Subtle chemical shift reverses prediabetes in Merck-partnered mouse trial

Scientists from the University of Utah and Merck manipulated fatty lipids called ceramides in obese mice and reversed signs of prediabetes, even though the animals did not lose weight. (Wikimedia Commons/Wellcome Trust)

University of Utah Health professor Scott Summers, Ph.D., refers to fatty lipids called ceramides as “the next cholesterol,” because a mounting collection of research suggests they play an important role in metabolic health. In fact, Summers led a study, newly published in Science, that shows how targeting ceramides could reverse insulin resistance and fatty liver—major risk factors for diabetes and heart disease.

Summers’ team collaborated with scientists at Merck Research Laboratories to develop a technique for lowering the amount of ceramides in the body. They accomplished that by shutting down an enzyme called dihydroceramide desaturase 1 (DES1). That, in turn, shifted two hydrogen atoms from ceramide, crippling the fatty lipid.

When the researchers made the chemical change in mice, it prevented prediabetes in animals that had been given a high-fat diet, and it reversed it in obese mice. Summers is now working with his co-senior author on the study, former Merck Research Laboratories scientist David Kelley, M.D., to develop drugs that can achieve the same chemical shift, according to a statement.

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Previous research in Summers’ lab had shown that reducing ceramides could prevent metabolic disorders, but attacking the lipids directly caused dangerous side effects. So they tried deactivating DES1 in genetically engineered mice using two techniques: either turning off the gene that makes the enzyme, effectively removing it from the body, or deleting the enzyme just from liver or fat cells.

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Both techniques worked, though interestingly, the mice didn’t lose weight during the two-month study period. Still, their livers cleared out excess fat and the mice responded to insulin and glucose just like healthy, skinny animals would.

“Their weight didn't change but the way they handled nutrients did,” Summers said in the statement. “The mice were fat but they were happy and healthy.”

Manipulating ceramides is tricky, because the fatty lipids play an important role in the body. Research done in Summers’ lab led the scientists to theorize that ceramides stiffen the cell membrane and promote fat storage, which helps prevent cells from rupturing. In the skin, ceramides help maintain a barrier against pathogens. But the flip side is that obesity keeps ceramide levels high, which can cause insulin resistance and fatty liver disease.

Some researchers in the field of metabolic disease are examining the potential of manipulating other enzymes to reverse prediabetes. Last year, a team at Duke University described their method for balancing a kinase enzyme that inhibits the breakdown of branched-chain amino acids in the body and a phosphatase that activates it. In rats, that resulted in improved glucose control and a lowering of fat in the liver.

Merck’s interest in Summers’ research at the University of Utah is no surprise, given the company’s long-standing work in metabolic disease. Most recently, the company has partnered with NGM Bio to collaborate on a variety of drugs, including one that acts on the β-Klotho/FGFR1c receptor complex in the fatty liver disease nonalcoholic steatohepatitis (NASH). Earlier this year, Merck expanded that partnership, though it did pull away from an obesity treatment NGM is developing.

Summers’ team at the University of Utah is now working on determining the long-term effect of lowering ceramides in mice. The potential effect in humans is still unknown. That said, some clinics already use ceramide screening to predict who may be at risk of developing heart disease—proof, he believes, that the fatty lipid could very well take on a similar role as cholesterol has in monitoring and maintaining health.

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