The Ketogenic Dietary Regimen

Ketosis a particular metabolic state of the organism to be regarded as a physiological condition that has enabled human beings to survive conditions of famine and prolonged absence of food. Ketosis (i.e., the increase of certain molecules called ketone bodies) can also occur in some pathological conditions, but apart from these conditions, it is to be considered a physiological adaptive response of the organism.

Two methods have historically been used to induce ketosis: either fasting or a diet of meat/fish and fat (such as in the Inuit). Now, on the other hand, it is also possible to implement a ketogenic regimen by using a so-called aglucidic diet that involves foods made to look like carbohydrates while containing no or minimal carbohydrates.

When carbohydrates, whether starches or simple sugars, are eaten, the body burns the glucose from which they are formed to obtain energy. Glucose obtained from food is used to produce energy; excess glucose is stored as glycogen in the liver and muscles. Glucose in excess and therefore not stored as glycogen or used immediately is converted into body fat. When needed for energy production, stored glycogen is converted back to glucose and used directly or transported by blood to other cells in the body for use.

On an aglucidic diet, as the liver glycogen needed to produce energy is reduced and the blood glycogen is also reduced (but not excessively so ), the body will derive energy from the breakdown of fatty acids in the diet and from stored fat in the body (while the glucose present will be used in other metabolic pathways). Under these conditions, therefore, the body will switch from a mixed metabolism (sugars/fat) to a predominantly fat-based one that will be derived from storage tissues (body fat) to produce the energy it needs.

This shift to almost exclusively fat-based energy sources can be measured by a simple test that analyzes oxygen consumption and carbon dioxide emission, and all research has confirmed this shift.

When the supply of glucose becomes insufficient, the circulating fatty acids are "broken up" into smaller compounds that, in the liver, are further broken down to create three small molecules: the ketone bodies precisely. They are produced, precisely, for the most part by the liver but not used by it because the liver lacks the enzyme necessary to metabolize them.

Ketone bodies then allow energy to be supplied to the various tissues (mainly the brain) by processing fats by alternative routes that then lead to their formation. The ketone bodies then enter the circulation, manage to reach the brain by passing the membrane surrounding it (and which fats unlike glucose cannot cross) and thus nourish the brain cells.

This compound is then cleaved into two acetyl-CoA molecules, which can be used in the mitochondria for energy production via the Krebs cycle. This mechanism allows mammals to overcome the limitation imposed by the blood-brain barrier (BEE), which normally prevents the passage of free fatty acids, thus providing an alternative energy substrate (ketone bodies) for the cells of the central nervous system (CNS) in the event of glucose deficiency (in fact, we know that, under normal conditions, the brain depends almost exclusively on glucose).

From an endocrine perspective, the regulation of keto-genesis (production of ketone bodies) and keto-lysis (utilization of ketone bodies) is complex and involves several hormones, including insulin, glucagon, cortisol, catecholamines, and growth hormone. After a meal, insulin activates the enzyme acetyl-CoA carboxylase, increasing levels of malonyl-CoA, a metabolite that stimulates fatty acid synthesis and inhibits the enzyme CPT1 (carnitine-palmitoyl transferase 1), thereby blocking fatty acid oxidation and, consequently, ketogenesis.

During a ketogenic diet (KD), however, the reduction of malonyl-CoA and activation of AMPK (also promoted by glucagon and epinephrine) inhibit acetyl-CoA carboxylase, allowing CPT1 to resume its activity. This leads to increased fatty acid oxidation and the production of large amounts of mitochondrial acetyl-CoA, the precursor of ketone bodies. In addition, reduced insulin inhibits HMG-CoA reductase, reducing cholesterol synthesis and increasing ketogenesis.

To have these effects, ketone bodies must rise above certain levels: For example, ketone bodies may start at about 0.1 mmol after overnight fasting, rise to 3 mmol after 3 days of fasting to 7-8 mmol in prolonged fasts (>24 days). Under these conditions, where at the same time blood sugar drops but still remains at physiological values, ketone body transporters can work efficiently.

Although still the word ketosis may create a certain fear in some people related to pathological frameworks, research has shown that the regulation of ketones in the body is very effective and in healthy individuals never exceeds the limit of 7-8 mmol/L, which can happen in insulin-dependent diabetics not adequately controlled by therapy. In recent years, research has not only debunked the common belief that ketones were somehow toxic products derived from "incorrect" fat burning during conditions of carbohydrate restriction, but rather, recent evidence shows that ketones are a crucial alternative source of metabolic fuel for living beings, with a positive metabolic role even under conditions of carbohydrate abundance (the so-called 'ketohormetic hypothesis').

Thus, physiological ketosis should not be confused with ketoacidosis, a pathological condition typical precisely of decompensated type 1 diabetes in which ketone bodies can reach dangerous levels leading to even lethal consequences. In fact, it can be argued that no species could have survived for millions of years if its members were unable to tolerate short and occasional periods of natural food deprivation, which in itself is ketogenic. During fasting, glucose and insulin concentrations fall while glucagon increases. These changes induce a sharp increase in free fatty acids at the time of transition from a nutritional to a fasting condition. As observed decades ago, after about 3 days, hunger drops significantly concurrently with the rise in ketone bodies to maximum levels of 4/6 mmol/L

This moderate ketosis is the body's natural adaptation to fasting and should therefore not be confused with the dangerous ketoacidosis associated with decompensated type 1 diabetes! In contrast to prolonged, absolute fasting conditions, ketogenic diets provide adequate amounts of protein that can preserve lean mass and be converted into the minimum amount of carbohydrate needed through the process known as gluconeogenesis.

In fact, when dietary sugars are eliminated in the body there is an intense production of glucose from glycogen reserves (glycogenolysis) and from the carbonaceous skeleton of amino acids (neoglucogenesis). The latter process is very expensive in terms of energy, i.e., our body spends a lot of energy to produce the amount of glucose it needs from protein, and this is one of the other reasons for the effectiveness of an aglucidic diet. In fact, the introduction of only 20-30 g of carbohydrates per day forces the body, in the early stages, to make another 60-65 g of glucose from protein by neoglucogenesis.

100 g of "average" protein provides about 57 g of glucose so that 110 g of protein is needed to produce the 60/65 g of glucose with an additional energy cost for this process of about (4/5 Kcal/gram) for a total of about 400/500 Kcal/day. For this reason, under conditions of prolonged ketosis, the body, after a few days, goes into "saving" mode by reducing the process of gluconeogenesis and emphasizing the process of mobilization and utilization of storage fat: a process known as lipolysis. In addition, a usually unimportant process, namely the transformation of glycerol binding 3 fatty acids in triglycerides (the storage form of fat in our body) into glucose, becomes instead essential to keep blood sugar constant by "sparing" proteins. This process of converting glycerol into glucose is an important source and glucose during ketosis and especially in people with obesity.

Lipolysis is the process of degrading triglycerides into fatty acids and glycerol, and is stimulated by decreased insulin levels and increased glucagon during a ketogenic diet. The reduction of insulin, an anabolic hormone, is crucial because it inhibits lipolysis and promotes lipogenesis. When insulin levels decrease, hormone-sensitive lipase (HSL), a key enzyme in adipose fat mobilization, is activated. HSL hydrolyzes stored triglycerides, releasing fatty acids into the bloodstream.

In parallel, increased levels of glucagon, a catabolic hormone, stimulate lipolysis. Glucagon activates AMP-activated protein kinase (AMPK), a cellular energy sensor that plays a key role in lipid metabolism. When energy reserves are low, as in conditions of ketosis, AMPK is activated, promoting lipolysis through phosphorylation of HSL and other enzymes involved in fatty acid metabolism.

AMPK activation not only stimulates lipolysis but also inhibits lipogenesis, creating a favorable environment for fat mobilization. In addition, AMPK promotes fatty acid oxidation by increasing the expression of enzymes such as carnitine palmitoyl transferase 1 (CPT1), which facilitates the transport of fatty acids into the mitochondria for beta-oxidation.

Another interesting mechanism involves steroid-regulated transcription factor 1 (SREBP-1), which is inhibited by activation of AMPK. SREBP-1 is involved in the regulation of lipogenesis, and by inhibiting it, AMPK further contributes to decreased fat synthesis and enhanced lipolysis.

In summary, lipolysis during a ketogenic diet is regulated by a complex interaction between insulin and glucagon, with a crucial role of AMPK. Decreasing insulin activates HSL and other metabolic pathways, while increasing glucagon stimulates AMPK activation, promoting fatty acid mobilization and oxidation. These mechanisms together promote efficient release of energy from adipose stores.

Ketosis, if modulated appropriately through a carefully designed diet and also with the use of aglucidic products that aid dietary adherence can be an important therapeutic aid in various disease conditions.