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Antioxidant Supplements Blunt Exercise-Induced Improvement of
Insulin Sensitivity
  Regardless of their previous exercise patterns, young men did not benefit from vitamin E or C supplementation.
Regular exercise increases insulin sensitivity and decreases risk for type 2 diabetes. One mechanism is known: Exercise stimulates glucose-transporter molecules to proliferate and move to the cell membrane, where they ferry glucose into the cell. Exercise also increases the formation of mitochondria, which give cells more energy but also create more harmful reactive oxygen species (ROS). An international team randomized 39 young men (19 nonconditioned and 20 with prior physical conditioning) to exercise either with or without having ingested daily antioxidant supplements (1000-mg vitamin C and 400-IU vitamin E). In the groups that did not receive antioxidants, mean insulin sensitivity was higher after exercise among both nonconditioned and conditioned men; exercise raised production of ROS but also activated natural antioxidant systems. However, in both antioxidant groups, researchers noted no improvement in insulin sensitivity, and natural antioxidant systems were blunted.
Comment: Surprisingly, use of antioxidant supplements blunts the beneficial effects of regular exercise on insulin sensitivity, even though diets that are rich in fruits and vegetables (and, thus, contain high concentrations of antioxidants) lower risk for developing type 2 diabetes. Overall, little evidence of benefit from regular use of vitamin C or E supplements exists, and this study offers one reason to discourage their use and to encourage diets that are rich in fruits and vegetables.
- Anthony L. Komaroff, MD
Published in Journal Watch General Medicine June 4, 2009
Ristow M et al. Antioxidants prevent health-promoting effects of physical exercise in humans. Proc Natl Acad Sci U S A 2009 May 26; 106:8665. (
Exercise and Antioxidants
Joan Stephenson, PhD
JAMA. June 17 2009;301(23):2432.
"antioxidant supplementation blocks many of the beneficial effects of exercise on metabolism."....Taken together, we find that antioxidant supplements prevent the induction of molecular regulators of insulin sensitivity and endogenous antioxidant defense by physical exercise. Consistent with the concept of mitohormesis, we propose that transiently increased levels of oxidative stress reflect a potentially health-promoting process at least in regards to prevention of insulin resistance and type 2 diabetes mellitus.
Antioxidant vitamins may mitigate some of the benefits of exercise, report scientists in Germany (Ristow et al. Proc Natl Acad Sci U S A. doi:10.1073/pnas.0903485106 [published online ahead of print May 11, 2009]). Exercise improves sensitivity to insulin. But when muscle cells metabolize glucose, "free radicals"-reactive oxygen species (ROS), which can cause cell damage-are produced. However, the researchers reasoned, because reduced mitochondrial metabolism has been linked with type 2 diabetes, ROS generated by exercise also may have a health-promoting effect that antioxidants suchas vitamin C or E might undermine.
The researchers compared insulin sensitivity and ROS levels in 40 men, half of whom were randomly assigned to receive vitamin C (1000 mg/d) and E (400 IU/d) supplements. After 4 weeks of exercise sessions, men who took the vitamins showed no change in ROS levels and no improvement in insulin sensitivity; ROS levels increased and insulin sensitivity improved in those who did not take the vitamins.
The findings suggest that supplementation with antioxidants might preclude exercise-related improvement of insulin resistance, the researchers said.
"These results indicate that antioxidants severely impair the insulin-sensitizing effects of physical exercise as quantified by several measures, including GIR during hyperinsulinemic euglycemic clamps and plasma adiponectin and fasting plasma insulin concentrations, and that this effect occurs irrespective of previous training status."...."Taken together, physical exercise induces numerous molecular regulators of insulin sensitivity and antioxidant defense, most of which are almost completely inhibited by antioxidant pretreatment in healthy young men (Fig. 3)."
Type 2 diabetes mellitus is increasing worldwide at epidemic rates and is associated with both microvascular and macrovascular complications (1). Type 2 diabetes mellitus is caused by a combination of insulin resistance involving a number of peripheral tissues, including skeletal muscle (2, 3), and an inadequate ß-cell response despite normal or even increased amounts of circulating insulin.
Physical exercise exerts numerous favorable effects on general health (4) and specifically has been shown to improve glucose metabolism in the insulin-resistant state (5). This effect may be independent of exercise-related changes in body mass (6). Moreover, physical exercise has been shown to be effective in preventing type 2 diabetes in high risk individuals (t; vertical-align: baseline; text-decoration: none; color: rgb(51, 51, 51); ">8) and may be even more effective than the most widely used anti-diabetic drug, metformin (9).
These beneficial effects of physical exercise on insulin resistance involve multiple mechanisms, including enhanced expression of glucose transporters and translocation of glucose transporters to the plasma membrane independent of insulin (10). Exercise, as well as weight loss, has been linked to activation of mitochondrial metabolism, and reduced mitochondrial metabolism has been functionally connected with type 2 diabetes (11). Mitochondria, however, are also the main source of reactive oxygen species (ROS), which are inevitable by-products of oxidative glucose metabolism. Muscle is also known to generate free radicals, especially during contraction and physical exercise (12). It has been suggested that ROS may mediate some health-promoting effects, at least in nonprimate model systems (13-17).
We here evaluated the possibility that ROS are required for the insulin-sensitizing capabilities of physical exercise in healthy humans and that commonly used antioxidants, such as vitamin C and vitamin E, may abrogate the health-promoting effects of both physical exercise and oxidative stress in humans.
This Article
Published online before printMay 11, 2009, doi:10.1073/pnas.0903485106 PNAS May 26, 2009 vol. 106 no. 21 8665-8670
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Supporting Information
Antioxidants prevent health-promoting effects of physical exercise in humans
Michael Ristowa,b,1,2, Kim Zarsea,2, Andreas Oberbachc,2, Nora Klotingc,Marc Birringera, Michael Kiehntopfd, Michael Stumvollc, C. Ronald Kahne andMatthias Bluherc,2
Author Affiliations
aDepartment of Human Nutrition, Institute of Nutrition, University of Jena, Jena D-07743, Germany;
bGerman Institute of Human Nutrition, Potsdam-Rehbrucke D-14558, Germany; cDepartment of Medicine, University of Leipzig, Leipzig D-04103, Germany; dInstitute of Clinical Chemistry and Laboratory Medicine, University of Jena, Jena D-07743, Germany; and eResearch Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA 02215 Contributed by C. Ronald Kahn, March 31, 2009 ↵2M.R., K.Z., A.O., and M. Bluher contributed equally to this work. (received for review March 14, 2009)
Exercise promotes longevity and ameliorates type 2 diabetes mellitus and insulin resistance. However, exercise also increases mitochondrial formation of presumably harmful reactive oxygen species (ROS). Antioxidants are widely used as supplements but whether they affect the health-promoting effects of exercise is unknown. We evaluated the effects of a combination of vitamin C (1000 mg/day) and vitamin E (400 IU/day) on insulin sensitivity as measured by glucose infusion rates (GIR) during a hyperinsulinemic, euglycemic clamp in previously untrained (n = 19) and pretrained (n = 20) healthy young men. Before and after a 4 week intervention of physical exercise, GIR was determined, and muscle biopsies for gene expression analyses as well as plasma samples were obtained to compare changes over baseline and potential influences of vitamins on exercise effects. Exercise increased parameters of insulin sensitivity (GIR and plasma adiponectin) only in the absence of antioxidants in both previously untrained (P < 0.001) and pretrained (P < 0.001) individuals. This was paralleled by increased expression of ROS-sensitive transcriptional regulators of insulin sensitivity and ROS defense capacity, peroxisome-proliferator-activated receptor gamma (PPARγ), and PPARγ coactivators PGC1α and PGC1ß only in the absence of antioxidants (P < 0.001 for all). Molecular mediators of endogenous ROS defense (superoxide dismutases 1 and 2; glutathione peroxidase) were also induced by exercise, and this effect too was blocked by antioxidant supplementation. Consistent with the concept of mitohormesis, exercise-induced oxidative stress ameliorates insulin resistance and causes an adaptive response promoting endogenous antioxidant defense capacity. Supplementation with antioxidants may preclude these health-promoting effects of exercise in humans.
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