An experiment in mice showed that the drug DNP restores insulin sensitivity to cells and encourages fat burning
Published in Science on 26.2.15, worked by Gilat Simon
A drug banned for use by the US government and defined as "very dangerous and not suitable for human consumption" is now getting a second chance, following a study conducted on mice. The researchers report that a slow release version of the drug compound is very useful (curative???) in the treatment of diabetes and liver disease BAFLD (nonalcoholic fatty liver disease), a disease that is currently untreatable and can lead to cirrhosis and liver cancer . Cirrhosis, or in its full name, cirrhosis of the liver (cirrhosis), is a disease in which the tissues of the liver are destroyed and replaced by scar tissue, which causes a disruption in blood flow to the liver cells and a disruption in its function.
As we know, diabetes has already become an epidemic and a considerable percentage of the population suffers from it. About 30% others suffer from a lesser-known metabolic disease, NAFLD, in which lipids - the family of molecules that includes fats - accumulate in the liver. Although the excess fat causes relatively few problems, among 10%-20% of people the excess fat in the liver causes the development of NASH, a serious disease in which inflammation and scarring can cause cancer and liver failure. To date, no drug has been found that can be used for these liver diseases. Hepatologist Lomba from the University of California in San Diego points out that "this is one of the great needs that have not yet been met in today's medicine"
To find an adequate answer, endocrinologist Gerald Shulman of the Yale University School of Medicine and his colleagues proposed to revive the drug with the dark past, aka 2,4,dinitrophenol DNP. The substance was originally used as an industrial chemical and explosive and caught the attention of researchers after French munitions workers were exposed to high levels of it during the First World War. One common result of the exposure was weight loss - although another result was sometimes death! After further research it was suggested that the compound accelerates weight loss in obese people and in the XNUMXs it was included in diet pills that were available without a prescription. The American FDA banned the use of the compound at the end of that decade, because it caused serious side effects such as cataracts and even deaths.
Despite the bad name given to DNP, the material also has some virtues. By changing the activity of the mitochondria - those tiny power plants that provide energy to the cells - DNP forces the body to burn fat. It provides additional metabolic benefits. For example, most people suffering from NAFLD or diabetes have insulin resistance, that is, their body cells do not respond normally to the hormone that controls blood sugar levels, but show resistance to high levels of it in the blood. When Shulman and his colleagues fed mice DNP, they found that the substance stimulated insulin sensitivity and actually reversed the resistance phenomenon.
The researchers decided to design a safer version of DNP that would take advantage of its benefits and reduce the risk of using it. First they tried to limit the harmful effects of the substance by creating a version that would be active mainly in the liver. In a study published in 2013, the researchers demonstrated that this version of the substance was only one tenth as toxic as the original substance. Furthermore, the new compound reduced the accumulation of fat in the liver of mice suffering from NAFLD and improved the animals' sensitivity to insulin.
The researchers were not satisfied with these results and tried to surpass them. In their new study, now published, they went back to the original version of DNP, and packaged it in pills that dissolve and release the substance in a slow, delayed release, over 12 to 24 hours. This strategy reduced the amount of the substance in the bloodstream. When the pills were given to mice that were eating a high-fat diet and developed the murine version of NAFLD, the slow-release substance cut their lipid levels by 90%!! Shulman and his colleagues reported on this in the prestigious journal Science. Mice that consumed the drug also showed an improvement in the sensitivity of their cells to insulin and blood glucose levels, hence the substance is effective in reversing diabetes to a normal state. In mice that suffered from NASH, the substance reduced fibrosis - the destruction that can cause cirrhosis and liver failure. Comparing the doses that lead to these improvements with the doses that trigger the dangerous side effects, led the researchers to conclude that the delayed-release version is safer than the liver-targeted version.
The research suggests that the milder version of DNP may be effective in treating diabetes and NAFLD, Shulman says. It reduces the accumulation of fat and corrects the defective glucose metabolism in the liver, thus "getting to the root of the problem that causes these diseases". The researchers are planning further studies in animals and hope to move to safe trials in humans as well.
Hepatologist Sean Cope of the University of Illinois at Chicago says the findings of the current study warrant an examination of DNP in humans. "They show that there is a wide window between a medicinal effect and toxic levels of the substance," he says. Lomba adds and says that the substance's ability to curb fibrosis, the characteristic hallmark of NASH, is very encouraging and he also supports safe experiments in humans "the published preclinical data are very exciting" he says.
Cope and Lumbe agree that if it is proven in further studies that DNP is safe to use and effective in its effectiveness, it may be approved for use by the FDA, despite its dark history. Toxins and prohibited substances have already enjoyed a revival in the past - with the clear example of this being thalidomide, which was outlawed in the sixties of the last century because it caused birth defects among babies of women who took the drug during pregnancy and now a niche has been found where it is used after it was found to be effective in the treatment of cancer and leprosy.
So what did we have here? A substance in different doses and conditions is a deadly poison but also a medicine for diabetes and liver disease; A substance that affects fat burning metabolism and insulin resistance/sensitivity; A delayed release mechanism that reduces toxicity and side effects in mice; Potential for further studies, also in humans...
