In this article we will discuss about:- 1. Formation of Ketone Bodies 2. Conditions Leading to Ketosis 3. Source 4. Utilisation 5. Interrelation with Carbohydrate Metabolism 6. Ratio 7. Relation of Ketosis with Blood and Urine Reaction 8. Role of Endocrine.
Formation of Ketone Bodies (Ketogenesis):
It has been observed that acetyl CoA produced during fatty acid oxidation condense with oxalo-acetic acid for oxidation in the TCA cycle. The oxalo-acetic acid formation is depressed when glucose supply is restricted so that in this condition acetyl CoA cannot be properly metabolized through citric acid cycle.
Thus acetyl CoA condenses to form aceto-acetyl CoA which in the liver produces aceto-acetic acid. The aceto-acetic acid is reduced to form β-hydroxybutyric acid which after decarboxylation forms acetones. Acetoacetic acid, acetone and β-hydroxybutyric acid are called ketone bodies.
The process of formation of ketone bodies is called ketogenesis. Normally the ketone bodies are utilized without being accumulated in the body, but they may be abnormally accumulated in body fluids known as ketosis and excreted through the urine called ketonuria (or acetonuria). Its accumulation in the blood is called ketonemia.
Site of Formation of Ketone Bodies:
Liver is perhaps the only site where ketone bodies are normally formed since concentration of ketone bodies have been found to be higher in the hepatic vein than in other veins.
Antiketogenic Substances:
These are substances which prevent the formation of ketone bodies.
They include the following:
(1) All carbohydrates,
(2) 60% of proteins (antiketogenic amino acids) from which sugar may be formed and
(3) 10% of fats (the glycerol part)
Conditions Leading to Ketosis:
The following conditions produce ketosis:
(a) Diabetes mellitus,
(b) Starvation,
(c) High fat or low carbohydrate diet, and
(d) Muscular exercise.
Source of Ketone Bodies (Ketogenic Substances):
The ketogenic substances arise from:
(a) All fatty acids (i.e., 90% of food fat. Glycerol part burns as carbohydrates. Hence, it is antiketogenic.)
(b) Proteins (ketogenic amino acids, 40%). These are the sources from which ketone bodies are formed.
Utilisation of Ketones (Fig. 10.24):
It has been shown that ketone bodies are utilized rapidly and independently in many tissues with the production of CO2 and H2O. A significant amount of the normal energy requirement of the body is derived from this source. It has been shown that even the tissues of the diabetic animals can oxidize the ketone bodies completely even if no sugar is burnt. Recently it has been established that human brain can utilize appreciable amount of ketone bodies during prolonged starvation.
Interrelation with Carbohydrate Metabolism in Ketone Bodies:
It has been observed above that the ketone bodies only appear when enough carbohydrate is not burnt. It has also been shown that ketones can be utilized freely, without any sugar being oxidized. The interrelation between sugar oxidation and ketone formation lies in the fact that in diabetes mellitus and starvation, the glycogen content of the liver becomes low.
Since in these two conditions the fatty acids are not esterified and ketone bodies are formed. On high carbohydrate diet free fatty acid oxidation is spared. The energy requirement of the body must therefore be supplied from the oxidation of fats. For this reason fats are mobilized from the depots in large quantities and brought to the liver. Liver (whose glycogen content is already low) becomes loaded with fats.
Consequently, fat oxidation takes place at a heightened rate and more ketones are formed. They come out of the cell and enter the blood stream and finally eliminated through urine. [It is due to such leakage that normal urine shows traces of ketones.] Obviously ketones are formed at a faster rate than can be utilised. Hence ketosis may not be even due to non-utilisation of the ketone bodies but is due to their overproduction.
Ketogenic/Antiketogenic Ratio:
While prescribing diets the proportion of the ketogenic and antiketogenic substances should be so regulated that ketosis may be avoided. It is found that if the ratio between the molecules of the ketogenic substances and the molecules of the antiketogenic substances exceeds 2, ketone bodies appear in the urine. The clinical rule is that the total fat (F) content of the diet must not exceed the sum of twice the carbohydrate (C) and half of the protein (P), i.e., F = or < (2C + 1/2 P).
i. Ketonemia:
Rise of ketone bodies in blood above normal value is known as ketonemia.
ii. Ketonuria:
When blood level of ketone bodies rises above the renal threshold, they are excreted in the urine. This is a condition known as ketonuria.
iii. Ketosis:
Accumulation of abnormal amount of ketone bodies in the tissue and tissue fluids is termed as ketosis where the urinary excretion of β-hydroxybutyric acid exceeds 200 mgm daily (normal, 5-10 mgm).
Relation of Ketosis with Blood and Urine Reaction:
During ketosis aceto-acetic acid, β-hydroxybutyric acid, etc., are formed. Since these are all acids, ketosis is usually associated with a condition of acidosis in the body and increased acidity of the urine. Due to this relation between acidosis and ketosis, acetone bodies are generally found in highly acid urine. But it must be remembered that acidosis is the result and not the cause of ketosis. A large part of acids in the urine exists— as anions. For the maintenance of neutrality cations like Na+ are lost. As a result sodium salts are lost from plasma and other body fluids and consequently there is loss of body fluid resulting dehydration.
It is highly interesting that even in genuine cases of alkalosis (with alkaline urine) ketone bodies may be found in the urine. This can be demonstrated in subjects in which experimental alkalosis is produced by prolonged voluntary hyperpnoea. It is probable that in this condition β-hydroxybutyric acid, aceto-acetic acid, etc., (which is soluble and diffusible) migrate out of the cells to neutralize alkalis and are excreted in the urine.
In hospital cases alkaline urine containing acetone lodies is not an infrequent observation.
It may be:
(a) Due to ammoniacal decomposition resulting from long standing,
(b) Due to therapeutic administration of alkalis to combat acidosis, and
(c) Due to true alkalosis as mentioned above.
Role of Endocrines on Ketosis:
i. Anterior Pituitary:
The growth or somatotrophic hormone (STH) of anterior pituitary produces ketosis in diabetes mellitus and starvation due to inhibition of insulin secretion and depression of glycogenesis.
ii. Insulin:
It prevents ketosis and its administration clears up the condition of ketosis in diabetes mellitus.
This effects is due to the following:
a. It increases liver glycogen, prevents mobilisation of fats from the depots and thus reduces liver fats. Consequently fat oxidation is discouraged and more carbohydrates burn. This leads to less ketone formation, so that ketosis disappears.
b. Insulin is antagonistic to the growth or somatotrophic hormone of anterior pituitary.
iii. Adrenal Cortex:
Glucocorticoids of adrenal glands are adipokinaetic, i.e., mobilise depot fat to the liver for oxidation.
iv. Thyroid:
Thyroxine increases ketosis under certain conditions. Its action is probably due to decrease in liver glycogen and its consequent loading with fat.