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Drugs that decrease insulin resistance may delay disease onset in women

Administering a drug to lower insulin resistance in women at high risk for type 2 diabetes appears to successfully prevent or stall onset of the disease, according to a study by researchers at the Keck School of Medicine of USC.

The researchers presented the study at the American Diabetes Association’s 61st Annual Scientific Sessions in June.

The Troglitazone in Prevention of Diabetes (TRIPOD) study tested whether reducing the demands placed on beta cells-which secrete insulin in response to glucose-could prevent type 2 diabetes in Latinas with recent gestational diabetes. Although gestational diabetes usually disappears after childbirth, patients commonly remain resistant to their own insulin and 30 to 50 percent of them develop type 2 diabetes within a few years after pregnancy, said Thomas A. Buchanan, USC professor of medicine, obstetrics and gynecology and physiology and biophysics.

Buchanan and colleagues gave 235 young Latinas with recent gestational diabetes a daily dose of either troglitazone or a placebo. At that time, physicians nationwide commonly prescribed troglitazone to treat type 2 diabetes, because it helps the body’s cells more effectively use insulin to absorb glucose. (The Food and Drug Administration recalled troglitazone in 2000, and USC researchers switched to prescribing pioglitazone, a similar-acting, FDA-approved drug in the ongoing study).

When the body’s muscle and fat cells grow resistant to insulin, the beta cells in the pancreas shift into overdrive to produce more insulin to compensate. Over time, this high workload causes beta cells to wear out in some people and produce less insulin, or stop altogether, causing type 2 diabetes. Buchanan and colleagues postulated that lessening the workload might keep the beta cells from failing, thereby preventing diabetes.

During the 30-month study, women in the placebo group were diagnosed with diabetes at a rate of more than 12 percent a year. Women taking troglitazone were diagnosed at a much lower rate-less than 5 percent a year.

Interestingly, troglitazone seemed most helpful to very insulin-resistant women. At the time these women began the study, their beta cells had to secrete a lot of insulin. But when they took troglitazone, they experienced a very large reduction in the work their beta cells had to do. None of these women developed type 2 diabetes. Women whose beta cells did not experience such a large reduction in workload were not as protected by troglitazone. Some developed diabetes despite taking the drug.

“This fits with the idea that beta cells can wear out through chronic insulin resistance,” Buchanan said. “The women whose beta cells worked hardest at the start of the study who had the greatest benefit from the drug. That was because their beta cells got the most ‘rest’ during treatment.”

However, he noted: “We don’t know whether we’ve really stopped the beta cells from failing completely or just slowed the failure down. It’s possible that there’s a threshold of work your pancreas can handle, and if you exceed that threshold at any particular time, your cells may start to deteriorate.”

A third, small group of women did not respond to troglitazone. “Their beta cells got no rest and they developed diabetes at the same rates as the women who took the placebo.”

Buchanan noted that the study’s most important finding may be that troglitazone did not merely temporarily mask diabetes, it actually prevented the disease.

Out of the 55 women who completed the study period without developing diabetes, 40 returned eight months later to see what happened when treatment was stopped. Based on their characteristics at the beginning of the study, 10 to 12 of these women should have developed diabetes if troglitazone had merely hidden diabetes, rather than prevented it. However, only one of the women developed diabetes after the drug was stopped.

“So, reducing secretory demands placed on beta cells by chronic insulin resistance slowed or stopped the underlying deterioration of beta cell function that leads to type 2 diabetes in these high-risk women,” Buchanan concluded.

Buchanan and colleagues are now trying to understand why some peoples’ beta cells wear out under high workloads, while others’ do not.

The National Institutes of Health and the American Diabetes Association funded the research. Investigators included Anny H. Xiang, Ruth K. Peters, Siri L. Kjos, Aura Marroquin, Jose Goico, Cesar Ochoa, Sylvia Tan and Stanley P. Azen.

Drugs that decrease insulin resistance may delay disease onset in women

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