Gluconeogenesis

Definition

• Gluco: Glucose
• Neo: New
• Genesis: Formation
• Formation of new glucose from non-carbohydrate sources (amino acids, glycerol, lactic acid).

Location

• Organs with gluconeogenic capacity:
  • Liver
  • Kidneys (proximal convoluted tubules)

When does it occur?

• Low blood glucose levels (Hypoglycemia)
• The brain relies on glucose as its primary energy source.
• In situations of prolonged fasting or lack of carbohydrates, the brain can use ketone bodies, which can lead to ketoacidosis.

Processes involved

Transport and phosphorylation of glucose

1. Glucose entry into the cell
   • GLUT transporters (GLUT2 in the liver, GLUT3 in kidneys)
2. Phosphorylation of glucose
   • Glucose → Glucose-6-phosphate
   • Glucose-6-phosphate → Fructose-6-phosphate
   • ...
   • Phosphoenolpyruvate → Pyruvate

The inversion of glycolysis

• Gluconeogenesis is the reverse of glycolysis, but certain irreversible steps must be bypassed.

Key steps

• Conversion of lactate to pyruvate:
  • Lactate (from muscles) → Pyruvate
• Conversion of pyruvate to oxaloacetate:
  • Enzyme: Pyruvate carboxylase
  • Pyruvate (3C) → Oxaloacetate (4C), adding CO₂
• Conversion of oxaloacetate to malate:
  • Oxaloacetate → Malate (reversible)
• Malate exits the mitochondria:
  • Malate → Oxaloacetate
  • Enzyme: Phosphoenolpyruvate carboxykinase (PEP-CK)
• Irreversibility and specific enzymes:
  • Fructose 1,6-bisphosphate → Fructose-6-phosphate (Enzyme: Fructose 1,6-bisphosphatase)
  • Glucose-6-phosphate → Glucose (Enzyme: Glucose-6-phosphatase from the smooth endoplasmic reticulum)

Contributors to gluconeogenesis

• Triglycerides:
  • Glycerol (head of the triglyceride)
  • Lipolysis: Triglycerides → Fatty acids + Glycerol
  • Glycerol → Glycerol-3-phosphate → Dihydroxyacetone phosphate (DHAP)
• Amino acids:
  • Protein catabolism → Amino acids
  • Transamination with keto acids (e.g., α-ketoglutarate) → Modified amino acids → Pyruvate/Acetyl-CoA
  • Important example: Alanine → Pyruvate
• Odd-chain fatty acids:
  • Insignificant in comparison.

Hormones regulating gluconeogenesis

• Glucagon (alpha cells of the pancreas)
• Norepinephrine and Epinephrine (catecholamines)
• Cortisol
• Thyroid hormones
• Growth hormone (GH)

Summary

• What it is: Formation of glucose from non-carbohydrate sources.
• Where it occurs: Liver and kidneys.
• Why it occurs: Low blood glucose levels and importance of the brain.
• Hormones involved: Glucagon, Catecholamines, Cortisol, Thyroid hormones, GH.