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Could New Liver Hormone Treat Diabetes?
25 April 2013 12:00 pm
A newly discovered hormone in mice prompts the rodents to boost their production of pancreatic β cells, the ones that make insulin and are missing or not productive enough in patients with diabetes. The hormone, called betatrophin, is made by people as well, and its discoverers hope that the effect in the human pancreas might be similar. That could make betatrophin a potential new therapy for diabetes, which affects more than 25 million people in the United States.
The body's cells typically use glucose, a kind of sugar, for their energy. The hormone insulin helps cells take up glucose, in turn regulating the level of glucose in the blood. In people with diabetes, the system doesn't work properly. In type 1 diabetes, an autoimmune response kills the β cells, and so the body lacks sufficient insulin. In type 2 diabetes, β cells are still present, but a complex set of factors keeps them from working as well as they should. Patients with type 1 diabetes and advanced cases of type 2 have to inject themselves with insulin to make up for what the pancreas can't produce.
For years, researchers have sought a way to help the body replace missing β cells—or augment existing ones—in people with diabetes so that they could produce enough insulin on their own. The healthy pancreas can at times boost its production of β cells, both in response to injury and to increased demand for insulin—for example, during pregnancy. Cell and developmental biologists Douglas Melton, Peng Yi, and Ji-Sun Park of Harvard University were trying to better understand the factors that control that process. In experiments described in a paper published online today in Cell, the researchers gave mice a molecule that blocks the insulin receptor on cells, tricking the animals' bodies into reacting as if they needed more insulin and producing more β cells.
This rodent reaction involved turning on and off a number of genes, and the team identified one activated in the liver and fat tissues. It piqued their interest as a possible hormone gene because it codes for a protein that is excreted by cells. When the researchers injected extra copies of the betatrophin gene into the liver of normal mice, the animals' pancreases responded by making as much as 30 times more β cells than usual. After a week, the injected mice had more than twice the number of β cells as animals that didn't get the extra genes. The increased betatrophin gene activity didn't seem to cause cells to replicate in other parts of the pancreas or in liver or fat tissue.
"It was fast, extensive, and fortunately very specific—the only cells that replicate were the β cells," Melton says. (He says he wanted to call the hormone "mobeta," but his colleagues voted that down in favor of betatrophin, which means β-nourishing or β-stimulating.) Nondiabetic mice that received the betatrophin gene injections were able to control their blood sugar even more effectively than control mice—performing better on the glucose tolerance test that is used to diagnose diabetes.
The results are intriguing, says diabetes expert Jay Skyler at the University of Miami Leonard M. Miller School of Medicine in Florida. "It's nice to see that there is a hormone that may be responsible for β cell growth," he says. The work is still preliminary, however. "They are gorgeous studies, but they are in mice," he says, noting that a number of previous promising diabetes treatments that have worked in mice have failed to help human diabetics.
Melton agrees and also notes that other hormones that seemed to offer simple explanations for metabolic processes turned out to be more complicated. "Remember leptin," he says, a hormone that in initial experiments made fat mice thin. Further studies showed that its effects are modulated by a complex set of other factors, and leptin has yet to be developed into a widespread human treatment.
"I like the simplicity of the [betatrophin] story now," Melton says. If it holds up, he suggests, diabetes patients might treat themselves with a weekly or even monthly injection of betatrophin instead of injecting insulin several times a day, because a dose of the new hormone could, in theory, prompt the growth of new β cells that could produce the insulin the patient needs. Melton and his colleagues are already working with Evotec, a company in Hamburg, Germany, and Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, to further study betatrophin and possibly move it toward clinical trials. For an early-stage drug candidate, "betatrophin is as good as it gets," says Evotec CEO Werner Lanthaler. "Is it a product? We don't know."
Skyler says that he, too, hopes the preliminary data are right and the effects in humans are indeed straightforward. "It could be game changing. I'd love to see it work."