Nature 511, 94–98 (2014)

One potential strategy to maintain insulin levels in type 2 diabetes patients is to block the activity of insulin-degrading enzyme (IDE), a zinc protease. To characterize the effect of slowing insulin degradation on glucose tolerance in animals, Maianti et al. identified the potent and highly selective IDE inhibitor 6bK by performing a selection on a DNA-templated macrocycle library for molecules that bind IDE. A crystal structure revealed that 6bK bound an allosteric site 11 Å away from the catalytic site, explaining its high selectivity. Treatment of lean and obese mice with 6bK produced different effects on glucose homeostasis depending on the method of glucose infusion: 6bK followed by oral glucose administration, which mimics meal intake, improved glucose tolerance, whereas 6bK followed by injection of glucose impaired glucose tolerance. Regardless of glucose delivery method, 6bK treatment in mice lacking IDE had no effect, suggesting that the different effects of 6bK may arise from the ability of IDE to degrade additional glucose-regulating hormones beyond insulin. The researchers indeed discovered that IDE regulates both glucagon and amylin in addition to insulin. The cause of 6bK-induced hyperglycemia in injected glucose tolerance tests could therefore be attributed to elevated glucagon levels, and administration of 6bK in glucagon receptor–deficient mice followed by glucose injection led to no hyperglycemic effect. These findings validate IDE inhibition as a new therapeutic strategy for the treatment of type 2 diabetes and suggest that a combination of treatments including an IDE inhibitor may be an especially effective strategy.