Gene editing can reverse prediabetes in mice – and potentially humans, study reveals

08 Jul 2019 --- Researchers have discovered a method that reverses prediabetes in mice, and is likely to apply to humans as well. Scientist at the University of Utah Health found that deactivating an enzyme that shifts the position of two hydrogen atoms can reverse prediabetes. This provides valuable insight into how used new therapies could be developed for prediabetes, as well as other metabolic disorders such as diabetes and heart disease. The researchers have created a company, Centaurus Therapeutics, in order to develop drugs targeting the deactivated enzyme.

Essentially, the deactivation of dihydroceramide desaturase 1 (DES1) stops the final hydrogens of ceramides (a fatty lipid) from being removed, thus lowering the total amount of ceramides in the body.

Fatty liver from an obese mouse (left), compared to a healthy liver after DES1 deactivation (right).“The findings are likely to apply to humans as well. People with high ceramides are greatly at risk for diabetes and heart disease, and clinics have recently started measuring them as a measure of cardiovascular risk, similarly to cholesterol. There are indications that people lacking one copy of the DES1 are very healthy, and perhaps even protected from disease,” Scott Summers, Ph.D., Chair of Nutrition and Integrative Physiology at U of U Health and co-senior author on the study, tells NutritionInsight.

Mice on a high-fat and high-sugar diet similar to cookie dough gained twice their body weight in three months and developed insulin resistance and fatty liver, which are both major risk factors for diabetes and heart disease. After DES1 deactivation, the mice stayed obese but fat cleared from the liver, and responded to both insulin and glucose like a healthy, lean mouse. They also remained healthy throughout the two-month investigation, unlike in previous interventions. 

“We were astonished that the mice handled the intervention so well. Deleting the gene before birth is really deleterious. Deleting it in adults elicited all of these beneficial effects without any toxicities. Because the intervention was so well-tolerated by the mice, we were able to learn a lot about how ceramides worked. Some of these findings about the mechanism were really surprising because they gave us a clue to learn how ceramides evolved to have their unique attributes,” says Summers. 

Summers’ group had previously found that signs of diabetes and metabolic disease could be reversed by lowering ceramides, but previous experiments had caused serious side effects, nixing the potential for therapeutic applications.

“We’ve been looking for a good way to lower ceramides safely. The first gene in the pathway didn’t work, as it created some harmful gut effects. Since this is such a subtle change in the ceramide molecule, we thought it might be tolerable. We also knew that a drug called fenretinide that is being used for cancer has an off-target effect of inhibiting DES1. Since it has been given to thousands of people, we thought a specific inhibition of this enzyme might be safe,” Summers continues.Researchers Bhagirath Chaurasia, Ph.D, Scott Summers, Ph.D., Trevor Tippetts. 

The role of ceramides
Summers’ group also measured how ceramides affect metabolism, to try to understand why we have them if they cause poor health. They found that they impair cells’ ability to use glucose as fuel and that they trigger mechanisms that promote the storage of fat in cells.

However, much about ceramides is still unknown, says Summers. “We know a little about how ceramides could be modified by diet, but not enough. And we certainly don’t know enough about diet-gene interactions in the control of ceramides and cardiometabolic health. Targeted studies relating different macronutrients to ceramides could be highly informative.”

There have been other recent breakthroughs which could help combat obesity-related illnesses. Last month, it was found that phenols in cocoa bean shells have strong effects on fat and immune cells in mice. This could be used to reverse chronic inflammation and insulin resistance, which are issues associated with obesity.

Additionally, Nestlé is launching a new weight management program where participants will consume just 800 calories a day. The program is a response to research showing that a drastically reduced calorie intake can help participants achieve remission from Type 2 diabetes.

By Katherine Durrell