Targeting Insulin-Degrading Enzyme in Insulin Clearance

Abstract

Hepatic insulin clearance, a physiological process that in response to nutritional cues clears ~50-80% of circulating insulin, is emerging as an important factor in our understanding of the pathogenesis of type 2 diabetes mellitus (T2DM). Insulin-degrading enzyme (IDE) is a highly conserved Zn²⁺-metalloprotease that degrades insulin and several other intermediate-size peptides. Both, insulin clearance and IDE activity are reduced in diabetic patients, albeit the cause-effect relationship in humans remains unproven. Because historically IDE has been proposed as the main enzyme involved in insulin degradation, efforts in the development of IDE inhibitors as therapeutics in diabetic patients has attracted attention during the last decades. In this review, we retrace the path from Mirsky's seminal discovery of IDE to the present, highlighting the pros and cons of the development of IDE inhibitors as a pharmacological approach to treating diabetic patients.

Keywords: insulin clearance; insulin resistance; insulin-degrading enzyme; liver; pharmacological inhibitors.

Figure 1

Structures of and common names for insulin-degrading enzyme (IDE) inhibitors.

Figure 2

Structure of human IDE and regions targeted by different inhibitors. (A,B), Illustration of a single monomer of IDE (center) and IDE-N (left, cyan) and IDE-C (right, green) depicted in ribbon (A) and surface (B) representations. Zinc-binding and catalytic residues within the active site of IDE-N are depicted in orange, with the zinc atom shown as a gray sphere. Residues within IDE-C that make up the second portion of IDE’s bipartite active site are shown in red. Cysteine residues targeted by thiol-modifying inhibitors are shown in yellow. The distal exosite is shown in magenta. In (B), note that the portions of IDE-N and IDE-C that are adjacent when the protease is in the closed conformation are depicted in black. Figures generated in Pymol [169] from PDB 2G54 [20].