NYU, Scripps finding offers new path for treatment of diabetes

The enzyme GAPDH was previously unknown to be a factor in the development of diabetes in humans. It has also been discovered that the inhibition of GAPDH attenuates the diabetic disease symptom in model animals.

The research team, which included NYU’s Departments of Biology and Chemistry and Scripps’ Department of Cell Biology, used the worm Caenorhabditis elegans (C. elegans) to identify a new therapeutic target protein for diabetic treatment. C. elegans is the first animal species where RNA interference (RNAi) is discovered and thus, an excellent model organism for chemical genetic research. In this study, the researchers screened hundreds of chemical compounds to find one hit compound, which rescues the mutant C. elegans (diabetics model) from diabetes. Then, they identified the target protein, which was found to be the enzyme GAPDH. GAPDH has long been known as one of the important glycolytic enzymes, and its function is affected by insulin. However, this is the first discovery that GAPDH actively regulates the insulin pathway.

The research team constructed all the molecules by incorporating the fishing tag (linker) from the beginning, and facilitated the target fishing. The hit compound was named GAPDS (GAPDH segregator) as GAPDS disassemble the multi-part structure of GAPDH into monomers. The segregation of GAPDH releases the suppressor of insulin signaling from the cell membrane, and thus activates the insulin signaling to eventually help to treat diabetes.

While the C-elegans is a recommended model for chemical genetic study, treating them with chemical compounds presented difficulties for the researchers because they grow on the surface of agar. To overcome these challenges, the researchers devised a soaking method in which the worms were placed in a compound solution for 24 hours. By this method, the worms were exposed to equitable concentration of the compounds. The mutant C-elegans are in a growth arrested status. By addition of compounds, a re-growing of the worms into normal size was observed by GAPDS, which is analogous to treating diabetes patients with a drug.

While there are many drugs on the market to treat diabetes, the number of known disease-producing protein targets is small. Because diabetes has many causes, targeting several different proteins offers the most promising method for treatment. The discovery of GAPDH adds another target that can be addressed in combating the disease.