Link Between Excessive Calorie Intake and Development of Insulin Resistance Found

With Salim Merali, PhD, and Eric Westman, MD

Man Looking in Refrigerator for Food OptionsHealthy men fed approximately 6,000 calories per day for 1 week experienced rapid weight gain as well as systemic and adipose tissue insulin resistance and oxidative stress, demonstrating for the first time in vivo a direct relationship between excessive nutrient intake and the development of insulin resistance, according to senior authors Salim Merali, PhD, Professor of Pharmaceutical Sciences at Moulder Center for Drug Discovery and Director of Proteomics/Metabolomics at Temple University School of Pharmacy, Philadelphia, PA, and Guenther Boden, MD, Laura H. Carnell Professor of Medicine at Temple School of Medicine.

“The oxidative stress was associated with extensive oxidation and carbonylation of numerous proteins, including carbonylation of the glucose transporter GLUT4 near the glucose transport channel and thus appeared to be the initial event that produced overnutrition-related insulin resistance,” Dr. Merali explained. The findings were reported in the September 9 issue of Science Translational Medicine.

Study Design
The study involved 6 men who were normal to overweight and otherwise healthy. The men were fed a median of 6,205 kcal/day of a typical Western diet (50% CHO, 35% fat, ~15% protein) for 7 days and were kept on bed rest at Temple University Hospital Clinical Research Unit.

“It is important to emphasize that 6,000 calories/day for a week were used in this study in order to mimic the effect of moderate overnutrition for months or years,” Dr. Merali said.

The subjects gained a median of 3.5 kg by day 7, all of which was determined to be fat. While the men did not show a significant change in fasting plasma glucose, serum insulin levels rose rapidly by day 2 were significantly increased on days 4-7 (P≤0.05). A similar significant increase in insulin resistance was found (P≤0.05 on days 2-7), as determined by the homeostasis model of assessment of insulin resistance (HOMA-IR).  

The development of insulin resistance was significantly associated with an increase in urinary 8-iso-PGF2a, which the authors noted is a reliable marker of oxidative stress. In contrast, insulin resistance was not associated with free fatty acid, inflammatory cytokines, and endoplasmic reticulum stress in adipose tissue.

While the study was not designed to determine whether oxidative stress precedes insulin resistance or vice versa, previous studies have shown that oxidative stress is the initial event, the study authors noted.

How Does Obesity Promote Insulin Resistance?
While a variety of factors have been postulated to cause insulin resistance—including increased plasma concentrations of free fatty acids, elevated plasma concentrations of proinflammatory cytokines, increased endoplasmic reticulum stress in liver and adipose tissue, and increased oxidative stress—these may be late events that develop after months of excessive nutrient intake, Dr. Merali explained. “Our study provides an understanding of the nature of the initial events that produce insulin resistance at the very beginning of excess caloric intake and weight gain,” Dr. Merali said.

“Our model of overnutrition induced oxidative stress insulin resistance and GLUT4 carbonylations provide a novel way to examine ways to reduce these changes. For instance, our model could be used to test the effect of different anti-oxidants,” Dr. Merali concluded.  

“This paper is important because it helps us to understand the mechanisms that link lifestyle factors to insulin resistance and its many consequences,” commented Eric Westman, MD, Chairman of the Board of the American Society of Bariatric Physicians.* “The most striking aspect of this study is that the initiation of the unhealthy process of insulin resistance can occur in just a few days of a high-carbohydrate, high-calorie, sedentary lifestyle,” Dr. Westman said.

“The lifestyle that was chosen to in the research model, to induce insulin resistance was a high carbohydrate, high-calorie diet (50% carbohydrate, 35% fat, 15% protein, 6,000 calories/day) and little physical activity,” Dr. Westman said. “This lifestyle was chosen because it is the most harmful,” Dr. Westman added.

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