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University of Florida study shows leptin could combat type 2 diabetes

September 21, 2006

Gene therapy technique reverses type 2 diabetes in mice

GAINESVILLE, Fla. - University of Florida researchers have discovered the appetite-controlling hormone leptin could also combat type 2 diabetes, a disease that has become a growing problem in the United States as more Americans pack on extra pounds.

Using a novel gene therapy technique, UF researchers were able to reverse type 2 diabetes in mice. The researchers found that in diabetic mice, leptin acts in the hypothalamus to keep the body from producing too much insulin even after constant exposure to a high-fat diet, which over time can lead to or worsen type 2 diabetes, according to findings published this month in the online edition of the journal Peptides.

Although more tests are needed, scientists are hopeful these findings will lead to better treatments for patients with type 2 diabetes, said Satya Kalra, Ph.D., a UF professor of neuroscience and the senior author of the article.

"We found that we were successful in keeping the blood levels of insulin low at the same time keeping blood glucose levels at a normal range," Kalra said. "In other words, we were able to correct diabetes in these animals under various challenges."

The researchers injected a gene embedded in a harmless virus into the brains of the mice to increase leptin production in the hypothalamus, which regulates the hormone. While past studies have shown leptin acts in the brain to regulate weight and appetite, this is the first time researchers have shown that leptin can independently affect insulin secretion as well, Kalra said.

Typically, eating rich and fatty foods causes blood sugar levels to rise, which in turn causes the body to produce more insulin, a protein that helps the body use carbohydrates. Patients with type 2 diabetes often become resistant to the insulin they do make, causing too much of it to build up in the body. After gene therapy, tests showed that the blood sugar and insulin levels in the mice that received it had returned to normal, even when they were fed a high-fat diet. Mice that ate a high-fat diet but that did not receive gene therapy, however, continued to overproduce insulin and have high blood sugar levels, which Kalra said are markers for type 2 diabetes. In another arm of the study, researchers also discovered that normal, nondiabetic rats that received leptin gene therapy produced lower levels of insulin as well.

"This was totally unexpected," Kalra said. "Until now there was no evidence that leptin action in the hypothalamus had control on insulin secretion. (With leptin gene therapy) we can reimpose that control."

More than 18 million people in the United States have diabetes and about 90 percent of them have type 2 diabetes, also called adult-onset diabetes, according to the Centers for Disease Control and Prevention. Most cases of type 2 diabetes result from leading a sedentary lifestyle, being overweight and overeating.

If left untreated, type 2 diabetes can also cause cardiovascular disease, kidney disease and blindness.

Aside from keeping blood sugar and insulin levels down, the rodents that received gene therapy also lived longer than obese rodents that did not, Kalra said.

"Currently we do not know if that is due to the correction of the diabetes or many of the diseases associated with diabetes," Kalra said. "It is clinically known that diabetic patients have early onset mortality. If the diabetes is managed, there is an improvement in lifespan."

Martin G. Myers, M.D., Ph.D., an associate professor of medicine and physiology at the University of Michigan Medical School who also studies leptin, said other studies in recent years have shown similar findings, albeit without the use of gene therapy.

"Most of what is in this paper is not surprising," Myers said.

While he noted that it was good to see the leptin was still working in the rodents for the full 15 weeks that UF researchers were conducting the study, Myers said it is unlikely that doctors will employ leptin gene therapy in humans.

Gene therapy would be an ideal treatment because it just takes one shot, Kalra said, adding it is also likely drugs could be developed to simulate leptin's action in a pill form, which is easier to give to patients.

"What we have shown in animals is very effective," Kalra said. "It can be done."

University of Florida