This document discusses gluconeogenesis, which is the formation of glucose from non-carbohydrate precursors in the liver and kidneys. Gluconeogenesis is important for maintaining blood glucose levels during periods of fasting or low carbohydrate intake. It involves 10 enzymatic steps, with 7 reversing the reactions of glycolysis. The key substrates used for gluconeogenesis include lactate, glycerol, certain amino acids, and intermediates of the citric acid cycle. Gluconeogenesis is regulated by hormones like insulin and glucagon, as well as feedback inhibition based on energy levels and metabolite concentrations.

1. Gluconeogenesis
Kamal Singh Khadka and Manoj Sigdel

2. Gluco neo genesis
glucose
pyruvate
lactate
Sugar new make/create
Glycolysis
Gluconeogenesis

3. Gluconeogenesis
• Formation of glucose or glycogen from non-
carbohydrate precursors
• Occurs in all animals, plants, fungi and microbes
• Occurs largely in the liver ( about 1 kg /day) ; some
in renal cortex and in the epithelial cells that line
the inside of the small intestine
• Mainly a cytosolic pathway, but the first step occur
in mitochondria
• Of 10 enzymatic steps, 7 are reversals of glycolytic
reactions

4. Conditions when
Gluconeogenesis is especially Active
• Active primarily when a person is in the fasted
state:
– When dietary carbohydrates have been utilized
or stored as glycogen, and
– When the plasma concentration of glucose has
declined
• Also increases during prolonged physical exercise
• In the neonates-first few hours after delivery

5. Significance of Gluconeogenesis
1) Maintains blood glucose homeostasis in the lack of
carbohydrate in the diet
2) Ensures a continuous supply of glucose to the
tissues which require a continuous supply of
glucose such as brain, RBCs, lens, cornea of the eye
and kidney medulla
Human brain alone requires about 120 gm of
glucose per day, out of 160 gm needed by the entire
body

6. 3) Clears the products of the metabolism of
other tissues from the blood, e.g.
-Lactate, produced by muscle and RBCs
and
-Gylcerol produced by adipose tissue

7. Substrates for Gluconeogenesis
The substrate for gluconeogenesis are:
–Lactate
–Glycerol
–Glucogenic amino acids
–Propionate, and
–Intermediates of citric acid cycle

8. Substrates for Gluconeogenesis
1) Lactate
– RBC
– muscle
– utilize Cori Cycle for new glucose formation
(glucose 6-phosphatase and fructose 1,6 bisphosphatase are
absent in skeletal muscle)

9. Substrates for Gluconeogenesis
2) Glycerol
– derived from adipocyte lipolysis
– hepatic glycerol kinase
Glycerol kinase is present in liver, kidney and absent in adipose tissue

10. Substrates for Gluconeogenesis
3) Amino acids
Glucogenic amino acids (all except leucine and lysine)
results in the formation of pyruvate or the
intermediates of TCA Glucose
4) Propionate
Propionyl CoA
Methyl Malonyl CoA
Succynyl CoA Glucose

11. • Of 10 enzymatic steps, 7 are reversals of
glycolytic reactions
• 3 irreversible steps are bypassed by a separate
set of enzymes
Gluconeogenesis Pathway

12. Glycolysis
Gluconeogenesis

13. .
absent in muscle, brain and
adipose tissue
absent in smooth muscle
and heart muscle

14. Energetics of Gluconeogenesis
• Gluconeogenesis needs the input of energy
• 2 pyruvate mols required to synthesize one glucose mol
• Energy is required at the following steps:
Pyruvate carboxylase 1 ATP ( × 2) = 2 ATP
PEP carboxykinase 1 GTP ( × 2) = 2 ATP
Phosphoglycerate kinase 1 ATP ( × 2) = 2 ATP
Total = 6 ATP
• The net yield of ATPs in glycolysis = 2
• Thus extra requirement of ATPs for gluconeogenesis= 4
• Glyceraldehyde-3-phosphate dehydrogenase rxn also
consumes 2 NADH

16. Regulation of Gluconeogenesis
• Glycolysis & gluconeogenesis are reciprocally regulated
• Physiological conditions that activate one pathway
concurrently inactivate the other
• The major regulated steps of gluconeogenesis are the
reactions that are catalyzed by:
– Fructose 1,6-bisphosphatase,
– Pyruvate carboxylase, and
– Phosphoenolpyruvate carboxykinase
• Regulated by 3 major mechanisms:
– Allosteric Regulation:
– Hormonal Regulation
– Transcriptional regulation (Induction and Repression)

17. Regulation of Gluconeogenesis
Induced by high G/I ratio
Induced by high G/I ratio

18. Regulation of Gluconeogenesis
Insulin activates
Glucagon
epinephrine
inhibit
Induced by high G/I ratio
Insulin Inhibits
Glucagon
epinephrine
activate

19. Regulation of Gluconeogenesis
Stimulation
Low blood Glucose
Glucagon
ATP
Citrate
Acetyl Co A
Pyruvate
Lactate
Alanine
OAA
Inhibition
– High blood Glucose
– Insulin
– Low Energy Charge ( AMP, ADP)
– Fructose - 2,6 - BisPhosphate