Gluconeogenesis
Gluconeogenesis is the synthesis of glucose from non-carbohydrate precursors. It occurs primarily in the liver (90%) and to a lesser extent in the kidney cortex (10%). It is essential during fasting, starvation, and prolonged exercise.
Precursors
- Lactate: From RBCs (anaerobic glycolysis), exercising muscle. Transported to liver — Cori cycle.
- Glycerol: From lipolysis of triglycerides in adipose tissue → DHAP via glycerol-3-phosphate.
- Glucogenic amino acids: All except Leucine and Lysine. Alanine is most important (Glucose-Alanine cycle with muscle).
- Propionate: From odd-chain fatty acids → Succinyl-CoA → OAA → glucose.
Bypassing Glycolysis Irreversible Steps
Glycolysis has 3 irreversible reactions (Hexokinase, PFK-1, Pyruvate Kinase). Gluconeogenesis must bypass these using specific enzymes:
- Bypass 1 (Pyruvate → PEP): Step 1: Pyruvate + CO₂ → OAA [Pyruvate Carboxylase — mitochondria, requires ATP + Biotin; activated by Acetyl-CoA]. Step 2: OAA → PEP + CO₂ [PEPCK — cytosol after malate shuttle; requires GTP (liver) or ATP (kidney)].
- Bypass 2 (Fructose-1,6-bisP → Fructose-6-P): Fructose-1,6-Bisphosphatase. Inhibited by AMP and Fructose-2,6-bisP (reciprocal to PFK-1 regulation).
- Bypass 3 (G6P → Glucose): Glucose-6-Phosphatase (in ER; present only in liver and kidney — explains why muscle CANNOT export glucose). Absent in muscle and brain.
Energetics
Gluconeogenesis is energy-expensive: requires 6 ATP equivalents per glucose synthesized (4 ATP + 2 GTP hydrolyzed, plus 2 NADH consumed). Energy comes from fatty acid oxidation (fasting state).
Regulation
- Glucagon: Major activator. Promotes gluconeogenesis by: ↑cAMP → PKA → phosphorylates PFK-2 (lowers F-2,6-bisP → removes PFK-1 activation) → relieves inhibition of F-1,6-bisphosphatase. Also induces PEPCK gene transcription.
- Cortisol: Induces transcription of gluconeogenic enzymes (PEPCK). Long-term stimulation.
- Insulin: Inhibits gluconeogenesis (opposes glucagon).
- Acetyl-CoA: Activates Pyruvate Carboxylase (anaplerosis) and inhibits PDC (redirects pyruvate into gluconeogenesis).
Cori Cycle & Alanine Cycle
Cori Cycle: Muscle (anaerobic glycolysis) → Lactate → Blood → Liver → Gluconeogenesis → Glucose → Blood → Muscle. Transfers lactate burden from muscle to liver. Net effect: converts 2 lactate → 1 glucose (costs 6 ATP in liver).
Glucose-Alanine Cycle: Muscle → Alanine (transamination of pyruvate) → Liver → Gluconeogenesis + Urea. Carries amino groups safely from muscle to liver.
Clinical
- Metformin (type 2 DM): Inhibits Complex I of ETC → ↑AMP/ATP → activates AMPK → inhibits gluconeogenesis (specifically PEPCK and G6Pase expression)
- Von Gierke's disease (GSD type I): G6Pase deficiency → cannot export glucose from liver → severe fasting hypoglycemia + hepatomegaly