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The Science Behind the Metabolic Process of Ketosis

The Science Behind the Metabolic Process of Ketosis

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Do you ever wonder how your body generates fuel? Did you know that your body can make a metabolic switch when glucose is insufficient? Today, we’re going to talk about ketosis. Ketosis is a normal physiologic state characterized by elevated ketones in your body.

Ketosis happens as a response to low glucose availability. When you’re in ketosis, your body uses ketones as its alternative fuel.

Beta-hydroxybutyrate (BHB), your most abundant ketone, produces more energy than glucose [1] in the form of ATP, the universal chemical currency of energy used by cells [2].

Note that the same amount of glucose produces less ATP [1].

That’s how great it is to be in ketosis.

However, there are tons of misconceptions that surround ketosis. These false beliefs prevent people from using nutritional ketosis correctly. In this guide, you’ll discover its science and some essential facts you need to know.

Keep reading.


ketosis science

Ketosis Explained: The Science Behind Ketosis

Keto might have caught your attention because celebrities and influencers recommend them.

Here’s what you should know: Ketosis is not a fad. It’s based on real science.

You may not know this yet, but ketosis had helped our ancestors survive when food was scarce. Millions of years ago, fruits and wild grains were limited. Our ancestors also hunted meat that had more fat, and ate portions of the animal with higher fat content [3].

Physicians also used ketosis since the 1920s for intractable epilepsy. Patients with epilepsy, regardless of age, benefited from this intervention [4].


Ketogenesis

You already know that your ketone levels increase in ketosis.

The question is, how are ketones made?

As the term implies, ketogenesis refers to the process of creating ketones or ketone bodies. (Keto = ketones, genesis = formation)

Ketogenesis happens in the mitochondria of your liver. But while your liver produces ketones, it cannot use them.

These 3 ketone bodies are:

  • Beta-hydroxybutyrate (BHB)
  • Acetoacetate (AcAc)
  • Acetone

The truth is that your body continually produces a small number of ketones. With ketosis running in the background, you can be sure that you get all the energy you need to function [5].

Ketogenesis increases when your body needs more energy and glucose is less available. These situations include fasting, even the overnight fast while you’re sleeping at night [5].

Here are the basic steps involved in ketogenesis:


Step 1: Glycogen depletion

Your body needs glucose to meet its energy needs. The usual scenario is that we get glucose from carbohydrate-rich foods. If you limit your dietary carbs, your body taps into glycogen - the storage form of carbohydrates.

Once your glycogen stores have already been used up, your body now starts using its stored fat. Triglycerides in your fat cells (or adipocytes) are broken down into free fatty acids and glycerol [6].

Enzymes called lipases perform this “breakdown process.”


Step 2: Free fatty acids are released

What happens to these free fatty acids? Well, they enter the circulation and are taken into the mitochondria of your liver. Inside your liver, ketogenesis takes place.


Step 3: Creation of the 3 ketone bodies

ketone bodies

The free fatty acids that entered your liver undergo beta-oxidation to form acetyl-CoA molecules.

An enzyme HMG-CoA synthase helps convert excess acetyl-CoA into HMG-CoA. HMG-CoA will be used to form the primary ketone body, BHB [7].

Your liver forms acetoacetate first. Acetoacetate undergoes a reduction process to form beta-hydroxybutyrate. Acetoacetate also turns into acetone, the third and least abundant ketone.

Step 4: Your liver releases ketones into the blood

Now, ketones exit the liver and enter your extrahepatic tissues. These tissues include your brain, heart, and skeletal muscles [8].


But what regulates ketogenesis?

To understand what drives ketogenesis up or down, you need to know the hormones that affect it. These hormones are insulin and glucagon.

Insulin prevents ketogenesis from happening. When your insulin levels increase, your ketone levels decrease. Insulin increases whenever you eat. Remember that your pancreas releases insulin whether you eat carbohydrates, fat or protein [9].

But can you guess which macronutrient raises insulin the most?

That’s right; it’s carbohydrates.

Glucagon promotes ketogenesis. When insulin is low, glucagon helps increase the availability of free fatty acids. Again, your liver uses free fatty acids to turn them into ketones [9, 10].


Why is ketogenesis important?

Ketogenesis ensures that your body gets a continuous supply of energy. It allows you to continue to function when glucose is low, and you need an alternative fuel.

Want to know the best part?

Aside from its main benefit, which is energy supply, its byproducts can be therapeutic. Studies show that ketone bodies help with various conditions, which include [11, 12]:

  • Brain disorders, including Parkinson’s disease and Alzheimer’s disease
  • Insulin resistance
  • Weight management
  • Metabolic syndrome

ketosis misconception

Typical Ketosis Misconceptions

Is ketosis dangerous?

Does it come with serious risks?

Will ketosis lead to certain diseases?

At this point, you’re already aware of the science behind ketosis. That makes us say that ketosis is not just another fad.

But to put your mind at ease, we’re going to debunk some common misconceptions. We’re also going to support the points below with the most recent studies.


Myth #1: Ketosis and ketoacidosis are the same.

Ketoacidosis is a complication of Type 1 or Type 2 Diabetes and alcoholism. Ketone concentrations higher than 20 mmol/L. Your blood becomes too acidic. This condition can damage your brain cells and lead to coma [13, 14].

People who don’t understand ketosis can get confused between ketosis and ketoacidosis. One reason is that they sound alike, and another is that ketone levels increase in both states.

Know that following a well-formulated ketogenic plan prevents ketoacidosis from happening. Remember that ketone concentrations for ketosis usually stay between 0.5-3.0 mM [15].

A trained physician should provide you with ongoing medical supervision. This is one of the things that make nutritional ketosis safe.

Myth #2: Nutritional ketosis decreases muscle mass and athletic performance.

Here’s another common myth to bust. Do you think that staying away from carbohydrates hampers your bodybuilding goals?

A ketosis plan affects your strength for the first few weeks since you’ve been used to burning carbs for fuel.

But know that your strength improves when you become fat-adapted. Being “fat-adapted” means that your body quickly gets its energy needs from fat [16].

Give your body the time it needs to adjust.

keto science

Protein is another concern in nutritional ketosis. We know for a fact that the amino acids in protein help build muscle.

But you’ll be surprised to know this:

While your protein needs in nutritional ketosis are moderate, you’ll realize that they’re higher than standard recommendations. Check them out below:

  • Well-formulated keto diet: 1.2 to 2.0 g of protein per kg body weight [17]
  • Standard American diet: 0.8 grams of protein per kg body weight [17]

This should be good news for you.


Myth #3: Fasting is a must to achieve ketosis.

A lot of people think that they need to fast to increase their ketone levels. Yes, fasting forces your body to burn through its stored glycogen. Therefore, it helps boost your ketones [18].

However, fasting is not the only option you should rely on.

Researchers at the University of Calgary studied the necessity of fasting on a keto diet. 14 children with epilepsy followed a standard ketogenic diet at full calories. 12 of them had seizures daily before starting the diet [19].

Results showed that the average time to the onset of ketosis was 33 hours. As you can see, these children entered ketosis without fasting [19].

Phinney and Volek of Virta Health mention that it’s safe to fast only within a 24 hour period. Fasting beyond 24 hours leads to a loss of body protein from lean tissue. They also state that medical supervision is a must for people with Type 2 Diabetes who plan to fast [20, 21].

Decreasing your carbohydrates is enough to force your body to change its metabolism. Consuming 20-50 grams of carbs daily mobilizes stored fat and increases ketone production [22].


Myth #4: Nutritional ketosis raises blood glucose.

Some people claim that ketosis increases your blood sugar levels. Furthermore, it puts you at risk for Type 2 Diabetes. Note that studies that have this claim were conducted on mice, and that muscle insulin sensitivity was not affected [23].

Just recently, Virta Health released a 2-year study about Type 2 Diabetes reversal [24].

(Bear in mind that the term “reversal” doesn’t mean “cured.” Instead, reversal means that Hemoglobin A1C has normalized and a patient can discontinue all diabetes medications except for metformin.)

Here’s more about the 2-year study [24]:

262 individuals with Type 2 Diabetes participated in a continuous care intervention (CCI). This intervention included nutritional ketosis which was a personalized low-carbohydrate diet.

The researchers considered their health goals and provided them with nutritional education. The participants were also asked to eat fat to satiety. To be specific, this included monounsaturated and saturated fats along with adequate quantities of omega-3 and omega-6 polyunsaturated fats.

The results?

At 2 years, these participants achieved improvements with their blood glucose and other clinical markers of diabetes and cardiovascular health. They also became less dependent on medication.

Furthermore, they experienced a reduction in visceral fat. Take note that visceral fat predicts insulin resistance. It also increases the risk of Type 2 Diabetes [25].


Myth #5: Nutritional ketosis is only ideal over the short term.

Some people warn that sticking to ketosis can raise disease risk. This is why they believe that ketosis should be a short-term goal - not a lifestyle change.

Let’s take a look at a 2004 study on obesity, a condition that’s linked to several health problems [26]. This study examined the effects of a long-term ketogenic diet on 83 obese patients.

approved science keto

After 24 weeks, these patients experienced a significant decrease in their total cholesterol levels. Their HDL levels increased while their LDL levels decreased. Furthermore, weight and body mass index were significantly decreased. The results of the study showed that nutritional ketosis is sustainable over an extended period of time [27].


Conclusion

A state of ketosis implies that your body uses a super fuel called “ketones” rather than glucose. Ketosis has been around since the beginning of mankind. It enabled people, millions of years ago, to survive despite food scarcity.

You are producing ketones each day in small amounts, but they increase when your body needs them the most. When you follow a high-carbohydrate diet, your insulin increases, which hinders ketosis. A decrease in insulin increases ketone production.

Many people hold beliefs about ketosis that need to be verified. People achieve the full benefits of ketosis if they follow a well-formulated plan and seek the help of a trained physician.

We hope this guide helps you prepare better for ketosis.


Takeaways

  • Ketosis happens when there isn’t enough glucose in the body to use as fuel.
  • The creation of ketones or ketogenesis happens in the liver.
  • As ketones exit the liver, they enter your tissues to fuel them.
  • Various studies show the benefits of ketogenesis for your body. Aside from energy production, it offers therapeutic effects.
  • A well-formulated keto plan prevents ketoacidosis, a life-threatening condition.
  • Nutritional ketosis can maintain your athletic performance. It also can support muscle growth.
  • Your blood glucose levels and other health markers improve with nutritional ketosis.
  • Being in ketosis long-term can reduce obesity, as shown by a 24-week study.

References:

  1. Masood W, Uppaluri KR. Ketogenic Diet. 2019 January - https://www.ncbi.nlm.nih.gov/books/NBK499830/
  2. Scitable. ATP. - https://www.nature.com/scitable/definition/atp-318
  3. Phinney S, Volek J. Paleo vs. Keto: What’s the Difference? 2017 November 16 - https://blog.virtahealth.com/paleo-vs-keto-whats-the-difference/
  4. Meira et al. Ketogenic Diet and Epilepsy: What We Know So Far. 2019 January 29 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6361831/
  5. Dhillon KK, Gupta S. Biochemistry, Ketogenesis. 2019 January - https://www.ncbi.nlm.nih.gov/books/NBK493179/
  6. BCcampus. 24.3 Lipid Metabolism. - https://opentextbc.ca/anatomyandphysiology/chapter/24-4-lipid-metabolism/
  7. ScienceDirect. HMG-CoA. - https://www.sciencedirect.com/topics/agricultural-and-biological-sciences/hmg-coa
  8. Puchalska P, Crawford PA. Multi-dimensional roles of ketone bodies in fuel metabolism, signaling, and therapeutics. 2017 February 7 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5313038/
  9. ScienceDirect. Ketogenesis. - https://www.sciencedirect.com/topics/medicine-and-dentistry/ketogenesis
  10. Alberti KG et al. Hormonal regulation of ketone-body metabolism in man. 1978 - https://www.ncbi.nlm.nih.gov/pubmed/749914
  11. Veech RL et al. Ketone bodies, potential therapeutic uses. 2001 April - https://www.ncbi.nlm.nih.gov/pubmed/11569918
  12. Gershuni V, Medici V, Yan SL. Nutritional Ketosis for Weight Management and Reversal of Metabolic Syndrome. 2018 August - https://www.researchgate.net/publication/327117270_Nutritional_Ketosis_for_Weight_Management_and_Reversal_of_Metabolic_Syndrome
  13. Fedorovich SV, Voronina PP, Waseem TV. Ketogenic diet versus ketoacidosis: what determines the influence of ketone bodies on neurons? 2018 December - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6199956/
  14. Phinney S, Virta Team. What is ketoacidosis? - https://blog.virtahealth.com/what-is-ketoacidosis/
  15. Phinney S, Virta Team. How do I get into nutritional ketosis? - https://blog.virtahealth.com/how-do-i-get-into-nutritional-ketosis/
  16. Phinney S, Virta Team. What does it mean to be fat adapted? - https://blog.virtahealth.com/fat-adapted/
  17. Phinney S, Volek J, Volk B. How Much Protein Do You Need In Nutritional Ketosis? 2018 February 21 - https://blog.virtahealth.com/how-much-protein-on-keto/
  18. Charlie Foundation. Intermittent Fasting. - https://charliefoundation.org/intermittent-fasting/
  19. Wirrell EC et al. Is a fast necessary when initiating the ketogenic diet? 2002 March - https://www.ncbi.nlm.nih.gov/pubmed/12026232
  20. Phinney S, Virta Team. Is fasting safe? - https://blog.virtahealth.com/is-fasting-safe/
  21. Phinney S, Volek J. To Fast or Not to Fast: What Are the Risks of Fasting? 2017 December 5 - https://blog.virtahealth.com/science-of-intermittent-fasting/
  22. Oh R, Uppaluri KR. Low Carbohydrate Diet. 2019 January - https://www.ncbi.nlm.nih.gov/books/NBK537084/
  23. Grandl G et al. Short‐term feeding of a ketogenic diet induces more severe hepatic insulin resistance than an obesogenic high‐fat diet. 2018 August 8 - https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP275173
  24. Athinarayanan SJ et al. Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial. 2019 June 5 - https://www.frontiersin.org/articles/10.3389/fendo.2019.00348/full
  25. Usui C et al. Visceral fat is a strong predictor of insulin resistance regardless of cardiorespiratory fitness in non-diabetic people. 2010 - https://www.ncbi.nlm.nih.gov/pubmed/20495292
  26. NIH. Health Risks of Being Overweight. - https://www.niddk.nih.gov/health-information/weight-management/health-risks-overweight
  27. Dashti HM et al. Long-term effects of a ketogenic diet in obese patients. 2004 - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2716748/

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