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What is Keto Gluconeogenesis?

What is Keto Gluconeogenesis?

What Exactly is the Keto Diet?

Before we dive into the nitty-gritty of Keto Gluconeogenesis, let us first understand the meaning of a Keto Diet. A keto diet is, very simply put, a low-carb and high-fat based diet where the body due to the lack of carbohydrates or carbs to burn and produce energy ends up burning fats to keep producing energy that will help the body in continuing its functions. The burning of fats causes the formation of ketones or ketone bodies in the blood.

The state in which the ketone bodies are formed in shape is known as ketosis, and the primary aim of undergoing a keto diet is to reach the state of ketosis as quickly as possible. Most people experience the keto diet as an easy and fast way to lose weight.

Without having to go hungry and this trend of the keto diet is the latest fad in the health industry so to say.

Now what is Gluconeogenesis and how is it related to the Keto diet? We will come to know of that and much more in the article below. Plus, there are answers to questions like whether the process of gluconeogenesis is harmful to the body or whether it is genuinely a natural process that is undergone by the body.

What is Gluconeogenesis?

Gluconeogenesis or GNG is a metabolic process that helps, or instead allows your kidneys and your liver to start making glucose from sources other than carbohydrates.

    • This can include fats, proteins, vitamins and many other nutrients.
    • This is a continuous process that is always happening inside our body
    • Depending on how fast or slow our rate of metabolism is, the process can slow down or increase.

The name Gluconeogenesis has three different components. ‘Gluco’ means glucose, ‘neo’ means new and ‘Genesis’ means creation or origin of something.

The term in its very literal sense means a new process of production of glucose, that is, the body creates its necessary glucose from anything other than carbohydrates. These three components together also help us understand the process of Gluconeogenesis itself.

Even when you are on a diet that is low on carbs, your body ends up making just the right amount of glucose to help your function by breaking down more complex compounds into energy. These compounds are called gluconeogenic substrates. Glucogenic means any substance that can turn into glucose.

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So, what are these substances that can turn into glucose in the body?

• Lactate:

Lactate or what is commonly known as lactic acid is one of the primary gluconeogenic substrates. It comes from pyruvate which is the direct result of the breakdown of glycogen or glucose in the body. This sort of breakdown takes place especially when you are doing an intense amount of workout.

Your body’s cell turn pyruvate into lactic acid because it can be used as a source of energy. The acid then accumulates in your muscles. However, it is interesting to note that lactic acid can once again be turned into pyruvate and later can be turned into glucose. This is through the process of gluconeogenesis.

• Proteins:

Proteins are also known as glucogenic amino acids. They can be divided into ketogenic- ones that help stimulate the production of ketones, glucogenic- one that helps boost the production of glucose or both. Every kind of amino acid can be turned into glucose apart from lysine and leucine which fall only in the ketogenic category. The primary amino acids used in the process of gluconeogenesis are alanine and glutamine. As per average, we need about 1.6 grams of amino acids to make one gram of glucose. This is one of the many reasons why our body makes use of ketone bodies during the keto diet instead of glucose that can be derived via amino acids.

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• Glycerol:

Glycerol is the third most-used substrate for glucose production after lactic acids and glutamine. This substance is derived from the breakdown of fats in the human body. This is the third most important source of glucose in the absence of carbs.

• Intermediates of the Citric Acid Cycle:

Any molecule that is a part of the citric acid cycle that is also known as the Krebs cycle can be converted into glucose.

While it might seem to us that there may be problems due to gluconeogenesis when you are trying to use a keto diet where the body should be burning ketones instead of glucose, that is not really the case. In fact, gluconeogenesis has an incredibly vital purpose in the functioning of our body, and it does not interfere with the keto diet.

Why is Gluconeogenesis Necessary?

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Now let us come to a discussion about why gluconeogenesis is a necessity.

When we eat something that has adequate amounts of carbs in it, our body can quickly replenish the glucose amount in our body. But have you ever wondered what happens inside our body when we have a shortage of glucose in our system like it happens when we are fasting or following a keto diet? Obviously, our collection will have to find another way to replenish the glucose that it needs to function. This is where gluconeogenesis comes into play. It acts as your body’s backup source for glucose.

The process of gluconeogenesis is your body’s way of ensuring that you stay alive even when there are no carbohydrates in your body from where the body can derive glucose. Gluconeogenesis has two critical work. They are:

• Preventing Hypoglycemia:

Your body very consciously regulates the amount of glucose that is present in your body. While too much of glucose in your bloodstream is considered as toxic, too little can also kill you. Therefore, your body must keep the levels of glucose above the zero level always. In most people who are deemed as healthy, the blood sugar level stays around 5.5-6 mmol/L during one whole day.

The maximum it can go up to is 9 mmol/L after a large intake of carbs, and the least it can or instead should go down is 3 mmol/L when you are in a state of fasting.

GNG prevents the glucose level from plummeting under the limits during a keto diet. Without the help of GNG, we could suffer from hypoglycaemia which is a state in which the body’s blood sugar level goes dangerously low, and it causes seizures, confusion, loss of consciousness and even in certain extreme cases, death.

• Energising Those Tissues in the Body that Cannot Utilise Ketones:

When you practise the keto diet, and your body gets adapted to burning fat as its primary source of fuel, many cells and tissues in your body need glucose to survive. Some of them are the red blood cells, the inner part of the kidney known as the kidney medulla and the testicles. These organs cannot burn ketones to use as energy so, during the period of a keto diet, the process of gluconeogenesis provides these organs with the necessary glucose level to stay healthy.

Apart from these organs, the brain too needs a bit of glucose to work well. However, ketones can cover almost seventy per cent of the brain’s energy needs- that includes the part that improves cognitive functions. Glucose from GNG can look after the rest of it.

How Does the Process of Gluconeogenesis Work?

The process of gluconeogenesis can happen in your kidneys and your liver but at different rates. It depends on which metabolic stage you are in. The sources other than carbohydrates that are preferred for this process is lactic acid, glutamine, alanine and glycerol.

We have formulated a list of compounds that contribute to the total GNG when you are either on a keto diet or fasting. Plus, their effect on both the liver and the kidneys.

    • Lactic acid: 1.88 μmol/ (kg min). Your kidney is responsible for 47% of this compound, and the rest 53% is by the liver.
    • Alanine: 0.68 μmol/ (kg min). The liver produces about 97% of the glucose that is made from alanine while the kidney produces about 3% of the glucose.
    • Glycerol: 0.53 μmol/ (kg min). The kidneys produce about 32% of the glucose while the liver produces the balance 68%.
    • Glutamine: 0.58 μmol/ (kg min). Your kidney will make about 62% of the glucose that is derived from glutamine, and the liver makes about 38%.

The rate of gluconeogenesis from the liver and kidneys keep changing the longer you do not eat. In fact, after fasting for a full night, most of our glucose comes from the liver. If the duration of the fast is short, then both the organs, that is the kidney, and the liver produces the same amount of glucose. But with an increasing period, the production of glucose in the kidney increases.

The Four Things About Gluconeogenesis You Need to Know About

The reason for this condition is that the two organs team up to preserve the balance of glucose in our body. They both help each other to accomplish this mission. This phenomenon is also called the hepatorenal glucose reciprocity. Based on specific research numbers that we have obtained we can deduce four different things about the process of gluconeogenesis. They are:

    1. Our liver is where the process of gluconeogenesis takes place the most. Lactic acids, in this case, are what is used most.
    2. The second most important source of gluconeogenesis is the kidney.
    3. Lactic acid is utilised about 2.7 times more than the amino acid alanine and about 3.2 times more than that of glutamine. This basically means that the body takes more time to start producing glucose from proteins like amino acids that most people would like to think.
    4. The kidneys seem to prefer glutamine as an alternate source of glucose in the absence of carbohydrates while he live seems to prefer alanine to produce its glucose.

What is the Gluconeogenesis Pathway?

The gluconeogenesis pathway is comprised of eleven different chemical reactions and is quite an essential element to the process of the reversal of glycolysis which is the breakdown of glycogen. There are a few tweaks here and there, but the process mostly remains the same.

We can think of it more easily. If glycolysis helps in the breakdown of glucose, gluconeogenesis helps build up the glucose in our body. But we must also remember that the body cannot track every step of glycolysis because it would take too much time and energy. To help navigate this issue, the cells in our body have developed three unique enzymes that make the process of gluconeogenesis possible. They are PEPCK, PC and MDH.

Summary: How Does Gluconeogenesis Work?

Thus, to summarise, this is how the process of gluconeogenesis takes place:

    1. The raw materials that include compounds like lactic acid, alanine, glutamine and glycerol go to either the kidney or the liver where they are slowly converted to pyruvate which is the first substance to be used in the process of gluconeogenesis.
    2. The pyruvate is turned into oxaloacetate in the mitochondria of the cell.
    3. Furthermore, the oxaloacetate is then converted into phosphoenolpyruvate or PEP with the help of these enzymes.
    4. The PEP then goes into a process of reverse glycolysis.
    5. Lastly, the glucose-6-phosphate is then turned into free glucose by the body. The glucose then enters the muscles through the bloodstream and again goes into a process of glycolysis.

The process of gluconeogenesis is substantially controlled by the body so that they prevent the operation of glycolysis and gluconeogenesis from cancelling each other and thereby causing harm to the body.

The Rate of Gluconeogenesis

So, after knowing all that we know now about the process of gluconeogenesis, what should be the optimum rate of gluconeogenesis?

The GNG rates are usually always stable and do not fluctuate much. Studies have even shown that even if there is an abundance in the raw materials like proteins and others available to the body, the rate of gluconeogenesis stays just about the same. This is also the case with people with people who suffer from type 2 diabetes.

When we now think about it, this must be one of the reasons why eating a lot of protein while on the keto diet is not nearly enough to turn up the levels of GNG.

What we can now look at is how gluconeogenesis function in different situations.

When Does Gluconeogenesis Happen?

When Gluconeogenesis Happens

The process of gluconeogenesis is a continuous process in the body, but the rate of gluconeogenesis seems to increase significantly when the level of carbohydrates in our body is on the lower side. Gluconeogenesis behaves differently in five different metabolic stages.

Stage 1 - After You Eat a Meal:

It might be true that your body relies on the external sources of carbohydrates after you eat a meal that is rich in carbs but there is always a small amount of glucose that is produced internally by the body even after you eat a meal. The process is not very important here, but it is still taking place in the background.

Stage 2 - When You Are Sleeping:

Your body cannot stop its production of glucose during that 7-8 hours you spend sleeping. If it did, you could have died by now. In this stage, glucose production comes from two different processes. They are:

      1. Glycogenolysis which is the breakdown of glucose, and
      2. Gluconeogenesis 

For a person who is on a low-carb diet or a keto diet, GNG makes about 30% contribution to the glucose that is produced while you are sleeping. The balance 70% comes from glycogenolysis. This happens because our body always likes to burn stored glycogen before burning any other substance to meet its energy requirements. But for someone who is already in the state of ketosis, GNG is more responsible to produce glucose.

Stage 3 - When You Fast for a Short While:

A quick, short fast helps boost the rate of gluconeogenesis in the body quite a lot. In cases like this, gluconeogenesis contributes almost half the total amount of glucose in the body. The other half comes from glycogenolysis.

Many studies have shown that fasting for about fifteen to twenty hours can sometimes lead to GNG producing about fifty to seventy-one per cent of the total glucose in your body. If your fast extends beyond this point, the process of GNG ends up taking more responsibility of your body’s glucose production.

Stage 4 - When You Fast for More Extended Periods:

The more time you fast for, the more is the decrease in your level of blood sugar more apparent. The rate of gluconeogenesis, however, even in this case, remains the same. The total amount of glucose in your body goes down only because glycogenolysis goes down as the stores of glycogen go down.


How Does the Rate of Glycogenolysis Vary?

The rate of glycogenolysis fluctuates from 2.6 to 8.2 μmol/kg/min in short-term fasting to about 0.3 to 1.8 μmol/kg/min in a long-term period of fasting. This causes the glucose levels to drop from 7.2-18 μmol/kg/min to 7.5-9.8 μmol/kg/min. The levels of GNG remain nearly the same.

What this basically means is that when the body finally runs out of glycogen, it decided to rely entirely on the process of gluconeogenesis to produce the necessary amounts of glucose needed for its daily functioning.

As for how the process of GNG slowly takes over the process of glucose production, the points below explain that bit well.

      1. After fasting for about forty hours, GNG contributes to about 90% of the total glucose in the bloodstream. While the number itself might sound quite high, it is the least amount of glucose the body produces while going through the process of GNG.
      2. After fasting for about 42 to 64 hours (which equals about 2 to 2.5 days), GNG contributes to about 96% of the total glucose in the bloodstream.
      3. Finally, after 66 hours of fasting, GNG contributes about 97% of the total glucose in the blood. At this stage, the body stretches its maximum level to produce the maximum amount of glucose that it can provide while it still undergoes gluconeogenesis.

Stage 5 - While You Are Undergoing a Keto Diet:

The keto diet let the process of gluconeogenesis take over the body as it happens during a period of prolonged fasting. The two metabolic stages that the body goes through when we first start the keto diet are:

        • The period of getting fat-adapted, and
        • The period where you are in the state of ketosis.

This is how GNG seem to work for both the periods.

Gluconeogenesis During the Period of Fat-Adaption:

After a few days of being into the ketogenic diet, the stores of glycogen in our body gets depleted, and the level of glucose goes down. Plus, you aren’t even producing enough ketone bodies yet. Hence your body needs glucose to stay alive. It has been per research, that after going five to six weeks without carbohydrate consumption, the body tends to depend on the internal supply of glucose to stay alive.

Gluconeogenesis During the State of Ketosis:

Once we have finally reached the stage of ketosis, there is a shift in the way things work. Studies have found that people how consumed a high-fat diet showed a decrease in their overall glucose level, but they also had a 15% increase in the process of gluconeogenesis.

The real find here is that gluconeogenesis was two times higher during ketosis than it was during long periods of fasting or in the mode of fat-adaption.

Thus, we can say that while obese but otherwise healthy people had a GNG rate of 3.6 μmoles/kg/min after 4-5 weeks of staying away from carbohydrates, people who practised the keto diet had a GNG rate of 9.7 μmoles/kg/min.

However, despite everything, why is it that people who go through a keto diet can survive on ketones like BHB without many issues?

The answer itself is straightforward. In ketosis, the glucose that is generated from the process of gluconeogenesis is not used as the primary energy source. Instead, it is only used for the nurturing of the very few issues that cannot utilise ketones to produce energy to meet their requirements. It also helps prevents hypoglycaemia and resupply the stores of glycogen.

Glycogen’s Supply

The resupply of glycogen is of utmost importance as most researchers were surprised to see that during the keto diet, the excess production of the glucose made from gluconeogenesis was stored in the form of glycogen instead of being used as a supply of energy.

Glycogen is an essential component for muscle recovery post an intense workout session. While many people believe the only way to repair the damage is by eating as many carbs as you can after a workout, but this is not the case when it comes to the keto diet.

Body’s Ability to Restock Glycogen

Researches have proven our body can restock on glycogen through the process of GNG during ketosis unless you are an athlete who works out intensely. It can even save the excess amount of glucose that your body might not need as part of energy so that it can use it on a later stage when the amount of glucose runs out.

However, this does not happen when you fast for long periods because in that period the body uses all the glucose as fuel from gluconeogenesis. In a keto diet, however, the body has a better source of fuel- the ketone bodies, and therefore it can afford to stock up excess glucose as glycogen.

This pattern of storage is the very opposite of fat accumulation. In a high carb-based diet, our body runs on glucose and stores the fat. However, on a low carb diet, it runs on ketones and stores the glucose in the form of glycogen.

We can all agree that it is better to store glucose for the recovery of our muscles than it is to store fat. That is why the keto diet is excellent for losing weight, burning fat and improving our performance during a workout.

However, despite continuous proof, many health authorities claim that ketosis can cause muscle deterioration due to a deficiency of glucose and glycogen. However, these claims are not right.

Ketones versus Gluconeogenesis

Gluconeogenesis and ketones are often claimed to be incompatible with each other. But this again is not true. During the state of ketosis, the body makes ketones the primary source of fuel just because they are more efficient compared to glucose but GNG keeps occurring in the background. This is because when you compare glucose to ketone bodies like BHP, they tend to provide more energy and help fight oxidation and protect your cells.

Research says that about a hundred grams of glucose generates about 8.7 kilograms of ATP while 100 grams of BHB can produce about 10.5 kilograms of ATP and 100 grams of acetoacetate can yield 9.4 kilograms of ATP.

However, there are more reasons for making the switch to ketones. That is because if the body keeps using the process of gluconeogenesis for a very long period as its primary source of energy, then there is an excellent chance that the person would die.

Is Gluconeogenesis Dangerous?

Now that we have discussed the functional aspects of the process of gluconeogenesis, we should examine whether the process is dangerous.

Like we have discussed earlier, the process of gluconeogenesis is not in the very least dangerous for the human body. It is, in fact, a significant sign of having a healthy body. Anybody or any site that believes that gluconeogenesis is dangerous ends up believing in the many myths that surround the keto diet.

Most myths surrounding the process of gluconeogenesis is not true. It is quite safe for the human body to undergo this process as, without it, there is every chance that a human being might just die in their sleep because of the acute lack of glucose in the body since human beings do not consume carbohydrates in their sleep.

Plus, if you want to keep your brain energised with only GNG at the standard rate of 110 to 120 g/day, the cells in your body must burn about 160 to 200 grams of proteins every day. Although it sounds terrible, the degeneration of muscles is the only problem by far.

And interestingly, as per research, if you try to cover the brain’s entire energy requirement via the help of proteins only, it would lead to the death of a person in about ten days instead of the average 57-73days.

This is precisely why the body wants to produce more ketones because that helps to decrease the need for gluconeogenesis and prevent the loss of muscles in the body and ultimately reduces the possibility of death.

Thus, now that you have enough information about the stage of gluconeogenesis, you must have realised that it is, after all, a natural process undergone by the body and that there is nothing sinister in the process that you need to be worried about. It is something that happens daily, and it is very healthy for the internal and in some cases external functions of the human body.




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