogenesis. Before glycerol can be

utilized in gluconeogenesis, it must first be activated via phosphorylation into glycerol-3-

phosphate. It is then converted into Dihydroxyacetone phosphate (DHAP), which is then

combined with glyceraldehyde 3-phosphate (GA3P) via the enzyme Aldolase. This

process is displayed in Figure 2. This will then go in the reverse order of glycolysis in

order to synthesis glucose. Glycerol will net one ATP molecule; this will allow the body to

have some energy in fasting or starving periods without carbohydrate consumption

(King, 2017).

The last substrate that is used in gluconeogenesis is lactate, which is considered the

predominant substrate used for gluconeogenesis (King, 2017). Lactate is produced

during anaerobic glycolysis, which can be converted back into pyruvate through the

enzyme Lactate Dehydrogenase. This involves the Cori Cycle (displayed in figure 3),

which breaks down glucose to lactate in anaerobic environments in the muscle, to then

resynthesize the lactate into glucose in the liver. This reformed glucose will go to the

muscles to be used as energy. This cycle consumes six ATP molecules and produces

two ATP molecules, so this process consumes energy (Chhabra, 2017). It is an example

of an inefficient process and cannot be sustained for long periods of time due to the

consumption of energy in the form of ATP (King, 2017). However this is a very important
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Figure 3 displays the Cori Cycle, and the flow of substrates between the two key sites for

the process. It also shows where the ATP molecules are being consumed and produced

(Chhabra, 2017).

pathway to ensure that muscle has adequate glucose available even in anaerobic

metabolism.

Gluconeogenesis is an important process within the body. Without

gluconeogenesis the body would need a constant consumption of glucose in order to

sustain not only physical activity but also brain activity. Life without the controlled

mechanism of gluconeogenesis may be sustainable in our culture with the easy access

to carbohydrates, but this would be very difficult for those who are already living on a

low-calorie diet. Also looking at this process from an evolutionary standpoint, this

mechanism was very important to early humans. Early humans went through periods of
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fasting periods when food could not be found, especially in the cold winter months. This

mechanism was very important for early humans to allow survival. This process is so

important nowadays in terms of diabetes. Some people with diabetes can have

uncontrolled gluconeogenesis, causing high blood glucose levels and ketoacidosis. This

is due to the exhausted and overworked beta cells of the pancreas not being able to or

poorly releasing insulin. This mechanism is important to control in order to have

adequate blood glucose levels in order to sustain brain and physical activity. There has

also been much debate about utilizing gluconeogenesis and ketogenesis with low

carbohydrate diets in order to lose weight. However this still warrants research, and

should be considered for on an individual-to-individual basis.

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References –
AVBERSEK-LUZNIK, I. and nishanth, s. (2017). Gluconeogenesis: Why this is very
Important? (Simple Notes). [online] BiochemDen.com. Available at:
http://www.biochemden.com/gluconeogenesis/ [Accessed 16 Oct. 2017].
Berg, J., Tymoczko, J. and Stryer, L. (2002). Biochemistry. 5th ed. New York: W H
Freeman, pp.Section 16.4.
Biology LibreTexts. (2017). 7.7: Amino Acid Metabolism. [online] Available at:
https://bio.libretexts.org/TextMaps/Map%3A_Biochemistry_Free_and_Easy_(Ahe
rn)/07%3A_Metabolism_II/7.07%3A_Amino_Acid_Metabolism [Accessed 2 Oct.
2017].
Chhabra, N. (2017). Semester Examination (November 2012) Model Answers (Set-2)-
Gluconeogenesis. [online] Biochemistry for Medics - Lecture Notes. Available at:
http://www.namrata.co/semester-examination-november-2012-model-answers-
set-2-gluconeogenesis/ [Accessed 16 Oct. 2017].
Edwards, S. (2017). Sugar and the Brain | Department of Neurobiology. [online]
Neuro.hms.harvard.edu. Available at: http://neuro.hms.harvard.edu/harvard-
mahoney-neuroscience-institute/brain-newsletter/and-brain-series/sugar-and-
brain [Accessed 16 Oct. 2017].
Gerich, J., Meyer, C., Woerle, H. and Stumvoll, M. (2017). Renal Gluconeogenesis: Its
importance in human glucose homeostasis.
Gluconeogenesis. (2007).
King, M. (2017). Gluconeogenesis: Synthesis of New Glucose. [online]
Themedicalbiochemistrypage.org. Available at:
http://themedicalbiochemistrypage.org/gluconeogenesis.php [Accessed 17 Oct.
2017].