Lowering Resistance To Insulin May Delay Or Prevent Onset Of Type 2 Diabetes

They presented their findings at the American Diabetes Association's 65th Scientific Sessions.

The Pioglitazone in Prevention of Diabetes (PIPOD) study tested whether the drug pioglitazone could protect women who had had gestational diabetes-a temporary form of diabetes during pregnancy-from developing type 2 diabetes later, explains study presenter Thomas A. Buchanan, M.D., professor of medicine, obstetrics and gynecology and physiology and biophysics at the Keck School.

Although most women with gestational diabetes do not remain diabetic right after delivery, they do commonly remain resistant to their insulin, and 30 to 50 percent of them develop type 2 diabetes within a few years after pregnancy. Because of that, studying women with gestational diabetes is useful for researchers seeking to understand diabetes and develop ways to prevent it.

In the study, researchers provided pioglitazone for three years to 89 women who had had gestational diabetes and who had already participated in their diabetes prevention study called TRIPOD, which used the drug troglitazone. Troglitazone reduced diabetes risk from 12 percent a year to only 5 percent a year. However, troglitazone was removed from use in 2000 because it caused rare but severe liver damage in those with type 2 diabetes.

For PIPOD, researchers used pioglitazone (also called Actos), which works similarly to troglitazone but is safe for the liver, to see if the diabetes rate would remain low. It did, less than 5 percent each year. Moreover, among those women who remained diabetes-free, beta-cell function did not change while the women were taking pioglitazone. Beta cells produce insulin.

As was true in the TRIPOD study, protection from diabetes in PIPOD was closely associated with reduced stress on the beta cells that results when physicians treat insulin resistance, Buchanan says.

"This study shows that our initial findings for diabetes prevention with troglitazone apply not only to this class of drugs-thiazolidinediones-but to the general mechanisms of reducing stress on beta cells by treating insulin resistance," Buchanan says. "Theoretically, weight loss and some other drugs may be able to do the same thing."

Buchanan explains that the body's cells need sugar, or glucose, for energy. Insulin helps cells grab glucose from the blood. But when cells grow resistant to insulin, beta cells must create more insulin to make up that resistance. Researchers believe that in some people, beta cells eventually buckle under the heavy load and wear out. Their failure leads to type 2 diabetes.

Pioglitazone makes the body's cells more sensitive to insulin, reducing beta cells' workload.

Researchers saw further evidence of the importance of treating insulin resistance to protect beta cells, too.

Under the previous study, TRIPOD, some women with gestational diabetes were given a placebo instead of troglitazone. When pioglitazone was substituted for troglitazone, though, all of the women-even those on placebo-were put on pioglitazone.

This is significant because many women who were on placebo during TRIPOD had seen their beta-cell function worsen; but when they were put on pioglitazone during PIPOD, their blood sugar and insulin levels improved, and most significantly, their beta-cell function stabilized.

Buchanan also reports that women who remained free of diabetes in PIPOD had certain factors in common. Before starting to take pioglitazone, they tended to have lower glucose levels and slightly higher insulin levels and their beta cells seemed to compensate more strongly for insulin resistance. After a year on pioglitazone, these women also had a greater reduction in insulin in the blood-a marker of a reduced load on their beta cells.

"This line of research is leading to a rational approach to diabetes prevention and early treatment," Buchanan says. "Patients at increased risk for type 2 diabetes should exercise and keep their weight as close to normal as possible. They should have regular check-ups to see if their glucose levels are stable, which means they are not progressing toward diabetes, or rising, which means they are progressing.

"If they continue to worsen, despite weight control and exercise, medications such as pioglitazone can be used to slow or stop their progression to diabetes."