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Despite its pervasiveness and association with many other diseases, we still don't fully understand how exactly weight gain pushes our bodies toward certain illnesses.
A new study tried to find the missing link - by putting six brave volunteers on a 6,000-calories-a-day diet.
We know that obesity makes our cells less responsive to insulin, a hormone produced by the pancreas that shuttles sugar from the blood into cells for use as fuel. Insulin keeps concentrations of glucose (a kind of sugar) in the blood low by decreasing the amount produced by the liver and increasing its absorption into muscle, fat, and liver cells.
When your body can't remove glucose from the bloodstream - a condition known as insulin resistance - you can get high blood sugar, which then can lead to diabetes. Insulin resistance can also contributes to other nasty diseases such as heart disease, stroke, and certain cancers.
But we still have no idea how the early stages of obesity actually make our cells stop responding to insulin.
To test how an unusually high calorie diet can push people's cells toward becoming resistant to insulin early on, researchers led by Guenther Boden, professor of medicine at Temple University School of Medicine in Philadelphia, fed six healthy middle-aged men a typical American diet consisting of 2 to 2.5 times their normal daily caloric intake - that's the staggering 6,000 calories per day - for a week. About 50% of the diet was carbohydrates, 35% fats, and 15% was protein.
Three of the men were normal weight, three were overweight, and none were obese or unhealthy at the start. They were all hospitalized for other, unspecified conditions at the time and remained on bed rest throughout the study.
The results by the end of the week were surprising.
'They all developed diabetes'
Each of the men gained an average of 8 pounds, nearly all from fat, which was about what the researchers expected. And by day two, all had a rapid and continuous rise in both blood insulin and insulin resistance levels, enough to cause "severe systemic and adipose tissue insulin resistance in every one of six study subjects," the researchers said in the paper.
"By definition, they all developed diabetes," Francis Stephens, a lecturer at the University of Nottingham in the UK not associated with the study, told New Scientist.
Granted, the men were not physically active at all during the study, but the team estimates that this only had a tiny effect on their weight gain and the onset of insulin resistance.
For years, researchers have struggled to understand exactly how weight gain initially causes insulin resistance. An increase of fatty acids in the blood, inflammation, stress on cells, and a process called "oxidative stress," in which certain molecules containing oxygen can damage a cell's components, are all involved in insulin resistance. But researchers have been unable to pinpoint which of those is the first to trigger the chain reaction that often ends in diabetes.
The new study, while small and preliminary, has some concrete evidence that finally suggests a possible answer.
"This work is extremely important to understand," Adam Salmon, an associate professor at the department of molecular medicine at the UT Health Science Center who was not involved in the study, told Tech Insider. "The most interesting part of this study is that they found within a few days the patients developed insulin resistance, but that this correlated only with an increase in oxidative stress and not in changes in other potential mechanisms thought to cause insulin resistance in this situation."
In other words: After analyzing the men's blood and urine, the team concluded that the initial cause of insulin resistance in the men's fat tissues was not due to increased fatty acids, inflammation, or cellular stress, but was in fact from oxidative stress, the process that can damage cells' lipids, proteins, and DNA.
"This is a brand new way to get from over-nutrition to insulin resistance," Boden said in an article for New Scientist.
An important first step
While the results, methodology, and data from this study are strong, Salmon says, it's important to remember that the researchers only looked at a very small group of middle-aged men of unknown race. If we want to extrapolate these findings widely, Salmon says, it will be important to replicate these results in a wider demographic.
Nevertheless, this could open doors to new treatments, including the potential use of antioxidants - whose general benefits are now up for debate - to help prevent the onset of type 2 diabetes by reducing oxidative stress on cells. Boden, the lead author on the study, told New Scientist that this approach is "conceptually possible," though it remains totally untested.
The study was published September 9 in the journal Science Translational Medicine.