Gluconeogenesis: How Your Body Creates Glucose from Protein

Gluconeogenesis (GNG) is the metabolic pathway synthesizing glucose from non-carbohydrate precursors—primarily amino acids (from protein), lactate, and glycerol. It occurs mainly in the liver (90%) and kidneys (10%).

Step-by-Step Pathway

1. Proteolysis: Muscle protein breakdown → amino acids released into blood (stimulated by cortisol, glucagon, low insulin).
2. Deamination: Amino groups removed (transamination/deamination) → ammonia (→ urea) + α-keto acids.
3. Carbon skeleton entry: Keto acids convert to pyruvate, oxaloacetate, or TCA intermediates.
   • Alanine → pyruvate (major gluconeogenic amino acid)
   • Glutamine → α-ketoglutarate → oxaloacetate
4. Gluconeogenesis proper (11 reactions):
   • Pyruvate → oxaloacetate (pyruvate carboxylase, biotin-dependent)
   • Oxaloacetate → PEP (PEPCK, GTP)
   • PEP → ... → fructose-1,6-bisphosphate → fructose-6-phosphate → glucose-6-phosphate → glucose
   • Key bypasses: pyruvate carboxylase/PEPCK, fructose-1,6-bisphosphatase, glucose-6-phosphatase (liver/kidney only).
5. Glucose release: Hepatic glucose-6-phosphatase frees glucose into blood; kidney releases directly into renal vein.

Regulation

• Hormonal: Glucagon/cortisol ↑ GNG; insulin ↓ GNG.
• Substrate availability: Amino acids, lactate, glycerol.
• Energy status: High ATP/acetyl-CoA favors GNG.

Physiological Role

• Maintains blood glucose during fasting, starvation, low-carb diets, intense exercise.
• Prevents hypoglycemia; spares glucose for brain (obligate glucose user).
• Excessive GNG → muscle wasting (cachexia, uncontrolled diabetes).

GNG is a survival mechanism; chronic activation has metabolic costs.