Gluconeogenesis: Bypass Reactions, Substrates and Regulation

Gluconeogenesis makes glucose from non-carbohydrate precursors. It happens mainly in the liver (and some kidney) during fasting. It is not the reverse of glycolysis: it shares the seven reversible steps and replaces the three irreversible ones.

Substrates

• Lactate (Cori cycle from muscle and red blood cells)
• Glycerol from triglycerides
• Glucogenic amino acids, especially alanine
• Propionyl-CoA from odd-chain fatty acids

Even-chain fatty acids give acetyl-CoA, which cannot make net glucose.

The four bypass enzymes

Pyruvate carboxylase and PEP carboxykinase together make the first bypass, so there are four enzymes in all. Glucose 6-phosphatase is the step that lets the liver release glucose into blood. Muscle lacks it.

Energy cost

Two pyruvate to one glucose costs 4 ATP + 2 GTP + 2 NADH, versus 2 ATP gained in glycolysis. The pathway runs on energy from fatty acid oxidation.

Regulation

• Glucagon and cortisol: raise gluconeogenesis.
• Insulin: lowers it.
• Fructose 2,6-bisphosphate: inhibits fructose 1,6-bisphosphatase and activates PFK-1. Glucagon lowers it, which switches the liver from glycolysis to gluconeogenesis.
• Acetyl-CoA: activates pyruvate carboxylase.

Cori and alanine cycles

• Cori: muscle lactate goes to liver, becomes glucose, returns to muscle.
• Alanine: muscle amino groups travel to the liver as alanine for the same purpose.

Common traps

• Thinking glycolysis runs backwards. Three steps differ.
• Saying muscle exports glucose. It lacks glucose 6-phosphatase.
• Forgetting that fatty acids cannot make net glucose (except odd-chain propionyl-CoA and the glycerol backbone).

One-minute recap

• Liver makes glucose from lactate, glycerol and amino acids.
• Bypass enzymes: pyruvate carboxylase, PEP carboxykinase, F1,6BPase, glucose 6-phosphatase.
• Glucagon activates; insulin inhibits.