How Diabetes Develops In Overweight People

Fat burning is touted as the key to weight loss, but it may also link obesity and diabetes, new research suggests. When fat is burning exclusively for fuel, blood sugars go up and insulin stops working.

Daniel P. Kelly, director of the Center for Cardiovascular Research at the university, and his colleagues were studying the heart when they made a discovery that could provide new understanding for how diabetes develops in overweight and obese people. The researchers noted that when fat gets into the heart, the organ stops burning sugar for energy.

"There’s this yin and yang between fat and sugars," Kelly said. Normally, cells use a sugar called glucose for energy, but they may also use fatty acids as less efficient fuel sources. When cells stop burning sugar and switch exclusively to fat fuel, blood sugar levels rise and insulin stops working. Those are two hallmarks of diabetes.

Kelly and his colleagues discovered that a molecule known in short as PPAR-alpha (its full name is peroxisome proliferator-activated receptor-alpha) acts in muscle cells as a fuel-source switch. The switch is thrown when animals – mice in Kelly’s research – and perhaps people take in more calories than they can use and become obese. Fat cells store the excess calories as fatty acids.

But "at some point the reservoir is full. You can only expand your fat tissue so much," Kelly said. The body may begin storing fat in tissues, such as muscle and liver, where it doesn’t belong, he said. And when the fat spills over into muscle, PPAR-alpha gets going. The molecule helps muscle cells bring in and burn fatty acids, and shuts down sugar consumption. "It’s telling the muscles `don’t listen to insulin anymore. We don’t need to burn sugar,’" Kelly said. The result is high blood sugar and insulin-insensitive cells. In other words, a step toward diabetes.

The scientists genetically engineered two different types of mice – one type that made excess PPAR-alpha in their muscles and another that lacked the molecule. The researchers found that mice that over-produce PPAR-alpha become diabetic even though they are thin. That’s because their muscle cells become fat-burning machines that ignore insulin and glucose.

Conversely, mice lacking PPAR-alpha were prone to growing heavy, but they seemed to be protected against getting diabetes. That could mean that drugs to block the action of the molecule could prevent diabetes, Kelly suggested.

The results are a mixed blessing, said Sam Klein, director of the Center for Human Nutrition at Washington University. "In terms of obesity, this is a cure. In terms of diabetes, this is a cause," Klein said.

No one knows if the mechanism also works in people. The mice in the study still had active pancreas cells, so the research did not address the full picture of diabetes, Klein said.

But the study may offer some clues about one reason why 65 percent to 90 percent of diabetics are also overweight, Klein said. Not everyone who is obese will develop diabetes – about 15 percent of obese people are diabetic – but overweight and obesity are risk factors for the disease. It is rare for someone who is of normal weight to get Type 2 diabetes, the form once known as adult-onset diabetes, Klein said.

The new study contradicts some of the conclusions of earlier studies with mice and is likely to be "provocative," Klein said. "It makes us more confused about what we thought we knew before," Klein said. But in scientific circles, that’s good news. Follow-up studies could help determine the steps that lead to diabetes in obese people and find ways to stop the disease from developing, he said.
Journal Cell Metabolism March 2005

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