Drug May Protect Diabetics Suffering Increased Protein Damage From Free Radicals

ATLANTA -- University at Buffalo researchers have demonstrated for the first time that diabetics experience increased damage to body proteins due to the oxidative action of free radicals.

In related research, they have shown that a new drug used to reduce insulin resistance in some diabetics also may help protect them from such free-radical oxidative damage.

The two studies were presented here today at the annual meeting of the American Diabetes Association.

Scientists have speculated for some time that free radicals damaged many kinds of tissues, and were implicated in heart disease, cancer, aging and other degenerative conditions.

They also have surmised that diabetes mellitus is associated with increased generation of oxygen free radicals and with many degenerative conditions.

Paresh Dandona, UB professor of medicine, specialist in biological endocrinology and leading diabetes researcher, earlier headed a research team at Millard Fillmore Hospital in Buffalo that demonstrated for the first time that diabetic men suffer increased free-radical oxidative damage to DNA of sperm and white blood cells, findings that revealed two pathways of cell degeneration. Their current work involved investigating whether protein, the basic building blocks of all tissue, also incurs increased free-radical damage in diabetics.

To test their hypothesis, the researchers measured the concentration of carbonylated proteins, an index of oxidative damage to proteins, in 15 persons with insulin-dependent diabetes mellitus (IDDM), 15 persons with non-insulin-dependent diabetes mellitus (NIDDM) and 15 healthy controls.

Results showed that IDDM patients sustained twice as much protein damage due to oxidation as healthy persons. Protein damage in NIDDM patients was about 37 percent higher than in controls.

Dandona said the clinical significance of these findings is unclear at this early stage of investigation, but they seem to indicate that diabetics are at risk of sustaining significant damage to all body cells as a result of oxygen-free radical oxidation, which may contribute to their higher risk of degenerative diseases.

The good news is that diabetics being treated with a new antihyperglycemic drug called troglitazone may be receiving a measure of protection from this damage, the UB scientists have found.

Dandona and his team are pioneers in the use of troglitazone, currently in Phase III FDA drug trials. The drug is being tested as a treatment for lowering insulin resistance in patients with NIDDM.

The researchers had noted troglitazone's structural similarity to tocopherol -- an alcohol that has the properties of Vitamin E, a known antioxidant -- and hypothesized that the new drug may have antioxidant, as well as antihyperglycemic, properties.

Researchers found that low doses of troglitazone inhibited production of three types of free radicals, while a larger dose reduced production of a fourth type.

Dandona said these findings showed that troglitazone's beneficial effects extend beyond its role as an insulin sensitizer.

"These data demonstrate clearly that troglitazone is a potent antioxidant, and that it may prevent oxygen free radical-related damage to lipids, proteins and DNA," he said. "It may help prevent cardiovascular complications of diabetes mellitus, and it may have use as an antihypertensive."

Researchers involved in the studies were Ahmad Aljada, Kuldip Thusu, and Ehad Abdel-Rahman, doctoral candidates working with Dandona; Donald Armstrong, Ph.D., chair of the UB Department of Clinical Laboratory Science; Thomas Nicotera, Ph.D., of Roswell Park Cancer Institute; Usha Khurana and John Love, research scientists at Millard Fillmore Hospital.