A Medication May Protect the Brain From Cognitive Decline
Natalie Rasgon, MD
Professor of psychiatry and behavioral sciences at Stanford University
American Diabetes Association Research Funding
Clinical Translational Research
Scientists studying the brain and the body have long worked separately, under the assumption that mental illness wasn’t connected to diseases such as diabetes. But increasingly, researchers are discovering that diabetes and obesity may be linked to illnesses of the brain, or central nervous system, such as dementia and depression.
These discoveries now have scientists working to find out whether drugs that treat diabetes and its risk factors might have a positive effect on cognition—and why. One possible culprit, they believe, is insulin resistance—the inability of the body’s cells to absorb glucose—which research has shown raises the risk of depression and Alzheimer’s disease.
Natalie Rasgon, MD, has spent the past decade and a half working to prove that trouble with the body’s ability to process glucose can lead to mood disorders. In 2015, she showed that the drug pioglitazone, often prescribed to improve insulin sensitivity in people with type 2 diabetes, improved symptoms of depression. Now she’s looking at a promising drug called liraglutide, a type 2 diabetes injectable medication marketed under the names Victoza and Saxenda that’s designed to mimic a hormone produced in the gut.
Called a glucagon-like peptide-1, or GLP-1, the hormone that liraglutide replaces is a vital part of maintaining steady glucose levels and controlling insulin resistance. It slows stomach emptying to help reduce after-meal blood glucose levels, prevents the liver from releasing glucose, and helps beta cells make more insulin to compensate for insulin resistance.
Liraglutide is used to treat type 2 diabetes and in many people reduces appetite and leads to some weight loss. It is used separately as a weight-loss drug.
In several recent animal studies, researchers showed that liraglutide, in addition to lowering high blood glucose levels, has positive effects on everything from depression to memory. One 2015 experiment suggested that liraglutide might even be able to heal mild brain injuries in mice. “It has profound neurotrophic [growing nervous tissue] effects in animals,” Rasgon says. “Whether it works in humans, we don’t know yet. If something that affects insulin resistance can have central nervous system effects, it’s pretty important.”
With the help of a grant from the American Diabetes Association, Rasgon is studying the brain-protecting effects of liraglutide. Over the past few years, her project looked at 80 adults between 50 and 70 years old. All of them were at genetic risk for Alzheimer’s—because a parent had the disease or they possessed certain genetic markers, for example. Participants were given a thorough, three-hour assessment—including memory and problem-solving tests—to evaluate brain function. Researchers also gave them a magnetic resonance imaging (MRI) scan and a full workup of their endocrine system to measure insulin resistance and other early indicators of type 2 diabetes.
The study participants were then randomly divided into two groups. The first group was given liraglutide; the second group was given a placebo. Rasgon’s team then followed up with both groups after three months, giving them another round of tests and MRI scans to see if there had been any change in their brain function.
Rasgon’s still analyzing her data, and she’s cautious about drawing too many conclusions from such a short study. “To truly see effects in the brain, you would need longer than three months,” she cautions. “But the trial will help us identify if there are positive effects on brain function from improving insulin resistance.” If liraglutide improves brain function—or slows cognitive decline—it raises some interesting questions, Rasgon says. The most important, of course, is how the drug works in the brain.
Rasgon hopes the results will point to one of two different possibilities. Mice have shown better results on brain tests after being given liraglutide, whether or not their response to insulin improves. This suggests that the liraglutide itself, not the improved insulin sensitivity, makes the difference.
“In animals, it’s independent of insulin resistance’s effects. In humans, we don’t know,” Rasgon says. “If we find they did not improve insulin resistance but had positive changes in the brain, that suggests liraglutide acts through a different mechanism.” If that’s the case, the drug could be useful as a medication to prevent cognitive decline in people without diabetes, too.
On the other hand, if the people in the study show improved insulin sensitivity and improved cognitive function over the course of the three-month trial, it’s strong evidence that insulin resistance might be at least partly responsible for brain troubles such as memory loss and dementia. “If it’s both, it probably acted through improving insulin sensitivity,” Rasgon says. “If we can ameliorate cognitive and brain function changes by dealing with insulin resistance, we can prevent people at risk from developing both.”
Ideally, her results will help show how liraglutide could be better used as a treatment option in the future. “We’re trying to disentangle the effects of liraglutide and weight loss from the neuroactive effects of insulin resistance,” she says.
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