Excessive ketone metabolism in muscles key to obesity-induced diabetes: study

Originally Published by UAlberta News.

A University of Alberta scientist has identified a drug that can prevent diabetes in obese individuals by interfering with the way the muscles metabolize ketones. 

John Ussher, associate professor in the Faculty of Pharmacy and Pharmaceutical Sciences and Canada Research Chair in Pharmacotherapy of Energy Metabolism in Obesity, recently published findings that show pimozide—a drug originally prescribed to treat Tourette’s syndrome—inhibits an enzyme that is key for the metabolism of ketones and is elevated in people with obesity-induced diabetes.

“We know that worldwide more than 600 million people are clinically obese with a BMI (body mass index) greater than 30,” said Ussher, who is also a member of the Alberta Diabetes Institute. “These individuals are at a greatly increased risk for diabetes, particularly Type 2 diabetes, and for various heart diseases.  

“If we can fix the way our body burns this fuel, then we can reduce the risk of diabetes and heart disease in people who are obese, and improve their quality of life,” Ussher said.

Ussher’s laboratory focuses on how the process of gaining weight can cause malfunctions in the body’s ability to burn fuel for energy. While much research has focused on the three fuels found in food—fat, sugar and protein—there is a fourth source of fuel produced by our liver—ketones—that are less well understood.

Ussher pointed out that ketones are produced by the liver during fasting or starvation, when following a low-carb or “ketogenic” diet, or when diabetes interferes with the function of insulin to metabolize carbohydrates. 

“When you’re starving or fasting and you have low sugar, the body compensates by having the liver burn fat and turn it into ketones, which can be metabolized by the brain,” Ussher said.  

Ussher’s laboratory first used genetic tools to isolate the major enzyme responsible for ketone metabolism and then turn it off in animal models. 

“Those mice gained weight just like regular mice that had this enzyme but they maintained healthy blood sugar control and weren’t getting diabetes,” he said. 

“This suggested to us that if you prevent muscles’ ability to burn ketones as a fuel source, that might be an exciting new way to treat diabetes with a potential new drug that can improve blood sugar control.”

Next, the lab used computer-aided molecular modelling to search databases and identify potential drugs that might inhibit the enzyme. Once they found pimozide, they treated diabetic mouse models with the drug and found their blood sugar levels improved. 

Ussher said inhibiting ketone metabolism represents a new approach to treating diabetes that could be used in combination with existing therapies that act on insulin.

The next step will be to move to testing in humans. Pimozide is known to cause side-effects including drowsiness and dizziness, so Ussher’s lab will pursue the development of new drugs that inhibit ketone metabolism without side-effects.

The U of A has filed a provisional patent on this technology, which is being commercialized with the assistance of its newly formed Technology Transfer Services office.

Ussher’s research is supported by the Canadian Institutes for Health Research and his Canada Research Chair.