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The obesity-diabetes link

<em>David Bernlohr, Ph.D.</em>

U scientists are advancing treatments for type 2 diabetes

It’s a vicious circle: The more resistant your body is to insulin, the higher your blood sugar goes. The higher your blood sugar, the more insulin your pancreas secretes. Left unchecked, high insulin levels result in your body’s inability to compensate for elevated blood sugars, the failure of pancreatic islets, and, ultimately, type 2 diabetes.

Those who are obese—more than 30 percent of the U.S. population, according to the Centers for Disease Controland Prevention—are at an especially high risk for developing type 2 diabetes.

University of Minnesota researcher David Bernlohr, Ph.D., has studied adipose biology—the biology of fat tissue—for more than 25 years. A Distinguished McKnight Professor and head of biochemistry, molecular biology, and biophysics at the Medical School, Bernlohr also leads a Center for Diabetes Research lab that’s focused on projects related to obesity-linked insulin resistance.

Battling insulin resistance

“Initially, we began studying the lipolysis, the process by which fat cells release fatty acids and those lipids circulate in the bloodstream and affect processes in the liver, muscle, and beta cells,” he says. “Over time, the work has shifted to focus more on how inflammation affects insulin resistance.”

That’s because inflammation plays a key role in diabetes. In type 2, insulin resistance results from the inflammation of fatty tissue, the liver, and other peripheral tissues.

In 2009, Bernlohr’s lab published a paper in the Journal of Medicinal Chemistry identifying a small molecule inhibitor of the fatty acid- binding protein. The inhibitor blocks the protein’s ability to traffic fatty acids within a cell and allows the cell to perform its normal function. This, in turn, leads to increased sensitivity of fat cells to insulin and reduced inflammation—both key to reducing the risk of type 2 diabetes.

New research approaches, treatments

Now University researchers, including Ann V. Hertzel, Ph.D., assistant professor and Bernlohr’s long-time project collaborator, are looking for additional or better molecules to treat type 2 diabetes.

“This is a new target that potentially will lead to a drug that will improve patients’ insulin sensitivity,” Hertzel says.

Such small-molecule drug treatments would provide an alternative treatment for patients who don’t respond well or lose the ability to respond well to classic type 2 drugs called insulin sensitizers.

Such treatments could help individuals who are insulin resistant and those who are obese.

Bernlohr notes that insulin resistance doesn’t just lead to diabetes but also to neuropathy and cardiovascular disease—health challenges that these small-molecule drugs could lessen.

Philanthropy making a difference

Bernlohr and his colleagues are also trying to determine when a fat cell loses its ability to convert energy into usable forms.

In 2010, Minnesota philanthropists Wendy and Douglas Dayton made a gift to support type 2 diabetes and breast cancer research at the University. Part of the gift was used to purchase a Seahorse XF24 Analyzer, which measures metabolic activity in muscle, stem cells, beta cells, and the liver. It allows Bernlohr to evaluate drugs that could improve insulin action.

“Without [those funds], we wouldn’t be able to do our experiments,” he says.

What would it mean to develop a drug that would help the millions of people affected by insulin resistance? “That’s the overall goal of most scientists,” says Hertzel. “It’s what we always hope and dream will come from our work.”

By Karin Miller

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