How can glucose be formed from non-carbohydrate sources?

December 26, 2025 •

2 min read

During a prolonged fast, the liver can produce over 84% of the body's glucose needs through gluconeogenesis. This remarkable metabolic pathway is precisely how glucose can be formed from non-carbohydrate sources, ensuring a steady energy supply for vital organs like the brain when dietary carbs are scarce.

Quick Summary

The metabolic process of gluconeogenesis synthesizes glucose from non-carbohydrate substrates such as lactate, glycerol, and glucogenic amino acids, primarily taking place in the liver and kidneys.

Key Points

Gluconeogenesis is the process: The liver and kidneys synthesize glucose from non-carbohydrate sources, primarily during fasting or low carb intake.
Lactate is recycled: The Cori cycle moves lactate produced by exercising muscles and red blood cells to the liver, where it's converted to glucose.
Glycerol comes from fat stores: The glycerol backbone of triglycerides, released during fat breakdown, can be efficiently used as a precursor for new glucose.
Amino acids serve as building blocks: Certain 'glucogenic' amino acids, derived from protein breakdown, can be converted into intermediates like pyruvate to enter the pathway.
Fatty acids are not glucogenic: While glycerol from fat is a source, even-chain fatty acids cannot be converted into glucose in humans.
Hormones regulate the process: Glucagon stimulates and insulin inhibits gluconeogenesis, ensuring appropriate blood glucose levels based on energy status.

Understanding Gluconeogenesis: The Body's Backup Glucose Plan

When dietary carbohydrates are limited, the body utilizes gluconeogenesis (GNG) to synthesize glucose from non-carbohydrate sources. This process, meaning 'new formation of glucose,' mainly occurs in the liver and kidneys and is crucial during fasting, intense exercise, or starvation. Gluconeogenesis is not a simple reversal of glycolysis but a distinct pathway using different enzymes to bypass irreversible steps. This energy-intensive process relies on energy from sources like fatty acid breakdown. The primary non-carbohydrate substrates are lactate, glycerol, and glucogenic amino acids.

Key Non-Carbohydrate Substrates

1. Lactate (The Cori Cycle)

Produced during anaerobic glycolysis in tissues like red blood cells and exercising muscles, lactate travels to the liver. Here, it's converted back to glucose via the Cori cycle, supplying glucose back to other tissues.

Pathway: Lactate from muscle/RBCs goes to the liver, converts to pyruvate, then glucose, which is released into the blood.

2. Glycerol (From Fats)

Lipolysis breaks down triglycerides in fat tissue during fasting, releasing fatty acids and glycerol. Glycerol, unlike even-chain fatty acids in humans, is a good precursor, taken up by the liver and easily entering the pathway.

Pathway: Glycerol from fat breakdown is taken up by the liver, phosphorylated to glycerol-3-phosphate, oxidized to DHAP (a glycolytic intermediate), and converted to glucose.

3. Glucogenic Amino Acids (From Protein)

When other substrates are low, muscle protein breaks down to provide glucogenic amino acids. These convert into pyruvate or other intermediates usable in gluconeogenesis. The glucose-alanine cycle is an example, moving alanine from muscle to the liver for glucose production.

The Glucose-Alanine Cycle: Muscle pyruvate becomes alanine, which travels to the liver, converts back to pyruvate, and is used for glucose synthesis, which returns to muscles.

Regulation of Gluconeogenesis

Regulation is vital to prevent simultaneous glucose breakdown (glycolysis) and synthesis. Key hormones include:

Glucagon: Stimulates gluconeogenesis when blood glucose is low.
Insulin: Inhibits gluconeogenesis when blood glucose is high.
Cortisol and Catecholamines: Also stimulate the process.

Gluconeogenesis vs. Glycolysis

These are distinct pathways with reciprocal regulation.


Feature	Gluconeogenesis	Glycolysis
Purpose	Glucose synthesis from non-carbs	Glucose breakdown for energy
Primary Location	Liver and kidneys	All cells cytoplasm
Energy Status	Low energy states (fasting)	High energy states (after meal)
Hormonal Control	Stimulated by glucagon, inhibited by insulin	Stimulated by insulin, inhibited by glucagon
Key Enzymes	Pyruvate Carboxylase, PEPCK, Fructose-1,6-bisphosphatase, Glucose-6-phosphatase	Hexokinase/Glucokinase, Phosphofructokinase-1, Pyruvate Kinase
Net Energy Change	Energy consuming	Energy producing

Conclusion: A Vital Metabolic Adaptation

Gluconeogenesis is a critical adaptation for maintaining glucose levels during carbohydrate scarcity. Using lactate, glycerol, and glucogenic amino acids, it ensures glucose-dependent tissues like the brain have fuel. Hormonal control and unique enzymes highlight the body's efficient energy management. Understanding how glucose can be formed from non-carbohydrate sources reveals the body's resilience.

Learn more about the intricate relationship between gluconeogenesis and glycolysis at the Biology LibreTexts metabolic pathway summaries.

Frequently Asked Questions

Gluconeogenesis is the metabolic pathway that synthesizes new glucose from non-carbohydrate sources, such as lactate, glycerol, and glucogenic amino acids.

Gluconeogenesis primarily occurs in the liver. To a lesser extent, it can also happen in the cortex of the kidneys, and under certain conditions, in the small intestine.

The main substrates for gluconeogenesis are lactate, glycerol (from the breakdown of fats), and glucogenic amino acids (from the breakdown of proteins).

In humans, even-chain fatty acids cannot be converted into glucose because they are broken down into acetyl-CoA, which cannot be converted back to pyruvate. However, the glycerol portion of triglycerides can be used.

This process is vital for maintaining blood glucose levels, particularly during prolonged fasting or intense exercise. It ensures a continuous supply of glucose for tissues like the brain and red blood cells that rely on it for energy.

The Cori cycle describes the movement of lactate produced by anaerobic glycolysis in muscles and red blood cells to the liver, where it is converted back into glucose via gluconeogenesis.

Gluconeogenesis is reciprocally regulated with glycolysis, primarily by hormones. Glucagon promotes the pathway, while insulin inhibits it, preventing a futile cycle of glucose production and breakdown.