A new approach to diabetes treatment has come to light thanks to Harvard scientists and other university researchers, who discovered a new compound that can slow the breakdown of insulin in animal trials. The findings, published in the journal Nature on Wednesday, will explain how the new compound can improve glucose tolerance.

Glucose tolerance plays a huge part in diabetics’ lives because diabetes is caused by too little insulin production or the resistance to insulin, which makes it difficult to process glucose. When food is digested, the sugar, also known as glucose, enters the bloodstream and is used as a fuel source for the body. Insulin, which is produced by the pancreas, moves the glucose from the bloodstream and into the muscle, fat, and liver cells.

When the pancreas doesn’t make enough insulin, or cells don’t respond normally to insulin, a person is diagnosed with diabetes because their body builds up with sugar. According to the National Library of Medicine, diabetes affects more than 20 million Americans, and an additional 40 million have pre-diabetes, which often develops into diabetes.

Harvard researchers, along with researchers from Stony Brook University, the Albert Einstein College of Medicine, University of California Irvine and the University of Chicago, believe the newly discovered compound will stop the insulin degrading enzyme (IDE). With the breakdown of insulin slowed down, patients will be able to maintain higher insulin levels and promote glucose tolerance, ultimately treating diabetes. It was created by DNA-templated synthesis, which is a self-assembled DNA sequence. When the DNA segments bind together, their building blocks begin to react with one another and form more complex molecules. They then placed the new molecules with IDE and found one compound that, not only reacted with it, but also stopped insulin breakdown in mice.

"This work validates a new potential target for the treatment of diabetes," said David Liu, an professor of chemistry and chemical biology at Harvard University. "What we show is that inhibiting IDE in an animal can improve glucose tolerance under conditions that mimic the intake of a meal if you administer this compound beforehand."

Previously, researchers have only treated diabetes with either injecting insulin straight into diabetics, providing drugs to stimulate insulin secretion, or use drugs to make the body more sensitive to insulin.  

"What's been missing has been the ability to regulate the degradation of insulin," said Alan Saghatelian, a chemistry and chemical biology professor at Harvard University. "The technological leap we've made was in identifying a molecule that allows that to happen. This opens up a new avenue to control insulin signaling in vivo."

In vivo, meaning, in the living organism, gave researchers the ability to see if the compound could remain in the body and regulate blood sugar levels in mice.

"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."

The compound they found is potent and has the ability to inhibit the loss of insulin in the body, which is key to moving around the sugar to its destinations in the muscles and other organs. Researchers hope to develop the compound into a therapeutic application for diabetics.

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

Harvard researchers believe that this is the new approach to diabetic treatment — to inhibit the factors that breakdown insulin, which would make it more available to the body and easier to move glucose. The discovery of the new molecule is a breakthrough; it may take time before the IDE drug inhibitor is developed and available for purchase.

"What this paper has done is given a proof of concept that targeting this protein is the way to go," Saghatelian said. "To make the leap from this molecule to a drug, there are other factors that need to be optimized, but we've hung the carrot out there for the pharmaceutical industry and other labs to start looking at IDE as a potential target for treating diabetes, and to push through the remaining obstacles that are there. We've shown it's worth the effort to look into this more deeply, and hopefully what we've done is opened people's eyes to IDE as a valid therapeutic target."

 

Source: Liu DR, Maianti JP, McFedries A, et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014.