Effect of antioxidant supplementation on insulin sensitivity in response to endurance exercise training

Journal Title (Medline/Pubmed accepted abbreviation): Am. J. Physiol. Endocrinol. Metab.
Year: 2011
Volume: 300
Page numbers:E761-E770
doi (if applicable): 10.1152/ajpendo.00207.2010

Summary of background and research design

Background: It has been shown that a high fat diet can lead to high amounts of reactive oxygen and nitrogen species, which cause oxidative stress and can lead to insulin resistance and type 2 diabetes. Antioxidant supplements may be helpful in preventing insulin resistance and diabetes. On the other hand, exercise produces oxidative species but, through parallel signaling pathways, increases insulin sensitivity and reduces the risk of type 2 diabetes. Some studies have shown that antioxidant supplementation can attenuate the benefits of exercise, meaning that benefits of exercise are not maximal with antioxidant supplementation.

Hypothesis: Exercise will increase the insulin sensitivity. However, exercise with antioxidant supplementation will attenuate the beneficial adaptations to exercise.

Subjects:There were 21 men, age 25-34, who participated. The subjects were healthy and active but did not exercise more than 2-3 times per week prior to the study.

Experimental design: randomized, double-blind, placebo-controlled
Treatment: Antioxidant supplement: vitamin C (500 mg ascorbic acid/day) and vitamin E (RRR-α-tocopherol succinate, 400 IU/day) or a placebo (composition not disclosed) for 12 wks.  These vitamin doses are about 5-15 times higher than the recommended daily allowances (RDAs).
Protocol: VO2max and peak power (Pmax) were determined on a stationary bicycle.  For the 12 wks of supplementation, subjects cycled for exercise 5 times a week.  On Mondays they performed the Pmax evaluation to determine their intensity for the week, then twice per week they performed interval training (75-91% Pmax for 60-80 min) and the other 2 days they cycled continuously at 55-66% Pmax for 85-155 min.

                In order to assess blood levels of the vitamins C and E, blood samples were acquired at 0, 4, and 12 wks.  Blood was also analyzed for high density and low density lipoprotein (HDL and LDL) and plasma free fatty acids before and after the training protocol.

                Before and after the supplementation/training period, the subjects were evaluated for insulin sensitivity by completing a euglycemic hyperinsulinemic clamp procedure.  They arrived at the laboratory after an overnight fast.  Insulin was infused at a rate of 100 IU/mL, which achieved a slightly elevated blood insulin level.  Glucose was then co-infused to achieve euglycemia (a healthy blood glucose level, 5 mM).  If the participant required high amounts of glucose (about 7.5 mg/min or more), the participant was considered insulin sensitive.  (The insulin is effectively telling the body to bring the glucose from the blood into body cells.)  However, if the participant required low amounts of glucose (4.0 mg/min or lower), that means that their body is not responding very well to the insulin, indicating greater relative insulin resistance.  Blood samples were acquired at 0, 60, 120, and 180 min and analyzed for glucose and insulin.  To assess quantity of mRNA for PPARγ (encodes for a protein involved in fat storage) and PGC-1α (regulates mitochondrial biogenesis) as well as protein levels of insulin receptor, hexokinase II, and GLUT4, muscle biopsies were acquired from the vastus lateralis (outer quadraceps) at time points 0 and 180 during the insulin clamp procedure.  Body fat percentage was assessed before and after the training period using dual-energy x-ray absorptiometry (DEXA).

Summary of research findings
  • Blood levels of vitamins C and E were elevated at 4 wks (p < 0.05) and remained elevated at 12 wks (p < 0.05).
  • VO2max and Pmax were increased by about 17% in the antioxidant group (p < 0.05 comparing before vs. after the 12 wk period) and 20% in the control group (p < 0.0001).  There were no differences between groups, however.
  • Insulin-stimulated glucose uptake was increased 15% in both the antioxidant group and the control group in response to exercise with no difference between groups (p = 0.68).
  • The total amounts of insulin receptor, hexokinase II, and GLUT4 increased after training for both groups.  The changes in all the metabolism proteins and signaling proteins (insulin receptor, hexokinase II, GLUT4, Akt and AS160, both phosphorylated and total) were not different between groups. 
  • The amount of mRNA for PPARγ increased in response to exercise for both groups, and the increase was somewhat more pronounced (although not statistically significant) in the antioxidant group (77% vs. 26% in the control group; p = 0.86 between groups). No differences were noted for PGC-1α in response to training or supplementation.
  • The control group lost more fat mass than the antioxidant group over the training period, but the differences were not statistically significant (p > 0.05).
  • Blood lipid parameters were improved for both groups in response to training with no significant differences between groups.  The only parameter that reached statistical significancefor within group comparisons was HDL (increased from about 1.4 mM to 1.7 mM in the antioxidant group and about 1.5 to 1.8 in the control group).

Interpretation of findings/Key practice applications

A 12-wk training protocol showed a clear increase in VO2max and insulin sensitivity as well as increases in Akt, GLUT4, and hexokinase II. Antioxidant supplementation did not appreciably alter the response to exercise for any of these variables. However, there was also no worsening of these parameters with antioxidant supplementation.


The sample size was small in this study and the authors studied only two antioxidant vitamins. It is possible that a wider range of antioxidant nutrients might have resulted in a different outcome.
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