- What is Gluconeogenesis?
- Why is Gluconeogenesis Necessary?
- How Gluconeogenesis Works
- When Does Gluconeogenesis Happen?
- Ketones vs Gluconeogenesis
- Will Eating Too Much Protein Activate Gluconeogenesis, Kick Me Out of Ketosis, and Break Down Muscle?
- Why Under-Eating Protein Is Bad For Your Health
Did you know that your cells can make glucose internally without using carbs?
Your body knows it can’t always count on receiving 3 carb-based meals per day — after all, our ancestors never ate that way — so it evolved a mechanism to make glucose out of different substances such as lactate and amino acids.
This process is called gluconeogenesis, and despite it being crucial to your survival, it’s highly misunderstood.
For instance, you may have heard that eating too much protein on keto can “activate” gluconeogenesis and spike your blood sugar in a snap. This is wrong.
You shouldn’t worry about gluconeogenesis at all when you’re in ketosis — and today you’ll learn why.
We’re diving into everything you need to know about gluconeogenesis, what it actually does when you’re in ketosis, and why it’s not a problem:
Gluconeogenesis (GNG) is a metabolic pathway that allows your liver and kidneys to make glucose from non-carbohydrate sources. It’s always happening in your body, but its rate can increase or decrease depending on your metabolic state.
Its name has three components:
- Gluco: Meaning glucose.
- Neo: Meaning new.
- Genesis: Meaning origin or creation.
Literally, it means a new origin of glucose. It’s the creation of glucose from anything but carbs.
This means that even when you are on a low carb or carnivore diet, your body still manages to make enough glucose to survive by breaking down other compounds, which are called gluconeogenic substrates (gluconeogenic = can turn into glucose). These are the main ones:
- Lactate: Lactate or lactic acid is the major gluconeogenic substrate. It’s derived from pyruvate — the direct product of glucose or glycogen breakdown. When you do an intense workout, your cells eventually turn pyruvate into lactate because it can be used for energy, and lactate accumulates in your muscles. What most people don’t know is lactate can be turned into pyruvate once again and back into glucose — aka gluconeogenesis.[*]
- Glucogenic amino acids (aka protein): Amino acids can be divided into ketogenic (stimulate ketone production), glucogenic (stimulate glucose production), or both. Every single amino acid can be turned into glucose except for lysine and leucine, which are exclusively ketogenic. The main amino acids used for gluconeogenesis are alanine and glutamine. On average, you need 1.6 g of amino acids to make 1 g of glucose, which is expensive. That’s one of the reasons your body uses ketones during a ketogenic diet instead of amino acid-derived glucose. More on that later.
- Glycerol: After lactate and glutamine, glycerol is the third most used substrate. It comes from fat breakdown.
- All citric acid cycle intermediates. Any molecule that participates in the Krebs cycle may be converted to glucose.
Now, gluconeogenesis may seem like a problem when you’re trying to run on ketones instead of glucose — and there’s a lot of misinformation online that says so– but the truth is gluconeogenesis has an incredibly important purpose and no, it won’t interfere with keto.
Watch this video by Perfect Keto founder Dr. Anthony Gustin, where he explains why you need GNG on keto:
When you eat carb-based meals, your body can easily make new glucose from those carbohydrates. But what happens when you stop having carbs because you’re fasting or following a ketogenic diet? Your cells have to find another way to supply glucose to those tissues that need it.
Enter gluconeogenesis — your body’s backup glucose source.
Essentially, your cells use gluconeogenesis to ensure you don’t die when there are no carbs in your system.
Gluconeogenesis has two important tasks:
#1: Preventing Hypoglycemia
Your body can’t ever drop glucose levels to zero, even on ketosis. Just as too much glucose is toxic, too little can kill you.
That’s why glucose levels are tightly regulated.
In healthy people, blood sugar stays around 5.5–6 mmol/L during 24 hours, with a maximum of 9 mmol/L after carb-based meals and a minimum of 3 mmol/L in a prolonged state of fast.[*]
GNG prevents glucose levels from falling under that limit when you’re not eating carbs, such as during a ketogenic diet, fasting, or a carnivore diet. Without it, you could get hypoglycemia — a state of dangerously low blood sugar that can cause seizures, confusion, loss of consciousness, and death.
#2: Fueling Those Tissues That Can’t Use Ketones
Even though you’re able to run on ketones when you’re fat adapted, there are specific cells in your body that can only use glucose to survive, such as:
- Red blood cells
- Kidney medulla (inner part of the kidney)
That’s right, these organs can’t metabolize ketones, so when you’re on ketosis, gluconeogenesis provides them with enough glucose to remain healthy.
The brain also needs a little bit of glucose to work optimally, but not only glucose. Ketones can cover up to 70% of your brain’s energy needs (which improves cognitive function), while glucose from GNG can cover the rest.
Gluconeogenesis happens both in your liver and kidneys at different rates depending on which metabolic stage you’re on. As mentioned before, the preferred non-carb sources are lactate, glutamine, alanine, and glycerol.
This is how much each substance contributes to total GNG when you’re fasting and the individual contributions of your liver and kidneys:
- Lactate: 1.88 μmol/(kg min). Your liver is responsible for 53% and kidneys for 47%.
- Alanine: 0.68 μmol/(kg min). Your liver contributes to 97% of alanine-derived glucose, and kidneys to 3%.
- Glutamine: 0.58 μmol/(kg min). Your kidneys make 62% of glutamine-derived glucose, while the liver makes 38%.
- Glycerol: 0.53 μmol/(kg min). The liver makes 68% while the kidneys make 32%.
The gluconeogenesis rate from the liver and kidneys also change the longer you fast: after an overnight fast, most glucose comes from the liver. After a short fast, the liver and kidneys make equal amounts. As fasting extends, the kidney may produce more glucose than the liver.[*]
This happens because liver and kidneys team up to preserve glucose balance. So, if the kidney can’t make enough glucose, the liver starts making more to make up for it, and vice-versa. This phenomenon is called hepatorenal glucose reciprocity.[*]
Based on those numbers, we can tell four things about gluconeogenesis:
- Your liver is where most of gluconeogenesis happens and lactate is its favorite substance.
- The kidney is the second most important gluconeogenesis source.
- Lactate is used 2.7 times more than the amino acid alanine and 3.2 times more than glutamine. This means your body doesn’t start making glucose out of protein (amino acids) as fast as most people think.
- Your kidneys prefer glutamine, while the liver prefers alanine.
The Gluconeogenesis Pathway
The gluconeogenesis pathway is made of eleven chemical reactions and it’s essentially the reverse process of glycolysis (the breakdown of glycogen), except with a few tweaks.
Think of it this way: If glycolysis breaks down glucose, gluconeogenesis builds up glucose.
However, your body can’t simply trace back each step of glycolysis because it would require too much energy.
To get around this issue, human cells evolved three unique enzymes that make gluconeogenesis possible: PEPCK, PC, and MDH.
In a nutshell, this is how gluconeogenesis happens:
- The raw materials (lactate, alanine, glutamine, or glycerol) go to the liver or kidney, where they are converted to pyruvate — the first substance in gluconeogenesis.
- In the mitochondria, pyruvate is turned into oxaloacetate.
- Oxaloacetate is converted to phosphoenolpyruvate (PEP) by one of those unique enzymes.
- PEP then follows the reverse steps of glycolysis.
- Finally, glucose-6-phosphate is turned into free glucose.
- Glucose goes to the muscles through the bloodstream, where it enters glycolysis.
This process is highly controlled to prevent glycolysis and gluconeogenesis from canceling each other out.
The Rate of Gluconeogenesis
The GNG rate tends to be extremely stable and hard to disturb. Studies show that even when there are more raw materials available — like protein –, the rate stays about the same.[*]
Even in people with type 2 diabetes, gluconeogenesis rate is similar to those of non-diabetic people.
This is one of the reasons that eating “too much” protein on keto is not enough to turn up GNG — but more on that later.
Let’s see how gluconeogenesis works in different situations:
Gluconeogenesis is always happening, however, it increases significantly when your carb consumption is low.
This is how gluconeogenesis behaves in 5 different metabolic states:
Although it’s true that after a carb-based meal your body relies mostly on the external glucose from carbs, internal glucose production (gluconeogenesis) is still happening, although at a small rate.
Gluconeogenesis is not significant here, but it is there.
Your body has to make glucose internally during the 7-8 hours you sleep every night. This glucose comes from two mechanisms:
- Glycogenolysis — the breakdown of glycogen.
For someone on a carb-based diet, GNG contributes to about 30% of total glucose made while sleeping, while the other 70% comes from glycogenolysis.
This is because your body will always prefer to burn stored glycogen before any other substance.
However, for someone on ketosis GNG is responsible for more glucose production.
Takeaway: During sleep, your body makes glucose from two mechanisms: glycogenolysis and gluconeogenesis. For someone on a carb-based diet, glycogenolysis makes more internal glucose than gluconeogenesis.
Intermittent fasting boosts the rate of gluconeogenesis quite a bit.
In this case, gluconeogenesis contributes to half of total glucose, while the other half comes from glycogenolysis.
Studies show that during a 15-20 hour intermittent fast, GNG can make up to 50-71% of total glucose.
When your fast extends beyond one day, gluconeogenesis takes even more responsibility for glucose production, as you’ll see below.
As you continue fasting, blood sugar gradually decreases. However, the rate of gluconeogenesis stays the same.
Total glucose goes down only because glycogenolysis declines as glycogen stores run out.
Glycogenolysis goes from 2.6–8.2 μmol/kg/min in intermittent fasting to 0.3–1.8 μmol/kg/min in extended fasting, which causes glucose levels to drop from 7.2–18 μmol/kg/min to 7.5–9.8 μmol/kg/min. Meanwhile, GNG levels stay the same.[*]
This means that when your body runs out of glycogen, it relies completely on gluconeogenesis.
This is how GNG slowly takes over glucose production:
- After a 40 hour fast (less than 2 days), GNG makes 90% of total blood glucose.
- After a fast between 42–64 hours (2-2.5 days), GNG is responsible for 96% of total glucose.
- After a 66 hour fast (2.7 days), GNG makes 97% of total glucose.
A keto diet kills glycogenolysis and makes gluconeogenesis take over, much like during an extended fast. However, the exact mechanisms are different.
There are two metabolic stages you go through when you first start a keto diet:
- Your fat adaptation period
- Actually being in ketosis
This is how GNG works in both:
#1: Gluconeogenesis During Fat Adaption
When you’re several days into a keto diet, your glycogen stores get depleted and your total glucose levels go down, but you aren’t producing quite enough ketones yet, so your body still relies on internal glucose to survive.
Research finds that after 5-6 weeks without carbs, all the internal glucose comes gluconeogenesis — no more glycogenolysis.[*]
#2: Gluconeogenesis During Ketosis
One study found that healthy people who ate a high fat diet containing 83% of calories from fat and 2% from carbs for 11 days had a decrease in total glucose but a 15% increase in gluconeogenesis.[*]
Now here’s the real kicker: Gluconeogenesis was 2x higher during ketosis than during the extended fast or fat-adaptation mode.
While obese but otherwise healthy patients had a GNG rate of 3.6 μmoles/kg/min after 4-5 weeks of not eating carbs, people on a keto diet had a GNG rate of 9.7 μmol/kg/min.
Despite this increase, people on a keto a diet can still run on ketones (like BHB) without a problem.
Because in ketosis, the glucose from gluconeogenesis isn’t used as the main fuel anymore. Instead, it’s only used to:
- Nurture the few tissues that can’t use ketones
- Prevent hypoglycemia
- Resupply glycogen stores
That last one is particularly important. Researchers were surprised to see that on keto, excess glucose made from gluconeogenesis was stored as glycogen instead of being used as fuel.
Glycogen is crucial for muscle recovery after workouts, and many people believe the only way to resupply it is by eating carbs as soon as you’re done working out. But those rules don’t apply to ketoers.
These findings prove that you can actually replenish glycogen through the GNG that happens during ketosis — at least if you’re not a professional athlete or participate in competitions.
This doesn’t happen during fasting or in the fat adaptation period because your body is using all the glucose from gluconeogenesis for fuel. On keto, your body already has a better, cleaner fuel — ketones –, so it can afford to store up excess glucose as glycogen.
This storage pattern is the exact opposite of accumulating fat:
- On a carb-based diet, you run on glucose and store fat.
- On a low carb, high-fat diet, you run on ketones and store glucose (in the form of glycogen).
You can probably agree it’s more beneficial to store glucose (for muscle recovery) than to store up excess fat.
Unfortunately, despite this evidence, health authorities and some media outlets continue to claim that ketosis may cause muscle loss due to a lack of glucose and glycogen.
The simple fact that your body can make glucose and glycogen through gluconeogenesis shows that’s not true.
So why the misinformation?
Turns out, data that “shows” low carb diets cause muscle loss comes from the deeply flawed Turkey Study, which appeared to proof reducing carbs reduces muscle, when in fact subjects were simply not getting enough protein, which was the real cause of muscle loss.[*]
Gluconeogenesis and ketones are often seen as incompatible, but they’re not.
On ketosis, your body simply makes ketones the main fuel because they’re more effective than glucose, but GNG is still running in the background, as you just learned.
Think of gluconeogenesis as being demoted, while ketones get promoted to chief energy source.
This happens because, in comparison to glucose, ketone bodies like BHB provide more total energy, fight oxidation, and protect your cells.
According to research, 100 g of glucose generates 8.7 kg of ATP, while 100 g of BHB can yield 10.5 kg of ATP and 100 g of acetoacetate 9.4 kg of ATP.[*]
But there’s another reason switching to ketones literally saves the day: if your body continued to use gluconeogenesis indefinitely as its primary fuel source, you’d die.
Just consider this:
If you wanted to keep your brain fueled only with GNG at the optimal rate of 110-120 g/day, your cells would have to break down 160-200 g of protein per day (close to 1 kg of muscle tissue) to make that glucose.[*]
That sounds bad enough, but muscle loss is by far the only problem.
According to research, covering your brain’s glucose needs with protein alone would lead to death in about 10 days instead of the standard 57-73 days.[*]
This is precisely why your body rushes to make ketones: to reduce the need for gluconeogenesis and hence prevent muscle loss and death.
This leads us to one of the hottest debates on the keto world right now:
Will Eating Too Much Protein Activate Gluconeogenesis, Kick Me Out of Ketosis, and Break Down Muscle?
Short answer: no. But stick around for the more interesting answer.
You may have read somewhere on the internet that eating too much protein on keto can trigger gluconeogenesis and put you right back on glucose-burning mode, but the truth is this isn’t something you should worry about.
There are 3 reasons GNG isn’t a real threat to your brain-boosting, fat-burning keto state:
#1: Gluconeogenesis Is Always Happening In Ketosis
To answer the first part of the question, protein can’t “activate” gluconeogenesis because GNG is already happening during ketosis, as you learned above.
The thing is, it’s happening at a low rate that keeps ketones as the primary fuel.
Bottomline: Protein or no protein, gluconeogenesis is happening, it’s helpful, and it’s not high enough to put you in glucose-burning mode.
#2. Ketosis Suppresses Gluconeogenesis, Not The Other Way Around
To answer the second part of the question, gluconeogenesis can’t pull you out of ketosis so easily.
Your body doesn’t like imbalances, which is why it’s always seeking homeostasis — a state of internal equilibrium.
Ketones are your body’s way of keeping gluconeogenesis under control and preserving homeostasis.
It knows that if GNG goes unchecked for too long, it will indeed start breaking down muscle and kill you, so it acts just in time to stop that from happening by releasing ketones.
In addition, the rate of gluconeogenesis tends to be stable and undisturbed regardless of how many resources are available, as you learned before.
It’s simply not that easy to amp up the GNG rate by eating more protein.
Bottomline: Your body fights to keep ketones as the main fuel and prevent gluconeogenesis from taking over, and the GNG rate is hard to disturb.
#3: Your Body’s Favorite Gluconeogenic Source Is Lactate, Not Protein
To answer the final part of the question, protein isn’t even the first choice for gluconeogenesis, and GNG actually helps to build up muscle.
Remember, lactate is your liver’s favorite gluconeogenic substance, and it’s consumed 2-3 times more than amino acids.
Evidence shows that after a fast of 12, 20, and 40 hours, the contribution of lactate to GNG was 41%, 71%, and 92%, respectively.[*]
Additionally, gluconeogenesis during ketosis is helpful for building muscle glycogen, which protects and heals muscles after exercise.
Bottomline: Don’t be afraid that eating too much protein on keto will put you in glucose-burning mode.
There’s one more reason you shouldn’t lower your protein intake on keto.
Because a lot of new keto-ers believe that too much protein will put them out of ketosis, most of them limit their protein intake too much — to the point they don’t eat enough protein to maintain muscle mass and regulate other important functions in your body.
Not eating enough protein on keto has serious side effects, including:
- Worsened workout performance: Without enough protein, you won’t be able to maintain muscle mass, let alone build muscle. As you lose muscle mass, you’ll feel weaker and less capable of exercising at the same level as before.
- Neuron atrophy: Your brain needs amino acids to function optimally. Research finds a protein-deficient diet can lead to atrophy and neuron loss[*].
- Weaker immune system: A deficiency in the amino acid arginine can contribute to the dysfunction of your T cells — the cells that regulate your immunity.
- Increased risk of diseases: A deficiency in amino acids can increase the risk of developing certain diseases, including: sickle cell disease, acute asthma, cystic fibrosis, pulmonary hypertension, cardiovascular disease, and certain cancers[*].
Gluconeogenesis Is an Essential Mechanism
Making glucose from non-carb sources is crucial for survival when you’re fasting, becoming fat-adapted, or in ketosis. It helps nourish glucose-needing tissues, build your muscle glycogen, and prevent hypoglycemia.
Don’t obsess over protein macros on keto — eating a lot of protein is not enough to increase the highly stable rate of gluconeogenesis, and your body prefers to use lactate before amino acids anyway.
Next time, don’t hesitate to go heavy on the meat if you feel like it — you’ll most likely stay in ketosis without a problem.