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Insulin Sensitizers Cut Cognitive Decline in AD

”There is a critical relationship between insulin resistance and key aspects of brain function.”

A growing body of evidence suggests that insulin sensitizers may avert cognitive decline in people with Alzheimer’s disease, Suzanne Craft, Ph.D., said at the Third World Congress on Insulin Resistance Syndrome.

In one randomized, placebo-controlled clinical trial, rosiglitazone appeared to be effective in preserving memory and selective attention in a small group of patients with early Alzheimer’s disease (AD) or mild cognitive impairment (MCI), said Dr. Craft of the University of Washington, Seattle.

Another randomized trial involved elderly patients with impaired glucose tolerance (IGT) or type 2 diabetes mellitus (T2DM) and contained three arms: placebo, pioglitazone, and nateglinide. Both pioglitazone and nateglinide improve glucose tolerance, but only pioglitazone improved insulin sensitivity and reduced insulin levels. In this trial pioglitazone, but not nateglinide or placebo, improved performance in a memory test.

“If you pick up an endocrinology textbook from about 15 years ago, you may very well read that ‘the brain is an insulin-insensitive organ,’” Dr. Craft said. “We’re coming to understand that’s very much not the case. There is a critical relationship between insulin resistance and key aspects of brain function.”

In fact, the brain contains many insulin receptors, which tend to be clustered in the hypothalamus, where insulin likely helps regulate eating behavior, and in cortical regions closely linked to cognition.

In earlier studies on healthy individuals Dr. Craft and her colleagues determined that experimentally induced hyperinsulinemia increases the production of the 42-peptide form of ß-amyloid (Aß), the precursor of the amyloid plaques that are the hallmarks of AD. The relationship between insulin levels and Aß turned out to be age related, and was especially apparent in people over the age of 70.

The rosiglitazone trial compared 20 patients taking 4 mg of the drug daily for 6 months with 10 patients taking placebo. All of the patients had a confirmed diagnosis of AD or MCI and averaged 73 years of age. Patients taking rosiglitazone did have significantly lower fasting plasma insulin levels than control patients, but there were no differences between the groups on fasting glucose, lipids, or liver enzymes (Am. J. Geriatr. Psychiatry 2005;13:950–8).

At 4 and 6 months into the study, patients taking rosiglitazone performed significantly better than those taking placebo on a delayed memory task (the Buschke Selective Reminding Test). Additionally, at the 6-month time point patients taking rosiglitazone performed significantly better on a measure of selective attention (the Stroop Color-Word Test).

The other trial, which has not yet been published, involved 71 patients over the age of 55 with IGT or T2DM. Patients were randomly assigned to receive placebo, pioglitazone (30 mg/day), or nateglinide (360 mg/day) for 4 months.

Compared with baseline, patients taking pioglitazone showed significant improvement in performance on a story recall test, while patients taking nateglinide or placebo showed no such improvement. Furthermore, among the patients taking pioglitazone, the improvement was directly proportional to the extent of their metabolic treatment response, as measured by a 2-hour oral glucose tolerance test.

A subset of these patients received PET scans at baseline and after 4 months of treatment. As expected, insulin-resistant patients showed hypometabolism in the left temporal lobe and the right parietal region, both areas that are known to be affected in the very early stages of AD.

In addition, while performing a task of word memory in the PET scanner, normal subjects showed a pattern of increased glucose metabolism in the right frontal lobe. Patients with IGT showed a significantly smaller increase in glucose metabolism in that area, and patients with T2DM showed a smaller increase still.

Third World Congress on Insulin Resistance Syndrome, Jan 2006