By Carolyn Y. Johnson
For years, diabetes treatments have aimed squarely at boosting insulin, a hormone that regulates the amount of sugar in the blood. Therapies span the gamut, from direct injections of insulin to drugs that spur the body to make more of it.
A team of Harvard University researchers announced Wednesday they had discovered a whole different method for maintaining insulin in the blood: by blocking the enzyme that breaks it down. It’s the difference between opening a faucet and blocking the drain.
The researchers discovered a small molecule that inhibits an enzyme that degrades insulin. When they administered that molecule to obese mice, there was marked improvement in their ability to regulate blood sugar levels after a meal.
“It’s important to have these different approaches, because patients respond differently,” said David Liu, a professor of chemistry and chemical biology at Harvard who led the work published in the journal Nature. In addition, he said that many diabetes drugs eventually stop working as effectively, highlighting the need for multifaceted approaches that could lead to drug combinations. For example, if a drug could slow the breakdown of insulin, people with either type 1 or type 2 diabetes might benefit. Some patients could potentially inject less insulin, less often. Others might benefit from combinations of drugs that stop the breakdown of insulin along with drugs that make their bodies more sensitive to it.
To find a candidate drug, the researchers screened a novel library of nearly 14,000 molecules developed by their laboratory. They came up with a handful of molecules that bound to IDE, or insulin-degrading enzyme. They eventually settled on one that appeared to be a good candidate for a drug. They have applied for a patent and hope to partner with a drug company in order to develop the basic research into a therapy that can be tested in people.
The big question was whether the molecule that disabled the enzyme would be viable in the body: would it work as beautifully in a living animal as it had in a laboratory dish? The researchers found that it performed well in animal tests, although they also discovered an unexpected quirk. When they delivered glucose to the animals by injecting sugar directly into their body cavity, the inhibitor had the opposite effect: it caused blood sugar levels to rise.
it also degrades other hormones that are linked to blood sugar regulation. That insight, in and of itself, may provide even more new targets for scientists trying to develop treatments.