Researchers have developed a compound that acts to keep insulin in the body longer, thereby potentially paving the way for a new class of drugs for treating diabetes, according to a study published in the May issue of PLoS ONE.
The compound inhibits the insulin-degrading enzyme (IDE), which cuts proteins or peptides into smaller pieces. When insulin, a peptide, is disrupted by IDE, the regulation of glucose is upset. By inhibiting IDE, insulin is allowed to stay in the body longer to help remove glucose from the blood.
Inhibitors have been developed for practically all biomedically important proteases in the body, and it was "very surprising that IDE inhibitors had not been developed before, particularly given IDE's special relationship with insulin, a very important hormone," according to Malcolm Leissring, PhD, from the Mayo Clinic in Jacksonville, Fla., and colleagues. "The inhibitors we describe are the first to potently and selectively inhibit IDE."
Researchers used powerful computational algorithms to search for novel peptide inhibitors of IDE. The resulting compounds are much more potent than existing inhibitors, non-toxic and surprisingly selective for IDE, they wrote.
"Significantly, our results reveal that insulin signaling is normally regulated by IDE activity not only extracellularly but also within cells, supporting the longstanding view that IDE inhibitors could hold therapeutic value for the treatment of diabetes," according to the study.
One compound, Ii1 (IDE inhibitor 1), is about a million times more potent than any previous IDE inhibitors, but additional work will be needed to turn it into a drug suitable for therapeutic use, Leissring said.
In a step towards this goal, researchers solved the 3D crystal structure of Ii1 bound to IDE. This crystal structure could facilitate the development of inhibitors that are more stable in the body than Ii1 is predicted to be.
The structure of IDE is unlike other proteases, the researchers said. It is shaped like a hinged clamshell that opens and shuts. Ii1 peptide acts like a magnetic latch that holds the clamshell (IDE) shut.
If IDE is inhibited, insulin remains in the body longer. Normally, about half of the insulin produced by the pancreas is immediately destroyed by the liver; no one knows why this occurs but it may be a way to regulate how much insulin enters the bloodstream, researchers said.
The study was funded by grants from the National Institutes for Health, the Ellison Medical Foundation, and by a gift from the Unforgettable Fund, a charitable foundation based in Palm Beach County, Fla. Scientists from the Scripps Research Institute in Jupiter, Fla., also participated in the study.