Fetal Gene May Contribute to Diabetes Risk

THURSDAY May 8, 2008 -- Reduced activity of an important gene during fetal development appears to increase vulnerability to type 2 diabetes later in life, new research suggests.

Intrauterine growth retardation (IUGR), which causes low birth weight in newborns, has been linked to the development of type 2 diabetes and other diseases when a child grows up.

And decreased activity of the Pdx1 gene during fetal development has been linked to susceptibility for type 2 diabetes later on. The gene plays an important role in the development and function of pancreatic beta cells, which produce the hormone insulin. Insulin is necessary to transport sugar from the blood stream to the body's cells for energy. People with diabetes either don't produce enough insulin or aren't sensitive enough to the insulin that is produced.

The Pdx1 gene, however, had no mutation in animals with IUGR, presenting a mystery to scientists: If there is no mutation, why is the gene permanently altered?

"What happens in the intra-uterine environment? Why does that lead to the development of diabetes later in life?" asked Dr. Rebecca A. Simmons, senior author of a paper published in the May issue of the Journal of Clinical Investigation.

"What in intra-uterine life makes that beta cell not work properly even after you've been born into a normal environment?" added Simmons, an associate professor of pediatrics at the University of Pennsylvania School of Medicine.

Using a rodent model of IUGR, the researchers found that "epigenetic" changes were responsible for the lowered activity -- the gene was not totally silenced but was "markedly reduced," Simmons said. Epigenetic changes are basically changes in the structure of the DNA that occur when the cell divides and the DNA is replicated. These changes interfere with the ability of DNA to be transcribed, or send messages out to the rest of the body, she said.

Researchers were previously able to normalize the activity of the Pdx1 gene in both newborn and adult animals with diabetes, using the drug Byetta (Exendin-4). It's not clear yet if the drug can also reverse epigenetic changes. The drug comes from Gila monster saliva, Simmons said.

But investigators face a huge technical hurdle trying to confirm these findings in humans.

"We do know this process [gene silencing] occurs in humans, particularly in cancer with tumor suppressor genes," Simmons explained. "What we don't know is if this process is responsible, in humans, for changes that we see in growth-retarded babies growing up."

"We'd like to think this is the case [that the same process is at work in humans], but we have no way right now to determine that," Simmons continued.

If the same mechanism is at work in humans, the Pdx1 gene may present a good target for drug therapy to prevent the development of type 2 diabetes, she said.

More information

Visit the American Diabetes Association for more on type 2 diabetes.

Posted: May 2008


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