ReportsINSULIN RESISTANCE

Excessive caloric intake acutely causes oxidative stress, GLUT4 carbonylation, and insulin resistance in healthy men

Science Translational Medicine  09 Sep 2015:
Vol. 7, Issue 304, pp. 304re7
DOI: 10.1126/scitranslmed.aac4765

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The irresistible effects of overfeeding

Obesity is very common in the United States and worldwide, and it is associated with a host of health problems collectively known as the metabolic syndrome. Insulin resistance is a key component of this syndrome, but the mechanism by which obesity promotes insulin resistance is not yet fully understood. Boden et al. studied a group of six healthy men who were subjected to overnutrition for 1 week while performing no physical activity. In that time, the men gained an average of 3.5 kg and showed signs of insulin resistance as well as oxidative stress. This process was associated with inactivation of GLUT4, a major insulin-facilitated glucose transporter, suggesting a potential approach for the development of future therapeutic agents.

Abstract

Obesity-linked insulin resistance greatly increases the risk for type 2 diabetes, hypertension, dyslipidemia, and non-alcoholic fatty liver disease, together known as the metabolic or insulin resistance syndrome. How obesity promotes insulin resistance remains incompletely understood. Plasma concentrations of free fatty acids and proinflammatory cytokines, endoplasmic reticulum ( ER) stress, and oxidative stress are all elevated in obesity and have been shown to induce insulin resistance. However, they may be late events that only develop after chronic excessive nutrient intake. The nature of the initial event that produces insulin resistance at the beginning of excess caloric intake and weight gain remains unknown. We show that feeding healthy men with ~6000 kcal/day of the common U.S. diet [~50% carbohydrate (CHO), ~ 35% fat, and ~15% protein] for 1 week produced a rapid weight gain of 3.5 kg and the rapid onset (after 2 to 3 days) of systemic and adipose tissue insulin resistance and oxidative stress but no inflammatory or ER stress. In adipose tissue, the oxidative stress resulted in extensive oxidation and carbonylation of numerous proteins, including carbonylation of GLUT4 near the glucose transport channel, which likely resulted in loss of GLUT4 activity. These results suggest that the initial event caused by overnutrition may be oxidative stress, which produces insulin resistance, at least in part, via carbonylation and oxidation-induced inactivation of GLUT4.

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