Download Pathology Ketone bodies are created at moderate

The Hows and Whys of Ketones There are two basic forms of fuel the body uses to keep maintain
cellular metabolism. The primary form is glucose. Glucose is obtained from digested carbs. Protein can
also be converted to glucose in a process called gluconeogensis. Fat when digested is broken down into
fatty acids and glycerol. Glycerol can be converted to glucose. Fatty acids can be used by the body or be
converted to ketones. In addition to food, the body has reserves of fuel in the liver called glycogen, which
can be converted to glucose when needed. There are also small stores of glycogen in muscle tissue. When
necessary protein can be stripped from muscle to convert to glucose in times of extreme need. Likewise
fatty acids can be converted to ketones by breaking down fat stored in adipose tissue.
It may seem like ketones have a bad reputation since we've seen problems occur with DKA but ketones
are actually used by the body everyday to provide energy to primary body organs like heart and used as
an alternate energy when glucose is lacking. They also reserve the glucose supply for those organs that
prefer it like brain. They can be found at normal basal levels in blood and urine. When we talk about
losing weight and burning fat, we are actually talking about using ketones. Dieters and people stranded
in the wilderness rely on ketones to survive.
Ketones only become problematic when they replace glucose as the primary energy source. It's the
excessive use of ketones which can cause the body's PH to lower and turn the blood acidic creating
metabolic disorders such as diabetic ketoacidosis. When ketones have reached the level where they can
be detected using urine test strips – that is the danger sign.
Who directs the body to use which fuel? Hormones in the body work like air traffic controllers
signaling positive and negative instructions regarding its energy needs and fuel supplies. Insulin for
example inhibits the production of ketone bodies by inhibiting the breakdown of fat (lipolysis) in adipose
tissue while in the liver it inhibits the conversion of free fatty acids into ketones. Glucagon, along with
natural insulin inhibits ketone formation however in diabetics when there is either none or little supply
of insulin, glucagon actually stimulates fat breakdown (lipolysis) in adipose tissue and enhances the
conversion of fatty acids into ketones in the liver (ketogenesis) and can cause DKA. Stress hormones
(catecholamines) such as epinephrine, norepinephrine, ACTH in addition to glucagon also stimulate
ketone formation.
Why does DKA occur? It occurs when glucose cannot reach cell. The body tries to compensate by
increasing the level of glucose. It does this by breaking down the glycogen reserve into glucose
(glycogenolysis) and by creating new glucose from protein and glycerol (gluconeogensesis). The body
will use whatever protein is available either from food or it will strip muscle from the body. Insulin
deficiency promotes the acceleration of ketone production by stimulating lipolysis. This causes
hyperketonemia and excessive polyuria causing dehydration, electrolyte loss and acidosis in blood.
Anorexia and/or insulin deficiency can lead to a lack of glucose at the cellular level which can lead to
DKA. To prevent DKA you must have a sufficient incoming glucose supply and be given insulin in order
to allow the glucose to enter the cells.
Ketogenesis is the process by which ketone bodies are
produced as a result of fatty acid breakdown.
Ketones are produced in the mitochondria of liver cells. Its
synthesis occurs in response to low glucose, and after
exhaustion of glycogen. The production of ketone bodies is then
initiated to make available energy that is stored as fatty acids
which are enzymatically broken down in β-oxidation to form
acetyl-CoA. Normally, acetyl-CoA is further oxidized and its
energy transferred as electrons to NADH, and FADH2 in the
citric acid cycle (TCA cycle). However, if the amounts of acetylCoA generated in fatty-acid β-oxidation exceeds the processing
capacity of the TCA cycle or if activity in the TCA cycle is low due
to low amounts of oxaloacetate, acetyl-CoA is then used instead
in biosynthesis of ketone bodies via acetoacyl-CoA and βhydroxy-β-methylglutaryl-CoA (HMG-CoA). Besides its role in
the synthesis of ketone bodies, HMG-CoA is also an
intermediate in the synthesis of cholesterol.
The three ketone bodies are:
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Acetoacetate; if not oxidized to form usable energy, it is the source of the two other ketone bodies:
Acetone and β-hydroxybutyrate. Each of these are synthesized from acetyl-CoA molecules.
Ketogenesis depends on levels of available carbs. This is closely related to the paths of acetyl-CoA:
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
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When the body has ample carbs available as energy source, glucose is completely oxidized to CO2;
acetyl-CoA is formed as an intermediate in this process, first entering the citric acid cycle followed
by complete conversion of its chemical energy to ATP in oxidative phosporylation.
When the body has excess carbohydrates available, some glucose is fully metabolized, and some
of it is stored by using acetyl-CoA to create fatty acids. Lipogenesis.
When the body has no free carbohydrates available, fat must be broken down into acetyl-CoA in
order to get energy. Acetyl-CoA is not being recycled through the citric acid cycle because the
citric acid cycle intermediates (mainly oxaloacetate) have been depleted to feed the
gluconeogenesis pathway, and the resulting accumulation of acetyl-CoA activates ketogenesis.
Pathology Ketone bodies are created at moderate levels in everyone's bodies, when no carbohydrates are
available. However, when ketogenesis is happening at higher than normal levels, the body is said to be in
a state of ketosis. Both acetoacetate and beta-hydroxybutyrate are acidic, and, if levels of these ketone
bodies are too high, the pH of the blood drops, resulting in ketoacidosis. This is very rare, and, in
general, happens only in untreated Type I diabetes binge drinking and subsequent starvation.