More than seven decades have passed since the discovery of a proteolytic activity within crude tissue extracts that would become known as insulin-degrading enzyme (IDE). Certainly much has been learned about this atypical zinc-metallopeptidase; at the same time, however, many quite fundamental gaps in our understanding remain. Herein, I outline what I consider to be among the most critical unresolved questions within the field, many presenting as intriguing paradoxes. For instance, where does IDE, a predominantly cytosolic protein with no signal peptide or clearly identified secretion mechanism, interact with insulin and other extracellular substrates? Where precisely is IDE localized within the cell, and what are its functional roles in these compartments? How does IDE, a bowl-shaped protein that completely encapsulates its substrates, manage to avoid getting “clogged” and thus rendered inactive virtually immediately? Although these paradoxes are by definition unresolved, I offer herein my personal insights and informed speculations based on two decades working on the biology and pharmacology of IDE and suggest specific experimental strategies for addressing these conundrums. I also offer what I believe to be especially fruitful avenues for investigation made possible by the development of new technologies and IDE-specific reagents. It is my hope that these thoughts will contribute to continued progress elucidating the physiology and pathophysiology of this important peptidase.
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