Catalytic site inhibition of insulin-degrading enzyme by a small molecule induces glucose intolerance in mice

Abstract

Insulin degrading enzyme (IDE) is a protease which cleaves insulin and other bioactive peptides such as amyloid-β. Knock-out and genetic studies have linked IDE to Alzheimer's disease and type-2 diabetes. As the major insulin degrading protease, IDE is a candidate drug target in diabetes. Here we use kinetic Target-Guided Synthesis to design the first catalytic site inhibitor of IDE suitable for in vivo studies (BDM44768). Crystallographic and SAXS analyses shows that it locks IDE in a closed conformation. Amongst a panel of metalloproteases, BDM44768 selectively inhibits IDE. Acute treatment of mice with BDM44768 increases insulin signaling and surprisingly impairs glucose tolerance in an IDE-dependent manner. These results confirm that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness of the inhibition of IDE catalytic activity to treat diabetes.

Metabolic relationship between diabetes and Alzheimer's Disease affected by Cyclo(His-Pro) plus zinc treatment

“…In diabetic subjects, IDE levels in the cytosol are reduced and consequently more and more IDE synthesis is needed for complete insulin degradation. Support for this mechanism of insulin resistance is indicated in the fact that inhibition of IDE with BDM44768 resulted in impaired glucose tolerance [85]. However, others have reported that IDE deficiency actually improved glucose tolerance [108] and based on this, some researchers are now proposing the use of IDE inhibitors as an anti-diabetes agent [86].…”

“…However, others have reported that IDE deficiency actually improved glucose tolerance [108] and based on this, some researchers are now proposing the use of IDE inhibitors as an anti-diabetes agent [86]. Deprez-Poulain et al [85] reported that IDE is involved in pathways that modulate short-term glucose homeostasis, but casts doubt on the general usefulness in the inhibition of IDE to treat diabetes. The effect of IDE levels on blood glucose control is therefore controversial.…”

Targeting Insulin-Degrading Enzyme to Treat Type 2 Diabetes Mellitus

“…Substantial in vitro and in cyto evidence supports the role of IDE in the clearance of insulin [1]. Furthermore, IDE null mutants, gene knockout, and pharmacological inhibition in rodents all result in elevated blood insulin levels (hyperinsulinemia) [5, 25, 26, 28, 29]. …”

“…With the advance in the structural analysis of IDE, at least five IDE inhibitors, including Ii1, BDM41367, 6bk, BDM44768, and NTE1, have been characterized structurally to elucidate how they bind IDE to inhibit its activity [5, 29, 67–70] (Figure 3). IDE inhibitor 1 (Ii1), the first reported high affinity IDE inhibitor (~2 nM), is a peptidomimetic hydroxamate that binds the catalytic site of IDE [67].…”

Inositol phosphates and phosphoinositides activate insulin-degrading enzyme, while phosphoinositides also mediate binding to endosomes

“…Evidence supporting a role for IDE in degrading insulin and Aβ in vivo includes associations of IDE gene variants with type 2 diabetes (1, 2) and Alzheimer's disease (3,4), decreased clearance of the two peptides in IDE-deficient mice (5,6), and antidiabetic activity produced by IDE inhibitors (7,8), although some reports have questioned its role in insulin degradation (9,10). In addition, IDE has been reported to have noncatalytic functions, such as acting as a receptor for varicella-zoster virus (11) and serving as a heat shock protein in stressed cells (12).…”