About one third of the US adult population is defined as obese (BMI > 30 kg/m2). While not all obese adults develop type 2 diabetes, most (~80%) people suffering from type 2 diabetes are obese1. The links are clear: overeating and a sedentary lifestyle lead to obesity and in a significant number of these individuals, insulin resistance which is the hallmark for type 2 diabetes. The mechanisms producing insulin resistance have remained unclear, however. Researchers have proposed a number of possibilities, including elevated levels of fatty acids, inflammation, endoplasmic reticulum stress and oxidative stress through the production of reactive oxygen species (ROS).
In a recent study, six healthy middle-aged men were subjected to a whopping 6,000 calorie/day diet while being confined to a hospital bed2. Within 2 days of the start of the study, the men began showing signs of insulin resistance; after a week, the men demonstrated on average a 50% decrease in their insulin-stimulated glucose uptake - a clear sign of insulin resistance. In that week, the men had gained an average of 3.5 kg - all of it fat. That fat was biopsied and tested for the possible mechanisms of insulin resistance outlined above. Only ROS production mirrored the dramatic increase of insulin resistance. It was found that numerous proteins associated with ROS production were up-regulated along with oxidation and carbonylation of a wide range of proteins, notably of the protein GLUT4, which translocates from intracellular vesicles to the plasma cell membrane due to insulin signaling. This protein’s structure in the fat biopsies demonstrated multiple oxidation and carbonylation sites, particularly where the glucose binding site is thought to be. This would make the glucose transporter dysfunctional and thus lead to insulin resistance.
To learn more about ROS and its physiological consequences, please download our white paper An Introduction to Reactive Oxygen Species.
1. Eckel, RH et al. Diabetes Care June 2011 vol. 34 no. 6 1424-1430.
2. The 6,000-Calorie Diet
By: BioTek Instruments, Peter Banks Ph.D., Scientific Director