Possible Mechanism for Link Between Diabetes and Alzheimer's Disease

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Possible Mechanism for Link Between Diabetes and Alzheimer's

Disease Discovered by Joslin Diabetes Center

Business Editors/Health/Medical Writers

BOSTON - (BUSINESS WIRE) - Feb. 16, 2004 - For some time,

researchers have known that people with diabetes have a greater risk of

developing Alzheimer's disease and other forms of dementia than those

without diabetes, but the exact cause of this link has not been known.

Now, a new study by researchers in Cologne, Germany, and at Joslin

Diabetes Center in Boston, to be published this week online in the

Proceedings of the National Academy of Sciences, suggests that insulin

resistance in brain cells can affect how they function, causing some of

the biochemical changes typically seen in Alzheimer's disease.

Insulin resistance is a major contributor to type 2 diabetes,

obesity and the metabolic syndrome, which affect nearly one-quarter of

the American population. In these insulin resistant states, tissues of

the body such as muscle, liver, and fat fail to respond normally to the

insulin produced by the pancreas, leading to a wide range of metabolic

abnormalities. In patients with diabetes, this includes elevated blood

sugar levels which, if uncontrolled, can lead to such vascular

complications as blindness, limb amputations, kidney disease, heart

disease, stroke and nerve damage.

Through research at Joslin Diabetes Center and elsewhere,

scientists only recently have come to realize that insulin receptors are

present on all tissues of the body, including the brain, and may affect

the function of these tissues. Furthermore, various research findings

have suggested that disruption of the insulin signaling system may occur

in such disorders as Alzheimer's disease and Parkinson's disease. In

fact, at least one large European study found people with diabetes to be

at least twice as likely to develop Alzheimer's disease as someone

without the disease. The risk was even higher among those people with

diabetes taking insulin.

To study the effects of insulin resistance in the brain, Jens C.

Bruning, M.D., formerly of Joslin Diabetes Center and now of the

University of Cologne, Germany, and his colleagues and C. Kahn,

M.D., of Joslin Diabetes Center in Boston, used genetically altered mice

called Neuronal Insulin Receptor Knockout (NIRKO) mice, which are

missing insulin receptors in their neurons (brain cells). Previously,

using these NIRKO mice, Bruning and Kahn had shown that neuron-specific

insulin resistance could contribute to type 2 diabetes, loss of normal

appetite control, obesity, and even infertility.

In the present study, the investigators used behavioral and memory

testing, high-tech imaging, as well as a variety of biochemical tests to

study metabolic processes within the brains of NIRKO mice and compare

them with those of normal mice. Compared with normal mice, NIRKO mice

had markedly reduced activity of insulin signaling proteins in the

brain. This was found to lead to overactivity of an enzyme called GSK3

beta, which in turn, led to excessive phosphorylation (or

hyperphosphorylation) of a protein called tau. Hyperphosphorylation of

tau is a hallmark of brain lesions seen in Alzheimer's disease and has

been suggested to be an early marker of this disease. On the other hand,

the NIRKO mice showed no changes in the proliferation or survival of

neurons, memory, or basal brain glucose metabolism, suggesting that

insulin resistance may interact with other risk factors to promote

full-blown Alzheimer's disease.

Although further research is clearly needed to clarify how insulin

resistance in the neurons in the brain interacts with other genetic and

biochemical abnormalities in the development of Alzheimer's and other

neurodegenerative diseases, Dr. Kahn points out, " This is the first

clear demonstration of a biochemical link between insulin resistance and

Alzheimer's disease, and it points to how understanding and developing

new treatments for insulin resistance may have impact not only in

diabetes, but in many other common chronic diseases. "

About Joslin Diabetes Center

Joslin Diabetes Center, the global leader in diabetes research,

care and education, is uniquely qualified to lead the battle against

diabetes in the 21st century. Joslin Research is a team of over 300

people at the forefront of discovery aimed at preventing and curing

diabetes. Joslin Clinic, affiliated with Beth Israel Deaconess Medical

Center in Boston, the nationwide network of Joslin Affiliated Programs,

and the hundreds of Joslin educational programs offered each year for

clinicians, researchers and patients, enable Joslin to develop,

implement and share innovations that immeasurably improve the lives of

people with diabetes. As a nonprofit, Joslin benefits from the

generosity of donors in advancing its mission. For more information on

Joslin, call 1-800-JOSLIN-1 or visit www.joslin.org.

CONTACT: Joslin Diabetes Center

Marge Dwyer, 617-732-2415

Marjorie.dwyer@...

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Mayo Clinic in Rochester

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