An industrial chemical, pesticide and explosive—DNP sounds like your ideal medicine, right? Well, this substance (2,4-dinitropheol) was actually turned into a diet pill back in the 1930s after scientists noticed it caused those exposed to it to lose weight. However, it was quickly banned and deemed unfit for human consumption after its horrible list of side effects became apparent, such as bone marrow problems and impairments to the nervous system. Oh, and death.

But this drug could soon be vindicated as, after a few tweaks, it now seems to be effective at reversing type 2 diabetes and fatty liver disease in rats. Although more safety studies are required, the encouraging results suggest it could represent a promising new treatment avenue for humans with these conditions, and that clinical trials would be worth pursuing to investigate this. The research has been published in Science.

Obesity is an epidemic, and while it’s easy to notice those extra pounds appearing as a spare tire around the waist, excess body fat also accumulates in places that we can’t see, such as the liver. Healthy livers should have barely any fat in them, but in some individuals fat can build up within liver cells. This can lead to a range of conditions collectively known as non-alcoholic fatty liver disease (NAFLD). Often it’s harmless and will go unnoticed, but in others it can worsen and develop into a condition known as nonalcoholic steatohepatitis (NASH), where the excess fat causes inflammation and damages the liver cells. Unfortunately, there are no treatments for NASH, and it can lead to serious problems such as scarring (cirrhosis), cancer and liver failure.

But things may be looking up for those with these problems as a reinvented diet pill seems to be very good at reversing fatty liver disease. The drug, DNP, was banned almost 80 years ago because of high toxicity, but despite this, it is very good at what it does: making the body burn fat. It achieves this by modifying the activity of the energy-making factories found in our cells called mitochondria. Furthermore, when given to rats, it was found to increase their insulin sensitivity, which is promising given that insulin resistance is associated with NAFLD and is a major factor in the pathogenesis of type 2 diabetes.

To reduce its toxicity, Yale scientists started off by making a version of DNP that is mostly active in the liver, which reduced the undesired effects on other areas of the body. Not only was this around one-tenth as toxic as unmodified DNP, but it also reduced liver fat levels in rat models of NAFLD. Although this was a vast improvement, the researchers then thought of a better way to tackle its toxicity: pack it into a slow-release pill to prevent blood concentrations from ever getting too high.

In rat models of NAFLD and type 2 diabetes, when administered once daily this version not only reversed fatty liver, but it also increased insulin sensitivity and improved blood glucose levels. Furthermore, in rats with NASH, it reduced the amount of scarring that can ultimately lead to liver failure. These promising results have got experts in the field excited, and scientists are hopeful it could one day lead to an effective treatment for these conditions in humans.

[Via Science, Sciencemag and Yale University]