Ketosis

Ketosis

November 1, 2019 0 By William Morgan


Ketosis is a metabolic state where most of
the body’s energy supply comes from ketone bodies in the blood, in contrast to a state
of glycolysis where blood glucose provides most of the energy. It is characterised by
serum concentrations of ketone bodies over 0.5 millimolar with low and stable levels
of insulin and blood glucose. It is almost always generalized, with hyperketonemia, that
is, an elevated level of ketone bodies in the blood throughout the body. Ketone bodies
are formed by ketogenesis when liver glycogen stores are depleted. The main ketone bodies
used for energy are acetoacetate and β-hydroxybutyrate, and the levels of ketone bodies are regulated
mainly by insulin and glucagon. Most cells in the body can use both glucose and ketone
bodies for fuel, and during ketosis free fatty acids and glucose synthesis fuel the remainder.
During the usual overnight fast the body’s metabolism naturally switches into ketosis,
and will switch back to glycolysis after a carbohydrate-rich meal. Longer-term ketosis
may result from fasting or staying on a low-carbohydrate diet, and deliberately induced ketosis serves
as a medical intervention for intractable epilepsy. In glycolysis higher levels of insulin
promote storage of body fat and block release of fat from adipose tissues, while in ketosis
fat reserves are readily released and consumed. For this reason ketosis is sometimes referred
to as the body’s “fat burning” mode. Ketosis should not be confused with the similar-sounding
ketoacidosis, a dangerous condition caused by a failure to produce insulin resulting
in high uncontrolled levels of both ketone bodies and glucose. Degree of ketosis
The concentration of ketone bodies may vary depending on diet, exercise, degree of metabolic
adaptation and genetic factors. Nutritional ketosis can be established when a low carbohydrate
and moderate protein diet is followed for more than 3 days. This table shows the concentrations
typically seen under different conditions Note that urine measurements may not reflect
blood concentrations. Urine concentrations will be lower with greater hydration, and
after adaptation to a ketogenic diet the amount lost in the urine drops while the metabolism
remains ketotic. In addition most urine strips only measure acetoacetate, while after adaptation
the predominant ketone body is β-hydroxybutyrate. Metabolic pathways
When glycogen stores are not available in the cells, fat is cleaved to provide 3 fatty
acid chains and 1 glycerol molecule in a process known as lipolysis. Most of the body is able
to use fatty acids as an alternative source of energy in a process called beta-oxidation.
One of the products of beta-oxidation is acetyl-CoA, which can be further used in the citric acid
cycle. During prolonged fasting or starvation, or as the intentional result of a ketogenic
diet, acetyl-CoA in the liver is used to produce ketone bodies instead, leading to a state
of ketosis. During starvation or a long physical training
session, the body starts using fatty acids instead of glucose. The brain cannot use long-chain
fatty acids for energy because they are completely albumin-bound and cannot cross the blood–brain
barrier. Not all medium-chain fatty acids are bound to albumin. The unbound medium-chain
fatty acids are soluble in the blood and can cross the blood–brain barrier. The ketone
bodies produced in the liver can also cross the blood–brain barrier. In the brain, these
ketone bodies are then incorporated into acetyl-CoA and used in the citric acid cycle.
The ketone body acetoacetate will slowly decarboxylate into acetone, a volatile compound that is
both metabolized as an energy source and lost in the breath and urine.
Ketoacidosis Ketone bodies are acidic, but acid-base homeostasis
in the blood is normally maintained through bicarbonate buffering, respiratory compensation
to vary the amount of CO2 in the bloodstream, hydrogen ion absorption by tissue proteins
and bone, and renal compensation through increased excretion of dihydrogen phosphate and ammonium
ions. Prolonged excess of ketone bodies can overwhelm normal compensatory mechanisms,
leading to acidosis if blood pH falls below 7.35.
There are two major causes of ketoacidosis: Most commonly, ketoacidosis is diabetic ketoacidosis,
resulting from increased fat metabolism due to a shortage of insulin. It is associated
primarily with type I diabetes, and may result in a diabetic coma if left untreated.
Alcoholic ketoacidosis presents infrequently, but can occur with acute alcohol intoxication,
most often following a binge in alcoholics with acute or chronic liver or pancreatic
disorders. Alcoholic ketoacidosis occurs more frequently following methanol or ethylene
glycol intoxication than following intoxication with uncontaminated ethanol.
A mild acidosis may result from prolonged fasting or when following a ketogenic diet
or a very low calorie diet. Diet
If the diet is changed from one that is high in carbohydrates to one that does not provide
sufficient carbohydrate to replenish glycogen stores, the body goes through a set of stages
to enter ketosis. During the initial stages of this process, blood glucose levels are
maintained through gluconeogenesis, and the adult brain does not burn ketones. However,
the brain makes immediate use of ketones for lipid synthesis in the brain. After about
48 hours of this process, the brain starts burning ketones in order to more directly
use the energy from the fat stores that are being depended upon, and to reserve the glucose
only for its absolute needs, thus avoiding the depletion of the body’s protein store
in the muscles. Ketosis is deliberately induced by use of
a ketogenic diet as a medical intervention in cases of intractable epilepsy. Other uses
of low-carbohydrate diets remain controversial. Induced ketosis or low-carbohydrate diet terms
have very wide interpretation. Therefore Stephen S. Phinney and Jeff S. Volek coined the term
“nutritional ketosis” to avoid the confusion. Carbohydrate deprivation to the point of ketosis
has been argued both to have negative and positive effects on health.
Diagnosis Whether ketosis is taking place can be checked
by using special urine test strips such as Ketostix. The strips have a small pad on the
end which is dipped in a fresh specimen of urine. Within a matter of seconds, the strip
changes color indicating the level of ketone bodies detected, which reflects the degree
of ketonuria, which, in turn, can be used to give a rough estimation of the level of
hyperketonemia in the body. Alternatively, some products targeted to diabetics such as
the Abbott Precision Xtra or the Nova Max can be used to take a blood sample and measure
the ketone levels directly. Normal serum reference ranges for ketone bodies are 0.5–3.0 mg/dL,
equivalent to 0.05–0.29 mmol/L. Also, when the body is in ketosis, one’s breath
may smell of acetone. This is due to the breakdown of acetoacetic acid into acetone and carbon
dioxide which is exhaled through the lungs. Acetone is the chemical responsible for the
smell of nail polish remover and some paint thinners.
Controversy Some clinicians regard restricting a diet
from all carbohydrates as unhealthy and dangerous. However, it is not necessary to completely
eliminate all carbohydrates from the diet in order to achieve a state of ketosis. Other
clinicians regard ketosis as a safe biochemical process that occurs during the fat-burning
state. Ketogenesis can occur solely from the byproduct of fat degradation: acetyl-CoA.
Ketosis, which is accompanied by gluconeogenesis, is the specific state with which some clinicians
are concerned. However, it is unlikely for a normal functioning person to reach life-threatening
levels of ketosis, defined as serum beta-hydroxybutyrate levels above 15 millimolar compared to ketogenic
diets among non diabetics which “rarely run serum B-OHB levels above 3 mM.” This is avoided
with proper basal secretion of pancreatic insulin. People who are unable to secrete
basal insulin, such as type 1 diabetics and long-term type II diabetics, are liable to
enter an unsafe level of ketosis, causing an eventual comatose state that requires emergency
medical treatment. The anti-ketosis conclusions have been challenged
by a number of doctors and advocates of low-carbohydrate diets, who dispute assertions that the body
has a preference for glucose and that there are dangers associated with ketosis. The Inuit
are often cited an example of a culture that has lived for thousands of years on a low-carbohydrate
diet. However, in multiple studies the traditional Inuit diet has not been shown to be a ketogenic
diet. Not only have multiple researchers been unable to detect any evidence of ketosis resulting
from the traditional Inuit diet, but the ratios of fatty-acid to glucose were observed to
be well below the generally accepted level of ketogenesis. The Inuit consumed as much
as 15-20% of their calories from carbohydrates, largely from the glycogen found in raw meats.
Furthermore, the blubber, organs, muscle and skin of the diving marine mammals that the
Inuit ate have significant glycogen stores that are able to delay postmortem degradation,
particularly in cold weather. Whether a no-carbohydrate diet would be safe
for non-Inuit is also disputed: Nick Lane speculates that the Inuit may have a genetic
predisposition allowing them to eat a ketogenic diet and remain healthy. According to this
view, such an evolutionary adaptation would have been caused by environmental stresses.
This speculation is unsupported, however, in light of the many arctic explorers, including
John Rae, Fridtjof Nansen, and Frederick Schwatka, who adapted to Inuit diets with no adverse
effects. Schwatka specifically commented that after
a 2- to 3-week period of adaptation to the Inuit diet he could manage “prolonged sledge
journeys,” including the longest sledge journey on record, relying solely on the Inuit diet
without difficulty. Furthermore, in a comprehensive review of the anthropological and nutritional
evidence collected on 229 hunter-gatherer societies it was found that, “Most of the
worldwide hunter-gatherer societies derived>50% of their subsistence from animal foods,
whereas only 14% of these societies derived>50% of their subsistence from gathered plant
foods,” suggesting that the ability to thrive on low carbohydrate diets is widespread and
not limited to any particular genetic predisposition. While it is believed that carbohydrate intake
after exercise is the most effective way of replacing depleted glycogen stores, studies
have shown that, after a period of 2–4 weeks of adaptation, physical endurance is unaffected
by ketosis, as long as the diet contains high amounts of fat. It seems appropriate that
some clinicians refer to this period of keto-adaptation as the “Schwatka Imperative” after the explorer
who first identified the transition period from glucose-adaptation to keto-adaptation.
Veterinary medicine In dairy cattle, ketosis is a common ailment
that usually occurs during the first weeks after giving birth to a calf. Ketosis is in
these cases sometimes referred to as acetonemia. A study from 2011 revealed that whether ketosis
is developed or not depends on the lipids a cow uses to create butterfat. Animals prone
to ketosis mobilize fatty acids from adipose tissue, while robust animals create fatty
acids from blood phosphatidylcholine. Healthy animals can be recognized by high levels of
milk glycerophosphocholine and low levels of milk phosphocholine.
In sheep, ketosis, evidenced by hyperketonemia with beta-hydroxybutyrate in blood over 0.7 mmol/L,
occurs in pregnancy toxemia. This may develop in late pregnancy in ewes bearing multiple
fetuses, and is associated with the considerable glucose demands of the conceptuses. In ruminants,
because most glucose in the digestive tract is metabolized by rumen organisms, glucose
must be supplied by gluconeogenesis, for which propionate is normally the principal substrate
in sheep, with other gluconeogenic substrates increasing in importance when glucose demand
is high or propionate is limited. Pregnancy toxemia is most likely to occur in late pregnancy
because most fetal growth occurs in the final weeks of gestation; it may be triggered by
insufficient feed energy intake, necessitating reliance on hydrolysis of stored triglyceride,
with the glycerol moiety being used in gluconeogenesis and the fatty acid moieties being subject
to oxidation, producing ketone bodies. Among ewes with pregnancy toxemia, beta-hydroxybutyrate
in blood tends to be higher in those that die than in survivors. Prompt recovery may
occur with natural parturition, Caesarean section or induced abortion. Prevention is
more effective than treatment of advanced stages of ovine ketosis.
See also Ketoacidosis
Ketogenic diet Ketonuria
Low-carbohydrate diet Fasting
Ketogenesis Spontaneous human combustion, for which acetone
produced by ketosis has been suggested as a cause.
Very-low-calorie diet References External links
Diabetic Ketoacidosis at eMedicine NHS Direct: Ketosis
Musa-Veloso K, Likhodii SS, Cunnane SC. “Breath acetone is a reliable indicator of ketosis
in adults consuming ketogenic meals”. Am. J. Clin. Nutr. 76: 65–70. PMID 12081817. 
The Merck Manual — Diabetic Ketoacidosis
Alcoholic Ketoacidosis