What is ketosis?
Ketosis is the end result of a shift in the insulin/glucagon ratio and indicates an overall shift from a glucose based metabolism to a fat based metabolism. Ketosis occurs in a number of physiological states including fasting (called starvation ketosis), the consumption of a high fat diet (called dietary ketosis), and immediately after exercise (called post-exercise ketosis). Two pathological and potentially fatal metabolic states during which ketosis occurs are diabetic ketoacidosis and alcoholic ketoacidosis.
The major difference between starvation, dietary and diabetic/alcoholic ketoacidosis is in the level of ketone concentrations seen in the blood. Starvation and dietary ketosis will normally not progress to dangerous levels, due to various feedback loops which are present in the body. Diabetic and alcoholic ketoacidosis are both potentially fatal conditions.
All ketotic states ultimately occur for the same reasons. The first is a reduction of the hormone insulin and an increase in the hormone glucagon both of which are dependent on the depletion of liver glycogen. The second is an increase in FFA availability to the liver, either from dietary fat or the release of stored bodyfat.
Under normal conditions, ketone bodies are present in the bloodstream in minute amounts, approximately 0.1 mmol/dl. When ketone body formation increases in the liver, ketones begin to accumulate in the bloodstream. Ketosis is defined clinically as a ketone concentration above 0.2 mmol/dl. Mild ketosis, around 2 mmol, also occurs following aerobic exercise.
Ketoacidosis is defined as any ketone concentration above 7 mmol/dl. Diabetic and alcoholic ketoacidosis result in ketone concentrations up to 25 mmol. This level of ketosis will never occur in non-diabetic or alcoholic individuals.
Ketonemia and ketonuria
The general metabolic state of ketosis can be further subdivided into two categories. The first is ketonemia which describes the buildup of ketone bodies in the bloodstream. Technically ketonemia is the true indicator that ketosis has been induced. However the only way to measure the level of ketonemia is with a blood test which is not practical for ketogenic dieters.
The second subdivision is ketonuria which describes the buildup and excretion of ketone bodies in the urine, which occurs due to the accumulation of ketones in the kidney. The excretion of ketones into the urine may represent 10-20% of the total ketones made in the liver.
However, this may only amount to 10-20 grams of total ketones excreted per day. Since ketones have a caloric value of 4.5 calories/gram, the loss of calories through the urine is only 45-90 calories per day.
The degree of ketonuria, which is an indirect indicator of ketonemia, can be measured by the use of Ketostix ™, small paper strips which react with urinary ketones and change color.
Ketonemia will always occur before ketonuria. Ketone concentrations tend to vary throughout the day and are generally lower in the morning, reaching a peak around midnight. This may occur from changes in hormone levels throughout the day. Additionally, women appear to show deeper ketone levels than men and children develop deeper ketosis than do adults. Finally, certain supplements, such as N-acetyl-cysteine, a popular anti-oxidant, can falsely indicate ketosis.
The distinction between ketonuria and ketonemia is important from a practical standpoint. Some individuals, who have followed all of the guidelines for establishing ketosis will not show urinary ketones. However this does not mean that they are not technically in ketosis.
Ketonuria is only an indirect measure of ketone concentrations in the bloodstream and Ketostix ™ measurements can be inaccurate.
What does ketosis represent?
The development of ketosis indicates two things. First, it indicates that the body has shifted from a metabolism relying primarily on carbohydrates for fuel to one using primarily fat and ketones for fuel. This is arguably the main goal of the ketogenic diet: to cause an overall metabolic shift to occur in the body. The reasons this shift may actually be desirable.
Second, ketosis indicates that the entire pathway of fat breakdown is intact. The absence of ketosis under conditions which are known to induce it would indicate that a flaw in fat breakdown exists somewhere in the chain from fat breakdown, to transport, to oxidation in the liver. This absence would indicate a metabolic abnormality requiring further evaluation.
Blood pH and ketoacidosis
A major concern that frequently arises with regards to ketogenic diets is related to the slight acidification caused by the accumulation of ketone bodies in the bloodstream. Normal blood pH is 7.4 and this will drop slightly during the initial stages of ketosis.
While blood pH does temporarily decrease, the body attains normal pH levels within a few days as long as ketone body concentrations do not exceed 7-10 mmol. Although blood pH is normalized after a few days, the buffering capacity of the blood is decreased, which has implications for exercise.
There is frequent confusion between the dietary ketosis seen during a ketogenic diet and the pathological and potentially fatal state of diabetic ketoacidosis (DKA). DKA occurs only in Type I diabetes, a disease characterized by a defect in the pancreas, whereby insulin cannot be produced. Type I diabetics must take insulin injections to maintain normal blood glucose levels.
In diabetics who are without insulin for some time, a state that is similar to dietary ketosis begins to develop but with several differences.
Although both dietary ketosis and DKA are characterized by a low insulin/glucagon ratio, a non-diabetic individual will only develop ketosis with low blood glucose (below 80 mg/dl) while a Type I diabetic will develop ketosis with extremely high blood glucose levels (Type I diabetics may have blood glucose levels of 300 mg/dl or more).
Additionally, the complete lack of insulin in Type I diabetics appears to further increase ketone body formation in these individuals. While a non-diabetic individual may produce 115-180 grams of ketones per day, Type I diabetics have been found to produce up to 400 grams of ketones per day. The drop in blood pH seen in DKA is probably related to the overproduction of ketones under these circumstances.
This increase in ketone formation is coupled with an inability in the Type I diabetic to use ketones in body tissues. Presumably this occurs because blood glucose is present in adequate amounts making glucose the preferred fuel. Thus there is a situation where ketone body formation is high but ketone body utilization by the body is very low, causing a rapid buildup of ketones in the bloodstream.
Additionally, in non-diabetic individuals there are at least two feedback loops to prevent runaway ketoacidosis from occurring. When ketones reach high concentrations in the bloodstream (approximately 4-6 mmol), they stimulate a release of insulin. This increase in insulin has three major effects. First, it slows FFA release from the fat cell. Second, by raising the insulin/glucagon ratio, the rate of ketone body formation in the liver is decreased .
Third, it increases the excretion of ketones into the urine. These three effects all serve to lower blood ketone body concentration.
In addition to stimulating insulin release, ketones appear to have an impact directly on the fat cell, slowing FFA release. This would serve to limit FFA availability to the liver, slowing ketone body formation. Ultimately these two feedback loops prevent the non-diabetic individual from overproducing ketones since high ketone levels decrease ketone body formation.
Type I diabetics lack both of these feedback loops. Their inability to release insulin from the pancreas prevents high ketone body levels from regulating their own production. The clinical treatment for DKA is insulin injection which rapidly shuts down ketone body formation in the liver, slows FFA release from fat cells, and pushes ketones out of the bloodstream.
Additionally, rehydration and electrolyte supplementation is necessary to correct for the effects of DKA.
The feedback loops present in a non-insulin using individual will prevent metabolic ketosis from ever reaching the levels of runaway DKA.
One additional pathological state which is occasionally confused with dietary ketosis is alcoholic ketoacidosis. Alcoholic KA occurs in individuals who have gone without food while drinking heavily. Ethanol also has effects on ketone body formation by the liver, causing a runaway ketotic state similar to DKA. In contrast to DKA, alcoholic ketoacidosis can be easily reversed by eating carbohydrates as this increases insulin and stops ketone formation.
Ketosis is a metabolic state where ketones and FFA replace glucose as the primary fuel of the body in most tissues. The presence of ketosis indicates that fat breakdown has been activated in the body and that the entire pathway of fat degradation is intact. The lack of ketosis in states such as fasting and a ketogenic diet known to induce ketosis would indicate the presence of a metabolic abnormality.
Ketosis can be delineated into ketonemia, the presence of ketones in the bloodstream, and ketonuria, the presence of ketones in the urine. Clinically, ketosis is defined as a ketone concentration of 0.2 mmol. A ketogenic diet or fasting will result in ketone levels between 4 and 8 mmol. Ketoacidosis is defined as 8 mmol or higher and pathological ketoacidosis, as in diabetic ketoacidosis, can result in ketone concentrations of 20 mmol or greater. Ketoacidosis, as it occurs in Type I diabetics and alcoholics and which is potentially fatal, will not occur in nondiabetic individuals due to built in feedback loops whereby excess ketones stimulate the release of insulin, slowing ketone body formation.
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