February 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 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. 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."