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David Bernlohr holds a tray containing a couple of mice.

Could protein alteration be behind insulin resistance? A small team of researchers led by David Bernlohr thinks so.

The missing link

Researchers home in on the connection between obesity and insulin resistance

By Mary Hoff

February 15, 2008

One out of five would be great odds if you were buying a lottery ticket. They're lousy, however, when you're talking about developing a chronic health problem. Yet one out of five Americans has insulin resistance, an obesity-related disorder in which cells lose their ability to respond to their pancreas's prompting to absorb glucose from the bloodstream. And insulin resistance often leads to type 2 diabetes. As America gains weight, the incidence of insulin resistance and diabetes is growing too, with huge health implications.

Understanding the link between obesity and insulin resistance is a goal of David Bernlohr, professor and head of the Department of Biochemistry, Molecular Biology and Biophysics in the College of Biological Sciences.

"We would like to know the molecular mechanism connecting obesity to type 2 diabetes to develop specific molecular therapies," he says, "or identify drug targets that might be efficient in treating obesity-linked disease."

To that end, Bernlohr, assistant professor Tim Griffin, and student Paul Grimsrud have been taking an inside look at key molecules within fat cells.

Their starting point is the fact that type 2 diabetes often goes hand in hand with a condition within cells known as oxidative stress. Oxidative stress leads to the production of molecules known as reactive aldehydes that alter the structure of proteins. Could protein alteration be behind insulin resistance?

The researchers began their quest for an answer by looking for altered proteins in the fat cells of lean and obese mice. Using a special technique they developed, they found that altered proteins were two to three times as common in the fat cells of overfed obese mice than in those of lean mice.

They also discovered that the concentration of an enzyme called GSTA4, which destroys the reactive aldehyde 4-HNE, was three to four times lower in the obese mice. When they looked into what was already known about the enzyme, they discovered that genetically engineered mice missing the gene for GSTA4 (and so less able than normal mice to destroy 4-HNE) are diabetic--strong support for their suspicion that 4-HNE's protein-altering ability contributes to insulin resistance.

"We kind of got lucky on that one," Bernlohr says.

How does protein alteration lead to insulin resistance? A look at one of the altered proteins, A-FABP, offers a promising clue. Mice unable to produce A-FABP are more insulin sensitive than are normal mice. And altered A-FABP molecules are less able than others to bind fatty acids. That suggests that alteration of the protein by reactive aldehydes could be key.

The researchers' next step is to genetically engineer mice that make plenty of GSTA4 even when they get fat. If these mice are able to stave off diabetes, it will further support modification of proteins by 4-HNE as a link in the chain connecting obesity and insulin resistance.

From Bio , fall 2007, the magazine of the College of Biological Sciences.