Tiny Molecular Change Reverses Prediabetes in Obese Mice; Remarkable Results Point to Potential Diabetes Drug Target and Highlight Possible Role for Ceramides in Sensing Nutrition

A small chemical change -- shifting the position of two hydrogen atoms -- makes the difference between mice that are healthy and mice with insulin resistance and fatty liver, major risk factors for diabetes and heart disease. Making the change prevented the onset of these symptoms in mice fed a high-fat diet and reversed prediabetes in obese mice. The scientists changed the trajectory of metabolic disease by deactivating an enzyme called dihydroceramide desaturase 1 (DES1). Doing so stopped the enzyme from removing the final hydrogens from a fatty lipid called ceramide, having an effect of lowering the total amount of ceramides in the body. The finding highlights a role for ceramides in metabolic health and pinpoints DES1 as a "druggable" target that could be used to develop new therapies for metabolic disorders such as prediabetes, diabetes, and heart disease -- that affect the health of hundreds of millions of Americans. Scientists at University of Utah Health and Merck Research Laboratories led the research, published online in Science on July 4, 2019. The article is titled “Targeting a Ceramide Double Bond Improves Insulin Resistance and Hepatic Steatosis.” "We have identified a potential therapeutic strategy that is remarkably effective, and underscores how complex biological systems can be deeply affected by a subtle change in chemistry," says Scott Summers (at right in photo), PhD, Chair of Nutrition and Integrative Physiology at U of Utah Health, who was co-senior author on the study with David Kelley, MD, formerly of Merck Research Laboratories. "Our work shows that ceramides have an influential role in metabolic health," says Dr. Summers. "We're thinking of ceramides as the next cholesterol.
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