Diabetes Forecast

Inside the Cells

Researching flaws in the body's "power stations"

By Andrew Curry , ,

Vladimir Ritov, PhD
Professor of Medicine, University of Pittsburgh
ADA Research Funding
Clinical Translational Research Award

Diabetes has a straightforward definition. Whether it's caused by the body's cells not being sensitive enough to insulin or by the pancreas not producing enough insulin in the first place, diabetes is about having too much glucose, a kind of sugar, in the blood.

That means the search for a cure often focuses on shifting glucose from the bloodstream into the cells. But Vladimir Ritov, a biochemist at the University of Pittsburgh, thinks that in some cases that single-minded focus may be problematic. In the past decade, he has studied what happens when glucose is processed in the cells of people with type 2 diabetes. It turns out that pushing glucose into diabetic cells may come at a cost.

People talk about glucose as though it's pure energy: Get it from food to the bloodstream to our cells somehow, and it'll make our muscles go. But there's actually a complex process that burns glucose and uses the resulting energy to produce the molecule that fuels our individual cells. It's up to structures inside the cells called mitochondria to produce that molecule, called ATP. The ATP made by the mitochondria produces energy for all the reactions in our body. "Generally, mitochondria are the power stations for our cells," Ritov says.

That's not all mitochondria do. Alongside their role in transforming glucose into energy, mitochondria churn out the body's building blocks, hundreds of different molecules, in addition to those produced elsewhere in the cell. They are used to build new cells and create chemical reactions in the body. "Mitochondria are not only a power station but also a production site," says Ritov. Another word for the chemical reactions that keep us alive is "metabolism." Mitochondria are responsible for producing and making use of the resulting "metabolites."

Yet some metabolites are toxic: One example is acetaldehyde, the chemical produced when mitochondria tackle the ethanol, or alcohol, in a glass of wine. When it comes to toxic metabolites, "it all depends on concentration," Ritov says. "For example, drinking [in moderation] produces acetaldehyde, but we survive." In small amounts, the body can usually handle the bad-for-you byproducts of metabolism. Inside the cell, the mitochondria keep working, breaking metabolites down once again into less harmful compounds or burning them off.

In people with type 2 diabetes, however, defective mitochondria may struggle to process, or "oxidize," the toxic metabolites. "This can be the cause of insulin resistance," Ritov says: The more glucose that cells take in, the more metabolites are produced, and those metabolites in turn build up inside the cell. As the cell fills with metabolites, it may become less sensitive to insulin, as though it's waving off what it knows it can't handle.

Ritov's research suggests that the focus on increasing insulin production and lowering blood glucose levels may come at a cost. As more glucose is absorbed into muscle cells equipped with faulty mitochondria, more toxic metabolites build up. "Currently, people are thinking about how to restore beta cells," which make insulin in the pancreas, says Ritov. "They hope they can increase the level of insulin and that's it, bingo. But that's not all. You have to help the muscle manage the glucose."

Ritov's research is aimed at understanding what's going wrong in the mitochondria of people with diabetes. If the flaws can be understood and isolated, perhaps a treatment could be found to help muscles better manage the metabolites and stave off insulin resistance. It's hard work—Ritov has been wrestling with the problem for almost a decade.

The latest stage of his research, funded by the American Diabetes Association, involves separating the mitochondria from cells to see what the differences are in people's cellular "power stations." Ritov uses tiny tissue samples from 45 different people—15 with type 2 diabetes, 15 people who are obese but do not have diabetes, and 15 lean people who do not have diabetes. "We put mitochondria to work in tubes, and see how they work, and use this media for analysis," Ritov says.

By nailing down the differences among mitochondria, Ritov will be one step closer to pinning down the flaw that makes it harder for people with type 2 diabetes to process glucose properly. "We need to understand what the problem is to help people and solve the problem," says Ritov. And understanding the problem is a big step toward fixing it.

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