Diabetes Forecast

Diabetes on the Brain

Probing the link between insulin resistance and depression

Natalie Rasgon, MD
Professor of Psychiatry and Behavioral Sciences, Stanford University
ADA Research Funding
Clinical Translational Research Award

In discussions of diabetes, a lot of attention is paid to the pancreas, a 6-inch-long gland nestled just behind the stomach. But it turns out that another organ—one situated on top of the neck and behind the eyes—may play a significant role in diabetes as well.

In recent years, researchers have begun to explore the role of the brain in regulating hormones like insulin. It turns out that people with diabetes are more likely to have mood disorders like depression and that depression increases the risk of diabetes. "A lot of people with depression have diabetes—about 40 percent overlap between the two populations," says Natalie Rasgon, MD, a psychiatry professor and director of the Stanford Center for Neuroscience in Women's Health.

Rasgon says the cause-and-effect relationship between depression and diabetes begins long before full-blown diabetes develops. For the past decade, she has focused on the links between depression and insulin resistance, a condition that is a precursor to type 2 diabetes. "About 20 to 30 percent, at least, of people who have depression have insulin resistance," she says.

That knowledge encouraged Rasgon to zero in on the connections between insulin resistance and a number of other diseases. "Insulin resistance is a recent prediabetic state," she says. "What a lot of people don't know is that diabetes is the final step in a long, long-running chain of events."

For people with insulin resistance, the body is producing insulin properly, but the muscle, fat, and liver cells that should be using it to process glucose don't respond properly. That, in turn, prompts the body to pump out more insulin in a struggle to catch up. Eventually, insulin resistance can lead to heart disease and type 2 diabetes, when the pancreas wears out and stops producing insulin altogether.

In a recent study, Rasgon found that insulin resistance—which may make it harder for the brain to get the glucose it needs to function properly—is associated with a brain region critical to memory and one of the first areas to be affected by Alzheimer's disease. Other studies have linked it to hypertension and heart disease. Yet one of the strongest links is that between depression and insulin resistance. There's still a "chicken and egg" problem: Rasgon can't tell if depression throws off the systems in the brain that control insulin sensitivity or whether insulin resistance makes it harder for the brain to properly regulate mood. Yet her research has made the connection clear. "What we've showed is that people who have mood disorders have elevated insulin, insulin resistance, and diabetes," she says. "The question becomes the link between mood, insulin, and cognition."

The reasons are still a matter of debate, but researchers do know that the brain—just like the rest of the body—depends on glucose to function properly. Fluctuations in insulin levels may wreak havoc on other pathways in the brain, causing changes in mood or trouble with basic tasks like memory and reasoning. "There's an intricate regulatory system in the brain," Rasgon says. "There's now a notion of insulin as a signaling factor and neuroactive agent which exerts influence in vital parts of the brain."

To understand the relationship more clearly, the Stanford researcher is conducting an experiment with the help of funding from the American Diabetes Association. Working with 100 people who have a history of depression or other mood disorders, Rasgon and her team are giving them a combination of tests to see how insulin levels affect the brain's ability to remember and reason.

The study will be the first to directly measure insulin resistance in patients with depression. Rasgon hopes it will be the basis for future research, making it possible to design and test treatments for insulin resistance.

If Rasgon can find out what causes insulin resistance, it might help head off the development of diabetes and other diseases. Even pinning down who's more likely to have insulin resistance might help doctors treat the problem earlier, averting problems later on. "If a person has a genetic vulnerability to developing diabetes, you are more prone to have insulin resistance," she says. "You can educate people about identifying insulin resistance and treating it aggressively."

A genetic vulnerability to diabetes, for example, might be foreshadowed by problems with insulin resistance earlier in life—and depression might be one signal. "One of the most important points for us is to identify the culprits before diabetes begins," Rasgon says. "Insulin resistance is a reversible condition. Diabetes is not."

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