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Researchers find promising drug for preventing serious complications of diabetes

17.02.2003


Results reported in Nature Medicine



Opening up the possibility of a new approach to the treatment of diabetes, researchers have shown in animal studies that a drug long available in Europe can simultaneously block three of the major biochemical pathways responsible for the blood-vessel damage that causes serious diabetic complications.

Dr. Michael Brownlee of the Albert Einstein College of Medicine was the senior researcher for the international consortium that carried out the study, which appears in the current issue of Nature Medicine.


Research over the past 30 years has identified four biochemical pathways by which diabetes injures blood vessels - damage that makes diabetes the leading cause of blindness, kidney failure, heart attacks and nontraumatic amputation of legs in the U.S. In this study, from the Einstein Diabetes Research Center, the drug benfotiamine completely blocked three of those pathways when tested in diabetic rats, animals often used as models for studying the disease. Benfotiamine is a synthetic derivative of thiamine (vitamin B1) and has been available for more than a decade in Germany. It is prescribed there for treating diabetic neuropathy, sciatica and other painful nerve conditions but has never been tested in placebo-controlled, double-blind clinical trials.

In people with diabetes, all cells are bathed in blood that contains elevated levels of glucose. Most cells still manage to keep their internal glucose at normal levels. But certain cells - particularly endothelial cells that line arteries and the capillaries of the retina and kidney - are unable to regulate glucose and instead develop high internal levels of the sugar, which they can’t completely metabolize. As a result, glucose-derived "intermediate" metabolic products accumulate inside these cells, where they activate pathways of cellular damage that can eventually lead to blindness and other complications.

Dr. Brownlee and his colleagues focused on two glucose-derived intermediates that activate three of the damaging biochemical pathways. They knew that both of these metabolic compounds (fructose-6-phosphate and glyceraldehyde-3-phosphate) are the end products of another biochemical pathway mediated by an enzyme called transketolase.

By boosting transketolase’s activity, the researchers reasoned, they might be able to reverse this pathway - essentially converting the two damage-triggering glucose metabolites into harmless chemicals and preventing all three damaging biochemical pathways from being activated. They also knew that transketolase, like many enzymes, depends on a cofactor for its activity - in this case thiamine.

In preliminary studies involving arterial endothelial cells, adding standard thiamine boosted transketolase’s activity by only 20 percent, so the researchers looked around for a more potent form of thiamine. Dr. Brownlee’s German colleagues suggested benfotiamine, a fat-soluble thiamine derivative.

"By pure serendipity, it turned out that benfotiamine boosted the activity of the enzyme transketolase by 300 to 400 percent - something we never could have predicted based on benfotiamine’s chemical structure," says Dr. Brownlee, who is professor of medicine and of pathology, and the Anita and Jack Saltz Professor of Diabetes Research at Einstein.

As reported in the Nature Medicine paper, benfotiamine successfully blocked all three major destructive biochemical pathways in experiments with arterial endothelial cells. Next, the researchers treated diabetic rats with benfotiamine and then examined their retinal tissue. (For comparison, they also examined the retinas of control diabetic rats and normal rats.)

Chemical analysis showed that all three biochemical pathways had been "normalized" in the benfotiamine-treated diabetic rats so that their retinas were biochemically identical to the retinas of normal rats. The drug also prevented diabetic retinopathy in the animals, since microscopic examination revealed that the retinas of benfotiamine-treated diabetic rats were free of vascular damage.

No drug for preventing the complications of diabetes is currently available. Dr. Brownlee is applying to the U.S. Food and Drug Administration to test benfotiamine as an Investigational New Drug. Noting that drugs that produce impressive results in animals do not always work in humans, Dr. Brownlee says he is reasonably confident that benfotiamine will at least prove to be safe: "Benfotiamine has been used extensively in Germany for many years, and to my knowledge there are no reported side effects."

Dr. Brownlee cautions people with diabetes against taking thiamine supplements, however, noting that there is no evidence that thiamine can activate transketolase sufficiently to prevent complications of diabetes.


In addition to Dr. Brownlee and his Einstein colleagues, authors of the Nature Medicine paper included scientists from Germany, Italy, China and Japan. The research was supported by grants from the National Institute of Diabetes and Digestive and Kidney Diseases, the American Diabetes Association and the Juvenile Diabetes Research Foundation.




Karen Gardner | EurekAlert!
Further information:
http://www.aecom.yu.edu/

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