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Study of an old Man's Profile - Galleria degli Uffizi - Firenze
THE ROLE OF CEREBRAL INSULIN RESISTANCE IN PROGRESSION OF THE ALZHEIMER DEMENTIA Torna agli editoriali

di
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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