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other than glucose, such as fatty acids and ketone fatty acids and KBs. KBs can provide up to 60 Ketogenic diets
bodies, which produce less oxidative stress and percent of the brain’s energy, thus sparing what
47 have a long
are, in fact, more efficient fuels. 14,46,47 little glucose is metabolized to supply the rest.
One way in which Aβ serves a potentially KBs are often viewed as toxic, but this is history of
helpful role is that it upregulates production of not the case. They are an absolutely normal part efficacy for
amyloid-β-peptide-binding alcohol dehydroge- of human energy metabolism that preferentially
nase, an enzyme capable of metabolizing alter- fuel the brain while much of the rest of the body disorders of
native fuels such as ketone bodies and alcohols. runs on fatty acids during times of carbohydrate the central
6
Another possibly protective role for Aβ is in cata- unavailability. The negative view of KBs stems nervous system.
50
lyzing the production of lactate dehydrogenase, from confusion of benign dietary ketosis (BDK)
which converts pyruvate to lactate under anaero- and diabetic ketoacidosis (DKA). BDK occurs as
bic conditions. Lactate is produced in glial cells a result of dramatic reductions in carbohydrate
6
and sent to neurons, where it is converted back consumption, while DKA is seen in untreated
to pyruvate and sent through the tricarboxylic type 1 diabetics, who do not produce insulin,
acid (TCA) cycle to produce ATP. Up-regulating have extremely limited capacity to burn glucose,
lactate production compartmentalized within and therefore are in a constant, uncontrolled
the brain could be the struggling brain’s way of state of catabolizing (breaking down) their own
providing a fuel substrate when glucose usage muscle and adipose tissue to use as fuel. De-
in the brain has been compromised. Here again spite both conditions indicating that the body is
we have two scenarios in which Aβ seems to be burning fat at a high rate, they are worlds apart
priming the brain to move away from glucose. in physiological implication. During BDK from
carbohydrate reduction, blood ketone concentra-
LOW CARBOHYDRATE DIETS tions are typically no higher than 4-6 mM, with
FOR AD THERAPY no change in blood acidity. In DKA, however,
If AD is primarily the result of a brain un- blood ketone concentration can reach up to 25
able to metabolize glucose properly, then inter- mM—orders of magnitude greater—and blood
ventions aimed at preventing or improving this pH can decrease to fatal levels that overwhelm
condition should include a transition to a fuel the body’s acid buffering capacity. 47
source other than glucose, reducing peripheral Ketogenic diets have a long history of ef-
insulin levels to restore sensitivity at the BBB, ficacy for disorders of the CNS, most notably
and providing an abundant supply of protective epilepsy. 46,47 KBs are more efficient than glucose
substances. As a model to guide therapy, we can and induce less oxidative damage. Additionally,
47
look to what happens during fasting, starvation, KBs are brought into the brain by monocarboxyl-
or carbohydrate restriction to see the processes ate transporters—independently of glucose and
by which a glucose-deprived body sustains itself. insulin—so their uptake is not hindered when
The major switch that occurs in the absence or insulin signaling fails.
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reduction of exogenous glucose is that the body This raises the question, if the brain is strug-
transitions to running on fatty acids, ketone bod- gling to use glucose, why does it not immediately
ies (KBs), and small amounts of glucose derived shift to fueling with ketones? The answer is that
from gluconeogenesis (making glucose from sufficient ketones aren’t available. Due to differ-
amino acids and other substances). 48,49 ing requirements of various tissue systems, the
It is often claimed that glucose is the brain’s body as a whole runs on glucose, fatty acids, and
only fuel, or that the brain requires upwards KBs concurrently to some extent. However, the
of 120 grams of glucose per day. This grossly pathways are largely antagonistic; where one pre-
oversimplifies human physiology. Glucose is dominates, another is inhibited. Glucose induces
regularly cited as the “preferred” fuel for the insulin secretion, and insulin inhibits CPT-1, an
body and brain. However, it is only preferred enzyme responsible for bringing fatty acids into
in the sense that it will generally be used first. the mitochondria to be used. Therefore, when
It is neither more efficient nor safer than two of insulin levels are high, fatty acids are not well
the other fuels the body and brain can run on: used as fuel and no significant ketogenesis oc-
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