By Michael Le Page The build-up of fat in the liver can lead to type 2 diabetesSEBASTIAN KAULITZKI/SCIENCE PHOTO LIBRARY An experimental drug has reversed the build-up of fat in the liver and lowered blood levels of fatty substances including cholesterol in non-human primates. The build-up of fat in the liver, known as non-alcoholic fatty liver disease, affects 1 in 3 people and can lead to type 2 diabetes as well as heart and kidney disease. “This is getting at what I believe to be the root cause of diabetes,” says Gerald Shulman at the Yale School of Medicine, whose team is developing the drug. Called CRMP, it works by making the liver waste energy so it uses more than normal. The energy that powers cells is produced by structures called mitochondria. As protons flow out of mitochondria, they drive molecular turbines that produce an energy-rich chemical called ATP. Advertisement Gut health: from the inside out: Megan Rossi at New Scientist Live CRMP lets protons flow out of mitochondria without generating ATP. It is a bit like opening a bypass gate on a hydroelectric dam, letting water flow out without generating power. However, that lost energy ends up as waste heat. A drug called dinitrophenol that was used for weight loss from the 1930s worked via the same mechanism. Its use was discontinued after many people suffered ill effects or died when they overheated. The deaths continue to this day as some people, such as bodybuilders, still self-medicate with dinitrophenol. CRMP, however, affects mainly liver cells rather than the entire body. “That’s very important for safety,” says Shulman. Tests in small numbers of cynomolgus and rhesus macaques suggest it is safe and effective at reversing fat build-up in the liver. The animals didn’t lose weight overall. “That’s the whole idea,” says Shulman. “This is not meant to be a weight loss drug.” Unpublished results from tests in mice suggest it can also reduce the risk of heart disease by lowering levels of cholesterol and triglycerides, says Shulman. Read more: Experimental diabetes drug may lower blood sugar and reduce obesity Given how dangerous dinitrophenol turned out to be, Shulman wants to carry out further animal tests of CRMP before moving on to human trials. If CRMP does prove safe in initial human trials, some subsequent trials might test it in combination with existing drugs for type 2 diabetes such as metformin. Journal reference: Science Translational Medicine, DOI: 10.1126/scitranslmed.aay0284 More on these topics: diabetes
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