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Nature DOI:10.1038/nature13297

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones.

Publication TypeJournal Article
Year of Publication2014
AuthorsMaianti, JPablo, McFedries, A, Foda, ZH, Kleiner, RE, Du, XQuan, Leissring, MA, Tang, W-J, Charron, MJ, Seeliger, MA, Saghatelian, A, Liu, DR
JournalNature
Volume511
Issue7507
Pages94-8
Date Published2014 Jul 03
ISSN1476-4687
KeywordsAnimals, Binding Sites, Blood Glucose, Catalytic Domain, Diabetes Mellitus, Type 2, Disease Models, Animal, Gastric Emptying, Genetic Predisposition to Disease, Glucagon, Glucose Tolerance Test, Hypoglycemic Agents, Insulin, Insulysin, Islet Amyloid Polypeptide, Macrocyclic Compounds, Male, Mice, Mice, Inbred C57BL, Models, Molecular, Obesity, Signal Transduction, Thinness
Abstract

Despite decades of speculation that inhibiting endogenous insulin degradation might treat type-2 diabetes, and the identification of IDE (insulin-degrading enzyme) as a diabetes susceptibility gene, the relationship between the activity of the zinc metalloprotein IDE and glucose homeostasis remains unclear. Although Ide(-/-) mice have elevated insulin levels, they exhibit impaired, rather than improved, glucose tolerance that may arise from compensatory insulin signalling dysfunction. IDE inhibitors that are active in vivo are therefore needed to elucidate IDE's physiological roles and to determine its potential to serve as a target for the treatment of diabetes. Here we report the discovery of a physiologically active IDE inhibitor identified from a DNA-templated macrocycle library. An X-ray structure of the macrocycle bound to IDE reveals that it engages a binding pocket away from the catalytic site, which explains its remarkable selectivity. Treatment of lean and obese mice with this inhibitor shows that IDE regulates the abundance and signalling of glucagon and amylin, in addition to that of insulin. Under physiological conditions that augment insulin and amylin levels, such as oral glucose administration, acute IDE inhibition leads to substantially improved glucose tolerance and slower gastric emptying. These findings demonstrate the feasibility of modulating IDE activity as a new therapeutic strategy to treat type-2 diabetes and expand our understanding of the roles of IDE in glucose and hormone regulation.

DOI10.1038/nature13297
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/24847884?dopt=Abstract

Alternate JournalNature
PubMed ID24847884
PubMed Central IDPMC4142213
Grant ListUL1 TR000430 / TR / NCATS NIH HHS / United States
R01 GM081539 / GM / NIGMS NIH HHS / United States
T32 GM008444 / GM / NIGMS NIH HHS / United States
T32 GM007598 / GM / NIGMS NIH HHS / United States
R00 GM080097 / GM / NIGMS NIH HHS / United States
DP2 OD002374 / OD / NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
P41 GM111244 / GM / NIGMS NIH HHS / United States
P30 DK057521 / DK / NIDDK NIH HHS / United States
F30 CA174152 / CA / NCI NIH HHS / United States
R01 GM81539 / GM / NIGMS NIH HHS / United States
R01 GM065865 / GM / NIGMS NIH HHS / United States