Patients may get lasting protection from type 2 diabetes through medications that take the load off of the body’s delicate insulin-producing cells, according to a study released June 11 by Keck School of Medicine researchers.
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 gestational diabetes�a temporary form of diabetes during pregnancy�from developing type 2 diabetes later, explained study presenter Thomas A. Buchanan, 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 gestational diabetes and who had already participated in the 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 in TRIPOD, protection from diabetes in PIPOD was closely associated with the reduction in stress on beta cells that results when physicians treat insulin resistance.
“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 said. “Theoretically, weight loss and some other drugs may be able to do the same thing.”
The body’s cells need sugar, or glucose, for energy, Buchanan said. Insulin helps cells grab glucose from the blood. But when cells grow resistant to insulin, beta cells create even more insulin to compensate. In some people, beta cells eventually buckle under the heavy load and wear out, researchers believe. Beta cells’ failure leads to type 2 diabetes. Pioglitazone sensitizes the body’s cells 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. Their beta cells continued to fail. However, when they were put on pioglitazone in the PIPOD study, their beta cells stopped failing.
Buchanan also reported 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 said. “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.”
In addition, USC researchers at the meeting reported on their progress on the B-Gene study, which searches for genes related to beta-cell vulnerability in families of Mexican-American women with gestational diabetes.
In the presentation, Richard Watanabe, assistant professor of preventive medicine, described how polymorphisms in the hepatocyte nuclear factor-4A gene (which helps regulate insulin secretion) are linked to beta-cell function in this population. Variation in HNF4A may play an important role in type 2 diabetes susceptibility in Mexican Americans.
Thomas A. Buchanan, Anny H. Xiang, Siri L. Kjos, Ruth K. Peters, Aura Marroquin, Jose Goico, Cesar Ochoa, Miwa Kawakubo, “Diabetes Rates and B-Cell Function in the Pioglitazone in Prevention of Diabetes Study,” American Diabetes Association 65th Scientific Sessions. Oral Presentation: Genetics, Glycemia, Gestation and General Health, 2:45 p.m.-4:45 p.m., June 11, Abstract No. 157-OR.