Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice

Nat Commun. 2015 Sep 23;6:8250. doi: 10.1038/ncomms9250.


Insulin-degrading enzyme (IDE) is a protease that cleaves insulin and other bioactive peptides such as amyloid-β. Knockout and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin-degrading protease, IDE is a candidate drug target in diabetes. Here we have used kinetic target-guided synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and small angle X-ray scattering analyses show that it locks IDE in a closed conformation. Among a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signalling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Caco-2 Cells
  • Catalytic Domain
  • Diabetes Mellitus / drug therapy
  • Drug Evaluation, Preclinical
  • Glucose Tolerance Test
  • Humans
  • Hydroxamic Acids / chemical synthesis*
  • Hydroxamic Acids / pharmacology
  • Hydroxamic Acids / therapeutic use
  • Insulysin / antagonists & inhibitors*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microsomes, Liver
  • Molecular Targeted Therapy
  • Random Allocation
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis*
  • Triazoles / pharmacology
  • Triazoles / therapeutic use


  • BDM44768
  • Hydroxamic Acids
  • Triazoles
  • Insulysin