Scientists have wondered for decades whether slowing the degradation of insulin in the body might be a way to treat type 2 diabetes. The gene that encodes a zinc metalloprotease called insulin-degrading enzyme (IDE) was identified several years ago as a diabetes susceptibility gene. David R. Liu and Alan Saghatelian of Harvard University and coworkers have now discovered from a DNA-templated macrocycle library a potent, highly selective, and physiologically active inhibitor of IDE. They found that inhibiting IDE affects not only the level of insulin in mice but also the levels of two other peptide hormones involved in glucose control, amylin and glucagon (Nature 2014, DOI: 10.1038/nature13297). In mouse studies, treatment with the inhibitor improved tolerance to orally administered glucose, which mimics intake of a meal, but impaired tolerance to injected glucose. These seemingly contradictory results led the researchers to hypothesize that IDE regulates other hormones involved in glucose homeostasis. Further experiments revealed that IDE indeed regulates both amylin and glucagon. These findings support IDE as a target for the treatment of diabetes and suggest specific IDE-inhibition strategies that may offer the most therapeutic benefit.