Watered-down version of First World War explosive reverses diabetes in mice

A new study has revealed that an agent, which caused munitions factory workers to lose weight inexplicably in the First World War and had originally been used for weight loss more than 70 years ago, reversed type 2 diabetes and fatty liver disease in rats.

Existing therapies for type 2 diabetes, and the closely associated conditions of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), have had limited success at treating the root causes of these diseases.

Yale University's researchers determined that toxicity associated with the agent mitochondrial protonophore 2,4-dinitrophenol (DNP) was related to its peak plasma concentrations and discovered that DNP's efficacy in reducing liver fat and liver inflammation could be achieved with plasma concentrations that were more than a 100-fold less than the toxic levels.

Lead author Gerald I. Shulman said that besides reversing fatty liver disease in a rodent model of NALFD, a low-dose intragastric infusion of DNP that was 100-fold lower than toxic levels also significantly reduced blood glucose, triglyceride, and insulin concentrations in a rodent model of NAFLD and type 2 diabetes.

In the next phase of the study, Shulman and his team developed a new oral, controlled-release form of DNP, known as CRMP, which maintained the drug at concentrations that were more than a 100-fold lower than the toxic threshold.

Administered once daily, CRMP delivered similar positive results, reversing fatty liver, insulin resistance, and hyperglycemia in rat models of NAFLD and type 2 diabetes, as well as liver inflammation and liver fibrosis in a rodent model of NASH, with no adverse effects.

Shulman added that given these promising results in animal models of NAFLD/NASH and type 2 diabetes, they are pursuing additional preclinical safety studies to take this mitochondrial protonophore approach to the clinic.

The study appears in Journal Science.