enzyme may save beta cells

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This article originally posted 31 December, 2009 and appeared in

Issue 502

Relieving Stress on Insulin-producing Cells May Prevent Diabetes

Cells in your body are constantly churning out poisonous forms of oxygen

(oxidants) and mopping them up with a countervailing force of proteins and

chemicals

(anti-oxidants). This balancing act of oxidative stress is particularly

likely to go haywire in beta cells, the insulin-producing cells that

malfunction

and then start to die off in Type 2 diabetes.

Scientists at Joslin Diabetes Center now have found that a relatively

little-studied enzyme plays a central role in defending beta cells against

oxidants,

but is damaged by the high levels of blood glucose produced in diabetes.

Joslin Principal Investigator Stanton, M.D., who led the research,

says the discovery raises hopes of finding drugs that protect the enzyme,

and

thus the beta cells and their insulin production. Such drugs could help to

stem the tide against Type 2 diabetes, which now afflicts more than a

quarter

of a billion people worldwide.

Scientists in the Stanton lab previously had found that lowered activity of

the enzyme G6PD, the main producer of an antioxidant called NAPDH, can

inflict

damage on several cell types.

In fact, Zhaoyun Zhang, a postdoctoral fellow and first author of the paper

was investigating G6PD activity's effect on other cell types when she made

the

initial discovery about beta cells.

In her earlier project, whose results were published in The FASEB Journal in

October, she was examining the diabetes-like complications that appeared in

a line of mice modified to produce less G6PD.

Zhang hadn't planned to look at the pancreas, which is where the

insulin-producing beta cells are packaged together with other

hormone-producing cells in

structures called islets.

But she and Chong Wee Liew, a postdoctoral fellow in the neighboring lab of

Principal Investigator Rohit Kulkarni, M.D., Ph.D., decided to take a look

at

islets in a pancreas from one of the experimental mice.

The islets were tiny compared to those in normal animals, suggesting

extensive damage to the beta cells. " It was very, very surprising, " she

recalls.

Zhang and her co-workers followed up with investigations of G6PD in beta

cells and islets, as well as studies of mice with variations in G6PD

activity (and

thus in production of the NAPDH antioxidant).

" The research showed that NAPDH, an essential antioxidant upon which all

cellular antioxidants ultimately depend, can regulate the growth and death

of beta

cells, " says Stanton, who also is Chief of the Nephrology Section at Joslin

Clinic and Associate Professor of Medicine at Harvard Medical School.

The Joslin team went on to demonstrate that increases in the level of blood

glucose cause a decrease in NAPDH that ends up killing beta cells-and that

increasing

the level of this antioxidant guards against this effect, at least in mouse

beta cells.

" Preventing the death of beta cells or stimulating beta cells to grow is a

kind of Holy Grail in diabetes prevention, " Stanton notes. " Treatments aimed

at increasing this essential antioxidant hold great promise for treating or

preventing diabetes in people. "

If this approach is successful, it could prove important for other illnesses

as well. Abnormally high level of oxidants are thought to be a major cause

of kidney disease, heart disease, hypertension, Alzheimer's disease and many

other conditions. " I hope that a new era of highly specific, targeted

treatments

will emerge that very effectively treat or possibly prevent many of these

diseases, " Stanton says.

Published in The FASEB Journal online on Dec. 23, 2009