Public Release:  A new strategy for diabetes treatment

Newly discovered compound slows natural degradation of insulin in the body

Harvard University


The new approach, described by Professor of Chemistry and Chemical Biology David Liu and Associate Professor of Chemistry and Chemical Biology Alan Saghatelian, uses a newly discovered compound to inhibit insulin degrading enzyme (IDE). Inhibiting IDE in mice, they show, elevates insulin levels and promotes insulin signaling in vivo. Eventually, the use of this compound in patients may help maintain higher insulin levels to improve glucose tolerance and therefore to treat diabetes. The discovery of the new compound, and tests demonstrating its efficacy in mice, are outlined in an May 21 paper in Nature.




To identify the new molecule, Liu, Saghatelian, and their co-workers turned to DNA-templated synthesis, a method for creating new molecules that self-assemble according to an attached DNA sequence.

The system works by combining DNA "templates" -short segments of DNA - with the chemical building blocks of molecules, each of which is linked to its own complementary piece of DNA. As the DNA segments bind together, the building blocks are brought together and react with one another, forming more complex molecules. The composition of the resulting molecules can be identified by sequencing their associated DNA strands.

"We took a library of about 14,000 DNA templates, and combined it with several sets of DNA-linked reagents," Liu said. "The resulting synthesis of about 14,000 small molecules was largely driven by, and programmed by, DNA base pairing. At the end of that process, we had 14,000 strands of DNA, each with a unique compound at its end."

Researchers then took that library of DNA-linked compounds, and incubated it with IDE in the hopes that some might bind to the enzyme.

"Our hypothesis was that the molecules that were retained by IDE might modulate IDE's activity," Liu said. "In this case, right out of the library, we found quite a potent and selective inhibitor. Perhaps most important, this molecular had a good half-life in animals, so it could be used to answer the 60-year-old question of what happens when you slow down the natural degradation of insulin in the body."





"In the process of resolving some seemingly paradoxical results, we discovered that IDE is actually somewhat misnamed," he said. "It doesn't just degrade insulin, it degrades at least two other important glucose-regulating peptide hormones - glucagon and amylin."

While the discovery of the new molecule is exciting, Liu emphasized that it may still be some time before the new compound finds its way onto pharmacy shelves.




