We use the term gluconeogenesis a fair amount here on BioKeto.com as it is a common subject of concern for those on the keto diet.

So, is gluconeogenesis on keto really something to worry about? Does too much protein take you out of ketosis?

To give you clearer answers to these questions, it’s important to understand what exactly gluconeogenesis is and how eating large amounts of protein influences it.

What Is Gluconeogenesis?

The technical definition of gluconeogenesis can be derived from the parts of the word itself;

  • Gluco is the prefix for glucose
  • Neo is the prefix for new
  • Genesis is a word meaning creation

Hence, gluconeogenesis is the scientific term used to describe the creation (synthesis) of new glucose molecules from molecules that are not carbohydrates.

In many cases, these molecules come from amino acids of protein you consume (and protein in your muscle tissue).

Gluconeogenesis on Keto: When Does It Occur?

If you’ve had the chance to read our Guide to the Ketogenic Diet, you might recall that your body uses carbohydrates to generate energy on a high-carb diet.

However, on the keto diet, your body prefers to utilize fat for energy, and in some cases, amino acids. Both glycerol and amino acids can be used for gluconeogenesis, but the latter tend to dominate when you’re on the keto diet.

Gluconeogenesis on keto typically occurs when you are exercising intensely for an extended period, or you are eating an excessive amount of protein.

Naturally, you don’t want your body to be producing an excessive amount of glucose from amino acids, as this can, in fact, interfere with ketosis.

However, your body doesn’t always convert excess protein into glucose, nor does gluconeogenesis prevail when your body is well-fed.

Also, the glucose your body does produce from gluconeogenesis on keto is often utilized for energy rather quickly, especially for physical activity.

How Gluconeogenesis Works

Gluconeogenesis is the inverse of glycolysis, which is the process of breaking down of glucose to produce energy.

The glucose metabolized through glycolysis produces a substance known as pyruvate, which is then fed into another energy cycle called the Kreb’s cycle (or the citric acid cycle).

Thus, gluconeogenesis is simply the reverse of that process, starting with pyruvate and working back up the chain to create glucose.

The substrates of gluconeogenesis (primarily glycerol, lactate, and certain amino acids) can be converted to pyruvate or other intermediates of the Kreb’s cycle by several metabolic reactions from which gluconeogenesis begins.

Impact of Amino Acids on Gluconeogenesis

Certain amino acids in your body and protein you eat are known as glucogenic amino acid, meaning they are able to produce glucose from a process called transamination.

Several amino acids are able to be converted directly to pyruvate, while others form other substances that are part of the Kreb’s cycle.

Alanine tends to be the body’s preferred amino acid for gluconeogenesis (especially in the liver), whereas glutamine is the predominant glucogenic amino acid in the kidneys.

The image below shows how the various glucogenic amino acids can be converted to the necessary intermediates of the Kreb’s cycle, which are then able to convert to glucose through gluconeogenesis.

1. Lactate

Exercise and muscular exertion causes your muscle tissue to produce lactic acid (lactate), which is responsible for the burning sensation you experience after sprinting or lifting heavy weights.

This lactate your muscles produce is sent to the liver where it gets converted to pyruvate and fed into the gluconeogenesis cycle; the glucose is then sent back to muscle tissue for energy production (reuse).

This process is known as the Cori cycle, depicted in the image below.

2. Glycerol

Glycerol is the backbone molecule of triglycerides in fat tissue.

Through the process of lipolysis (fat breakdown), it is released into the blood and carried to the liver where it is converted to pyruvate and enters the gluconeogenesis pathway.

3. Acetyl-CoA

When fasting (or during starvation), the breakdown of fatty acids results in the formation of acetyl-CoA in the liver.

Ketones can also be converted to acetyl-CoA. Acetyl-CoA acts as an activator of the enzyme pyruvate carboxylase, which converts pyruvate to oxaloacetate which is then able to enter gluconeogenesis.

Gluconeogenesis Regulation

The human body will do just about anything it can for survival. As such, when your body detects an excess of a certain substance or nutrients (even fats you eat on the keto diet), it triggers various reactions that either utilize or store those substances for later use.

When your body is lacking a certain substance that it wants, mechanisms take place that help form the substance from other available sources. This is the basis of how your body regulates many processes.

Since gluconeogenesis is the exact opposite of glycolysis, they are regulated in a reciprocal fashion.

In other words, the factors that promote gluconeogenesis inhibit glycolysis and vice versa.

This interplay between gluconeogenesis and glycolysis is how your body maintains a healthy balance of blood glucose. What determines which process takes place is largely dependent on substrate availability and hormonal status.

How substrate availability regulates gluconeogenesis on keto

Eating excessive amounts of protein will elevate glucogenic amino acids in the blood, which in turn promote gluconeogenesis.

What is “excessive,” you ask? The answer isn’t so clear-cut, but it’s safe to say that if you’re eating anywhere between 25-40% of your total calorie intake from protein on the keto diet, then gluconeogenesis isn’t going to be an issue.

Also, be sure to spread your protein intake out over the course of several meals throughout the day.

If you need help determining the proper protein intake on the keto diet, click here.

Hormonal Regulation of Gluconeogenesis on Keto

Your endocrine system is, in part, responsible for controlling blood glucose levels. Thus, gluconeogenesis on the keto diet is influenced by hormones such as insulin, glucocorticoids, and glucagon.

Gluconeogenesis and cortisol

Glucocorticoids, especially cortisol, are synthesized in the adrenal glands in response to stress. For example, intense exercise is well-known to stimulate cortisol secretion.

Another example: during times of extensive fasting your body produces more cortisol in order to stimulate the breakdown of lean tissue, which then gives your body the necessary glucogenic amino acids to provide for gluconeogenesis.

Gluconeogenesis and insulin

Insulin is a peptide hormone synthesized by the beta cells of the pancreas, primarily working to reduce blood glucose values by shuttling glucose into cells.

Glucose in cells helps produce ATP (cellular energy), which then goes onto stimulate insulin secretion. Intuitively, insulin inhibits gluconeogenesis (since insulin is generally released in response to a carb-rich meal).

Adrenaline inhibits insulin secretion while glucagon promotes insulin secretion. It’s also important to note that certain amino acids cause insulin to increase; if anything, this would further reduce concerns of gluconeogenesis on keto since you should be eating mainly fat and protein.

Gluconeogenesis and glucagon

Glucagon is created by alpha cells in your pancreas, and is essentially “reverse-insulin”. While insulin works to shuttle glucose into your cells, glucagon does the opposite.

Glucagon tends to increase when your blood glucose levels drop below normal, and this stimulates gluconeogenesis.

Where Does Gluconeogenesis Take Place in the Body?

There are two primary sites in the body where gluconeogenesis occurs – the liver and kidneys. These are the major organs in your body with all of the necessary enzymes for gluconeogenesis, though the small intestine carries out some gluconeogenesis during times of fasting.

Gluconeogenesis in the liver

The liver is your body’s predominant site of gluconeogenesis. When you eat a diet that contains a modest amount of carbs, your liver stores a generous amount of glycogen for longer-term fuel reserves.

During the initial 10-12 hours of fasting, glycogen in your liver is depleted rapidly and gluconeogenesis starts to kick in.

Your liver mainly uses L-alanine, glycerol, acetyl-CoA, and lactate for gluconeogenesis. In the case of the keto diet, your liver should already be rather glycogen-depleted;

however, this doesn’t mean the liver will carry out more gluconeogenesis on keto since your body will be using fatty acids as its main source of energy.

Gluconeogenesis in the kidneys

While your liver is the major organ of gluconeogenesis, the kidneys also play a role in maintaining blood glucose balance. The kidneys primarily use lactate, L-glutamine, and glycerol for gluconeogenesis on keto.

Renal gluconeogenesis is strongly stimulated by cortisol (and other glucocorticoids) and inhibited by insulin. Renal gluconeogenesis is especially crucial for individuals with liver disease since the kidneys are doing essentially double the workload without a healthy liver.

Gluconeogenesis on Keto: Key Takeaways

  • Gluconeogenesis is the process by which your body creates new glucose molecules from non-carbohydrate substrates (such as amino acids, lactate, and glycerol).
  • Gluconeogenesis typically occurs when your body is lacking energy (fasting or starving) or when you consume excessive protein. To determine the right protein intake for keto and your goals, head over to our Optimal Protein Intake article.
  • Since your body is essentially “fat-adapted” on the keto diet, gluconeogenesis will not take place to a significant degree so long as you don’t eat exorbitant amounts of protein.
  • Stress can increase gluconeogenesis on keto via cortisol (and other glucocorticoids). However, cortisol is a necessary hormone for health and longevity, just make sure not to let stress become a chronic and debilitating factor in your life.
  • Eating too much protein can take you out of ketosis, but the amount you need to eat to reach a significant impact is quite impractical for the vast majority of people on the keto diet (assuming you follow the recommended protein intake guidelines).