Using Antidiabetic Therapies to Treat Alzheimer Disease

Editor's Note:
A new study^[1] published in JAMA Neurology adds to existing data suggesting a relationship between insulin resistance and the risk of developing Alzheimer disease (AD), and also that insulin could potentially be used to treat or slow cognitive decline. Medscape recently spoke with Roger S. McIntyre, MD, professor of psychiatry and pharmacology at the University of Toronto, about how insulin influences cognition and brain health.

Medscape: A great deal of recent research has looked at the relationship between insulin, insulin resistance, and cognitive decline. On the basis of current evidence, can you summarize what is known about this association?

Dr McIntyre: This is very much like the interface between inflammation and the brain, in that it's an area that has exploded in activity recently. There are a couple of reasons why people are now spending more time thinking about the role of insulin metabolism in contributing to or causing psychopathology, such as cognitive impairment, or even frank psychiatric disorders, such as AD, depression, and bipolar disorder.

You may have seen some of the recent evidence^[2] showing an association between type 2 diabetes and various mental illnesses, including posttraumatic stress disorder (PTSD). People today are living longer with type 2 diabetes than they were 20, 30, or 40 years ago, so they're now presenting with some of the brain consequences of diabetes.

Second, diabetes significantly increases a patient's risk of developing not only vascular dementia but also AD. It's now thought that a considerable percentage of AD cases are directly attributable to type 2 diabetes, and a larger percentage are probably attributable to other factors that march in the same direction as diabetes, including obesity, smoking, habitual inactivity, and bad diet. Here you have people living longer with diabetes, and we're seeing the brain consequences, which include cognitive problems such as dementia.

We have a diabetes epidemic going on. We have an obesity epidemic going on. I think all of these public health factors are creating a bit of a perfect storm that greatly affects the brain.

Medscape: What role does insulin and insulin resistance appear to play in impaired cognition?

Dr McIntyre: In 2015, we do not have any evidence yet that insulin is produced in the human brain in addition to the pancreas. The insulin itself is produced in the periphery; however, there are receptors in the brain. Everyone knows that insulin plays a critical role in facilitating glucose utilization in the human body, and it stands to reason—but is in fact not true—that insulin is also necessary to the brain to utilize sugar.

Insulin is responsible for such organs as the heart to utilize sugar. But Mother Nature has evolved us in such a way that the brain—obviously an extremely critical organ—can utilize sugar directly and does not need insulin. So the question is, if insulin is not required in the brain for glucose utilization (which it is everywhere else in the body), then why does the brain have insulin receptors?

We can look at where in the brain these insulin receptors are and where insulin is active, and a couple of observations have been made. One is that insulin receptors are distributed throughout the brain; however, their distribution is overrepresented in those brain circuits that are responsible for cognitive function, and that's very interesting. The brain regions that we rely on to think, to encode memories, to recall events of the past, are all are heavily populated by insulin receptors.

Related to this, let's take animal research. If you knock out the insulin or insulin receptor gene entirely—or even just partially—the brains of rats and mice don't develop properly, resulting in structural abnormalities. So that's pretty compelling proof that insulin is responsible for the structural architecture of the brain in addition to being located on those cognitive circuits.

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