For the sake of science, six brave men endured a week of Caligula-class consumption and gained close to eight pounds, consuming 6,000 calories a day while confined to a room in a Philadelphia hospital ward.
It took fewer than three days, however, for investigators to spot what they were looking for, and its likely cause. Between days 2 and 3, researchers could detect the onset of insulin resistance in the men, who were more than doubling their usual caloric intake.
The cause of the men's insulin resistance, indisputably, was the sudden onset of gluttony. More specifically, however, their bodies' efforts to manage the onslaught of fuel was found to unleash a flood of oxygen byproducts that are toxic to nearby cells.
The collateral damage from all this oxidative stress, according to the new research: the GLUT4 transport channel, an army of proteins that responds to insulin by rounding up glucose circulating in the blood and transporting it to muscle and organs. A couple of days into the weeklong gorging, researchers found 38 proteins that are produced in response to oxidative stress in daily samples of the men's fat and urine.
We can thank those big eaters for contributing to new insights into an urgent question: How, why and when does chronic overeating lead to metabolic problems and to Type 2
Knowing the answer could allow scientists to break the link between obesity and diabetes--an important challenge because more than a third of American adults are obese, and therefore at higher risk.
The latest findings, published Wednesday in the journal Science Translational Medicine, suggest that antioxidant therapies (such as supplementation with vitamin C, vitamin E, coenzyme Q10 or selenium) may prevent those carrying too much weight from developing metabolic problems. Scientists may also look for ways to fortify the GLUT4 transport channel against stress to break the chain.
If they continued this pattern of "chronic overnutrition," the men in this experiment might well have gotten on the fast track to developing Type 2 diabetes. As the system that transports sugars into the muscles and organs slows, two things happen: High concentrations of glucose remain at large in the blood, causing damage to blood vessels and nerves; and, in a bid to get fuel to muscles and organs, special cells in the pancreas begin working overtime to produce extra insulin, exhausting themselves in the process.
For all the potential subjects at their disposal, obesity researchers have long been unsure why excess weight makes the development of Type 2 diabetes more likely. Among the possible explanations are that carrying excess fat deposits ignites inflammation throughout the body--a surmise supported by the finding that diabetics generally have high inflammation levels.
Scientists have also long suspected that high levels of fatty acids circulating in the blood, as are seen in both diabetics and the obese, may somehow play a role. And they have considered whether there's a role for a form of cell stress that results in proteins folding themselves incorrectly.
In the current study, researchers looked for evidence that any of these factors preceded the appearance of insulin resistance. If inflammation, free fatty acids or cell stress were present before insulin resistance were evident, that would strengthen the argument that they played a role in catalyzing metabolic problems.
"We ... believe that oxidative stress likely preceded the development of insulin resistance, and that oxidative stress, not inflammatory or [endoplasmic reticulum] stress, was the initial event that occurred after overnutrition," the authors concluded.