Targeting liver enzyme may combat obesity-induced diabetes

Diabetes drugs such as Merck’s Januvia work by inhibiting an enzyme called DPP4, which is a factor in the disease because it interferes with a hormone that’s vital for insulin production. Researchers at Columbia University Irving Medical Center have discovered a new link between DPP4 and obesity—an insight that could inspire new treatments for Type 2 diabetes.

The Columbia team discovered that in obese mice, the liver boosts its production of DPP4, which then travels to belly fat and prompts inflammation. They demonstrated that they could relieve the inflammation by shutting down DPP4 production in the liver. The mice didn’t lose weight, but their insulin resistance improved. The research was published in the journal Nature.

Interestingly, though, Januvia and other drugs in the “gliptin” class did not reduce fat inflammation in the mice. Lead author Ira Tabas, M.D., Ph.D., believes that the problem is that gliptins act in the gut, not the liver.

“But we have some evidence that DPP4 inhibitors in the gut also end up promoting inflammation in fat, said Tabas, a professor at Columbia University Vagelos College of Physicians and Surgeons,” in a press release. “That cancels out the anti-inflammatory effects the drugs may have when they reach inflammatory cells, called macrophages, in the fat."

So could DPP4 inhibitors be redirected to liver cells? Tabas’ team is examining a way to do that with small interfering RNAs (siRNAs) that can turn off the gene that produces DPP4. They’re attaching the siRNAs to sugars that are naturally attracted to liver cells.

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Manipulating enzymes is a popular idea among researchers searching for new ways to combat diabetes and obesity. In January, a team of Japanese researchers described a type of Sirt2 enzyme that they believe could be targeted to improve glucose uptake in the liver. Scientists at the University of California in San Diego found that enzymes called IKKε and TBK1 are elevated in obese mice—and that they may be able to be controlled with an old asthma drug called amlexanox.

The Columbia researchers believe that DPP4 increases inflammation in fat by interacting with a molecule on macrophages.

“If we could block that interaction, we might be able stop the enzyme from causing inflammation and insulin resistance," Tabas said.