Don’t Fret, Just Sweat

For individuals suffering from schizophrenia, second-generation antipsychotic drugs such as olanzapine have had a remarkable impact on quality of life. Yet, drugs like olanzapine can also cause several side-effects that harm a person’s metabolism.

“These drugs are really effective psychologically, but not metabolically,” says Dr. David Wright, an investigator in the Department of Human Health and Nutritional Sciences.

Researchers have found that the drugs cause a pronounced increase in blood sugar and a loss of sensitivity to the metabolic hormone insulin, two symptoms commonly associated with obesity and type II diabetes.

Wright and PhD student Hesham Shamshoum sought a solution to what they describe as a “balancing act of mental state and physical state”.

To do this, a simple treatment was considered: voluntary physical activity. Or, voluntary wheel running if you were a mouse who participated in the study.

Exercise has profound and well-documented effects in regulating sugar metabolism. This made it an ideal candidate to test in the management of olanzapine-induced metabolic disturbances.

The team wanted to understand how, and for how long, a single bout of voluntary exercise might mitigate the effects of olanzapine. Three types of mice were studied: healthy mice, obese mice and a genetically modified mouse lacking a protein in the liver that would normally help protect against spikes in blood sugar. The latter two groups represented two different ways that olanzapine can negatively impact metabolism, creating more than one problem for exercise to solve.

What the researchers found was truly impressive. All of the mice allowed to exercise before being treated with olanzapine showed a lower blood sugar response compared to mice that did not exercise. By measuring blood after the olanzapine dose, the team determined that exercise suppressed the ability of olanzapine to trigger the release of glucagon, a hormone that causes the liver to increase the production of blood sugar.

Based on these findings, Wright and his colleagues believe the liver is playing a mediating role in the beneficial effects of exercise.

The genetically modified mice eloquently demonstrated this liver-specific effect. The liver is the main organ responsible for sugar production, and these mice are predisposed to generating too much sugar. But analysis of the mice’s livers showed that exercise led to reduced activation of the metabolic pathways used for sugar production. This means that despite the double whammy effects of a pre-existing liver impairment and the known side-effects of olanzapine, exercise was still able to salvage blood sugar and insulin sensitivity levels.

“When you put the pieces together, this is really a story of the liver,” says Wright.

A similar result played out with the obese, non-genetically modified mice, which are a closer model to humans. Just like obese humans, obese mice are predisposed to metabolic complications. However, even obese mice that were allowed to exercise before being given olanzapine had metabolic variables comparable to mice that did not receive the drug.

When the researchers looked at the timing of exercise, they found that exercise immediately or 7 hours before receiving olanzapine conferred benefits, but not 24 hours before.

“This likely means daily or frequent exercise is necessary, making exercise adherence the most important variable,” says Wright.

In the future, Wright and his team hope to collaborate with mental health researchers to study exercise’s metabolic benefits on individuals already taking drugs like olanzapine. “It will be a massive undertaking but an important one.”

Until such trials can be carried out, Wright emphasizes the benefits of exercise for everyone as there is bound to be other effects beyond just metabolism – likely even mental health.

This study was funded by the Canadian Institutes of Health Research.

Read the full study in the Journal of Applied Physiology.

Read about other CBS Research Highlights.