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January 4, 2011
ScienCentral

Diabetes Clues


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The Genetics of Diabetes



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Researchers are closer to learning the root cause of insulin resistance, which is what leads to diabetes. As this ScienCentral News video explains, they're doing so by studying the healthy children of diabetics.

Diabetes Epidemic

Monty Littlejohn, a 28-year-old medical student at SUNY Buffalo, is young, fit, and active. But because both of his grandmothers have diabetes, the family history of the disease has him concerned. Diabetes is usually associated with obesity, aging and lack of exercise, but as a medical student Littlejohn knows that diabetes also has a strong genetic component. "It is a little bit scary to think that no matter what I do, this is sort of looming over me in my future," he reflects.

Now researchers hope that studying the exceptions to the rule can provide insight into the underlying biological mechanisms of the disease.

Physiologist Gerald Shulman and his colleagues at Yale University studied 20-year-olds whose parents are diabetic. Despite being young, healthy and lean, all of the test subjects had high levels of insulin resistance. Insulin resistance is often referred to as "pre-diabetes" because it's the first sign that the body is not processing sugar properly.





A mitochondrion
After eating a meal, the digestive system breaks most food down into units of glucose, a simple sugar that is one of the basic energy sources for the body. Insulin is a hormone made by the pancreas, which triggers cells to absorb the glucose and use it. Once inside the cell, small energy factories called mitochondria convert the glucose sugar into a chemical called ATP. ATP powers every cellular and bodily function, from thinking to moving. When someone is insulin resistant, his or her cells aren't able to absorb sugar from the bloodstream to make ATP, which leaves the cells starving for energy even though it's right there just outside the cell wall.

Another thing that these young patients with family histories of diabetes had in common is that despite being lean, they actually had more fat inside their cells. And as Shulman says, "Fat inside the muscle cell causes insulin resistance; so the real question becomes, 'Why is the fat building up?'"





One of the goals of the team's research was to figure out exactly what was happening on a cellular level to cause this fat buildup. Shulman says there were two possible explanations, "So it became a question of, are there defects in the fat cells in the body, releasing more fat to liver and muscle, causing the buildup? Or are there defects in the mitochondria… the factories in all the cells of our body that produce energy?"




His group designed several experiments that used a technology called Nuclear Magnetic Resonance (NMR) spectroscopy to actually measure different things inside the volunteers' cells. One kind of NMR allowed them to directly measure the amount of fat both inside and outside the muscle cells. They also developed two other kinds of NMR spectroscopy — one to measure the activity of the mitochondria inside the cells and another to quantify how quickly the mitochondria were making ATP. "So we use all three NMR tools here to get an integrated picture of metabolism in human skeletal muscle," Shulman explains.

They found that compared to normal volunteers, the insulin-resistant group had much less mitochondrial activity. So it was, in fact, the mitochondria that were to blame for the fat building up inside the cells and not a defect in fat cells.

Shulman says that discovering that reduced mitochondrial activity is to blame is a key step in coming up with treatments and prevention. "I'm very excited about this because, really, if you understand the mechanisms to the disease, this will allow us to develop pharmacologic interventions to correct the disease or ideally prevent it," he says.

In an even more recent study published in the Journal of Clinical Investigation, Shulman's team revealed that the lower mitochondrial activity in these insulin-resistant patients is actually due to the fact that they have fewer mitochondria. As a result, the team is also focusing on identifying the genes that might be responsible for this reduced mitochondria count.

Until treatments are available, though, Shulman says there's a lot we can do to keep the risk of diabetes at bay. In another study, his team actually observed a total reversal of insulin resistance as a consequence of — you guessed it — regular exercise. "We've taken the same group of individuals and had them exercise four times a week on a stairmaster, and have totally reversed the insulin resistance in skeletal muscle," he says.

Monty Littlejohn is doing his best to take this advice to heart by eating a healthy diet and exercising almost daily. Shulman's recommendation is that we all do the same, "Try to watch [your] weight, stay lean, and more importantly, stay active."

Shulman's work was funded by the National Institutes of Health, the American Diabetes Association, the United States Public Health Service, and the Yamanouchi USA Foundation.


 
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