Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats

Science. 2015 Mar 13;347(6227):1253-6. doi: 10.1126/science.aaa0672. Epub 2015 Feb 26.


Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and nonalcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol (DNP) has beneficial effects on NAFLD, insulin resistance, and obesity in preclinical models but is too toxic for clinical use. We developed a controlled-release oral formulation of DNP, called CRMP (controlled-release mitochondrial protonophore), that produces mild hepatic mitochondrial uncoupling. In rat models, CRMP reduced hypertriglyceridemia, insulin resistance, hepatic steatosis, and diabetes. It also normalized plasma transaminase concentrations, ameliorated liver fibrosis, and improved hepatic protein synthetic function in a methionine/choline-deficient rat model of NASH. Chronic treatment with CRMP was not associated with any systemic toxicity. These data offer proof of concept that mild hepatic mitochondrial uncoupling may be a safe and effective therapy for the related epidemics of metabolic syndrome, T2D, and NASH.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2,4-Dinitrophenol / administration & dosage*
  • 2,4-Dinitrophenol / toxicity
  • Animals
  • Blood Glucose / metabolism
  • Delayed-Action Preparations / administration & dosage*
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / metabolism
  • Glucose Tolerance Test
  • Insulin Resistance
  • Lipid Metabolism
  • Liver Cirrhosis / drug therapy
  • Male
  • Mice
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / metabolism
  • Muscle, Skeletal / metabolism
  • Non-alcoholic Fatty Liver Disease / drug therapy*
  • Non-alcoholic Fatty Liver Disease / metabolism
  • Oxidation-Reduction
  • Proton Ionophores / administration & dosage*
  • Proton Ionophores / toxicity
  • Random Allocation
  • Rats
  • Rats, Zucker


  • Blood Glucose
  • Delayed-Action Preparations
  • Proton Ionophores
  • 2,4-Dinitrophenol