Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

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.

TrendsIDE is involved in the process of cellular protein homeostasis (proteostasis) by degrading the monomeric forms of many amyloidogenic peptides to prevent the formation of toxic aggregates and amyloid fibrils.Consistent with the role of IDE in the clearance of insulin, amylin, and glucagon, three hormones that are vital for glucose homeostasis, IDE defects lead to age-dependent glucose intolerance and are associated with T2DM.IDE represents a promising therapeutic target for the treatment of T2DM because IDE inhibitors that do not bind the IDE catalytic cleft improve glucose tolerance.Understanding the catalytic cycle of IDE provides a roadmap toward designing substrate-selective inhibitors for IDE.