New Drug Target for Type 2 Diabetes

For the 15.7 million Americans with type 2 diabetes, good health means daily vigilance. To head off the eye, kidney, and heart damage the disease can cause, sufferers must follow strict diet and exercise regimes to prevent their blood sugar levels from soaring. Because those measures don't work for everyone, however, some people also need drugs to keep their blood sugars in check. Now researchers report in tomorrow's Science a major new target for a drug to treat type 2 diabetes--and possibly for anti-obesity drugs as well.

The team, led by molecular biologist Brian Kennedy of the Merck Frosst Center for Therapeutic Research in Pointe Claire-Dorval, Quebec, and biochemist Michel Tremblay of McGill University in Montreal, created a line of mice lacking an enzyme called protein tyrosine phosphatase-1B (PTP-1B). They were following up on test tube studies showing that PTP-1B removes certain phosphates from the receptor that transmits insulin signals to the cell interior (type 2 diabetes is thought to result from an inability to respond to insulin). The addition of those phosphates, which occurs when insulin binds the receptor, touches off a cascade of enzyme reactions inside muscle and liver cells. This tells the cells to take up glucose and sock it away as the storage carbohydrate glycogen, thus lowering blood sugar concentrations. Removal of the phosphates by PTP-1B should therefore turn off the signal cascade, and that's what researchers had found in the test tube studies.

To see whether the enzyme does the same in the body, the McGill team inactivated the PTP-1B gene in live mice. Those animals, the researchers found, are more much sensitive to insulin's blood sugar-lowering effects than control animals. The mutant mice also turned out to undergo a more surprising change: Unlike normal mice, they could eat a high-fat diet without gaining much weight. The researchers do not yet understand this connection, but the result suggests that PTP-1B-blocking drugs might be useful for treating obesity, too.

Still unclear is how enhanced signaling through the insulin pathway protects against obesity, although the researchers speculate that it might boost energy consumption by liver and muscle cells. Also unknown is whether PTP-1B overactivity plays a role in excess weight gain in normal animals--or in people. But even if it doesn't, that might not matter for developing an anti-obesity drug, says diabetologist Barry Goldstein of Thomas Jefferson University in Philadelphia: "The fact that the results are so clean, that there are apparently no other phenotypic changes, makes [PTP-1B] a very exciting drug target."