In prior research, investigators from Translational Genomics Research Institute (TGen) and the University of Southern California's Keck School of Medicine had found that genetic variations in the peroxisome proliferator-activated receptor-g (PPARG) gene were associated with the metabolism and biological effects of a class of insulin-sensitizing drugs called thiazolidinediones (TZDs). (TZDs are used to treat type 2 diabetes by directly and indirectly affecting adipose tissue and muscle to improve insulin sensitivity. Such TZD drugs as Actos can significantly lower the incidence of diabetes in people at risk, potentially preventing the disease.) While the researchers knew that the genetic variations in the PPARG gene contributed to the therapeutic response associated with TZD, the variations did not fully explain why up to 40 percent of patients fail to respond to the drug. This led them to believe that other factors may be involved.

The researchers set to work to identify other variants that may predict response to TZDs. Toward this end, they performed a genome-wide analysis of 115,352 single nucleotide polymorphisms, as well as systematically screened 28 key genes involved in TZD metabolism or PPARG-stimulated pathways. They found five critical markers that may predict response to TZD mono-therapy. 

"We identified genetic variants that may predict how well someone will respond to the common anti-diabetes drug, Actos," says Dr. DiStefano, Director of TGen's Diabetes, Cardiovascular and Metabolic Diseases Division. "The implications of these findings include determining which patients will best respond to the drug for the prevention or treatment of diabetes." The next step in the research process, says Dr. DiStefano, will be to characterize the functional effects of the polymorphisms and determine the effect of these variants in other patients.

"This work may help treat the right people with the right drug, design better drugs that will effectively improve insulin sensitivity for more people, and possibly safeguard against adverse side reactions seen with some members of this drug class," she explains. "Importantly, these findings will enable us to dissect the pharmacogenetics of TZD response, which will expand our understanding of the genetic determinants of insulin resistance and its treatment, provide critical baseline information for the development and implementation of genetic screening into the therapeutic decision making process, and lay the foundation for "individualized medicine" for patients with  type 2 diabetes."

News Release: TGen researchers find genetic markers to help fight diabetes www.tgen.org June 15, 2009