A drug the U.S. government once branded “extremely dangerous and not fit for human consumption” deserves a second chance, a study of rats suggests. Researchers report that a slow-release version of the compound reverses diabetes and nonalcoholic fatty liver disease (NAFLD), an untreatable condition that can lead to cirrhosis and liver cancer.
Diabetes has already become an epidemic. And up to 30% of people around the world may have a lesser known but related metabolic illness, NAFLD, in which lipids—the family of molecules that includes fats—amass in the liver.
Although the extra fat often causes few problems, about 10% to 20% of people develop nonalcoholic steatohepatitis (NASH), a serious illness in which inflammation and scarring can provoke cancer and liver failure. So far, there are no approved drugs for treating either condition.
To address that need, endocrinologist Gerald Shulman of the Yale University School of Medicine and colleagues proposed resurrecting a drug with a dark history: 2,4 dinitrophenol (DNP). Originally used as an industrial chemical and explosive, the compound captured researchers’ attention after French munitions workers were exposed to high levels of it during World War I.
One frequent consequence of this exposure was weight loss—although another consequence was sometimes death. After further research suggested the compound spurred obese people to shed pounds, drugmakers in the 1930s included DNP in diet pills that were available without a prescription.
The U.S. Food and Drug Administration (FDA) banned the compound at the end of the decade, however, because it caused side effects such as cataracts and was responsible for a handful of deaths.
The researchers decided to design a safer version of DNP that would retain its benefits. First they tried to limit the effects of the drug by creating a version that is active mainly in the liver. In a study published in 2013, the researchers demonstrated that this version of the drug was about one-tenth as toxic as standard DNP. Moreover, the targeted drug reduced fat buildup in the livers of rats that had NAFLD and improved the animals’ insulin sensitivity.
But the researchers thought they could do even better. In their new study, they packed the original form of DNP into a pill that slowly dissolves and releases the drug over 12 to 24 hours. This strategy reduces the amount of the drug in the bloodstream.
When fed to rats that devour a fat-laden diet and develop their own version of NAFLD, the slow-release drug slashed their liver lipid levels by about 90%. Rodents that consumed the drug also saw improvements in their insulin sensitivity and blood glucose quantities.
In rats with NASH, the drug reduced fibrosis, the scarring that can cause cirrhosis and liver failure. The team also showed that it reversed diabetes in rats. Comparing the doses that provide these benefits with the doses that trigger side effects, the researchers determined that the slow-release version is safer than the liver-targeted drug.
Perry RJ, Zhang D, Zhang X-M, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. http://www.sciencemag.org/content/early/2015/02/25/science.aaa0672.abstract
Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol 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, 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.
Diabetes has already become an epidemic. And up to 30% of people around the world may have a lesser known but related metabolic illness, NAFLD, in which lipids—the family of molecules that includes fats—amass in the liver.
Although the extra fat often causes few problems, about 10% to 20% of people develop nonalcoholic steatohepatitis (NASH), a serious illness in which inflammation and scarring can provoke cancer and liver failure. So far, there are no approved drugs for treating either condition.
To address that need, endocrinologist Gerald Shulman of the Yale University School of Medicine and colleagues proposed resurrecting a drug with a dark history: 2,4 dinitrophenol (DNP). Originally used as an industrial chemical and explosive, the compound captured researchers’ attention after French munitions workers were exposed to high levels of it during World War I.
One frequent consequence of this exposure was weight loss—although another consequence was sometimes death. After further research suggested the compound spurred obese people to shed pounds, drugmakers in the 1930s included DNP in diet pills that were available without a prescription.
The U.S. Food and Drug Administration (FDA) banned the compound at the end of the decade, however, because it caused side effects such as cataracts and was responsible for a handful of deaths.
The researchers decided to design a safer version of DNP that would retain its benefits. First they tried to limit the effects of the drug by creating a version that is active mainly in the liver. In a study published in 2013, the researchers demonstrated that this version of the drug was about one-tenth as toxic as standard DNP. Moreover, the targeted drug reduced fat buildup in the livers of rats that had NAFLD and improved the animals’ insulin sensitivity.
But the researchers thought they could do even better. In their new study, they packed the original form of DNP into a pill that slowly dissolves and releases the drug over 12 to 24 hours. This strategy reduces the amount of the drug in the bloodstream.
When fed to rats that devour a fat-laden diet and develop their own version of NAFLD, the slow-release drug slashed their liver lipid levels by about 90%. Rodents that consumed the drug also saw improvements in their insulin sensitivity and blood glucose quantities.
In rats with NASH, the drug reduced fibrosis, the scarring that can cause cirrhosis and liver failure. The team also showed that it reversed diabetes in rats. Comparing the doses that provide these benefits with the doses that trigger side effects, the researchers determined that the slow-release version is safer than the liver-targeted drug.
Perry RJ, Zhang D, Zhang X-M, Boyer JL, Shulman GI. Controlled-release mitochondrial protonophore reverses diabetes and steatohepatitis in rats. Science. http://www.sciencemag.org/content/early/2015/02/25/science.aaa0672.abstract
Nonalcoholic fatty liver disease (NAFLD) is a major factor in the pathogenesis of type 2 diabetes (T2D) and non-alcoholic steatohepatitis (NASH). The mitochondrial protonophore 2,4 dinitrophenol 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, 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.
