Overfeeding Reduces Insulin Sensitivity and Increases Oxidative Stress, without Altering Markers of Mitochondrial Content and Function in Humans

Dorit Samocha-Bonet,Lesley V Campbell,Nigel Turner,Leonie K Heilbronn,Trevor A Mori,Kevin D Croft,Jerry R Greenfield,Raul M Luque

doi:10.1371/journal.pone.0036320

Abstract

BackgroundMitochondrial dysfunction and increased oxidative stress are associated with obesity and type 2 diabetes. High fat feeding induces insulin resistance and increases skeletal muscle oxidative stress in rodents, but there is controversy as to whether skeletal muscle mitochondrial biogenesis and function is altered.Methodology and Principal FindingsForty (37±2 y) non-obese (25.6±0.6 kg/m2) sedentary men (n = 20) and women (n = 20) were overfed (+1040±100 kcal/day, 46±1% of energy from fat) for 28 days. Hyperinsulinemic-euglycemic clamps were performed at baseline and day 28 of overfeeding and skeletal muscle biopsies taken at baseline, day 3 and day 28 of overfeeding in a sub cohort of 26 individuals (13 men and 13 women) that consented to having all 3 biopsies performed. Weight increased on average in the whole cohort by 0.6±0.1 and 2.7±0.3 kg at days 3 and 28, respectively (P<0.0001, without a significant difference in the response between men and women (P = 0.4). Glucose infusion rate during the hyperinsulinemic-euglycemic clamp decreased from 54.8±2.8 at baseline to 50.3±2.5 µmol/min/kg FFM at day 28 of overfeeding (P = 0.03) without a significant difference between men and women (P = 0.4). Skeletal muscle protein carbonyls and urinary F2-isoprostanes increased with overfeeding (P<0.05). Protein levels of muscle peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and subunits from complex I, II and V of the electron transport chain were increased at day 3 (all P<0.05) and returned to basal levels at day 28. No changes were detected in muscle citrate synthase activity or ex vivo CO2 production at either time point.ConclusionsPeripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was however increased, and may have contributed to the reduction in insulin sensitivity observed.Trial Registration ClinicalTrials.gov NCT00562393

Highlights

Obesity is closely linked with insulin resistance, and increasing evidence suggests that reactive oxygen species (ROS) generated in muscle mitochondria may impair insulin signalling in animal and cellular models [1,2,3]
The mitochondrial dysfunction hypothesis of insulin resistance has arisen mainly from studies showing reduced expression of genes involved in mitochondrial biogenesis or reduced ATP production in healthy relatives of type 2 diabetes individuals [6]
We have previously reported that individuals with a family history of type 2 diabetes (FH+) exhibited similar insulin sensitivity, fasting blood glucose and plasma insulin at baseline to age, and fatness matched individuals without a family history of type 2 diabetes (FH-) [17]

Summary

Conclusions

Peripheral insulin resistance was induced by overfeeding, without reducing any of the markers of mitochondrial content that were examined. Oxidative stress was increased, and may have contributed to the reduction in insulin sensitivity observed. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

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