Diabetes Forecast

Untangling One Cause of Prediabetes

Leigh Perreault, MD

Leigh Perreault, MD
Endocrinology Researcher, University of Colorado–Denver School of Medicine, Aurora, Colo.
ADA Research Funding
Career Development Grant

The biggest risk factor for type 2 diabetes is not obesity. Nor is it genetics, gender, race, or diet. It's prediabetes, a collection of conditions that show up as high blood glucose levels.

In America alone, 79 million people—a quarter of the entire population—have prediabetes. For doctors and public health experts, it's a terrifying number. "Not everyone who has prediabetes gets to [type 2] diabetes, but 50 to 70 percent of them will," says Leigh Perreault, a researcher at the University of Colorado–Denver School of Medicine.

Yet recent research has shown that not all prediabetes is created equal. Though the results—high blood glucose and insulin resistance—look similar, the underlying causes are different. About a third of Americans with prediabetes, or about 27 million people, have impaired fasting glucose, something the American Diabetes Association (ADA) recognized as a prediabetic condition in 2004.

This is how impaired fasting glucose works: Between meals, the body normally produces and stores a certain amount of insulin. After the next meal, the insulin is called upon to turn the glucose into energy to fuel the body's cells. When we eat, those insulin reserves are released and used up. If the stored insulin isn't enough to get all the sugar in the bloodstream absorbed, the body senses it and makes more—like a thermostat automatically turning on the air-conditioning when the house gets too hot.

But for people with impaired fasting glucose, "that's exactly what's not happening," Perreault says. "Something's wrong with the glucose thermostat." For people with this kind of prediabetes, the signals that tell the body to make more insulin when its stores run dry don't turn on until glucose levels rise too high. It's as though you set the thermostat in your house to a comfortable 70 degrees, but the cool air didn't kick in until you were sweating in an 85-degree sauna.

With the help of a grant from the ADA, Perreault is researching why the "glucose thermostat"—actually an enzyme called glucokinase—doesn't work normally in people with this type of prediabetes. By unraveling the causes of impaired fasting glucose, she hopes to give some of the millions of people with prediabetes a way to slow the onset of type 2 diabetes or avoid it entirely. "If we want to prevent or cure diabetes, we need to tell what happens first," she says. "With diabetes, it's pandemonium. Everything's going wrong. With prediabetes, we can single out some of the mechanisms."

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Her most recent experiment involved 38 people, divided into two groups and matched for things such as age and weight. One group—the "control"—didn't have any evidence of prediabetes. The other group had impaired fasting glucose.

Perreault's goal was to figure out why. For most people with impaired fasting glucose, it's not clear what's causing the condition. They're no more overweight or older than the control group, she notes.

Each patient in the study was put on a controlled diet for three days, spent a night in the hospital, and was scanned and tested, all while hooked up to different IVs. The results, Perreault says, were dramatic: In the people with impaired fasting glucose, the glucokinase enzyme simply didn't work. "After running these very long and involved studies, it's very striking that glucokinase is defunct in all of these people," she says.

The next step is to figure out what's knocking the glucokinase "thermostat" out of whack. For a tiny percentage of people, she says, the problem can be traced to their genes. But for most the problem lies somewhere else. "We think maybe they're exposed to some sort of environmental pollutant that interferes with glucokinase," Perreault says.

Perreault is already experimenting to see if she can narrow down what might be responsible. The possibilities are nearly endless, "everything from saturated fats to plasticizers and pesticides," she says. "We're screening all the weird, icky junk that's out there."

If an environmental pollutant is the trigger, it could be very good news—because Perreault's research also suggests the glucokinase problem is reversible. "Perhaps if I can somehow take some pollutant away, all of a sudden those 27 million Americans would not be on the pathway to type 2 diabetes," she says. "Perhaps we don't need to give somebody a drug—we just need to take something out of the environment that makes them sick."



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