Could cutting two proteins stop type 2 diabetes?

Researchers have found a way to reverse type 2 diabetes and liver fibrosis in mice.

In two new studies, the researchers also show that the underlying processes are conserved in humans.

In the first study in Nature Communications, researchers found an important connection between how the body responds to fasting and type 2 diabetes. Fasting “switches on” a process in the body in which two particular proteins, TET3 and HNF4a, increase in the liver, driving up production of blood glucose. In type 2 diabetes, this “switch” fails to turn off when fasting ends, as it would in a nondiabetic person.

Researchers hypothesized that if they could “knock down” the levels of these two proteins, they could stop diabetes from developing.

Yingqun Huang, associate professor in obstetrics, gynecology, and reproductive sciences at Yale University, and colleagues injected mice with genetic material known as small interfering RNAs (siRNAs) packaged inside viruses that targeted TET3 or HNF4a. They found that blood glucose and insulin dropped significantly—effectively stopping diabetes in its tracks.

In the Cell Reports study, researchers looked at how TET3 contributed to the development of fibrosis in the liver, and found that the protein was involved in fibrosis on multiple levels. Almost all fibrosis, regardless of the organ involved, starts from abnormal protein signaling, Huang says.

The researchers discovered that TET3 plays a role in the fibrosis signaling pathway in three different locations—and acts as an important regulator in fibrosis development. This means there are likely opportunities to develop drugs that inhibit TET3 to slow or reverse fibrosis, says Da Li, an associate research scientist in genetics and coauthor of both studies.

Both diseases—type 2 diabetes and fibrosis of the liver and other organs—are common, but have few treatment options. Around 28 million people in the US have type 2 diabetes, characterized by high blood sugar levels, a condition that can lead to many other health problems, including heart disease, stroke, and kidney failure.

Cirrhosis is one of the leading causes of death worldwide and is marked by liver fibrosis—a buildup of scar tissue on the liver, says coauthor James Boyer, professor and emeritus director of the Yale Liver Center.

The researchers note that several drugs, such as metformin, are currently available to control blood sugar levels in patients with diabetes. But these have a range of unpleasant side effects, and patients can develop resistance to these drugs. And there is little medical relief for fibrosis sufferers.

“Right now, there are no effective drugs for the treatment of fibrosis,” says Xuchen Zhang, an associate professor in pathology and coauthor of the fibrosis study.

The next step, Huang says, will be to identify where to best target TET3 and HNF4a and to develop the most effective siRNAs or small molecules to treat type 2 diabetes or fibrosis.

Huang has filed for a patent related to her discoveries with support from the Yale Office of Cooperative Research.

Support for both studies came from the National Institute of Diabetes and Digestive and Kidney Diseases at the US National Institutes of Health.

Source: Brita Belli for Yale University

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