Using Antidiabetic Therapies to Treat Alzheimer Disease

Bret S. Stetka, MD; Roger S. McIntyre, MD


August 27, 2015

In This Article

Insulin and Amyloid

Medscape: What is the relationship between insulin and beta-amyloid?

Dr McIntyre: This part is really interesting from the point of view of cognition, particularly the link to AD. Insulin, like every other protein in the body, has to be degraded; it's part of our body's recycling process. The enzyme in the central nervous system that degrades insulin goes by the name, appropriately, insulin-degrading enzyme (IDE). IDE, in addition to degrading insulin, also degrades other proteins, one of which is amyloid. Amyloid has been implicated as the protein that contributes to AD.

In the course of diabetes, the body begins to have insulin resistance; to compensate for that, the body produces more insulin. In the very early stages of type 2 diabetes, if you were to look at someone's insulin level in their blood, it's a little bit higher than normal. This is a compensatory hyperinsulin response.

What happens is that increased amounts of insulin go across the blood/brain barrier and into the brain. Now the brain is confronted with a relatively higher level of insulin—higher than it would be exposed to under normal physiologic conditions. The IDE is now charged with the responsibility of degrading the additional insulin, which it does readily. The by-product of that is it's no longer able to biodegrade amyloid to the same extent.

In the early stages of diabetes in humans, you begin to see amyloid deposits in the brain. Once you deposit amyloid in the human brain, it's a bit like going into a very dry forest or dry hills of California right now and dropping a match. A fire is set off; a cascade of neurodegenerative events take place after that. This is not a theory—it's been shown in rodents when you render them diabetic. People can have cognitive problems as part of diabetes that may not be AD, but instead might be related to the structural changes mentioned earlier.

What if we were to introduce insulin as a treatment? Having diabetes leaves you with higher risk for AD, but if you take insulin for your diabetes, your risk for AD is lower.

But there's also something about antidiabetic medication in general going on here. There are other treatments, such as metformin and the new generation of antidiabetic drugs known as incretins, that have been shown in animal models to have a pro-cognitive effect.[3]


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