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Study explains why key diabetes drug fails in some patients

Patients face frustration when a medication that helps many other diabetes sufferers does not work for them; but now researchers at the Keck School of Medicine have taken a major step toward understanding that mystery.

Writing in the November issue of Diabetes, the USC researchers reported that women who did not respond to common diabetes drugs called thiazolidinediones had certain variations in a key gene.

Thiazolidinediones include drugs such as pioglitazone, known by the trade name Actos.

Thiazolidinediones are a valuable part of physicians’ life-saving arsenal against type 2 diabetes because they help the body to better use insulin to pull sugar out of the bloodstream and into the cells that need sugar for energy.

But 30 percent or more of patients who try the drugs do not see any improvement.

By identifying genetic variations that are linked to this resistance to the medications, the researchers may have opened the door to customized treatment plans for patients in the future.

“The long-term implications are that it might be possible to identify specific genetic variants that can be tested to determine if someone will or will not respond to specific medications,” said Richard M. Watanabe, assistant professor of preventive medicine at the Keck School and senior author of the article.

Watanabe is part of a team of USC diabetes researchers behind the Troglitazone in the Prevention of Diabetes, or TRIPOD, study, which formed the basis for the Diabetes paper. The study became the Pioglitazone in the Prevention of Diabetes, or PIPOD, study after the United States Food and Drug Administration withdrew troglitazone from the market in 2000. The two drugs work similarly.

The studies tested whether taking troglitazone, and later pioglitazone, could protect Latinas who had gestational diabetes—a temporary form of diabetes during pregnancy—from eventually developing type 2 diabetes.

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.

Although the two drugs successfully kept many women in the studies from developing type 2 diabetes—troglitazone reduced diabetes by 55 percent in TRIPOD, for example—the drugs did not help a portion of the women.

Researchers theorized that genetics plays a part in the lack of a response to the thiazoldinedione drugs. To investigate that, they analyzed the DNA of 93 women participating in TRIPOD (63 who responded to troglitazone and 30 who did not).

Specifically, they looked within the DNA at a gene that codes for a protein called peroxisome proliferator-activated receptor gamma, or PPARG for short. It may have an unwieldy name, but PPARG is known to be important in the development of type 2 diabetes.

Moreover, thiazolidinedione drugs are meant to help PPARG work better in the body.

Although the PPARG gene codes for the same basic protein across the population, slight tweaks in various parts of the genetic code that makes up PPARG can create slightly different versions of the protein from person to person. Bits of genetic code within a gene may occur in a few different varieties across the population; these variations are called polymorphisms.

In analyzing various parts of the PPARG gene in the 93 participating women, the researchers found that eight polymorphisms within the gene were associated with response to troglitazone. However, these polymorphisms did not account entirely for patients’ response to the drug, so researchers believe that groups of genetic code across several genes may contribute to the effectiveness of the drugs in each patient.

Also, Watanabe noted that some women who respond to one thiazolidinedione drug do not respond to another. “The data are too preliminary to be definitive, but we are hypothesizing that different genetic variants within the same gene may be responsible for the difference in response to troglitazone versus pioglitazone,” Watanabe said.

Eventually, when more related genes and polymorphisms are identified and the findings are borne out by further studies, the scientists hope that genetic testing may help physicians choose the most effective medications for each patient.

The research is unique because Watanabe’s group is one of only two research teams across the nation systematically studying the pharmacogenetics of diabetes medications—the interaction between genetic makeup and drug action.

“This is an area of research that appears to be under-studied,” Watanabe added.

Johanna K. Wolford, Kimberly A. Yeatts, Sharanjeet K. Dhanjal, Mary Helen Black, Anny H. Xiang, Thomas A. Buchanan and Richard M. Watanabe, “Sequence Variation in PPARG May Underlie Differential Response to Troglitazone,” Diabetes. Vol. 54, No. 11, pp. 3319-3325.

Study explains why key diabetes drug fails in some patients

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