Sci. Aging Knowl. Environ., 16 June 2004
Vol. 2004, Issue 24, p. nf58
[DOI: 10.1126/sageke.2004.24.nf58]


Too Much of a Good Thing

Extra doses of antioxidant protein spur insulin resistance

R. John Davenport

If security forces overreact, they can hamper normal activities. Similarly, an overly zealous disaster response disrupts sugar processing in mice, new work reveals. The study suggests that oxidants play a crucial role in molecular communication.

Compounds known as reactive oxygen species (ROS) might foster aging by tarnishing DNA and other molecules (see "The Two Faces of Oxygen"). Researchers are eager to understand how oxidant defenses work and whether activating them slows aging. One such defense is the enzyme glutathione peroxidase, which quenches hydrogen peroxide. Nutritional biochemist Xingen Lei of Cornell University in Ithaca, New York, previously found that cells with extra glutathione peroxidase resist damage from the ROS. To understand how the enzyme functions in animals, Lei and colleagues scrutinized mice with an extra copy of the gene that encodes it.

Surprisingly, the rodents fared poorly. They outweighed normal animals and packed twice as much fat. They also showed signs of insulin resistance, a harbinger of diabetes. For instance, their blood carried excessive concentrations of sugar and insulin, and they absorbed unusually small amounts of sugar after receiving an insulin shot. Additional studies suggested why the animals can't handle sweets. Quantities of the active forms of the insulin receptor and Akt--two proteins that prompt cells to absorb glucose after exposure to insulin--had plummeted.

Oxidants have a bad reputation, says Lei, but they might help cells function. Hydrogen peroxide blocks enzymes that trim phosphate groups from proteins, an event that turns off the insulin receptor and Akt. The glut of glutathione peroxidase might deplete hydrogen peroxide, thus prompting the insulin-response machinery to shut down, he says. Too many oxidants might wreak havoc by damaging DNA or proteins, but too few might hamper signaling events vital for controlling sugar metabolism, says Lei.

"It's an intriguing result," says biochemist Kenneth Beckman of Children's Hospital Oakland Research Institute in California. "The idea that oxidants are more than just dangerous byproducts is hot right now. But there aren't a whole lot of good data for it." The new work supports the hypothesis, he says, although questions remain. For instance, says Beckman, the researchers haven't proven that bonus glutathione peroxidase depletes hydrogen peroxide in the animals or that the absence of ROS promotes insulin resistance. Whether the finding illuminates causes of human diabetes remains unclear; diabetic people and animals typically suffer from elevated oxidative stress. However, previous studies revealed that glutathione peroxidase is unusually vigorous in pregnant women with insulin resistance. "We were surprised by [that] finding," says metabolic physiologist Peter Stein of the University of Medicine and Dentistry of New Jersey (UMDNJ) in Newark, who made the discovery. The new work offers "a mechanism that's very plausible and might explain our result." Conditions in the womb can influence health later in life (see "From Womb the Bell Tolls"); an escalation of glutathione peroxidase during pregnancy might predispose babies to diabetes during adulthood, says Stein's collaborator Theresa Scholl, also of UMDNJ. Future work should clarify when antioxidants should jump into action--and when they should hold back.

June 16, 2004

Suggested by Greg Liszt.

  1. J. P. McClung et al., Development of insulin resistance and obesity in mice overexpressing cellular glutathione peroxidase. Proc. Natl. Acad. Sci. U.S.A., 7 June 2004 [e-pub ahead of print]. [Abstract] [Full Text]
Citation: R. J. Davenport, Too Much of a Good Thing. Sci. Aging Knowl. Environ. 2004 (24), nf58 (2004).

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