Page 40 - Summer2014

Some inside the body, but the brain cells are not able of Aβ plaques in a hyperglycemic brain can ini-

progressive to harness energy from it. The parallels to T2D tiate chain reactions of glycation and oxidation
are striking, making the term “type 3 diabetes” that serve to exacerbate mitochondrial dysfunc-
researchers apropos. tion, decreased ATP production, and cognitive
have suggested For non-ApoE4 carriers, diabetes alone is decline.
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that insulin a significant risk factor for AD. The combina- It is unlikely that Aβ plaques are a primary
tion of diabetes and carrying an ApoE4 allele causative factor in AD because the effects of
resistance increases the risk even further—five-fold over reduced glucose uptake in the brain are observed
at the blood non-diabetic, non-E4 carriers. 16,17,19 Better glyce- long before the plaques are evident. The plaques
brain barrier is mic control has been correlated to better cogni- more logically result from functional inhibition
tive performance in type 2 diabetics. Moreover, of IDE due to peripheral hyperinsulinemia. Some
the brain's way these same subjects had improved performance progressive researchers have suggested that in-

of forcing a on memory tests quickly after an acute dose of sulin resistance at the BBB is the brain’s way of
slowdown 50g of easily digestible carbohydrate, but this forcing a slowdown in the metabolism of glucose.
was followed by decreased performance after an This seems illogical if glucose is the brain’s pri-
in the extended waiting period, reflecting the aforemen- mary fuel (assuming a carbohydrate-rich diet).
metabolism tioned observations of acute versus chronically Why would the brain seek to limit the uptake of
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of glucose. elevated insulin levels and glucose utilization. its main fuel? Several mechanisms are at work,
The question, then, is whether diabetes plays a and they all indicate that the brain is protecting
causal role in AD. Research does not support its own survival while trying to minimize further
this, as not all AD patients are diabetic, and not damage.
all diabetics develop AD. Due to the overwhelm- First, high levels of glucose in brain in-
ing evidence of insulin and glucose signaling terstitial fluid are glycating. Glycated proteins
derangement as the strongest factors in AD, it and cellular structures have altered function,
seems more likely that T2D and AD are different increased vulnerability to oxidative damage, and
manifestations of the same underlying causes: reduced degradation and clearance. Slowing the
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in T2D, the peripheral muscles and organs are entry of glucose into the brain would delay these
affected; in AD damage is localized to the brain. processes and possibly give the body’s defenses
more time to dispose of the AGEs.
DISCUSSION Second, glucose metabolism causes a heavy
Like that of many of its complex neurode- burden of oxidative stress. The running of the
generative counterparts, AD research is stymied mitochondrial electron transport system (ETS)
by the problem of identifying what the first steps is the greatest source of reactive oxygen spe-
are in a vicious cycle wherein an underlying cies (ROS) and free radicals in the body, and
disturbance is perpetuated by the very results neurons are particularly susceptible to oxidative
of the disturbance. The physiological and bio- stress because their metabolic rate is higher than
chemical changes observed in AD point to a that of other brain cells. Moreover, neuronal
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brain that is struggling to maintain its viability. membranes are rich in long-chain PUFAs and
It downregulates the uptake of glucose, upregu- cholesterol, which are highly vulnerable to oxi-
lates mechanisms to use alternative fuels, and dation. AGEs have been shown to induce lipid
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increases production of protective substances. peroxidation, so exposure of fragile membrane
Many researchers see the accumulation of PUFAs to a hyperglycemic environment can be
Aβ as the triggering event in AD pathology. considered toxic. In an organ that is potentially
However, a more integrated view of the innate so highly damaged from a lifetime of dietary and
wisdom of the human body suggests that Aβ environmental abuse, downregulating the usage
initially serves a protective role, just as a fever of a fuel whose metabolism creates even more
is a protective mechanism rather than something damage can be seen as a last-ditch effort just to
to be annihilated unquestioningly. Nevertheless, survive.
just as a fever spiking too high can create prob- Third, the brain could be redirecting its
lems of its own, increasing numbers and density metabolic machinery toward utilization of fuels
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