Scientists at the Joslin Diabetes Center, Boston, MA, led by Principal Investigator Robert Stanton, M.D., have discovered that high blood glucose levels damage a key enzyme that guards insulin-producing beta cells. Their surprising finding raises hopes of finding drugs that protect the enzyme, and thus the beta cells and their insulin production. The discovery focuses on a cellular process known as "oxidative stress."
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Dr. Stanton explains that 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 (antioxidants). This balancing act of oxidative stress is particularly likely to go haywire in beta cells, which malfunction and then start to die off in people with diabetes.
Scientists in the Stanton lab previously showed that lowered activity of a relatively little-studied enzyme called G6PD, which is the main producer of an antioxidant called NAPDH, can inflict damage on several other types of cells.
While studying mice modified to produce less G6PD, and thus NAPDH, postdoctoral fellow Zhaoyun Zhang found herself wondering about the effects on the pancreas, which is where beta cells are found in structures called islets.
Not an expert on beta cells, she talked with Chong Wee Liew, a postdoctoral fellow studying beta cells in the neighboring lab of Principal Investigator Rohit Kulkarni, M.D., Ph.D. ("That's the advantage of working at Joslin," she remarks. "There are so many people you can talk to who have so much expertise.")
The two researchers looked at a pancreas from one of the experimental mice, with startling results. Its islets were tiny compared to those in normal animals -- suggesting that the beta cells had been extensively damaged.
In follow-up research, Dr. Zhang and her colleagues showed that NAPDH can regulate the growth and death of beta cells. The Joslin team went on to demonstrate that increases in blood glucose levels cause a decrease in NAPDH that ends up killing beta cells -- and that boosting production of this key antioxidant guards against the damage, at least in mouse beta cells.
"This research discovery, which identifies a key enzyme that regulates oxidation and pancreatic cell death, brings us closer than ever to getting at the root of diabetes," comments Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal.
"Preventing the death of beta cells or stimulating beta cells to grow is a Holy Grail in diabetes prevention," says Dr. Stanton. "Treatments aimed at increasing this essential antioxidant hold great promise for treating or preventing diabetes."
With Dr. Stanton's guidance, his research team has begun to study drugs that are promising candidates for guarding against damage to beta cells.
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