What Is Gluconeogenesis and What Does It Have to Do with the Keto Diet?

It sounds like a new spin-off of the Matrix series, but gluconeogenesis is actually a process by which your body makes glucose (sugar energy) itself, without having to get it from carbs. Is this good or bad for keto, a diet in which you’re trying to switch the body from relying on glucose energy to burning fat instead (for ketone energy)? Well, gluconeogenesis does happen when you’re transitioning to ketosis, and we have the answers for what you should do about it.

What Is Gluconeogenesis?

Gluconeogenesis (abbreviated GNG) is an essential metabolic pathway that allows your kidneys and liver to create glucose using non-carbohydrate material. This is happening on some scale in your body right now, and while it is a constant occurrence, it can increase or decrease in response to the state of your metabolism. Its meaning is in its name: new (neo) glucose creation (gluco-genesis), or the formation of glucose from a new source other than carbs.

Gluconeogenic Compounds

Your body can’t just take anything and turn it into glucose: however, there are a few compounds that are gluconeogenic substances, meaning they have the ability to turn into glucose. These compounds include:

• Glycerol: A viscous liquid that is found in both soap manufacturing and in our bodies because it comes from the breakdown of fat (adipose tissue). It’s an emollient and a laxative, and can be used for making antifreeze and explosives.
• TCA cycle intermediates: These are any molecules used in the TCA (tricarboxylic acid) or Krebs energy cycle that can be converted into glucose.
• Lactic acid: Lactate or lactic acid is the main gluconeogenic compound, derived from pyruvate (a salt) that comes from the breakdown of glucose. You may know lactic acid as the substance that accumulates in your muscles (thanks to the Cori cycle) during a vigorous workout, and may cause later onset soreness. Lactic acid comes from glucose via pyruvate, and it can convert back to glucose again, making it gluconeogenic.
• Glucogenic amino acids: Also known as protein, our essential amino acids are classified as either glucogenic (for glucose production), ketogenic (for ketone body production), or both. Specifically, most amino acids can become glucose, except for leucine and lysine which are 100% exclusively ketogenic. Ketogenic aminos are converted to either acetyl-CoA (or acetoacetyl-CoA) during the Krebs cycle, whereas glucogenic amino acids are made into pyruvate or citric acid cycle intermediates, which can convert right back into glucose. Glutamine and alanine are the primary amino acids used in gluconeogenesis.

As you can see, it’s all one big cycle. The important part to understand in relation to keto is that, since it takes more than 1 gram (1.6) of amino acids to produce 1 gram of glucose, your body isn’t interested in wasting that energy. That is why when your blood glucose levels are low due to a keto diet, your body resorts to burning up fat at fast rates for energy.

The Science of the Krebs Cycle

Let’s review the Krebs cycle just to be as clear as possible for those who haven’t brushed up on their chemistry notes in a while.

The Krebs cycle is so-called after its discoverer, Sir Hans Adolf Krebs, but it is also known as the TCA cycle or the citric acid cycle. Lysine and leucine (the two ketogenic amino acids) are the only aminos acids that can produce acetyl CoA or acetoacetyl CoA without any glucogenic byproducts.

Acetyl CoA is the precursor of ketone bodies, and it and acetoacetyl CoA are the first steps of the Krebs cycle of energy production, which combines glycolysis (the breakdown of glucose by enzymes) and pyruvate with the citric acid cycle, which itself involves α-ketoglutarate, fumarate, succinyl CoA, and oxaloacetate—all byproducts of glucogenic amino acids. 

All of this is in order to produce adenosine triphosphate (ATP) from the food we consume. ATP is known as the “molecular currency” of our cells, able to store and transport chemical energy. 

Gluconeogenesis pathways consume ATP gained from the oxidation of fatty acids (fat burning), and use several enzymes involved in glucose breakdown (glycolysis) to work backwards. There are some enzymes from the irreversible steps of glycolysis it must bypass (6-phosphofructokinase, hexokinase, and pyruvate kinase), and it does so with four unique reactions (phosphoenolpyruvate carboxykinase, fructose-1,6-bisphosphatase, pyruvate carboxylase, and glucose-6-phosphatase, which is located in the endoplasmic reticulum).

Now the question remains: does the gluconeogenic pathway and all this glycolytic gobbledegook help you stay in ketosis, or kick you out because it’s making glucose out of your low-sugar, low-carb diet?

Why You Need Gluconeogenesis

If the scientific specifics surrounding the regulation of gluconeogenesis are above your pay grade, we understand, but glucose homeostasis is still necessary for your health: just because you’re switching to a predominantly ketogenic metabolism doesn’t mean you can do without glucose concentrations in your blood. 

One of the highlights of ketones is that they’re the preferred energy source of the mind, able to cross the blood-brain barrier, but there are some vital parts of your body that prefer (and more importantly need) glucose and certain glucose transporters to function. So, just as your body came pre-installed with a backup metabolism, it also has a way to make glucose out of non-carbs. Here’s why you need that.

1. Some Parts of Your Body Can’t Use Ketones

Ketones are built to sub in for glucose molecules in most circumstances, so 9 times out of 10, wherever you were using sugar energy to function, you can now use fat-derived ketones. The places where that isn’t true? Your red blood cells, your kidneys, and (for men) the testicles. Luckily gluconeogenesis is there to create just enough glucose to keep all your vital organ functions running smoothly.

2. Avoiding Hypoglycemia

Hyperglycemia is when your blood glucose gets too high, hypoglycemia is when it gets too low. Even in a state of ketosis, your glucose levels cannot drop to zero without putting you in life-threatening danger. This is why glucose production is set up with a failsafe like gluconeogenesis, which is also highly controlled: there is a reciprocal inhibition between glycolysis and gluconeogenesis that prevents what’s known as “a futile cycle” from occurring, where the body breaks down the glucose it creates over and over again. 

When You Need Gluconeogenesis

Gluconeogenesis never stops in the human body, but it is more active in some moments, including:

• While you sleep: Using the mechanisms of gluconeogenesis (30%) and glycogenolysis (70%), your body makes glucose while you sleep because at the end of the day (literally) your body prefers to burn up stored glycogen before accessing any other energy source like fat.
• During intermittent fasting: When you carefully control when you eat and schedule 12- to 18-hour periods of not eating, your body reacts according to how we were built to survive in times of famine. The longer you fast, the more gluconeogenesis takes on the role of glucose production—it’s understandable, because as far as your body knows, you may be starving.
• During a keto diet: While eating a ketogenic diet, you go through a period of fat adaptation (in which you may experience keto flu symptoms), and then the state of ketosis in which your body burns fat primarily for energy.

Gluconeogenesis In Ketosis: The Breakdown

Here is how gluconeogenesis operates during the keto diet.

Before Ketosis

As you change your diet and cut out carbs during the first week or so of your ketogenic diet, your body quickly depletes its glycogen stores. Now you’re in a situation where you have no glycogen in reserve, you’re not eating the amount of sugar your body’s accustomed to, and you’re not yet adapted to burning fat for ketones. Here’s what’s happening:

1. You’re probably experiencing keto flu symptoms like brain fog, fatigue, and keto headache.
2. You may find that giving your body exogenous ketones (from outside the body) helps bridge the gap (like MCT and BHB oils).
3. Gluconeogenesis begins to take over from glycogenolysis because there’s no longer enough outside sugar being consumed. 

During Ketosis

Once you’re in ketosis, gluconeogenesis activity increases by 15% not because it’s trying to sabotage you, but because you’ve drastically cut your glucose input, and there’s a certain amount of glucose that is minimally required for healthy human functioning. Gluconeogenesis is twice as high during ketosis than it is during fasting, almost as if your body understands that this is the new world order, and it is prepared to adapt.

The Genesis of the Ketogenic Diet

People worry when they hear about gluconeogenesis that it is going to derail their ketogenic efforts, but rest assured: ketosis controls gluconeogenesis, not the other way around. Gluconeogenesis is all about balance, and about preserving certain vital functions that cannot operate on ketones alone. Far from being your enemy, gluconeogenesis is one of your most essential mechanisms, programed into the human body’s design to keep us in a happy state of homeostasis, no matter what we eat.