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Nov/Dec 2000
Vol. 3, No. 9, p. 20.

news in brief

An insulin replacement?

Figure 1. Schematic representation of Caco-2 permeablility assay.

Blood sugar treatment?. Researchers at Merck think that 2,5-dihydroxy-3-(1-methylindol-3-yl) -6-phen-yl-1,4-benzoquinone may be the answer for people suffering from non-insulin-dependent diabetes mellitis.

Thanks to an African fungus, a research team at the Merck Research Laboratories in Rahway, NJ, has developed a new molecule that could one day kick-start the crucial but faulty blood sugar uptake system that characterizes type 2 or non-insulin-dependent diabetes mellitus (NIDDM).

Insulin is critical for normal protein, fat, and carbohydrate metabolism and is best known for its ability to regulate blood glucose levels. But for millions of Americans with NIDDM, that system begins to break down and insulin becomes less effective. This condition typically occurs in overweight people whose excess fat prevents normal insulin activity in ways not yet fully understood.

Eating less and exercising can fix the problem, but the reality is that most people do not stick to such a regimen. “It’s a very frustrating thing for a doctor,” says Roger Unger, director of the Diabetes Research Center at the University of Texas Southwestern Medical Center in Dallas. For some patients, boosting insulin levels can help correct the situation. Other treatments exist, but they are all associated with unwanted and potentially dangerous side effects.

With that in mind, Kun Liu and the Merck team set out to find a better solution by testing tens of thousands of synthetic and natural compounds for one that could mimic the effects of insulin. An extract from an African fungus turned out to be what they were looking for. It decreased blood glucose levels in mice, apparently by acting downstream in the chemical reactions triggered by insulin to kick-start the process of glucose uptake (J. Med. Chem. 2000, ASAP Article).

To maximize the compound’s effectiveness, the researchers created thousands of similar compounds and, through trial-and-error, synthesized a simpler and more effective molecule—2,5-dihydroxy-3-(1-methylindol-3-yl)-6-phenyl-1,4-benzoquinone.

The new molecule has several important advantages. Unlike insulin, it is a small molecule that will not break down in the stomach and thus can be taken orally rather than intravenously. Also, on the basis of studies in mice, too much of the compound is not harmful. Finally, tests have found no undesirable effects.

“This is a potentially extraordinarily exciting finding,” says Unger.

“Although there is much work to do before the new compound could ever be available commercially,” he says, “this is an important first step, and I’m quite excited about it.



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