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.
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.
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:
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.
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?
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.
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.
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.
Gluconeogenesis never stops in the human body, but it is more active in some moments, including:
Here is how gluconeogenesis operates during the keto diet.
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:
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.
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.