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

Juan Pablo Maianti, Amanda McFedries, Zachariah H. Foda, Ralph E. Kleiner, Xiu Quan Du, Malcolm A. Leissring, Wei Jen Tang, Maureen J. Charron, Markus A. Seeliger, Alan Saghatelian, David R. Liu

Research output: Contribution to journalArticle

104 Citations (Scopus)

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 IDEâ™ 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.

Original languageEnglish (US)
Pages (from-to)94-98
Number of pages5
JournalNature
Volume511
Issue number7507
DOIs
StatePublished - 2014

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Insulysin
Enzyme Inhibitors
Hormones
Insulin
Glucose
Islet Amyloid Polypeptide
Type 2 Diabetes Mellitus
Metalloproteins
Obese Mice
Gastric Emptying
Glucagon
Libraries
Oral Administration
Zinc
Catalytic Domain
Homeostasis
Therapeutics

ASJC Scopus subject areas

  • General

Cite this

Maianti, J. P., McFedries, A., Foda, Z. H., Kleiner, R. E., Du, X. Q., Leissring, M. A., ... Liu, D. R. (2014). Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature, 511(7507), 94-98. https://doi.org/10.1038/nature13297

Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. / Maianti, Juan Pablo; McFedries, Amanda; Foda, Zachariah H.; Kleiner, Ralph E.; Du, Xiu Quan; Leissring, Malcolm A.; Tang, Wei Jen; Charron, Maureen J.; Seeliger, Markus A.; Saghatelian, Alan; Liu, David R.

In: Nature, Vol. 511, No. 7507, 2014, p. 94-98.

Research output: Contribution to journalArticle

Maianti, JP, McFedries, A, Foda, ZH, Kleiner, RE, Du, XQ, Leissring, MA, Tang, WJ, Charron, MJ, Seeliger, MA, Saghatelian, A & Liu, DR 2014, 'Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones', Nature, vol. 511, no. 7507, pp. 94-98. https://doi.org/10.1038/nature13297
Maianti JP, McFedries A, Foda ZH, Kleiner RE, Du XQ, Leissring MA et al. Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. Nature. 2014;511(7507):94-98. https://doi.org/10.1038/nature13297
Maianti, Juan Pablo ; McFedries, Amanda ; Foda, Zachariah H. ; Kleiner, Ralph E. ; Du, Xiu Quan ; Leissring, Malcolm A. ; Tang, Wei Jen ; Charron, Maureen J. ; Seeliger, Markus A. ; Saghatelian, Alan ; Liu, David R. / Anti-diabetic activity of insulin-degrading enzyme inhibitors mediated by multiple hormones. In: Nature. 2014 ; Vol. 511, No. 7507. pp. 94-98.
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