Source: Nature News, Ewen Callaway
Date: November 28, 2007

Chemical cousin of red-wine extract restores insulin sensitivity in mice


Drugs that mimics the health-protection effects of a chemical compound in red wine could form the basis of the next generation of treatment for diabetes.

An extract of red wine, resveratrol, is known to temper the damage done by fatty diets, helping to extend healthy life and battle fat-related disease. But tests in mice have suggested that gallons of vino or a super-sized pill would be necessary for humans to stand a chance of getting the same benefits.

Now scientists have discovered several chemicals that mimic resveratrol but have positive effects at more modest doses. The drugs have already been shown to do as well as another type 2 diabetes treatment in rodent tests of the disease, and will soon be tested in people.

The drugs could be an alternative to diabetes treatments such as Avandia (rosiglitazone) that lower blood sugar but have caused heart problems for some (see Weighing up the evidence).

Metabolic switch

In mice, resveratrol reverses the toll of gluttony, keeping their livers healthy and insulin down. Scientists think this effect is thanks to the compound’s ability to activate a protein that affects metabolism – called Sirt1. To confirm this, and to search for a more potent pharmaceutical, Christoph Westphal, a biologist and CEO of Sirtris Pharmaceuticals in Cambridge, Massachusetts, and his team went looking for other compounds that rev up Sirt1.

After sifting through half a million chemicals, the group found several that activate Sirt1 at much lower doses than resveratrol does. One of the compounds, SRT1720, is about a thousand times more potent in biochemical tests.

Westphal’s team gave a small dose of SRT1720 to fattened-up mice, and the rodents’ blood sugar fell compared with fat mice not given a drug. The drug matched a proven type 2 diabetes treatment in restoring insulin sensitivity in the obese animals. SRT1720 also lowered blood sugar in two other rodent models used to test diabetes drugs, they report today in Nature.

Resveratrol also fights diabetes by restoring insulin sensitivity, but it took at least five times more of it than SRT1720 to do the job.

SRT1720 has few side effects on the mice, perhaps because Sirt1 and its cousins – called Sirtuins – are turned on naturally when animals diet, says Westphal. “When you calorie restrict and exercise your Sirtuin levels go up, and no one's telling you that's unsafe,” he says.

Beyond diabetes

Clinical safety trials for SRT1720 as a diabetes drug are set to begin in the first half of 2008. There’s no assurance that it will prove safe and effective in people, says Guilo Pasinetti, a biologist at Mount Sinai School of Medicine in New York. “The acid test is always to move on to humans," he says.

Westphal’s team is also eyeing other conditions that it might be useful for. The effects of boosting Sirt1 aren’t limited to diet, says Leonard Guarente, a biologist at the Massachusetts Institute of Technology in Cambridge, who consults for Sirtris Pharmaceuticals. Activating the protein could help stave off the cellular damage that causes other diseases that come with age, such as cancer, Alzheimer's and heart disease.

“One wants to believe that this target is broader than just metabolic diseases,” he says. “In the perfect world the target would be all diseases of ageing.”

References:
Baur, J. et al. Nature 444, 337-342 (2007)
Milne, J. et al. Nature 450, 712-716 (2007)