The Ketogenic Diet: How to gain back control over your diet and health. Part 2

In the second part of our series, I will discuss the application and physiological background of the Keto Diet.

Physiological background

Modern Application of Keto Diet

Despite great advances in medicine, poor lifestyle choices remain a worldwide health hazard. The majority of chronic diseases like diabetes Type 2, hypertension, cardiovascular diseases, chronic inflammation, fibromyalgia and dementia are the products of unhealthy lifestyles accompanied by poor dietary habits(1).

The Keto Diet is a proven dietary regimen low in carbs and high in fat, and is effective for rapid weight loss, continuous weight management, lowering blood sugar levels, improving cardiovascular health and increasing productivity. (2, 3)

In general, based on a 2000 kcal per day diet, dietary macronutrients are divided into approximately 70-80% fat, 20-25% protein, and less than 10% carbohydrates.

Ketogenic Diet food

Physiology of the Keto Diet

Our body, primarily our brain, uses carbohydrates as the primary source for energy production in mitochondria. (4)

Hypothetical role of ketogenic diet in cancer metabolic rewiring. Cancer cells rely upon metabolic rewiring characterized by increased glucose uptake (red arrow) and glycolysis, increased glutaminolysis and TCA cycle rates, which sustain biomass expansion and tumor growth. Ketogenic diet, by reducing glucose oxidation (green arrow), does not further support cancer cells proliferation, thereby impairing tumor expansion.

In the Keto Diet, carbohydrate uptake is significantly lowered, and the body is deprived of this source of energy.(5) Continuous low carb intake significantly reduces insulin secretion and depletes glycogen stores. The body then enters the so-called “catabolic state” (breaking down). In this state, the body starts breaking down both fat and muscle to produce energy and generate glucose internally to feed the brain and the muscles that rely on glucose. Large, complex molecules found in food are cut into smaller bits, which are then used to generate glucose from noncarbohydrate sources, specifically fat and muscle.

Gluconeogenesis describes the generation of glucose within the body from these fat and muscle bits, occurring in the liver and kidneys. It is an “anabolic process” (building up) that aims to provide sustenance and maintenance.

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)

Anabolism and Catabolism are part of our physiology. During Anabolism, our body gains mass and weight. In contrast, during Catabolism, our body loses mass due to the breakdown of fat and muscles.

Glucose deprivation in the Keto Diet prevents mass gain as all the glucose generated by the body is used to maintain glucose-dependent functions, but not to increase fat and muscle mass. In contrast, the excessively consumed carbohydrates in a poor diet are only partially used for maintenance and energy production. The unused majority of carbs are converted and stored as fat, resulting in weight gain.

In the Keto Diet, the limited dietary intake of glucose cannot keep up with the demand for energy, and the body searches for alternative sources of energy, and ketogenesis begins.

Gluconeogenesis describes the generation of glucose within the body from these fat and muscle bits

Ketogenesis is the body’s ability to form ketone bodies as an alternate source of energy. Ketone bodies replace glucose as a primary source of energy.

During ketogenesis, the body uses lactic acid, glycerol, amino acids, and glutamine, but also deaminated amino acids such as leucine, to generate ketone bodies.

Biochemistry of Ketogenesis

During ketogenesis, the body starts to break down fats first into fatty acids and then into acetoacetate, which is then converted (“metabolized”) into beta-hydroxybutyrate and acetone. Ketogenesis and the production of ketone bodies occur mostly in the mitochondria of liver cells.

Ketone bodies are processed for energy and broken down by a process called beta-oxidization, forming the energy-rich molecule acetyl-CoA. In a regular diet, acetyl-CoA is used by mitochondria for energy generation in the TCA-Krebs cycle. In the Ketogenic Diet, acetyl-CoA is significantly more abundant, and its availability exceeds the processing capacity of the TCA-Krebs cycle. In this case, the excess acetyl-CoA is used to generate Ketone bodies. As the name indicates, both processes require CoA or Coenzyme A. The availability of CoA in the liver cells is another limiting factor in the processing of acetyl-CoA.

KETOGENESIS, biochemical pathway

The breakdown of a single acetyl-CoA yield three different ketone bodies:

  1. Acetoacetate, which is then converted into beta-hydroxybutyrate
  2. Acetone, which is then further metabolized to few more intermediate steps into energy-rich molecules pyruvate, lactate, and acetate.
  3. Beta-hydroxybutyrate (from acetoacetate), the most abundant form of ketone bodies.

Both acetoacetate and beta-hydroxybutyrate can pass through cell membranes and provide fuel for cells. Most importantly, both ketone bodies can pass through the blood barrier and can be used by the brain as an energy source. In contrast, fatty acids cannot be metabolized in the brain(6).

When deprived of glucose, the brain can cover about 70% of its energy needs from ketone bodies.

When deprived of glucose, the brain can cover about 70% of its energy needs from ketone bodies. Here, ketone bodies are broken down in a process called ketolysis and converted into energy through processing by the enzyme succinyl-CoA.

Acetone is a byproduct of ketogenesis and is excreted through the lungs. It is also responsible for the name of this diet as it is called a “ketone” in chemical terminology. Acetone, a chemical found in nail polish remover, is also responsible for the bad breath caused by this diet.

Regulation of Ketogenesis

Ketogenesis is triggered by the lack of glucose but is tightly regulated to avoid ketoacidosis, a potentially fatal condition. Both the production and consumption of ketone bodies must be in balance. The ketone bodies acetoacetate and beta-hydroxybutyrate are both acidic. Their uncontrolled accumulation can increase the acidity of the blood and decrease blood pH, resulting in ketoacidosis. This life-threatening condition affects people with uncontrolled diabetes (diabetic ketoacidosis), but also affects people with improper use of the keto diet (nutritional ketoacidosis). Weakness, fatigue, flushed face, fruity-smelling breath with acetone odor, stomach pain, trouble breathing, and nausea/vomiting are common symptoms of ketoacidosis. Call 911 if you are experiencing these symptoms. Before starting the Keto Diet consult your licensed physician!


G. M. Broom, I. C. Shaw, J. J. Rucklidge, The ketogenic diet as a potential treatment and prevention strategy for Alzheimer’s disease. Nutrition 60, 118-121 (2019).

2.         S. Bruce, A. Devlin, L. Air, L. Cook, Changes in quality of life as a result of ketogenic diet therapy: A new approach to assessment with the potential for positive therapeutic effects. Epilepsy Behav 66, 100-104 (2017).

3.         M. Magner, H. Kolarova, T. Honzik, I. Svandova, J. Zeman, Clinical manifestation of mitochondrial diseases. Dev Period Med 19, 441-449 (2015).

4.         V. J. Miller, F. A. Villamena, J. S. Volek, Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. J Nutr Metab 2018, 5157645 (2018).

5.         L. R. Saslow et al., An Online Intervention Comparing a Very Low-Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial. J Med Internet Res 19, e36 (2017).

6.         A. L. Hartman, M. Gasior, E. P. Vining, M. A. Rogawski, The neuropharmacology of the ketogenic diet. Pediatr Neurol 36, 281-292 (2007).

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