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Gene Defect Causes Rare Form of Diabetes

By Nancy Touchette

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Researchers in the United Kingdom have discovered a gene mutation that leads to a rare form of inherited diabetes. Although the mutation it is unlikely to cause the more common forms of the disease, the finding is giving researchers an important clue as to how the disease develops.

The mutation, in a gene called AKT2, was found in several members of a family who developed severe insulin resistance and diabetes in their early 30s. Unlike most people with type 2 diabetes, members of this family were not obese or sedentary.

The vast majority of people with the disease have type 2 diabetes, which occurs when people either don’t produce enough insulin, don’t respond to insulin, or both. As a result, the cells in the body can’t use glucose and disease develops.

Researchers have already discovered several gene mutations that trigger a severe form of diabetes called MODY, for mature onset diabetes of the young, which is caused by insufficient insulin production. But this is the first gene mutation that leads to a form of diabetes caused by insulin resistance. The findings appear today in Science.

By identifying single gene mutations that lead to these severe forms of the disease, researchers hope to better understand how more subtle gene variations might predispose a person to common forms of type 2 diabetes.

“Type 2 is a complex disease,” says Iñes Barroso of the Wellcome Trust Sanger Institute in Cambridge, United Kingdom, who led the recent research. “We will never uncover mutations that on their own cause type 2 diabetes. Rather, we will find polymorphisms, or gene variations, that predispose a person to the disease.”

Researchers have already found single mutations in genes that affect insulin production and cause MODY. This has led to the discovery of more subtle variations in the same genes that predispose a person to some forms of type 2 diabetes.

Barroso is now testing whether any people with more common forms of type 2 diabetes harbor variations in the AKT2 gene.

Barroso and her colleagues have been looking for gene mutations in more than 100 patients with severe insulin resistance. They focused on the AKT2 gene because studies in mice had shown that knocking out the gene often led to diabetes.

AKT2 codes for a protein that is part of the insulin signaling pathway, a sort of relay system that allows cells to respond to insulin and eventually let glucose into the cell.

Barroso’s discovery is significant, because it is the first time a defect in the insulin signaling pathway has been shown to contribute to diabetes in humans. It is likely, she says, that other proteins involved in insulin signaling may also contribute to insulin resistance and diabetes.

“Studying these extreme examples of disease may give us clues to other genes playing roles in more common forms of diabetes,” says Barroso. “We may find additional proteins that could be targeted and lead to new drug treatments.”

For more news see GNN’s Diabetes Page.

George, S. et al. A Family with Severe Insulin Resistance and Diabetes Due to a Mutation in AKT2. Science 304, 1325-1328 (May 28, 2004).

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