Insulin May Have Therapeutic Potential in Alzheimer's Disease

Insulin Suppresses AD-Associated Proteins in Peripheral Blood Cells

Megan Brooks

April 08, 2011

April 8, 2011 — For the first time, researchers have found that peripheral blood mononuclear cells express amyloid precursor protein (APP) and 3 other proteins involved in the pathogenesis of Alzheimer's disease (AD) and that their expression is suppressed by a low-dose intravenous infusion of insulin.

"Our results show clearly that insulin has the potential to be developed as a therapeutic agent for Alzheimer's,” lead researcher Paresh Dandona, MD, PhD, from the Division of Endocrinology, Diabetes and Metabolism at the State University of New York at Buffalo, noted in a statement.

The findings are published online March 16 in the Journal of Clinical Endocrinology and Metabolism.

In an interview with Medscape Medical News, Dr. Dandona explained that the literature shows a "clear epidemiological relationship" between obesity and type 2 diabetes and AD, with rates of AD twice as high in this population relative to the normal population. In addition, recent autopsy studies of AD patients have shown a lack of insulin and insulin signaling in the brain.

More recently, it was shown that adding β-amyloid to cultured neurons induces oxidative stress and inflammation, “but when you add insulin, this is neutralized. “The next question was can we marry these 2 findings in our work,” Dr. Dandona said.

In studies with peripheral blood mononuclear cells, he and his colleagues have now shown, for the first time to their knowledge, that these cells express APP and 3 other proteins linked to AD pathogenesis — presenilin-1 (PS1), presenilin-2 (PS2), and glycogen synthase kinase-3β (GSK-3β).

'Landmark Observation'

"This is a landmark observation," Dr. Dandona said, "because it means we discovered a model, other than the brain, where we can study these genes involved in Alzheimer's."

The researchers infused 10 obese type 2 diabetic patients with a low dose of insulin (2 U/h with 100 mL of 5% dextrose) for 4 hours. On 2 other "control" days, the same patients were infused with 5% dextrose per hour or normal saline for 4 hours.

On all test days, blood samples were obtained at 0, 2, 4, and 6 hours. All of the study subjects were using oral antidiabetes medication, but none were taking insulin or any antioxidant or nonsteroidal anti-inflammatory drugs.

The researchers found that the insulin infusion suppressed not only the expression of APP, from which β-amyloid is derived, but it also suppressed PS1 and PS2, enzymes that convert APP into β-amyloid, which forms the amyloid plaques.

Insulin also suppressed GSK-3β, which phosphorylates to another neuronal protein, tau, to form neurofibrillary tangles seen in the AD brain.

"If this effect of insulin proves, in larger studies, to be systemic, then insulin may well be a potential therapeutic agent in treating Alzheimer's disease," said Dr. Dandona. "The challenge is to deliver insulin directly into the brain, thus avoiding its hypoglycemic effect."

On that front, a preliminary study has shown that intranasal delivery of insulin twice daily to Alzheimer's patients enters the brain along the olfactory nerves, but not the systemic circulation, and seems to improve cognitive function.

Figuring out the role of insulin in AD “is very exciting work and I think should be a priority in AD research,” Dr. Dandona said.

Dr. Dandona is supported by grants from the National Institutes of Health, the American Diabetes Association, and Merck, Amylin, and Abbott Pharmaceuticals.

J Clin Endocrinol Metab. Published online March 16, 2011. Abstract


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