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Proteome analysis may aid in diabetes research
  
By Lone Frank


Researchers use two-dimensional electrophoresis to separate all the proteins in a tissue.

Scientists at the Center for Proteome Analysis (CPA) in Odense, Denmark, have identified a natural protein that seems to protect the body's insulin-producing beta cells from attack. Their approach is to analyze the thousands of gene products in cells and tissues, with special interest in galectin, a small protein that is vital in insulin dependent diabetes mellitus (IDDM). Every cell, no matter what tissue it's in, carries the same full set of genetic information, the species' genome. Now that genomic information is pouring in at a breathtaking pace, scientists are rushing to understand which proteins a particular type of cell synthesizes, how much the cell synthesizes, how cells modify proteins after synthesis and how all those proteins interact. This is the new science of proteomics.

Among the first to realize the potential of proteomics, biologists Peter Mose Larsen and Stephen Fey founded CPA in 1997. And even today, when proteome centers are sprouting up everywhere, this research compound, situated in the green fields outside Odense (the birthplace of Hans Christian Anderson), remains at the forefront of proteomics. CPA is a noncommercial research center of the University of Southern Denmark.

"The complete list of human genes will soon be at hand, but the vast majority of them will be of unknown function," Mose Larsen observes. "Proteome analysis comes in both as a means to get at the function and as a powerful shortcut to identifying genes that interact and are involved in disease development."

The identification of galectin illustrates his point. Traditionally, Denmark has been strong in diabetes research, and Mose Larsen and Fey have been working to uncover the mechanism of diabetes for seven years. The cause of the disease is thought to be an oversensitivity of the insulin-producing beta cells in the pancreas to immune system chemicals, called cytokines, that flag cells for destruction.

The idea behind the CPA project is to pin down which proteins play a role in the destruction and protection of beta cells. The team grew rat beta cells in the laboratory, from both diabetes-prone and diabetes-resistant rat strains. They then challenged the cells with cytokines. They spent two years identifying proteins expressed in the two types of cells, compared the amounts of each protein produced and entered all the data into a large database. Subsequently, the researchers repeated the experiments with normal and diabetic human beta cells flown in from the Miami Diabetes Transplantation Center in Florida.

"Out of the thousands of proteins produced in the cells," Fey says, "we found that only about one hundred of them change the levels of expression as the cells are dying." From that hundred, the CPA team zeroed in on galectin. Whenever beta cells were not destroyed by cytokine treatment, this protein seemed to be increased in both rat and human beta cells. The team then used a harmless virus to insert the gene into diabetes-prone rat beta cells, thereby artificially boosting the production of galectin. The rat cells survived the cytokine challenge.

The next step is trying to rescue human beta cells by inserting the galectin gene. If this succeeds, several possibilities for treating or even preventing diabetes open up. "One obvious method would be to use gene therapy and transfect a patient's own beta cells with the gene for galectin to prevent further breakdown and halt progression of the disease.

"But our dream, of course, is to be able to identify people at high risk for developing diabetes and treat them before they get sick," says Mose Larsen. Such an identification hinges on genetic knowledge. Other research groups are currently mapping regions of DNA that seem to determine an individual's predisposition to diabetes, and eventually genetic tests will be available. For the treatment of the future, an alternative to gene therapy is drugs that stimulate the natural galectin production inside beta cells, and the CPA researchers plan to use proteome analysis to look at interesting candidates.



Sixteen million Americans have diabetes, and one in three does not know it. The American Diabetes Association, a nonprofit organization providing diabetes research, information and advocacy, has constructed a simple, online test to assess your risk of having diabetes. Scoring high on the test does not mean you have or will get diabetes. But it may mean you should see your health-care provider for a check-up. Click here to take the test. (www.diabetes.org)

 


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