Anna Giulia Cattaneo - Dipartimento di Biotecnologie e Scienze
della Vita - Università dell'Insubria - Varese.
Next April 23, 2013, the New York Academy of Sciences will
hold a symposium to review the state of the art in an intriguing
hypothesis, linking the insulin resistance with the progressive
dementia seen in Alzheimer disease (AD).
The epidemiologic finding, of a nearly doubled risk for developing
AD in subjects affected by type 2 diabetes or metabolic syndrome
was the first warning about the possible interference of these
apparently distinct diseases. This observation was supported
by earlier reports, suggesting disturbances of glucose metabolism
in the brain of people affected by AD. A new term was proposed,
type 3 diabetes mellitus, to describe the condition associating
high cerebral disturbance of insulin sensitivity and glucose/lipid
metabolism with decline of cognition in AD, even in the absence
of systemic hyperglycemia.
More recently, a longitudinal study of aging in Northern
New York City (José A. Luchsinger, Columbia University)
showed a relation between several parameters common in elevated
adiposity and type 2 diabetes, and AD; however the data were
controversial when individuals in advanced age were considered.
Later in life the link between adiposity, diabetes and peripheral
insulin resistance with AD seemed to be attenuated.
Although the present trends in research seems to exclude
that insulin resistance "per se" could represent
a cause to develop AD, however the defective binding of insulin
to receptors, in selected areas of the brain, is associated
with altered metabolism of the amyloid precursor protein,
and of the phosphorylation of the tau protein. In subjects
with AD, even with normal blood glucose levels, the insulin
receptor binding appears to be reduced in selected areas of
the brain, mainly the hypothalamus and the hippocampus. The
clinical consequence of these defects seems to be a rapid
progression of dementia.
Experimental data obtained in mice reproduced a condition
similar to that observed in human dementia, and characterizing
hyppocampal degeneration, in rodents in which cerebral insulin
resistance was chemically induced. In humans, a similar chemical
insult could be represented, in the presence of a metabolic
syndrome, by the crossing of the blood brain barrier by neurotoxic
lipids generated by the fatty liver.
In summary, it must be underlined that, in the brain, the
damage of metabolic pathways able to reduce the levels of
the tau protein and the rate of amyloid deposition, as well
as the insulin resistance, are both mediated by mechanisms
located on the neuron membrane or at the synapses, and triggered
by the reactive oxygen species.
If it does not seem time to rename AD as a new type of diabetes,
the role played by cerebral insulin resistance should be considered
for newer methods for reduce the progression of dementia in
AD. Drugs used in AD models in rodents. Clinical trials implementing
similar treatment have been approved and are undergoing, such
as the use of intranasal insulin and of antidiabetic drugs
in AD. The current status of such trials will be examined
in a near future, at the previously cited symposium.
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