"Insulin levels in the blood reflect the balance between how much is secreted and how fast it is broken down," says the study's lead researcher, Professor Malcolm A. Leissring, from Mayo Clinic's Department of Neuroscience. "Blocking the breakdown of insulin is simply an alternative method for achieving the same goal as many existing diabetes therapies."
The researchers tested this idea by studying mice in which insulin-degrading enzyme (IDE) was "knocked out," or deleted genetically. IDE is a molecular "machine" that normally chews up the insulin hormone, breaking it down into smaller pieces. Levels of insulin in the blood are controlled, in part, by this process.
Compared to normal mice, IDE knockout mice had more insulin overall, weighed less, and were more efficient at controlling their blood sugar. They were, in effect, "super mice" with respect to their ability to lower their blood sugar after a meal, the process that is disrupted in diabetes, explains Leissring.
"The reason we studied IDE knockout mice was to help us understand whether IDE inhibitors would be useful for treating diabetes," says Professor Samer Abdul-Hay, first author on the study. But the IDE knockout mice are not a perfect model of how a drug will perform, he notes. "They are actually a better model of overdosing on an IDE inhibitor. We would never want a drug that inhibits IDE 100 percent in all tissues throughout life."
The effect of deleting all IDE in the mice was so strong, in fact, that the effect eventually backfired, the researchers say. Despite being "super mice" when young, as the IDE knockout mice aged, they slowly became resistant to the elevated insulin, gained weight, and lost control of their blood sugar. As a result, the older mice developed classic type 2 diabetes.
"The finding that older IDE knockout mice develop diabetes has confused a lot of people," says Leissring. "It's an example of too much of a good thing becoming bad for you." Drugs that inhibit IDE only partially or only transiently would not be expected to cause diabetes, he says. "Deleting all IDE is overkill."
MEDICA.de; Source: Mayo Clinic