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Looking beyond insulin

Work in rodents suggests new hormone targets for treating type 1 diabetes

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4:14pm, August 25, 2008
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A little extra leptin can bring terminally ill rodents with type 1 diabetes back from the brink of death.

Leptin, a hormone made by fat cells, helps control eating behavior. A new gene therapy study suggests that it can also treat diabetes, the first demonstration that the disease can be treated without replacing insulin.

Roger Unger and colleagues at the University of Texas Southwestern Medical Center at Dallas used adenovirus to insert extra copies of the leptin gene in diabetic mice and rats. The rodents recovered from the most severe side effects of diabetes, even though the mice do not make insulin and weren’t given insulin, the researchers report in an early online publication August 25 in the Proceedings of the National Academy of Sciences.

“This is something that is extremely original, totally new and a little unexpected,” says Pierre Lefèbvre of the University of Liège, Belgium, and president of the Seattle-based Global Diabetes Alliance.

Type 1 diabetes, also known as juvenile diabetes, is an autoimmune disease in which the immune system attacks and kills insulin-producing cells in the pancreas. About 10 percent of people with diabetes have this form of the disease.

“We as physicians have been trained since 1922 that the only treatment for diabetes is insulin,” says Unger. So when diabetic animals making extra leptin recovered, the researchers had trouble believing it themselves, he says. “This was like science fiction. We couldn’t tell anybody because we thought they would laugh.”

But the terminally ill diabetic rodents making extra leptin recovered with no trace of insulin in their bodies. And leptin produced more sustained health improvements than insulin injections did. These included normalizing blood sugar for up to 80 days without insulin, stopping the overproduction of glucose by the liver, improving sugar use in the muscles, and allowing the animals to gain weight. The gene therapy also corrected ketosis — a process characteristic of diabetes in which the body burns fat, producing sweet-smelling chemicals called ketones.

“The idea that only insulin can rescue terminal insulin deficiency is incorrect,” Unger says. “There are other ways.”

Excess leptin seems to block the action of glucagon, a hormone that works as a counterpoint to insulin, which helps cells use glucose for energy. Glucagon signals the liver to produce glucose from fats and other non-carbohydrate sources. In diabetics, high glucagon levels just raise blood sugar levels even higher and lead to other side effects.

Unger says he cannot predict whether injections of leptin will work as well as making extra leptin in the liver does. That is the next set of experiments he has planned.

People given injections of leptin for other reasons do show some improvement in blood sugar levels, says Paul Burn, the senior vice president for research and development of the Juvenile Diabetes Research Foundation. The new study is evidence that altering glucagon activity could have beneficial effects for diabetics, he says.

“While this is excellent exploratory research supporting these ideas, I think it’s a long way from the clinic,” Burn says.

Unger also sounds a cautious note. “It’s very hopeful, but a long way from having any tangible influence on anything other than opening our eyes that there are alternatives to insulin.”

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