Fourth of five parts
Joe Gosselin of Raleigh is working hard to avoid becoming one of the 643,000 people in North Carolina with diabetes.
Three years ago when Gosselin was 61, his doctor at SAS, where he works as a computer programmer, told him he was overweight and pre-diabetic. The condition, marked by elevated levels of sugar in the blood, afflicts tens of millions of adults in the U.S., including an estimated 376,000 in North Carolina.
It is among the leading lethal consequences of obesity.
Gosselin, who weighed 230 pounds at 5 feet 10 inches tall, was grateful for the early warning of trouble ahead. Actually, research shows, a lot had already gone wrong inside his body over a long time, although scientists are only beginning to understand and identify some of the earliest indications of problems.
Researchers in North Carolina and elsewhere hope that earlier detection of type 2 diabetes could save lives and money. In North Carolina alone, the disease leads to 8,400 deaths a year and $5.3 billion in medical expenses. Especially at the stage of Gosselin's high blood sugar, diet and exercise can restore health.
As they delve into the origins of diabetes, scientists at UNC-Chapel Hill, Duke University and East Carolina University are following different paths, forging beyond the starches and sugars most often considered the bad actors in diabetes. Instead, they are finding that gobs of fats and proteins appear to instigate many of the early cellular malfunctions associated with diabetes, particularly when combined with little or no exercise.
The problem is excess. Even in the Atkins diet, which emphasizes eating fats and proteins over carbohydrates, calories are restricted. So a day that starts with sausage biscuits, includes a biggie burger and fries for lunch and ends with a big plate of lasagna for dinner would need to be accompanied by a similarly huge amount of exercise to balance out.
"We're living sedentary lifestyles, eating Western diets high in fat and animal protein, and it's the worst combination of things," said Dr. Svati Shah, a cardiologist at Duke who is examining early markers that signal distress in the metabolic system. "That could be explaining some of the explosion of diabetes in America."
The gut galaxy
At UNC-CH, researchers have discovered problems inside a world so little understood it might as well be another galaxy.
Gut bacteria - tiny microbes deep in the bowels - flourish in an ecosystem where diverse populations of organisms work in harmony to aid digestion and keep the immune system on track.
Problems can arise when one species or another proliferates, upsetting the balance.
Pauline Lund and colleagues at UNC Gillings School of Global Public Health have found that a diet of fatty foods works like fertilizer for certain populations of gut bacteria. Studies have shown that obese people have a different array of gut bacteria from lean people.
To begin to understand what that might mean, Lund's lab has studied mice. The team found that high-fat meals cause mice to grow fat while some strains of bacteria flourish. At the same time, their immune systems launch low-grade attacks that can be detected even before they develop insulin resistance. That's when the body still produces insulin, but does not use it properly, making one more likely to develop type 2 diabetes.
"There's early information in the gut that a high-fat diet and bacteria may actually have a causative role in stimulating problems," said Lund, a molecular physiologist. Diabetes and an immune system heightened into an inflammatory state have long been linked. So exploring the role of gut bacteria may shed light on how the immune system begins to flare.
As the fatty diet prompts weight gain, the immune response escalates beyond the gut and into the enlarging fat cells. These cells, scientists now know, are not just idle repositories of stored energy; they are highly active participants in metabolism, immune responses and other functions.
"Obesity is an inflammatory response," Lund said, adding that the ongoing inflammation may eventually impair the body's ability to process glucose, leading to diabetes. "The inflammatory mediators prevent insulin from working as it should."
More studies are needed to prove the correlation beyond animal models, Lund said, but testing gut bacteria in obese people could provide a very early warning that conditions for diabetes are developing.
Markers in the blood
A different disease pathway is being studied at Duke. Christopher Newgard, director of the Sarah W. Stedman Nutrition and Metabolism Center, heads a laboratory that specializes in analyzing metabolites, the thousands of chemicals that are left as the body breaks down fats, proteins and carbohydrates.
Newgard's team has repeatedly found early chemical markers in the blood indicating that obese people have trouble processing fats and proteins when such foods are eaten to excess.
By measuring these metabolites, his team can predict who will eventually develop cardiovascular conditions. They are working to discover a similar metabolic predictor for diabetes and are keying in on the fats and proteins.
In a recent project, Newgard's group studied a potential link between pre-diabetes in obese people and a high-fat, high-protein diet.
Using blood tests, Newgard's group found different chemical components between lean and obese people. That signals a problem in how well some obese people may process animal proteins. Some scientists suspect that a breakdown of this metabolic process is made worse when combined with a fatty diet.
To test that theory, Newgard's group fed three groups of rats different diets: One group ate standard chow, a second ate high-fat chow and the third got a reduced-calorie load, but with lots of protein and fat.
Not surprisingly, rats in the high-fat group gained weight and became insulin-resistant. But rats in the high-fat and high-protein group also became insulin resistant, even though they didn't bulk up. The implication was that the food they ate, not weight gain alone, caused problems.
Newgard said the animal studies help provide direction for future human studies. His group is exploring whether an obese individual's initial chemical "profile" can predict whether insulin sensitivity would improve with diet and exercise.
"The significance here is that we're starting to use these metabolomics tools - biomarkers - to help us predict the outcomes of interventions," Newgard said of the new study.
The Duke team suspects these tiny markers don't just passively signal future problems or benefits; instead, they may actively cause illness, setting in motion a series of events that leads to diabetes and heart disease.
"It's not just that this is a byproduct of insulin resistance," said Shah, who has collaborated with Newgard on the metabolite studies. "It looks like the branched chain amino acids [in animal proteins] could be a part of the cause of insulin resistance."
A fat flood's effect
The work at Duke is bolstered by findings from ECU scientists in Greenville, who have the added urgency of a patient population in Eastern North Carolina with the state's highest diabetes rates.
Funded in part by the National Institutes of Health and the N.C. Golden Leaf Foundation, which supports projects that benefit people in areas once dependent on tobacco, an ECU team has been exploring the intricate cellular workings that go awry when people consistently eat high-fat foods that dominate American diets.
Darrell Neufer, a physiologist and director of the East Carolina Diabetes and Obesity Institute at ECU, said even a single high-fat meal such as a big burger and fries floods the muscle cells if that energy isn't burned off.
Like a car getting too much gas, tiny engines inside muscle cells called mitochondria - which convert fats and proteins into energy - spew pollutants if the overload of fuel isn't countered by a brisk walk or some other form of activity.
This pollution is a form of oxygen - the so-called free radicals that women know as their enemies in the war against wrinkles - and it's highly caustic, eventually eroding the body's ability to clear glucose from the bloodstream.
A body can easily handle this imbalance every now and again.
But in studies of mice, Neufer's group has found that the animals grow obese on a steady diet of fatty foods, combined with little exercise, causing the industrious mitochondria in their muscle to become damaged by the pollution. Eventually, the mitochondria are shut down.
"The cells know what they're doing," Neufer said. "They're getting rid of the bad engines to try to save themselves. But eventually you lose so many engines, you lose the whole muscle fiber."
An insidious cycle results. Diminished muscle mass can't process the overload of fats and proteins efficiently and starts spewing toxins, which diminish muscle mass, which can't clear the nutrients efficiently.
And muscle is hugely important, not only for processing fats and proteins but also for metabolizing carbohydrates. It's responsible for clearing 80 percent of the glucose out of the bloodstream.
Neufer's group, which is now studying the mitochondria in obese and lean people, is working to illuminate how the dysfunctional machinery for processing fats and proteins contributes to insulin resistance.
"It may be the appropriate thing for the cell to do is become insulin-resistant," Neufer said. "It's trying to limit more fuel from coming in, because it's already had enough."
The ECU group is already encouraged that its insights could offer new approaches to diabetes. Neufer and his team have tested a high-powered antioxidant in mice that helps eliminate the cellular pollution, protecting the animals from becoming diabetic even when they repeatedly gorge on fatty foods.
The hope is to develop an antioxidant therapy that could protect people from developing diabetes.
"We now have experiments going on to try to figure out how insulin resistance develops and whether it's something going on in all of us after we eat a big meal," Neufer said. "What's the difference between normal and a person who's insulin resistant? The difference is the amount of time spent in metabolic imbalance."
For people like Gosselin with pre-diabetes, there is a way to alter destiny.
Gosselin made simple, if difficult, dietary changes, eliminating lunchtime desserts and nightly cheese snacks he said fueled his weight gain. Now 64, he gradually lost 40 pounds that he has kept off for three years, and his blood sugar levels are back to normal.
He still refuses to exercise, however, which the experts frown upon. When it comes to putting the body back into metabolic balance, Neufer said old-fashioned exercise is as close to a magic pill as modern science has to offer.
"The great thing about nature is, if you become more active, the cell has the ability to make more mitochondria," he said. "That's why exercise is so important."
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