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New Clues Found to Diabetes and Obesity

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Science  05 Mar 1999:
Vol. 283, Issue 5407, pp. 1423-1425
DOI: 10.1126/science.283.5407.1423

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. And with nearly 200,000 people dying of diabetes complications each year, better drugs are still sorely needed. On page 1544, a research team based in Canada reports that it has identified a major new target for such a drug—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, came to that conclusion by creating a line of mice lacking an enzyme called protein tyrosine phosphatase-1B (PTP-1B). Those animals, the researchers found, are more much sensitive to insulin's blood sugar-lowering effects than control animals. Because type 2 diabetes is thought to result from an inability to respond to insulin, rather than to an inability to make the hormone as is the case for the type 1 form of the disease, the findings raise the possibility of treating type 2 diabetes with drugs that block PTP-1B activity.

Turn off.

PTP-1B inactivates the insulin receptor (IR) by removing phosphates added when insulin binds.

SOURCE: CHIDAMBARAM RAMACHANDRAN

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. Phillip Gorden, director of the National Institute of Diabetes and Digestive and Kidney Diseases, calls the findings “very interesting and very important.”

In the current work, Kennedy, Tremblay, and their colleagues were following up on test tube studies by their group and others showing that PTP-1B removes certain phosphates from the receptor that transmits insulin signals to the cell interior. 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 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. That “was the way to show whether the enzyme was important or not,” Tremblay says.

And important it was. Mice lacking the gene maintained normal blood glucose levels after a meal, even though they had half as much insulin in their blood as normal mice. In addition, a shot of insulin caused some of the PTP-1B-deficient mice to move so much glucose into their cells that they passed out from low blood sugar—something that never happened to the wild-type mice that received the same dose, Kennedy says. Together, those results showed that the knockout mice were more sensitive to the hormone than their wild-type cousins.

The group also showed that these effects are due to increased insulin receptor activity in the knockout animals. The receptor is a tyrosine kinase, an enzyme that when activated, in this case by insulin, adds phosphates to residues of the amino acid tyrosine in its target proteins. The researchers found that in the absence of PTP-1B, the receptor attached 2.5 times as many phosphate groups to the next protein in the insulin signaling cascade than it normally does.

So far, all the results had been in healthy mice, rather than diabetic ones. Obesity predisposes to type 2 diabetes in ways researchers do not fully understand. So to see if knocking out PTP-1B helps diabetic mice become more insulin-sensitive, the researchers tried to induce the condition by fattening both normal and mutant animals on rodent chow with 10 times the normal amount of fat. Only the normal mice became obese and showed signs of diabetes. “We expected both [strains] to become fat,” Kennedy says, “but right off the bat it became obvious that the knockout mice didn't gain as much weight.”

Equally important, the mice without PTP-1B appear healthy. Because tyrosine phosphatases may help check cell growth, “you might have had a beneficial effect on insulin signaling, but you also might have had tumors,” says endocrinologist Jeffrey Flier of Harvard Medical School. But the PTP-1B knockout mice have now passed the advanced age of 2 years and show no signs of cancer.

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.”

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