• 6000-Calorie Diet Reveals Mechanisms of Obesity-Linked Insulin Resistance

6000-Calorie Diet Reveals Mechanisms of Obesity-Linked Insulin Resistance

A study in which researchers place healthy individuals on 6000-calorie per day diets has identified biologic changes that take place during the early stages of obesity and could lead to insulin resistance. The study, published in the 9 September issue of Science Translational Medicine, pinpoints oxidative stress as the potential missing link between obesity and insulin resistance.

Strategies to reduce oxidative stress might therefore help prevent or treat obesity-linked insulin resistance.

Obesity, fast growing as an epidemic in many countries, is thought to be the most common cause of insulin resistance, which raises the risk of diabetes, high blood pressure, liver disease, and metabolic disorders. However, it is not clear how obesity produces insulin resistance.

Fatty acids, inflammation, cell stress, and oxidative stress have all been proposed as culprits, but these factors mainly occur during the later stages of the disease, after individuals have already gained excess weight.

In search for an initial trigger of obesity-linked insulin resistance, Guenther Boden et al (Temple University School of Medicine) studied 6 healthy, normal to overweight men fed 6000 calories of a typical American diet a day (about 50% carbohydrate, 35% fat, and 15% protein) in a hospital ward. They were closely monitored and not allowed physical activity for 1 week. Each subject gained on average of 3.5 kg and, in 2–3 days, all developed insulin resistance.

Analyzing patients’ urine and fat tissues, the researchers detected a spike in proteins associated with oxidative stress, but not in inflammation or endoplasmic reticulum stress.

Space-filling model of GLUT4 showing the close proximity of the modified amino acids to the glucose transport channel (red arrowheads). Source: Science Translational Medicine

Space-filling model of GLUT4 showing the close proximity of the modified amino acids to the glucose transport channel (red arrowheads). Source: Science Translational Medicine

Kevin Niswender (Vanderbilt University Medical School) told ABC News that the high number of subjects that developed oxidative stress was worrying because this leads to inflammation and other metabolic problems.

Boden et al found that in adipose tissue, the oxidative stress produced extensive oxidation and carbonylation of numerous proteins, including carbonylation of GLUT4 (also called SLC2A4), an insulin-regulated glucose transporter. The modifications occurs near the glucose transport channel (see figure), and are likely to result in loss of GLUT4 activity.

The authors propose that the carbonylation impairs its ability to take up glucose in response to insulin, which may have led to insulin resistance in the men.

Naveen Uli (Co-director of the Healthy Kids and Healthy Weight Program at the University Hospitals Rainbow Babies and Children’s Hospital in Cleveland) told ABC news that although much more research is needed, the study was an interesting way to look at obesity and diabetes. Uli says “The next step would be to apply to it a larger group and see if this is true of other populations as well.”

“It’s a pretty cool finding,” Francis Stephens (University of Nottingham, UK) told The New Scientist. He says that although oxidative stress and a damaged glucose-transporting protein may be the most important factors that contribute insulin resistance, other mechanisms are probably still involved. “Overeating can also cause fat to build up in muscles and the liver – we still don’t know the mechanisms behind this”, he said.

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