Genetic Key to Type 2 Diabetes Identified

Altered proteins in liver, pancreas at root, study finds

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By
HealthDay Reporter

THURSDAY, Feb. 26, 2004 (HealthDayNews) -- Mutations in proteins that turn genes on and off in the pancreas and liver may make you more likely to develop late-onset type 2 diabetes, researchers report.

Late-onset type 2 diabetes is the result of poor regulation of blood sugar. Today in the United States there is an epidemic of type 2 diabetes, primarily due to obesity.

Diabetes can lead to heart attacks, stroke and poor circulation, which can lead to amputation of the feet or legs. Diabetes can also lead to problems with vision that can cause blindness. Kidney and nerve problems are also common complications.

Now researchers find that alterations in proteins that control the function of genes in the liver and pancreas also play a major role in type 2 diabetes.

"We are making major advances in understanding the genetic problems that lead to type 2 diabetes," says lead researcher Dr. Duncan Odom, a postdoctoral fellow at the Whitehead Institute in Cambridge, Mass., which is affiliated with the Massachusetts Institute of Technology. "Diagnosing and predicting your probability of getting diabetes is going to be much easier in the next few years."

Recent studies have shown there are special proteins, called transcription factors, that regulate how genes are turned and off.

Mutations in the transcription factors that control the genes that manage insulin production and blood sugar can cause problems in liver and pancreatic cells, which in turn can cause type 2 diabetes, Odom explains.

Working with human liver and pancreatic tissue, the researchers studied which genes these transcription factors affect. Their findings appear in the Feb. 27 issue of Science.

"We found that one of these transcription factors plays a role in many liver and pancreatic genes, which was unexpected," Odom says. This transcription factor, called HNF4-alpha, controls about half of all the genes needed in forming the pancreas and liver, the researchers report.

Without HNF4-alpha, the liver and pancreas cannot function normally, Odom says. In addition, mutations in HNF4-alpha make it more likely for someone to develop type 2 diabetes.

"This transcription factor [HNF4-alpha] is the key to diabetes," Odom says. HNF4-alpha is a carrier of other transcription factors. If there are problems in any of these transcription factors, they create problems in HNF4-alpha, he adds.

"People who have mutations in any of these transcription factors will have late-onset type 2 diabetes," Odom says.

Odom says that other research, which is expected to be published next month, shows that mutations in the genes that control HNF4-alpha make you much more likely to develop type 2 diabetes if you are obese.

Odom believes that "if you can bring HNF4-alpha back to its normal behavior, you might be able to treat diabetes more effectively." He speculates it might be possible to develop a drug that can do just that.

There are other transcription factors linked to diabetes, Odom says. And his team is continuing to investigate them to see what role they play in diabetes and in how the liver and pancreas function.

"We hope that this investigation will give us really good insights into what causes diabetes and provide additional targets for therapy," he says.

Dr. Rohit N. Kulkarni, an investigator at the Joslin Diabetes Center and an assistant professor of medicine at Harvard Medical School, says "this new data is really important."

This study, together with others that show that mutations in these transcription factors increase the probability of getting type 2 diabetes, indicate these transcription factors are significant in human disease, Kulkarni says.

These factors provide a target that scientists can focus on to treat diabetes, particularly mutations in HNF4-alpha, which seems to be the key one, he adds.

More information

The National Institute of Diabetes and Digestive and Kidney Diseases has a page on risk factors for type 2 diabetes, as well as how to prevent getting the disease.

SOURCES: Duncan Odom, Ph.D., postdoctoral fellow, Whitehead Institute, Cambridge, Mass.; Rohit N. Kulkarni, M.D., Ph.D., investigator, Joslin Diabetes Center, and assistant professor, medicine, Harvard Medical School, Boston; Feb. 27, 2004, Science

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