Possible mechanism for link between diabetes and Alzheimer's disease ...( and his colleagues and C. Ronald Kahn...)

, and his colleagues and C. Ronald 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."

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Contact: Marge Dwyer
marjorie.dwyer@joslin.harvard.edu
617-732-2415
Joslin Diabetes Center
16-Feb-2004

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