The insulysin (insulin degrading enzyme) enigma

@article{Hersh2006TheI,
  title={The insulysin (insulin degrading enzyme) enigma},
  author={Louis B. Hersh},
  journal={Cellular and Molecular Life Sciences CMLS},
  year={2006},
  volume={63},
  pages={2432-2434}
}
  • L. Hersh
  • Published 4 September 2006
  • Medicine
  • Cellular and Molecular Life Sciences CMLS
Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.
TLDR
The factors that modulate insulin reformation by IDE and interaction of IDE are summarised and some recent reports on IDE inhibitors against AD and T2D are summarized.
Insulin-Degrading Enzyme: Paradoxes and Possibilities
TLDR
Although these paradoxes are by definition unresolved, the author offers herein his 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.
Hydroxypyridinethione Inhibitors of Human Insulin‐Degrading Enzyme
TLDR
In an effort to discover new, zinc‐targeting inhibitors of IDE, a library of ∼350 metal‐binding pharmacophores was screened against IDE, resulting in the identification of 1‐hydroxypyridine‐2‐thione (1,2‐HOPTO) as an effective Zn2+‐binding scaffold.
Reassessment of an Innovative Insulin Analogue Excludes Protracted Action yet Highlights Distinction between External and Internal Diselenide Bridges.
TLDR
Although [C7UA , C7UB ] does not confer protracted action, nonetheless its comparison to internal diselenide bridges promises to provide broad biophysical insight.
Multimodal Chemical Imaging of Amyloid Plaque Pathology in Alzheimer’s Disease
TLDR
Aβ plaque pathology is much more complex than what it is currently considered during ordinary post-mortem neuropathological assessments and needs to be researched with the help of advanced methods, to provide important information about how, where and why Aβ and other biomolecular factors contribute to the development of AD.
Amyloid formation and metabolism in induced pluripotent stem cell derived neural models
TLDR
This work focuses on the development of models for models of dementia and Alzheimer’s disease using iPSC-derived and iPSCs-derived models, which have shown promising results in relation to dementia and genetic risk factors.
Site directed mutagenesis of insulin-degrading enzyme allows singling out the molecular basis of peptidase versus E1-like activity: the role of metal ions.
Four specifically designed IDE mutants have been used to unveil the molecular basis of peptidase versus E1-like activity of the enzyme. We have found that physiological concentrations of copper(ii)
The core sequence of PIF competes for insulin/amyloid β in insulin degrading enzyme: potential treatment for Alzheimer's disease
TLDR
A new pregnancy derived peptide, PreImplantation Factor (PIF), inhibits neuro-inflammation and crosses the blood-brain-barrier and the predicted RIKP sequence and especially the specific I4 and P6 amino acids are essential for hydrophobic interactions with the IDE complex.
Impaired hepatic amyloid-beta degradation in Alzheimer’s disease
TLDR
The results support the possibility that impaired hepatic Aβ degradation could be a factor contributing to increased brain Aβ accumulation and AD.
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References

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Insulin-degrading enzyme.
TLDR
It is proposed that insulin-degrading enzyme (IDE), an evolutionarily conserved, neutral thiol-metalloendopeptidase, plays a crucial role in the degradation of internalized insulin in many types of cells and must have important functions and multifaceted biological significance.
Insulin degradation by insulin target cells.
Identification of insulin-degrading enzyme on the surface of cultured human lymphocytes, rat hepatoma cells, and primary cultures of rat hepatocytes.
TLDR
Antisera specific for insulin-degrading enzyme (IDE) and glutathione-insulin transhydrogenase were used as probes to identify these enzymes on the surface of cells to demonstrate increased binding of the IDE-antibodies to the IM-9 cell.
Degradation of Amyloid β-Protein by a Metalloprotease Secreted by Microglia and Other Neural and Non-neural Cells*
TLDR
It is concluded that secreted A β1-40 and Aβ1-42 peptides are constitutively degraded by a metalloprotease released by microglia and other neural cells, providing a potential mechanism for the clearance of Aβ in brain tissue.
Overexpression of insulin degrading enzyme: cellular localization and effects on insulin signaling.
  • K. Seta, R. Roth
  • Biology, Engineering
    Biochemical and biophysical research communications
  • 1997
TLDR
The hypothesis that this enzyme may function in insulin signaling by degrading the insulin molecule is supported by the results of this study.
Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo.
TLDR
In vivo findings suggest that IDE hypofunction may underlie or contribute to some forms of AD and DM2 and provide a mechanism for the recently recognized association among hyperinsulinemia, diabetes, and AD.
Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures
TLDR
Evidence suggests that IDE could be an important therapeutic target to decrease the amount of Aβ in the cerebrovasculature as much of the IDE present in HCECs was biotin‐labeled by a plasma membrane impermeable reagent.
In vivo association of [125I]-insulin with a cytosolic insulin-degrading enzyme: detection by covalent cross-linking and immunoprecipitation with a monoclonal antibody.
TLDR
A role for this protease in the cellular processing of insulin is supported using a cytosolic insulin-degrading enzyme found to be cross-linked to [125I]-insulin in intact human hepatoma cells, HepG2, incubated with the hormone and treated with the bifunctional cross-linker, disuccinimidyl suberate.
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