Last edited: 1/5/2022

REGULATION OF GLUCONEOGENESIS
Regulation of Gluconeogenesis: Cori Cycle & Glucose-Alanine Cycle Medical Editor: Jona Frondoso

OUTLINE

I) INTRODUCTION
II) REACTION STEPS OF GLYCOLYSIS
III) GLUCONEOGENESIS
IV) HORMONES REGULATING GLUCONEOGENSIS
V) APPENDIX
VI) REVIEW QUESTIONS

I) INTRODUCTION
Gluconeogenesis is the conversion of glucose from non-carbohydrate sources.
(2) Conversion of G1P to G6P
(1) Conversion of muscle glycogen to G1P
Glucose-1-phospate → Glucose-6-phosphate (G6P)
Glycogeni → Glucose-1-phospate (G1P) (Figure 1) (Figure 1)
Catalyzed by muscle glycogen phosphorylase (MGP) Catalyzed by phosphoglucomutase (PGM)

Figure 1. Formation of glucose-6-phosphate from glycogen.

Remember:
Why Cori cycle and Glucose-Alanine cycle are
important?
G6P can’t get out of the muscle cell
Muscle do not have glucose-6-phosphatase
o Found in the smooth endoplasmic reticulum
o Removes the phosphate from G6P to convert it to
glucose
o Glucose can get out of the cell
Glucose is disguised in a different form so that it can be
taken out of the cell via
o Cori cycle
o Glucose-alanine cycle

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 II) CORI CYCLE
Flow of lactate and glucose between the muscles and the liver
Occurs when anaerobic conditions occur in active muscle and glycolysis produces lactate [Nelson & Cox, 2017]
Operates during gluconeogenesis
o When lactate moves through the blood to the liver, where it is oxidized back to pyruvate
o Converts pyruvate to glucose,
Glucose is carried back to the muscle

Figure 3. Reactions of Cori cycle in the liver.

(3) Conversion of lactic acid to pyruvate

Lactic acid → pyruvate (Figure 3)
Catalyzed by liver lactate dehydrogenase
Figure 2. Reactions of Cori cycle in the muscle.
o Takes NAD+ reducing it into NADH

(1) Conversion of G6P to pyruvate

(4) Conversion of pyruvate to G6P
Glucose-6-phosphate → → →Pyruvate (Figure 2)
Pyruvate → glucose-6-phosphate (Figure 3)
o Via the glycolytic pathway
Net ATP formed = 2 ATP
(5) Conversion of G6P to glucose

(2) Conversion of pyruvate to lactic acid G6P enters the smooth endoplasmic reticulum (SER)
via T1 transporters (Figure 3)
Pyruvate → lactic acid (Figure 2) Glucose-6-phosphatase
Catalyzed by muscle lactate dehydrogenase o Found in the SER of the liver, kidney, and GIT tissues
o Unloading NADH to pyruvate forming NAD+ specifically the duodenum
o Reversible enzyme o Removes a phosphate from G6P forming glucose
Lactic acid exits the muscle cell Glucose exits the SER via T2 transporters
Liver – takes up the lactic acid Glucose exits the liver to the blood via GLUT 2
transporters
(6) Conversion of glucose to G6P
Free glucose in the blood enters the muscle cell
Glucose → glucose-6-phosphate
o Catalyzed by hexokinase

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 III) GLUCOSE-ALANINE CYCLE
Also known as Cahill cycle [Nelson & Cox, 2017]
Involves muscle protein being degraded to prove more glucose to generate additional ATP for muscle contraction.
Allows pyruvate and glutamate to be transported out of muscle tissue to the liver where gluconeogenesis takes place to supply
the muscle with more glucose [Nelson & Cox, 2017]
Alanine can come from glycolysis or amino acid metabolism [Nelson & Cox, 2017]

Figure 5. Regeneration of pyruvate in the liver via the Glucose-

Alanine cycle in the liver.

(3) Regeneration of pyruvate

Alanine exits the muscle cell, goes to the blood, and enters
the liver cell
Alanine + α-ketoglutarate → Pyruvate + glutamate (Figure
Figure 4. Reactions of Glucose-Alanine cycle in the muscle.
5)
o Alanine transfers its amine group to α-ketoglutarate
(1) Conversion of G6P to pyruvate  α-ketoglutarate → glutamate
o α-ketoglutarate transfers its oxygen from alanine
Glucose-6-phosphate → → →Pyruvate (Figure 4)  Alanine → pyruvate
o Via the glycolytic pathway
Net ATP formed = 2 ATP
(4) Oxidative deamination of glutamate

(2) Conversion of pyruvate to alanine Glutamate → NH3 + α-ketoglutarate (Figure 5)

Pyruvate + glutamate → alanine + α-ketoglutarate (Figure

4) o Forms α-ketoglutarate
o Glutamate transfers its amine group to pyruvate
 Glutamate → α-ketoglutarate NH3 will enter the urea cycle
o Pyruvate gains the amine group from glutamate (5) Conversion of pyruvate to G6P
 Pyruvate → alanine
Pyruvate → glucose-6-phosphate (Figure 5)

(6) Conversion of G6P to glucose

G6P enters the smooth endoplasmic reticulum (SER)
via T1 transporters
Figure 6)
o Catalyzed by glucose-6-phosphatase
Glucose exits the SER via T2 transporters
Glucose exits the liver to the blood via GLUT 2
transporters

(7) Conversion of glucose to G6P

Free glucose in the blood enters the muscle cell
Glucose → glucose-6-phosphate (Figure 6)
Figure 6. Conversion of pyruvate to glucose in the liver via the o Catalyzed by hexokinase
Glucose-Alanine cycle.

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 IV) REGULATION OF ENZYMES
Three enzymes specific to gluconeogenesis are being (D) PYRUVATE CARBOXYLASE
regulated
Catalyzes the irreversible conversion of pyruvate to
Phosphoenolypyruvate carboxykinase (PEPCK) oxaloacetate (OAA)
Pyruvate carboxylase (1) Allosteric activators
Fructose-1,6-bisphosphatase
Acetyl CoA
These enzymes are regulated in two ways
↑ Acetyl CoA = ↑ Krebs cycle activity → ↓ need to
Gene activation breakdown glucose → ↑ synthesis of glucose (Figure 7)
Allosteric regulation Via gene regulation by cortisol and glucagon
(B) REGULATION BY GENE ACTIVATION (Figure 7)
(1) Cortisol (2) Allosteric inhibitors
Steroid hormone Adenosine diphosphate (ADP)
Primary regulator of the synthesis of PEPCK, pyruvate
carboxylase, and fructose-1,6-bisphosphate (Figure 7) ↑ ADP = ↓ energy signals → ↑ glucose breakdown
Triggers: → ↑ ATP (Figure 7)
o ↓ blood glucose (hypoglycemia)
(E) FRUCTOSE-1,6-BISPHOSPHATASE
o Chronic stress
o Fever Via gene regulation by cortisol and glucagon
↓ blood glucose → ↑ Cortisol = (+) PEPCK, pyruvate (Figure 7)
carboxylase, and fructose-1,6-bisphosphatase
Must Know:
Regulation of F-2,6BPase by Glucagon
Phoaphofructokinase-2 / Fructose-2,6-bisphosphatase
o PFK-2 / F-2,6BPase (Figure 8)
o Binuclear enzyme

PFK-2
Converts fructose-6-phosphate to fructose-2,6-
bisphosphate
F-2,6BP
o Strongest stimulator of phosphofructokinase-1
(PFK-1)
o ↑ F-2,6BP → (+) PFK-1 → ↑ glycolysis

Protein kinase A (PKA)
Figure 7. Regulation of PEPCK, pyruvate carboxylase, and
fructose-2,6-bisphosphatase.
(2) Glucagon
Hormone secreted by the alpha cells of the pancreas
↓ blood glucose → ↑ Cortisol = (+) PEPCK, pyruvate
carboxylase, and fructose-1,6-bisphosphatase (Figure 7)
Mainly stimulates the synthesis of PEPCK
Fructose-2,6-bisphosphate (F-2,6BP)
o Powerful inhibitor of fructose-1,6-bisphosphatase
Fructose-2,6-bisphosphatase
Rips of the phosphate from F-2,6-BP
Converts it back into fructose-6-phosphate
o Activated by glucagon, epinephrine, and norepinephrine
(Figure 8)
o (+) PKA → phosphorylates PFK-2 / F-2,6BPase
 Phosphorylated PFK-2 = inhibited
 Phosphorylated F-2,6-BPase = stimulated → (+)
conversion of F-2,6BP to F6P → ↓ F-2,6BP
concentration → ↓ PFK-1 stimulation & (+) F-
1,6BPase

(C) PHOSPHOENOLPYRUVATE CARBOXYKINASE

Also known as PEPCK
Catalyzes the conversion of OAA to PEP
Regulated based upon synthesis
(1) Activators

Via gene regulation by cortisol and glucagon

(Figure 7)
(2) Allosteric inhibitors

Adenosine diphosphate (ADP)

↑ ADP = ↓ energy signals → ↑ glucose breakdown
→ ↑ ATP (Figure 7)

Figure 8. Regulation of Fructose-2,6-bisphosphatase by glucagon.

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 V) APPENDIX

Figure 9. Overview of the regulation of gluconeogenesis.

VI) REVIEW QUESTIONS VII) REFERENCES

1) Why are Cori cycle and glucose-alanine cycle
important? Nelson, D., & Cox, M. (2017). Lehninger Principles of
a) Because glucose-6-phosphate can’t get through the Biochemistry (7th ed.). New York: W.H Freeman and Company.
cell
b) Because muscle doesn’t have glucose-6-
phosphatase
c) To convert G6P to glucose
d) All of the choices are correct.
2) Which of the following statements about the Cori
cycle is correct?
a) Pyruvate is converted to lactate by lactate
decarboxylase
b) Lactate can’t get through out of the cell
c) Glucose-1-phosphate is converted to glucose by
glucose-1-phosphatase
d) Occurs when anaerobic conditions occur in active
muscle and glycolysis produces lactate
3) Which of the following statements about the
glucose-alanine cycle is correct?
a) Pyruvate reacts with α-ketoglutarate to form alanine
and glutamate
b) It is also known as the Cahill cycle.
c) Glutamate, in the liver, is broken down to directly
form α-ketoglutarate and urea
d) Glutamine exits the muscle and enters the liver.
4) Which of the following will promote
gluconeogenesis?
a) Chronic stress
b) Acetyl CoA
c) Hypoglycemia
d) All of the choices are correct
5) Which of the following will inhibit gluconeogenesis?
a) Fever
b) Glucagon
c) ↑ ADP
d) Epinephrine

CHECK YOUR ANSWERS

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