Does Gluconeogenesis Happen During Fasting? The Metabolic Switch Explained

December 8, 2025 •

3 min read

After an overnight fast, the average person's blood glucose concentration is naturally maintained between 80 to 90 mg/dl. This remarkable stability is possible because, as stored glycogen diminishes, the body activates a critical process known as gluconeogenesis to create new glucose.

Quick Summary

During fasting, the body activates gluconeogenesis to synthesize new glucose primarily in the liver, using precursors like amino acids, lactate, and glycerol to prevent low blood sugar.

Key Points

Timing is key: Gluconeogenesis is the primary glucose-producing mechanism after liver glycogen is depleted, typically after 24 hours of fasting.
Fat and protein are fuel sources: The body uses non-carbohydrate precursors like glycerol from fat and glucogenic amino acids from protein to synthesize new glucose.
Hormones regulate the process: Glucagon and cortisol levels rise during fasting to activate gluconeogenesis, while insulin levels fall.
Ketogenesis is a protein-sparing mechanism: As fasting continues, the liver produces ketone bodies from fatty acids, which can fuel the brain and reduce the need for glucose from protein.
Significant muscle loss is a myth: The body's metabolic adaptations and recycling processes are designed to preserve muscle tissue during fasting, contrary to common fears.

Understanding the Body's Fuel Strategy During Fasting

When you stop eating, your body doesn't just shut down; it intelligently switches fuel sources to keep vital organs, especially the brain, functioning. This metabolic flexibility is a key to survival. The process occurs in phases, starting with the most readily available fuel and shifting to more complex methods as the fast continues.

The Initial Phase: Glycogenolysis

In the first 12 to 24 hours of fasting, the body relies on stored glycogen from the liver. This process, called glycogenolysis, involves breaking down the glycogen into glucose and releasing it into the bloodstream to maintain stable blood sugar levels. However, the liver's glycogen reserves are limited and can only sustain this for a short period.

The Shift to Gluconeogenesis

As glycogen stores are depleted, a more complex process takes over: gluconeogenesis (GNG). This is the synthesis of new glucose from non-carbohydrate precursors, mainly in the liver and, to a lesser extent, the kidneys. GNG is essential for maintaining blood glucose for cells that depend on it for energy, such as red blood cells and neurons.

The Key Precursors of Gluconeogenesis

During fasting, precursors for gluconeogenesis are mobilized from different tissues and transported to the liver and kidneys. These include lactate from red blood cells and muscles, glycerol released from the breakdown of triglycerides in fat tissue, and glucogenic amino acids primarily from protein breakdown.

Hormonal Regulation: A Tightly Controlled System

The metabolic switch during fasting is regulated by hormones. Falling blood sugar leads to decreased insulin and increased glucagon from the pancreas. Glucagon stimulates gluconeogenesis, glycogenolysis, and lipolysis, providing substrates for glucose production. Cortisol levels also increase in prolonged fasting, further promoting gluconeogenesis.

The Rise of Ketone Bodies

With continued fasting, the liver processes fatty acids into ketone bodies (acetoacetate, beta-hydroxybutyrate, and acetone). These ketones become an alternative fuel for most tissues, including the brain, reducing the body's need for glucose and sparing muscle protein.

Comparison of Glycogenolysis and Gluconeogenesis


Feature	Glycogenolysis	Gluconeogenesis
Timing in Fasting	Predominant in the first 12-24 hours.	Primary source after 24 hours of fasting.
Source	Stored glycogen in the liver.	Non-carbohydrate precursors (lactate, glycerol, amino acids).
Process	Breakdown of existing glycogen stores.	Synthesis of new glucose molecules.
Location	Primarily the liver.	Primarily the liver, with kidney contribution increasing in prolonged fasting.
Energy Cost	Releases stored energy.	Energy-intensive process requiring ATP.

Is Muscle Loss an Issue During Fasting?

Contrary to concern, significant muscle loss during fasting is not a foregone conclusion. The body employs protein-sparing mechanisms. While amino acids are used for gluconeogenesis early on, increased ketogenesis in prolonged fasting reduces the reliance on protein. Studies suggest muscle function can be maintained or even improve. Initial muscle volume reduction is often due to loss of glycogen and water, not structural protein.

Conclusion

Yes, gluconeogenesis is vital during fasting, becoming the main glucose source once liver glycogen is depleted. This process, controlled by hormones like glucagon, uses fats and proteins to fuel glucose-dependent tissues. Combined with ketogenesis, it shows the body's adaptation to fasting while preserving muscle. Understanding this metabolic switch clarifies fasting's effects. For further details on fasting physiology, explore the National Institutes of Health website.

Frequently Asked Questions

Gluconeogenesis is the metabolic pathway that results in the synthesis of new glucose molecules from non-carbohydrate precursors, such as lactate, glycerol, and certain amino acids.

The process of gluconeogenesis occurs mainly in the liver, but the kidneys also play a significant role, particularly during prolonged periods of fasting.

Gluconeogenesis is always running, but its contribution increases significantly as liver glycogen stores are used up. This typically becomes the primary source of glucose after about 24 hours of fasting.

While gluconeogenesis can use amino acids from protein, the body has protein-sparing mechanisms, such as burning fat and producing ketones, to minimize muscle loss, especially during longer fasts.

In the initial phase, the body uses glucose from stored glycogen. Once that is depleted, it switches to producing glucose via gluconeogenesis while simultaneously burning fat and producing ketone bodies.

During fasting, falling insulin levels and rising levels of glucagon and cortisol trigger and regulate gluconeogenesis by signaling the liver to produce and release more glucose.

During prolonged fasting, the brain can use ketone bodies produced by the liver as an alternative fuel source, which significantly reduces the need for glucose and helps conserve protein.