Gluconeogenesis

Dr Hanaa Hajeer
 Objectives

• Know the sources of glucose in the body.

• Explain gluconeogenesis.
• Understand the regulation of gluconeogenesis.
• Compare gluconeogenesis to glycolysis.
• Know the precursors of gluconeogenesis and energy
source.
• Understand Cori cycle and glucose alanine cycle

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 Glucose Homeostasis

• Brain, RBCs, kidney medulla, lens, cornea, testes, exercising muscle

require continuous supply of glucose.
• The liver maintains glucose levels in blood during fasting through
either glycogenolysis or gluconeogenesis.
• These pathways are promoted by glucagon and inhibited by insulin.
• Liver glycogen can supply for 10-18 hrs of fasting.
• In fasting, glycogen reserves drop dramatically in the first 12 hours,
during which time gluconeogenesis increases.
• After 24-48 hours of fasting, gluconeogenesis represents the only
source of glucose.
• During an overnight fast, gluconeogenesis occurs 90% in liver and 10%
in kidneys.
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Sources of Glucose And Its Consumption
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Glucose - Alanine Cycle

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 Opposing Pathways of Glycolysis and
Gluconeogenesis

• Gluconeogenesis does not occur by

simple reversal of glycolysis.
• Seven glycolytic reactions are
reversible and are used in the
synthesis of glucose from lactate or
pyruvate.
• Three glycolytic reactions are
irreversible
• These steps must be bypassed in
Gluconeogenesis.
 Opposing Pathways of Glycolysis and
Gluconeogenesis

Glycolysis Gluconeogenesis

Pyruvate carboxylase
Pyruvate kinase PEP-CK
Fructose 1,6 bisphosphatase
PFK-1
Glucokinase/Hexokinase Glucose 6-phosphatase
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 Source of ATP for Gluconeogenesis

• Gluconeogenesis requires ATP that is provided by β-oxidation (break

down) of fatty acids.
• Hepatic gluconeogenesis is always dependent on β-oxidation of fatty
acids in the liver.
• During hypoglycemia, adipose tissue releases these fatty acids by
breaking down triglycerides.
• β-oxidation generates acetyl-coA which activates pyruvate
carboxylase.

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Coordinate Regulation of Pyruvate Carboxylase
And Pyruvate Dehydrogenase By Acetyl-CoA

• Acetyl CoA diverts pyruvate away

from oxidation in Krebs cycle and
toward gluconeogenesis
• High Acetyl coA will stimulate
the enzyme pyruvate
carboxylase to make more
oxaloacetate
• High level of Acetyl-co A inhibits
PDH complex (PDH converts
pyruvate to Acetyl coA)
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 Reverse of Glycolysis
• Then, PEP is acted on by the reactions of glycolysis running in the
reverse direction until it becomes fructose 1,6-bisphosphate.

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• Levels rise with high insulin (fed state)
Remember: Fructose 2,6 Bisphosphate

• Levels fall with high glucagon (fasting state)

• Drives glycolysis versus gluconeogenesis

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Gluconeogenesis
Glucagon is the main
regulator of gluconeogenesis.
It acts by repressing (- )
pyruvate kinase, thus
increasing the availability of
PEP for gluconeogenesis.
Glucagon also increases the
expression ( + ) of PEP
carboxykinase.
Glucose Glucose-6-P
Fructose-6-P
- + F-2,6-BP - Glucagon
Fructose-1,6-bis-P
Glyceraldehyde-3-P Dihydroxyacetone-P
1,3-Bisphosphoglycerate
3-Phosphoglycerate
Finally, glucagon represses
2-Phosphoglycerate the formation of F-2,6-BP,
which is a repressor of
Phosphoenolpyruvate
Fructose-1,6-bisphosphatase
+ - Glucagon
in gluconeogenesis (while it is
Lactate Pyruvate
an activator of PFK-1 in
CO2 glycolysis).
ATP
GTP
Oxaloacetate
 Other Hormones

• Epinephrine
– Raises blood glucose
– Activates gluconeogenesis and glycogen breakdown
• Cortisol
– Activates gluconeogenesis
– Hyperglycemia common side effect steroid drugs
– Patients treated with steroids (prednisone) can develop
steroid-induced diabetes
• Thyroid hormone
– Activates gluconeogenesis

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 Clinical Correlation

• Metformin is a
medication for type 2
diabetes.
• It is an inhibitor of
gluconeogenesis.