Step by Step
What
What gluconeogenesis is
Gluconeogenesis (GNG) is the synthesis of glucose from non-carbohydrate precursors: lactate, amino acids (especially alanine and glutamine), glycerol, and propionate. It occurs primarily in the liver (90%) and kidney cortex (10%). It is the body's way of maintaining blood glucose during fasting, starvation, and intense exercise.
Memory trick: GNG = Glucose Not from Glucose. It's the reverse of glycolysis — mostly.
Byp
Bypassing the 3 irreversible steps of glycolysis
Glycolysis has 3 irreversible steps that GNG must bypass with special enzymes: (1) Pyruvate kinase → bypassed by pyruvate carboxylase (pyruvate → OAA) + PEPCK (OAA → PEP). (2) PFK-1 → bypassed by fructose-1,6-bisphosphatase (FBPase-1). (3) Hexokinase → bypassed by glucose-6-phosphatase (only in liver/kidney — explains why muscle can't do GNG).
Memory trick: PFK-1 blocked → FBPase-1. Hexokinase blocked → G6Pase. Pyruvate kinase blocked → PC + PEPCK.
Cost
Energy cost of GNG
GNG is energetically expensive: 6 ATP equivalents per glucose synthesized. It requires 2 pyruvate + 4 ATP + 2 GTP + 2 NADH. Compare to glycolysis which PRODUCES 2 ATP — GNG costs 3× more than glycolysis yields.
Reg
Regulation — reciprocal with glycolysis
GNG and glycolysis are reciprocally regulated: when one is active, the other is inhibited. Key regulator: fructose-2,6-bisphosphate (F-2,6-BP). High F-2,6-BP → activates PFK-1 (glycolysis) AND inhibits FBPase-1 (GNG). Glucagon (fasting) lowers F-2,6-BP → promotes GNG. Insulin (fed) raises F-2,6-BP → promotes glycolysis.
Applied Walkthrough
1
During overnight fasting: blood glucose falls, glucagon rises, insulin falls.
2
Glucagon activates PEPCK and other GNG enzymes in the liver. Lactate from muscle and alanine from protein breakdown arrive at the liver.
3
The liver converts lactate → pyruvate → OAA → PEP (bypassing pyruvate kinase), then reverses glycolysis steps, and uses G6Pase to release free glucose into blood.
4
Blood glucose is maintained at ~70-100 mg/dL even after 12+ hours of fasting — entirely due to hepatic gluconeogenesis.
Exam Application
Exams test the 3 bypass points and their enzymes (PC+PEPCK, FBPase-1, G6Pase), the substrates for GNG, why muscle cannot perform GNG (lacks G6Pase), the energy cost (6 ATP equivalents), and regulation by F-2,6-BP/glucagon/insulin. The Cori cycle (lactate from muscle → glucose in liver) is a classic exam question.
⚠ Common Trap
Students think GNG is simply the reverse of glycolysis — it isn't. Three steps are irreversible and require completely different bypass enzymes. Also: muscle CANNOT perform GNG because it lacks glucose-6-phosphatase. Muscle can make G6P but cannot convert it to free glucose for export to blood.
✓ Quick Self-Check
1. What are the main substrates for gluconeogenesis?
Lactate, amino acids (alanine, glutamine), glycerol, and propionate (from odd-chain fatty acids).
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2. Why can't muscle perform gluconeogenesis?
Muscle lacks glucose-6-phosphatase — it can make glucose-6-phosphate but cannot convert it to free glucose for export.
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3. What enzyme bypasses pyruvate kinase in gluconeogenesis?
Pyruvate carboxylase (pyruvate → OAA) + PEPCK (OAA → PEP) — working in sequence.
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4. How does glucagon promote gluconeogenesis?
Glucagon lowers fructose-2,6-bisphosphate levels, which inhibits PFK-1 (slowing glycolysis) and activates FBPase-1 (promoting GNG).
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5. What is the energy cost of gluconeogenesis?
6 ATP equivalents per glucose synthesized.
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