title: Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus.
abstract: Insulin-degrading enzyme (IDE) selectively degrades peptides, such as insulin, amylin, and amyloid β (Aβ) that form toxic aggregates, to maintain proteostasis. IDE defects are linked to the development of type 2 diabetes mellitus (T2DM) and Alzheimer's disease (AD). Structural and biochemical analyses revealed the molecular basis for IDE-mediated destruction of amyloidogenic peptides and this information has been exploited to develop promising inhibitors of IDE to improve glucose homeostasis. However, the inhibition of IDE can also lead to glucose intolerance. In this review, I focus on recent advances regarding our understanding of the structure and function of IDE and the discovery of IDE inhibitors, as well as challenges in developing IDE-based therapy for human diseases, particularly T2DM.
authors.affiliation: Ben-May Department for Cancer Research, the University of Chicago, Chicago, IL, USA. Electronic address: wtang@uchicago.edu.
authors.forename: Wei-Jen
authors.initials: WJ
authors.lastname: Tang
mesh_terms: D000544:Alzheimer Disease / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000201:enzymology* / Q000235:genetics / Q000378:metabolism*; D018149:Glucose Intolerance; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007339:Insulysin / Q000378:metabolism; D058228:Islet Amyloid Polypeptide / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; D007328:Insulin; D058228:Islet Amyloid Polypeptide; D007339:Insulysin
keywords: Alzheimer's disease; insulin degrading enzyme; small molecule inhibitors; type 2 diabetes mellitus