Gluconeogenesis

Gluconeogenesis is the synthesis of glucose from nonsugar precursors, such as

lactate, pyruvate, and the carbon skeleton of glucogenic amino acids.

From: Encyclopedia of Endocrine Diseases (Second Edition), 2018

Related terms:

Glycogenolysis, Glucose, Fatty Acids, Amino Acids, Hypoglycemia, Enzymes, Glyco-

gen, Glucagon, Insulin, Protein

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Gluconeogenesis
Larry R. Engelking, in Textbook of Veterinary Physiological Chemistry (Third Edi-
tion), 2015

Abstract:
Gluconeogenesis occurs in the liver and kidneys. 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. PEP carboxykinase catalyzes the rate-limiting reaction in gluconeogenesis.
The dicarboxylic acid shuttle moves hydrocarbons from pyruvate to PEP in glu-
coneogenesis. Gluconeogenesis is a continual process in carnivores and ruminant
animals, therefore they have little need to store glycogen in their liver cells. Of the
amino acids transported to liver from muscle during exercise and starvation, Ala
predominates. b-Aminoisobutyrate, generated from pyrimidine degradation, is a
(minor) gluconeogenic substrate.

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Carbohydrate Metabolism II
N.V. Bhagavan, Chung-Eun Ha, in Essentials of Medical Biochemistry, 2011

Publisher Summary
Gluconeogenesis refers to synthesis of new glucose from noncarbohydrate pre-
cursors, provides glucose when dietary intake is insufficient or absent. It also
is essential in the regulation of acid-base balance, amino acid metabolism, and
synthesis of carbohydrate derived structural components. Gluconeogenesis occurs
in liver and kidneys. The precursors of gluconeogenesis are lactate, glycerol, amino
acids, and with propionate making a minor contribution. The gluconeogenesis
pathway consumes ATP, which is derived primarily from the oxidation of fatty
acids. The pathway uses several enzymes of the glycolysis with the exception of
enzymes of the irreversible steps namely pyruvate kinase, 6-phosphofructokinase,
and hexokinase. The irreversible reactions of glycolysis are bypassed by four alternate
unique reactions of gluconeogenisis. The four unique reactions of gluconeogenesis
are pyruvate carboxylase, located in the mitochondrial matrix, phosphoenolpyru-
ate (PEP) carboxykinase located in mitochondrial matrix and cytosol, fructose-1,
6-bisphosphatase located in the cytosol and glucose-6-phosphatase located in the
endoplasmic reticulum (ER).

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Molecular Biology of Parathyroid Hor-

mone
Jean-Pierre Vilardaga, Peter A. Friedman, in Textbook of Nephro-Endocrinology
(Second Edition), 2018

4.4.2 Ammoniagenesis
Gluconeogenesis is linked to ammoniagenesis because both are stimulated by
acidosis and by PTH. Moreover, l-glutamine, which is the major gluconeogenic
precursor, is also a substrate for ammoniagenesis. These and other observations
raised the possibility that gluconeogenesis and ammoniagenesis are metabolically
and functionally linked. This may be the case in acidosis but not under nonacidotic
conditions, where inhibition of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase (PEPCK) failed to blunt ammoniagenesis. Hence, the two processes
appear to proceed through independent metabolic mechanisms under physiological
conditions but may involve convergent pathways in acidosis.

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Molecular Biology of Parathyroid Hor-

mone
Peter A. Friedman, in Textbook of Nephro-Endocrinology, 2009

8.5.4.2 Ammoniagenesis
Gluconeogenesis is linked to ammoniagenesis because both are stimulated by
acidosis and by PTH. Moreover, L-glutamine, which is the major gluconeogenic
precursor is also a substrate for ammoniagenesis. These and other observations
raised the possibility that gluconeogenesis and ammoniagenesis are metabolically
and functionally linked. This may be the case in acidosis but not under non-acidotic
conditions, where inhibition of the gluconeogenic enzyme phosphoenolpyruvate
carboxykinase (PEPCK) failed to blunt ammoniagenesis. Hence, the two processes
appear to proceed through independent metabolic mechanisms under physiological
conditions but may involve convergent pathways in acidosis.

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Neonatal Physiology and Metabolic

Considerations
Agostino Pierro, ... Simon Eaton, in Pediatric Surgery (Seventh Edition), 2012

Gluconeogenesis in the Neonate

Key enzymes of gluconeogenesis are present in the fetus from early in gestation and
increase throughout gestation and during the neonatal period. However in vivo fetal
gluconeogenesis has not been demonstrated and it is not known whether cytosolic
phosphoenolpyruvate carboxykinase (necessary for gluconeogenesis from amino
acids or lactate) or glucose-6-phosphatase (necessary for gluconeogenesis from all
substrates and for glucose export after glycogenolysis) is expressed adequately to
support gluconeogenesis by fetal liver. Glucose-6-phosphatase expression is low in
the fetus but increases in activity within a few days of birth in term neonates.84
Studies measuring gluconeogenesis from glycerol in preterm infants have sug-
gested that some gluconeogenesis from glycerol can occur85 but can only partly
compensate a decrease in exogenous glucose supply in preterm infants, probably
because of limitation at the level of glucose-6-phosphatase.86 Parenteral glycerol87
supports enhanced rates of gluconeogenesis in preterm infants, whereas no increase
in gluconeogenesis was observed by provision of mixed amino acids88 or alanine89
to preterm neonates, supporting the hypothesis that gluconeogenesis from amino
acids or lactate is limited by lack of phosphoenolpyruvate carboxykinase activity in
preterm infants. Parenteral lipids stimulate gluconeogenesis in preterm infants,88
probably by providing both carbon substrate (glycerol) and fatty acids. Fatty acid
oxidation is indispensable for gluconeogenesis; although fatty acid carbon cannot be
used for glucose, fat oxidation provides both an energy source (ATP) to support glu-
coneogenesis and acetyl coenzyme A (acetyl-CoA) to activate pyruvate carboxylase. In
experimental animals the increase in the glucagon/insulin ratio at birth stimulates
maturation of the enzymes of gluconeogenesis, particularly phosphoenolpyruvate
carboxykinase, although little is known about the induction of gluconeogenesis in
human neonates. Gluconeogenesis is evident within 4 to 6 hours after birth in term
neonates.90,91

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Gluconeogenesis and Glycogen Metab-

olism
John W. Pelley, in Elsevier's Integrated Review Biochemistry (Second Edition), 2012

Gluconeogenesis—Oxaloacetate to Glucose
Gluconeogenesis is an anabolic pathway that synthesizes glucose from nonglucose
precursors (lactate, amino acids, and glycerol). Since the nonglucose precursors
must be mobilized and transported to the liver, this source of glucose does not have
the rapid response found with glycogen mobilization (covered later in more detail).

The gluconeogenic pathway is not a simple reversal of glycolysis (Fig. 8-1). There are
three steps in glycolysis that are energetically irreversible: hexokinase, phosphofruc-
tokinase (PFK), and pyruvate kinase. The gluconeogenic pathway is thus a mixture
of six enzymes that are needed to bypass these three irreversible steps, plus the
remainder of the glycolytic steps, which are reversible.
Figure 8-1. The gluconeogenic pathway. Pi, inorganic phosphate; F6P, fructose
6-phosphate; NADH, nicotine adenine dinucleotide; PEP, phosphoenolpyruvate;
GDP, guanosine diphosphate; BPG, bisphosphoglycerate; PG, phosphoglycerate. See
text for expansion of other abbreviations.

Bypass for Pyruvate Kinase (Phosphoenolpyruvate → Pyruvate)

Pyruvate carboxylase

Carboxylation of pyruvate produces oxaloacetate (OAA). This is an energy-requiring

reaction that uses adenosine triphosphate (ATP).

Malate dehydrogenase (mitochondrial)

Reduction of OAA produces malate, which can be transported out of the mitochon-
drion. This step simultaneously transports carbon skeletons and reduces equivalents
to the cytoplasm for gluconeogenesis.
Malate dehydrogenase (cytoplasmic)

Oxidation of malate in the cytoplasm regenerates OAA and nicotine adenine dinu-
cleotide. The latter is needed at reaction step 8 (glyceraldehyde-3-phosphate dehy-
drogenase; see later discussion).

Phosphoenolpyruvate carboxykinase

Decarboxylation of OAA to produce phosphoenolpyruvate is accompanied by phos-

phorylation using guanosine triphosphate (GTP) instead of ATP.

Key Points About Gluconeogenesis

▪Gluconeogenesis is not a simple reversal of glycolysis; three irreversible glycolytic

steps must be bypassed.▪The gluconeogenic pathway begins in the mitochondrion
and ends in the cytoplasm; it consumes 6 ATP per glucose.▪Gluconeogenesis is
regulated at the pyruvate carboxylase step, where acetyl-CoA from fatty acid oxi-
dation serves as an allosteric activator; glycolysis is reciprocally regulated to avoid
futile cycles.▪The carbon skeletons come from amino acids, lactate, and glycerol,
and never from acetyl-CoA.

Bypass for Phosphofructokinase (F1,6-BP → F6P)

Fructose 1,6-bisphosphatase

Dephosphorylation of fructose 1,6-bisphosphonate (F1,6-BP) produces fructose

6-phosphate and inorganic phosphate.

Bypass for Hexokinase (G6P → Glucose)

Glucose-6-phosphatase

Dephosphorylation of glucose 6-phosphate (G6P) produces free glucose that can be

released into the bloodstream.

> Read full chapter

Gluconeogenesis and Glycogen Metab-

olism
John W. Pelley PhD, in Elsevier's Integrated Biochemistry, 2007
Gluconeogenesis—Oxaloacetate to Glucose
Gluconeogenesis is an anabolic pathway that synthesizes glucose from nonglucose
precursors (lactate, amino acids, and glycerol). Since the nonglucose precursors
must be mobilized and transported to the liver, this source of glucose does not have
the rapid response found with glycogen mobilization (covered later in more detail).

The gluconeogenic pathway is not a simple reversal of glycolysis (Fig. 8-1). There are
three steps in glycolysis that are energetically irreversible: hexokinase, phosphofruc-
tokinase (PFK), and pyruvate kinase. The gluconeogenic pathway is thus a mixture
of six enzymes that are needed to bypass these three irreversible steps, plus the
remainder of the glycolytic steps, which are reversible.

Figure 8-1. The gluconeogenic pathway.

Bypass for Pyruvate Kinase (Phosphoenolpyruvate → Pyruvate)

Pyruvate carboxylase. Carboxylation of pyruvate produces oxaloacetate (OAA). This
is an energy-requiring reaction that uses ATP.
Malate dehydrogenase (mitochondrial). Reduction of OAA produces malate, which
can be transported out of the mitochondrion. This step simultaneously transports
carbon skeletons and reducing equivalents to the cytoplasm for gluconeogenesis.

KEY POINTS ABOUT GLUCONEOGENESIS

▪Gluconeogenesis is not a simple reversal of glycolysis; three irreversible glycolytic

steps must be bypassed.▪The gluconeogenic pathway begins in the mitochondrion
and ends in the cytoplasm; it consumes 6 ATP per glucose.▪Gluconeogenesis is reg-
ulated at the pyruvate carboxylase step, where acetyl-CoA from fatty acid oxidation
serves as an allosteric activator; glycolysis is reciprocally regulated to avoid futile
cycles.▪The carbon skeletons come from amino acids, lactate, and glycerol, and never
from acetyl-CoA.

Malate dehydrogenase (cytoplasmic). Oxidation of malate in the cytoplasm regen-

erates OAA and nicotinamide adenine dinucleotide (NADH). The latter is needed at
reaction step 8 (glyceraldehyde-3-phosphate dehydrogenase; see below).

Phosphoenolpyruvate carboxykinase (PEPCK). Decarboxylation of OAA to produce

PEP is accompanied by phosphorylation using guanosine triphosphate (GTP) instead
of ATP.

Bypass for PFK (F1,6-BP → F6P)

Fructose 1,6-bisphosphatase. Dephosphorylation of F1,6-BP produces fructose
6-phosphate (F6P) and inorganic phosphate.

Bypass for Hexokinase (G6P → Glucose)

Glucose-6-phosphatase (G6Pase). Dephosphorylation of glucose 6-phosphate
(G6P) produces free glucose that can be released into the bloodstream.

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Carbohydrate Metabolism II: Gluco-

neogenesis, Glycogen Synthesis and
Breakdown, and Alternative Pathways
N.V. BHAGAVAN, in Medical Biochemistry (Fourth Edition), 2002

Metabolic Role
Gluconeogenesis (literally, “formation of new sugar”) is the metabolic process by
which glucose is formed from noncarbohydrate sources, such as lactate, amino
acids, and glycerol. Gluconeogenesis provides glucose when dietary intake is insuf-
ficient to supply the requirements of the brain and nervous system, erythrocytes,
renal medulla, testes, and embryonic tissues, all of which use glucose as a major
source of fuel. Gluconeogenesis has three additional functions.

1 Control of acid-base balance. Production of lactate in excess of its clearance

causes metabolic acidosis, and resynthesis of glucose from lactate is a major

route of lactate disposal. Since glycolysis is almost totally anaerobic in erythro-

cytes, renal medulla, and some other tissues, even under normal conditions
lactate is continually released. Other tissues, particularly muscle during vigor-
ous exercise, can produce large amounts of lactate, which must be removed or
lactic acidosis will result (Chapter 21). The continuous conversion of lactate to
glucose in the liver and of glucose to lactate by anaerobic glycolysis, particularly
in muscle, forms a cyclical flow of carbon called the Cori cycle (Chapter 22).
Deamination of amino acids prior to gluconeogenesis in the kidney also
provides a supply of NH3 to neutralize acids excreted in the urine (Chapter
39).

2 Maintenance of amino acid balance. Metabolic pathways for the degradation

of most amino acids and for the synthesis of nonessential amino acids involve
some steps of the gluconeogenic pathway. Imbalances of most amino acids,
whether due to diet or to an altered metabolic state, are usually corrected in the
liver by degradation of the excess amino acids or by synthesis of the deficient
amino acids through gluconeogenic intermediates.
3 Provision of biosynthetic precursors. In the absence of adequate dietary
carbohydrate intake, gluconeogenesis supplies precursors for the synthesis of
glycoproteins, glycolipids, and structural carbohydrates.

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Carbohydrate Metabolism II
N.V. Bhagavan, Chung-Eun Ha, in Essentials of Medical Biochemistry (Second
Edition), 2015

Metabolic Role
Gluconeogenesis (literally, “formation of new sugar”) is the metabolic process by
which glucose is formed from noncarbohydrate sources, such as lactate, amino
acids, and glycerol. Gluconeogenesis provides glucose when dietary intake is insuf-
ficient to supply the requirements of the brain and nervous system, erythrocytes,
renal medulla, testes, and embryonic tissues, all of which use glucose as a major
source of fuel. Gluconeogenesis has three additional functions:

1. Control of acid–base balance. Production of lactate in excess of its clearance

causes metabolic acidosis, and resynthesis of glucose from lactate is a major
route of lactate disposal. Since glycolysis is almost totally anaerobic in erythro-
cytes, renal medulla, and some other tissues, even under normal conditions,
lactate is continually released. Other tissues, particularly muscle during vigor-
ous exercise, can produce large amounts of lactate, which must be removed;
otherwise, lactic acidosis will result (Chapter 19).The continuous conversion of
lactate to glucose in the liver, and of glucose to lactate by anaerobic glycolysis,
particularly in muscle, forms a cyclical flow of carbon called the Cori cycle.
Deamination of amino acids prior to gluconeogenesis in the kidney also
provides a supply of NH3 to neutralize acids excreted in the urine (Chapter
37).
2. Maintenance of amino acid balance. Metabolic pathways for the degradation of
most amino acids and for the synthesis of nonessential amino acids involve
some steps of the gluconeogenic pathway. Imbalances of most amino acids,
whether due to diet or to an altered metabolic state, are usually corrected in the
liver by degradation of the excess amino acids or by synthesis of the deficient
amino acids through gluconeogenic intermediates.
3. Provision of biosynthetic precursors. In the absence of adequate dietary car-
bohydrate intake, gluconeogenesis supplies precursors for the synthesis of
glycoproteins, glycolipids, and structural carbohydrates.

Gluconeogenesis from pyruvate is essentially the reverse of glycolysis, with the

exception of three nonequilibrium reactions (Figure 14.1). These reactions are
Figure 14.1. Pathway of gluconeogenesis from pyruvate to glucose. Only enzymes
required for gluconeogenesis are indicated; others are from glycolysis. The overall
reaction for the synthesis of one molecule of glucose from two molecules of pyru-
vate is 2 Pyruvate+4ATP4−+2GTP4−+2NADH+2H++6H2O→Glucose+2NAD++4ADP3−-
+2GDP3−+6Pi2−+4H+.

(14.1)

(14.2)

(14.3)

In gluconeogenesis, these reactions are bypassed by alternate steps also involving

changes in free energy and also physiologically irreversible reactions.

Conversion of pyruvate to phosphoenolpyruvate involves two enzymes and the

transport of substrates and reactants into and out of the mitochondrion. In gly-
colysis, conversion of phosphoenolpyruvate to pyruvate results in the formation
of one high-energy phosphate bond. In gluconeogenesis, two high-energy phos-
phate bonds are consumed (ATP→ADP+Pi; GTP→GDP+Pi) in reversing the reaction.
Gluconeogenesis begins when pyruvate, generated in the cytosol, is transported
into the mitochondrion—through the action of a specific carrier—and converted to
oxaloacetate:

Like many CO2-fixing enzymes, pyruvate carboxylase contains biotin bound through
the -NH2 of a lysyl residue (Chapter 16).

The second reaction is the conversion of oxaloacetate to phosphoenolpyruvate:

In this reaction, inosine triphosphate (ITP) can substitute for guanosine triphosphate
(GTP), and the CO2 lost is the one gained in the carboxylase reaction. The net result
of these reactions is

Pyruvate carboxylase is a mitochondrial enzyme in animal cells. In humans (and

guinea pigs), PEPCK occurs in both mitochondria and cytosol.

In humans, oxaloacetate must be transported out of the mitochondrion to supply

the cytosolic PEPCK. Because there is no mitochondrial carrier for oxaloacetate and
its diffusion across the mitochondrial membrane is slow, it is transported as malate
or aspartate (Figure 14.2). The malate shuttle carries oxaloacetate and reducing
equivalents, whereas the aspartate shuttle, which does not require a preliminary
reduction step, depends on the availability of glutamate and -ketoglutarate in
excess of tricarboxylic acid (TCA) cycle requirements. The proportion of oxaloacetate
carried by each shuttle probably depends on the redox state of the cytosol. If most
of the pyruvate is derived from lactate, the NADH/NAD+ ratio in the cytosol is
elevated. In this situation, there is no need to transport reducing equivalents out
of the mitochondria, and the aspartate shuttle predominates. However, if alanine is
the principal source of pyruvate, no cytosolic reduction occurs, and the glyceralde-
hyde-phosphate dehydrogenase reaction (which requires NADH) requires transport
of reducing equivalents via the malate shuttle. In species in which oxaloacetate is
converted in mitochondria to phosphoenolpyruvate (which is readily transported
to the cytosol, perhaps via its own carrier system), no transport of oxaloacetate or
reducing equivalents is required.
Figure 14.2. Shuttle pathways for transporting oxaloacetate from mitochondria into
the cytosol. The shuttles are named for the molecule that actually moves across
the mitochondrial membrane. 1 and 3=malate dehydrogenase; 2=malate translo-
case; 4 and 7=aspartate aminotransferase; 5=glutamate dehydrogenase; 6=aspartate
translocase.

Phosphoenolpyruvate is converted to fructose-1,6-bisphosphate by reversal of gly-

colysis in the cytosol via reactions that are at near-equilibrium and whose direction
is dictated by substrate concentration. Conversion of fructose-l,6-bisphosphate to
fructose-6-phosphate is a nonequilibrium step, catalyzed by fructose-l,6-bisphos-
phatase:

Fructose-6-phosphate is then converted to glucose-6-phosphate by reversal of an-

other near-equilibrium reaction of glycolysis. In the last reaction in gluconeogene-
sis, glucose-6-phosphate is converted to glucose by glucose-6-phosphatase:

Glucose-6-phosphatase is part of a multicomponent integral membrane protein

system that consists of six different proteins located in the endoplasmic reticulum
of liver, kidney, and intestine, but not of muscle or adipose tissue. Deficiency of any
one of these five proteins leads to glycogen storage disease (discussed later).

Thus, gluconeogenesis requires the participation of enzymes of the cytosol, mi-

tochondrion, and smooth endoplasmic reticulum, as well as of several transport
systems, and it may involve more than one tissue. The complete gluconeogenic
pathway, culminating in the release of glucose into the circulation, is present only
 in liver and kidney. Most tissues contain only some of the necessary enzymes.
These “partial pathways” are probably used in glycerogenesis and in replenishing
tricarboxylic acid (TCA) intermediates. Muscle can also convert lactate to glycogen,
but this probably takes place only in one type of muscle fiber and only when glycogen
stores are severely depleted and lactate concentrations are high, such as after heavy
exercise.

Under normal conditions, the liver provides 80% or more of the glucose produced
in the body. During prolonged starvation, however, this proportion decreases, while
that synthesized in the kidney increases to nearly half of the total, possibly in
response to a need for NH3 to neutralize the metabolic acids eliminated in the urine
in increased amounts (Chapter 20).

Gluconeogenesis is a costly metabolic process. Conversion of two molecules

of pyruvate to one of glucose consumes six high-energy phosphate bonds
(4ATP+2GTP→4ADP+2GDP+6Pi) and results in the oxidation of two NADH molecules
(Figure 14.1). In contrast, glycolytic metabolism of one molecule of glucose to two of
pyruvate produces two high-energy phosphate bonds (2ADP+2Pi→2ATP) and reduces
two molecules of NAD+. For gluconeogenesis to operate, the precursor supply and
the energy state of the tissue must be greatly increased. Using some gluconeogenic
precursors to provide energy (via glycolysis and the TCA cycle) and to convert the
remainder of the precursors to glucose would be inefficient, even under aerobic
conditions. Usually, the catabolic signals (catecholamines, cortisol, and increase in
glucagon/insulin ratio) that increase the supply of gluconeogenic precursors also
favor lipolysis, which provides fatty acids to supply the necessary ATP.

When amino acid carbons are the principal gluconeogenic precursors, the metabolic
and physiological debts are particularly large compared to those incurred when
lactate or glycerol is used. Amino acids are derived through breakdown of muscle
protein, which is accompanied by a loss of electrolytes and tissue water.

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