Leicester: Advance in study of diabetes drug target

Research lead

John Schwabe and his team at Leicester Department of Biochemistry working with researchers in Japan and Hungary have elucidated how PPAR gamma, a major drug target in treating Type II diabetes is naturally activated in the body.

Using X-ray Crystallography the scientists have shown how PPAR gamma binds to eight different fatty acids, derived in part from the diet. Many of these fatty acids joined irreversibly with the PPAR gamma, leading to its long term activation. They have also shown that sometimes two fatty acids bind simultaneously, which might mean that PPAR gamma could be targeted by a mixture of drugs.

Schwabe said, “The finding that natural activators for PPAR gamma couple irreversibly to the PPAR gamma receptor, dramatically changes our understanding of how this receptor is activated.”

“It may also allow for the design of drugs that provide longer-term activation of PPAR gamma, at lower doses, without some of the side effects of the current generation of drugs.

While PPAR gamma is activated by two widely prescribed drugs, Actos and Avandia, until now the natural activators for PPAR gamma were unclear.

“Our breakthrough is important because it reveals for the first time that how this protein is activated by naturally occurring fatty acids,” said Schwabe. “This knowledge will help in the design of future novel pharmaceutical agents."