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Sci Transl Med. 2015 Sep 9;7(304):304re7. doi: 10.1126/scitranslmed.aac4765.

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

Author information

1
Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Unit, Temple University School of Medicine, Philadelphia, PA 19140, USA. bodengh@tuhs.temple.edu smerali@temple.edu.
2
Division of Endocrinology/Diabetes/Metabolism and the Clinical Research Unit, Temple University School of Medicine, Philadelphia, PA 19140, USA.
3
Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery, Proteomics/Metabolomics Facility, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.
4
Department of Surgery, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA.
5
Department of Obstetrics and Gynecology, School of Osteopathic Medicine, Rowan University, Stratford, NJ 08084, USA.
6
Department of Surgery, Temple University School of Medicine, Philadelphia, PA 19140, USA.
7
Department of Pharmaceutical Sciences and Moulder Center for Drug Discovery, Proteomics/Metabolomics Facility, Temple University School of Pharmacy, Philadelphia, PA 19140, USA. bodengh@tuhs.temple.edu smerali@temple.edu.

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.

PMID:
26355033
PMCID:
PMC5600191
DOI:
10.1126/scitranslmed.aac4765
[Indexed for MEDLINE]
Free PMC Article

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