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New Therapeutic Target for Diabetes and Wolfram Syndrome

Researchers identify key molecule in cellular inflammation

At Washington University School of Medicine in St. Louis, Mo., scientists have identified a key molecule in the cell stress-modulated inflammation that causes insulin cells to die.

The new study was published on August 8 in the online edition of Cell Metabolism.

Local inflammation within cells can be caused by a specific type of cell stress called endoplasmic reticulum (ER) stress, whereas systemic inflammation involves the activation of immune-system cells. The molecule identified by the Washington University researchers is involved in the initiation of local inflammation, which can lead to systemic inflammation.

That molecule, thioredoxin-interacting protein (TXNIP), provides scientists with a target to direct therapies for diabetes and Wolfram syndrome. The latter disorder causes kidney problems as well as hearing and vision loss. As patients get older, they develop ataxia (a brain dysfunction that causes a loss of muscle control and coordination), and many patients die before their 40th birthday.

The ER is responsible for producing proteins and for synthesizing cholesterol in cells. Each cell in the body has an ER, which also is involved in transporting proteins to the parts of the cell where they are needed.

In ER stress, misfolded proteins accumulate, activating a response in the cell designed to correct the problem by making fewer proteins and by eliminating the misfolded ones. But if the stress cannot be resolved, the cells self destruct.

The researchers analyzed genes that were activated in insulin-producing cells under ER stress and found that TXNIP was manufactured in large amounts in the stressed cells. Past research demonstrated that the protein was involved in inflammation, and as experiments progressed, the researchers were able to link TXNIP both to ER stress within the cell and to inflammation outside of specific populations of cells that can have an effect throughout the body.

The researchers found that TXNIP levels are significantly increased in insulin-secreting cells in animal models of Wolfram syndrome. Other recent research has found that verapamil, a commonly used blood-pressure medication, can interfere with TXNIP production. The research team is therefore testing verapamil in animals with Wolfram syndrome to learn whether the drug can delay disease progression.

The TXNIP protein provides the best available target for therapies because the only other known molecule involved in cell death under ER stress conditions is located in the cell nucleus. TXNIP, on the other hand, exists outside the nucleus and may more easily interact with potential therapeutic agents.

For more information, visit the Washington University in St. Louis Web site.

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