June 10, 2004
Excessive Antioxidant Activity Risk Factor For Type II Diabetes

Too much glutathione peroxidase activity contributes to development of type II diabetes.

ITHACA, N.Y. -- A study by researchers at Cornell University suggests that higher-than-normal amounts of a selenium-containing enzyme could promote type 2 diabetes. The researchers found that mice with elevated levels of the antioxidant enzyme develop the precursors of diabetes at much higher rates than did control mice.

Selenium, a common dietary supplement, is an antioxidant, materials that help mop up harmful free radicals, molecules that can damage cell membranes and genetic material and contribute to the development of cancer and heart disease. Many of the benefits of selenium are related to its role in the production of glutathione peroxidase (GP), an antioxidant enzyme that helps detoxify the body.

"Although free radicals are known to be harmful and antioxidants helpful, our study suggests that we actually need some free radicals to regulate insulin sensitivity," says Xingen Lei, associate professor of animal science at Cornell and an author of the study, published in the June 15 issue of the Proceedings of the National Academy of Sciences , and now available online. The lead author is James McClung, who received his Ph.D. from Cornell this spring and is now a diabetes researcher at a U.S. Army laboratory in Boston.

...

McClung notes that high levels of GP appear to promote diabetes by mopping up too many free radicals, which are needed to help switch insulin signaling on and off in glucose (blood sugar) metabolism.

"Most people believe that both selenium and the selenium-containing enzyme GP are good for health by protecting cells and tissues from oxidation. However, this study suggests that they are a double-edged sword," says Lei. "Antioxidants can be harmful by neutralizing too many free radicals and interfering with insulin signaling, which results in promoting obesity, insulin resistance and possibly diabetes."

He points out that these findings are consistent with a recent study of pregnant women that reported on a link between high levels of GP, insulin resistance and gestational diabetes.

"Before people blindly supplement their diets with antioxidants, such as selenium and vitamins E and C, more research is needed," he concludes. Next, Lei plans to put the obese mice from this study on a diet to see if weight loss and fat loss can prevent or improve the mice's insulin sensitivity.

Diabetes, both type I and type II, effectively accelerates aging in a number of ways. Therefore anything that might contribute to the incidence of type II diabetes should be seen as a potential aging accelerator. Obesity is the largest risk factor for type II dabetes and the rising incidence of obesity is contributing to a rising incidence of type II (so-called adult onset or insulin insensitive) diabetes.

What is unanswered by this current study is whether a higher level of selenium in the diet or through supplementation will cause an unhealthily high level of glutathione peroxidase (GP) activity. Maybe not. In this experiment the scientists made the mice produce more GP. Just taking more selenium may not up GP activity to a level that will be unhealthy since the supply of GP will become a rate-limiting factor once all GP enzymes have selenium in their active centers. Still, the fact that excessive antioxidant activity can contribute to type II diabetes is important news.

Denman Harman, the original developer of the free radical theory of aging, has argued that, yes, there is such a thing as too much antioxidants. He found that taking too much antioxidant vitamins made him feel sluggish. This makes sense. Starting in the 1970s scientists have discovered that free radicals to be involved in an increasing number of signalling pathways in the body. If all our free radicals were quenched by extremely powerful antioxidants we'd literally die and rather quickly.

There are very likely optimal levels and ratios of antioxidant vitamins and minerals. But unfortunately at this point we do not know what those levels are. This latest study suggests that useful insights could be gotten from the measurement of precursors to type II diabetes in animals and people taking large amounts of various types of antioxidants.

Share |      Randall Parker, 2004 June 10 05:00 PM  Aging Studies


Comments
Fly said at June 10, 2004 8:28 PM:

I remember Aubrey de Grey discussing this issue in a news group a few years ago. Evolution is very opportunistic. Hence it was likely that critical systems would develop that depended on free radicals. (The immune system also uses free radicals to kill invaders.) That was one reason why he was skeptical that anti-oxidant strategy could prevent cellular aging. Instead he recommended the “patch the roof” strategy of repairing damage after it occurs.

RonG said at June 11, 2004 2:36 PM:

So instead of an anti-oxidant anti-aging solution, we really should look at diets that minimize insulin production?

Randall Parker said at June 11, 2004 3:33 PM:

RonG,

There is no single thing to pursue that makes a diet ideal. But among other things I think we need to look at:

A) Diets and lifestyles that minimize the generation of free radicals that are not for signalling purposes. For instance, don't eat charbroiled beef. It is like taking a free radical supplement. The free radicals in it are not for cellular signalling. They are totally avoidable, harmful, and serve no constructive purpose.

B) Yes, as you say, we should eat diets that minimize insulin production. One way to do that is to eat a low glycemic index diet. For instance, eat basmati rice rather than the really sticky gooey rice that Chinese restaurants serve. The difference in glycemic index between the two is quite large. Also, pasta is lower in glycemic index than bread because of the different type of wheat used to make both.

C) We know that vegetables are good period. The more vegetables people eat the healthier they are and that trend continues up to an average of 10 servings of vegetables per day.

AOR Technical Support said at June 14, 2004 8:32 PM:

The news story is about the finding (1) that mice overexpressing cellular glutathione peroxidase (GSH-Px) are more likely to develop insulin resistance and obesity than control mice. Randall then asks, "What is unanswered by this current study is whether a higher level of selenium in the diet or through supplementation will cause an unhealthily high level of glutathione peroxidase (GP) activity. Maybe not. In this experiment the scientists made the mice produce more GP. Just taking more selenium may not up GP activity to a level that will be unhealthy since the supply of GP will become a rate-limiting factor once all GP enzymes have selenium in their active centers."

Good guess! In this particular case, we already have the answer -- in the negative. The idea has been extensively tested in animals and to a lesser extent in humans, and found to be untrue. In fact, the RDA is primarily derived from the fact that at this level of intake (total Se intake of ~70 mcg, corresponding to plasma levels of 90-100 ng/mL; even low-Se diets, as observed in New Zealand, apparently provde 30 mcg/day), levels of se-depdendent enzymes -- including GSH-Px -- reach a plateau (2-5).

The relationship between selenium intake (on the one hand) and Se-dependent enzyme levels and anticancer effect (on the other) is illustrated in a figure in (6), which is redrawn as Figure 1 in this article on Se-methylselenocysteine (SeMC):

http://www.aor.ca/mags/SeMC_2003_Spring.pdf

This article explains the recent discoveries about the effects of various selenium metabolites on apoptosis and the cell cycle, and the resulting discovery of SeMC as a superior anticancer form of the mineral.

To your health!

AOR

1: McClung JP, Roneker CA, Mu W, Lisk DJ, Langlais P, Liu F, Lei XG.
Development of insulin resistance and obesity in mice overexpressing cellular
glutathione peroxidase. PNAS [Epub ahead of print]

2. Thomson CD, Rea HM, Doesburg VM, Robinson MF. Selenium concentrations and glutathione peroxidase activities in whole blood of New Zealand residents.
Br J Nutr. 1977 May;37(3):457-60.

3. Whanger PD, Beilstein MA, Thomson CD, Robinson MF, Howe M. Blood selenium and glutathione peroxidase activity of populations in New Zealand, Oregon, and South Dakota. FASEB J. 1988 Nov;2(14):2996-3002.

4. Duffield AJ, Thomson CD, Hill KE, Williams S. An estimation of selenium requirements for New Zealanders. Am J Clin Nutr. 1999 Nov;70(5):896-903.

5. Yang GQ, Zhu LZ, Liu SJ, Gu LZ, Qian PC, Huan JH, Lu MD. Human Selenium requirements in China. In Combs GF, Levander OA, Spallholz JE, Oldfield JE (eds). Selenium in Biology and Medicine. 1987; Van Nostrand Reinhold, New York: 589-607.

6. Combs GF Jr, Gray WP. Chemopreventive agents: selenium. Pharmacol Ther. 1998 Sep;79(3):179-92.

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