Researchers at Rutgers and Yale may have identified a drug that treats Type II Diabetes (T2D) in rats — but is already on the shelves for treatment of tapeworm infections. The study was completed in May and published Oct. 5 in Nature Medicine.
Using two groups of rats — one with type II diabetes caused by diet, and the other carrying the disease through genetics — the researchers fed niclosamide ethanolamine (NEN), an altered form of an already FDA-approved drug, to their animal subjects. Fat in the liver of both groups of rats decreased, indicating that the drug selectively targeted the liver. Because the original form of the drug functions by decoupling tapeworms’ mitochondria from their cells, the researchers thought it could serve the same function in rat cells. Scientists have attempted to decouple mitochondria in the past for weight loss, but to no avail —the technique leads to spikes in body temperature when done a certain way, and subjects ended up dying of hyperthermia. The new drug treatment, then, is not novel in its technique, but novel in its safety.
“The beauty of NEN is that it is equally effective as DNP [a mitochondrial uncoupler used for weight loss in the 1930s that led to several deaths], but it does not associate with the adverse effects like increase in body temperature,” senior author and pharmacology professor at Rutgers Medical School Victor Jin said. “This suggests that the cause of T2D, which is ectopic accumulation of lipids in muscle and liver, could be targeted safely.”
Compared to the control group, rats that received mitochondria uncoupling therapy exhibited improved glycemic control, insulin sensitivity and weight loss after eight weeks of NEN consumption.
The mechanism of uncoupling mitochondria is particularly effective in targeting weight loss because it decreases the proton gradient in cells, making it more difficult to produce the energy needed to survive. Increased difficulty means more fat will be used to produce each molecule of fat, increasing inefficiency, but also the amount of fat the body burns.
According to Gerald Shulman, senior author and professor of cellular and molecular physiology at the School of Medicine, uncouplers like NEN cause “mitochondria to burn more fat to generate the same proton gradient to drive ATP synthase. It’s a very simple mechanism that if done in a liver-targeted manner, can be done safely.”
Other mitochrondrial uncouplers like DNP — which is no longer approved by the FDA for weight loss — have been effective in decreasing lipid content, but have produced harmful side effects, Jin said. The novelty of the study lies in the safety of the drug and the specificity of its action to the liver — other drugs, unable to target specific areas, would uncouple mitchondria in cells throughout the body.
According to Shulman, the study provides evidence for his theory that T2D is caused by accumulation of fat in the liver and muscles. Shulman has proposed that intracellular fats interfere with insulin’s ability to transport glucose between the bloodstream, liver and muscle cells. That obstruction makes cells less efficient at processing glucose and leads to elevated glucose levels in the blood, resulting in T2D, Shulman has theorized. Richard Kibbey, professor of cellular and molecular physiology at the School of Medicine, who was not involved in the study, agreed that the findings lend credence to Shulman’s idea.
“This finding is exciting because it supports the role that melting away fat in the liver is the key to improving glucose homeostasis,” he said.
In contrast to most T2D drugs, this class of drugs aims to target the root cause of the disease instead of just alleviating symptoms, Jin said.
But according to Yale chemistry professor David Spiegel MD ’04 GRD ’04, there may be some road-blocks in getting this drug to the public.
“Uncouplers tend to have very narrow therapeutic ratios. The effective or therapeutic dose is often very close to the toxic dose,” he said. “So the uncoupling mechanism is one that makes pharma quite uncomfortable.”
To follow up on their results, both researchers at Rutgers and Yale are preparing for IND (investigative new drug)-enabling studies that will involve modified formulations of NEN and new compounds that they hope will be more efficacious, Jin and Shulman said. Approval of IND-enabling studies is the key step before initiating clinical trials in humans — the ultimate goal.
“With the existing drugs, patients have to take them for the rest of their lives, and lots of them will become resistant to the drugs and develop complications like blindness, kidney failure, cardiovascular disease and heart failure,” Jin said. “We need to develop new drugs that will target the cause of this disease and could therefore hold a cure for some patients.”
Jin cofounded a privately funded biotech company, Mitobiopharm, that owns the rights to use NEN from this study for commercial use and clinical trials.
Shulman’s group at Yale is also working to develop a new compound, similar to NEN, that he hopes to test in primates before moving to IND-enabling trials. His work is motivated by the rapidly increasing rates of T2D.
“Diabetes is an epidemic, and the cost to U.S. society alone exceeds $200 billion a year in direct and indirect costs,” Shulman said. “In less than 15 years, over a third of a billion people will be impacted by this disease.”
Currently about 10 percent of the U.S. population is affected by T2D.