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Gene Review

IDE  -  insulin-degrading enzyme

Homo sapiens

Synonyms: Abeta-degrading protease, Insulin protease, Insulin-degrading enzyme, Insulinase, Insulysin
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Disease relevance of IDE

  • Together with emerging genetic evidence, our 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 [1].
  • Moreover they raise the possibility that IDE inhibition or inactivation is a pathogenic mechanism that may open novel strategies for the treatment of cerebrovascular Abeta amyloidoses [2].
  • Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy [2].
  • Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease [3].
  • Since IGF-II is the major autocrine/paracrine growth factor for neuroblastoma cells, we studied the expression and the role of IDE in this system [4].

Psychiatry related information on IDE


High impact information on IDE

  • Transfection of cell lines impaired for VZV infection with a plasmid expressing human IDE resulted in increased entry and enhanced infection with cell-free and cell-associated virus [7].
  • Downregulation of IDE by siRNA, or blocking of IDE with antibody, with soluble IDE protein extracted from liver, or with bacitracin inhibited VZV infection [7].
  • IDE increases proteasome and steroid hormone receptor activity, and this activation is reversed by insulin [8].
  • Most evidence supports IDE as the primary degradative mechanism, but other systems (PDI, lysosomes, and other enzymes) undoubtedly contribute to insulin metabolism [8].
  • Recent studies suggest that insulin-degrading enzyme (IDE) in neurons and microglia degrades Abeta, the principal component of beta-amyloid and one of the neuropathological hallmarks of Alzheimer's disease (AD) [9].

Chemical compound and disease context of IDE

  • A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2 [1].
  • Furthermore, cysteine is adjacent to the glutamate residue (HXCEH) in human, rat, and Drosophila IDE, although it is not conserved in their close homologue, Escherichia coli protease III [10].
  • These data show that nelfinavir inhibits IDE, decreases insulin's ability to inhibit protein degradation via the proteasome and provides another possible mechanism for the insulin resistance seen in protease inhibitor-treated HIV patients [11].
  • Functions and expression of insulysin, an enzyme involved in the degradation of neurotoxic amyloid peptides and insulin, are usually impaired or reduced in Alzheimer's disease and diabetes [12].

Biological context of IDE

  • RAF activity co-purified with a 110-kDa protein, the partial amino acid sequence of which shares 97.5% identity with insulin degrading enzyme (IDE), a metalloendoprotease implicated in the intracellular degradation of insulin [13].
  • Further investigation of the relationship between APOE genotype, IDE genetic variants, and the expression and activity of hippocampal IDE is warranted [5].
  • We here report IDE gene promoter region variants that are associated with AD in subjects without an epsilon4 allele [5].
  • Others have independently identified haplotypes in the chromosome 10q region harboring IDE that show highly significant association with intermediate AD phenotypes and with risk for AD [14].
  • IDE is located on chromosome 10q23.3 close to a region of linkage for LOAD [15].

Anatomical context of IDE

  • IDE was present in BV-2 cytosol, as expected, but was also released into the medium by intact, healthy cells [16].
  • To confirm the extracellular occurrence of IDE in vivo, we identified intact IDE in human cerebrospinal fluid of both normal and Alzheimer subjects [16].
  • Our results show that cultured human cerebrovascular endothelial cells (HCECs), a primary component of the blood-brain barrier, express IDE and may respond to exposure to low levels of Abeta by upregulating its expression [17].
  • Further, our evidence suggests that degradation by IDE occurs on the plasma membrane, as much of the IDE present in HCECs was biotin-labeled by a plasma membrane impermeable reagent [17].
  • A peroxisomal location for insulin-degrading enzyme (IDE) has been defined by confocal immunofluorescence microscopy of stably transfected CHO cells overexpressing IDE and digitonin-permeabilization studies in normal nontransfected fibroblasts [18].

Associations of IDE with chemical compounds

  • The interactions of AR and GR with IDE may have important implications for both insulin- and steroid-mediated signaling [13].
  • We sought to characterize the haplotype structure of IDE in detail and replicate the association of common variants with type 2 diabetes, fasting insulin, fasting glucose, and insulin resistance [19].
  • Moreover, intracellular A beta in the detergent-insoluble fraction extracted with 70% formic acid or 6 M guanidine hydrochloride decreased markedly in the cells overexpressing IDE [20].
  • To identify a downstream zinc ligand, we substituted a glutamine for glutamate at either Glu182 or Glu189, both of which are conserved in human, rat, and Drosophila IDE [21].
  • The role of the cysteine in IDE catalysis and inhibitor sensitivity was examined by mutating Cys110 to glycine or serine [10].
  • We have shown that the catalytic activity of cytosolic IDE to degrade insulin is reduced in affected versus unaffected subjects of these families [22].

Physical interactions of IDE

  • CONCLUSIONS: We propose that prolonged HAART and aging may contribute to an overall increase in amyloid deposition, potentially mediated by inhibition of insulin degradation enzyme (IDE) or disruption of the axonal transport of the amyloid precursor protein [23].

Regulatory relationships of IDE


Other interactions of IDE

  • Insulin-degrading enzyme (IDE) has been implicated as a candidate enzyme responsible for the degradation and clearance of Abeta in the brain [28].
  • The possible association of IDE with AD, as well as the link between APOE status and insulin metabolism, led us to examine the expression of IDE in AD [28].
  • In addition, many studies have identified a possible role of IDE in the degradation of amyloid beta-protein and the intracellular amyloid precursor protein (APP) domain released by gamma-secretase processing [15].
  • Insulin-degrading enzyme and Alzheimer disease: a genetic association study in the Han Chinese [15].
  • The allele-specific decrease of IDE in epsilon4+ AD patients is not associated with neuronal loss since neuron-specific enolase levels were comparable between the AD groups, regardless of APOE status [28].

Analytical, diagnostic and therapeutic context of IDE

  • In microvessels from Alzheimer's disease cases with CAA, IDE protein levels showed a 44% increase as determined by sandwich enzyme-linked immunosorbent assay and Western blot [2].
  • Subcellular fractionation, immunofluorescent confocal microscopy, and immunogold-electron microscopy reveal that the 15b-IDE protein occurs in both cytosol and mitochondria [29].
  • Direct proteolysis of the leader peptide of prethiolase was confirmed by HPLC; degradation was inhibited by immunodepletion with an antibody to IDE [18].
  • Western-blot analysis with monoclonal antibodies indicated the presence of both IDE and PDI in the cytosolic fraction of human and monkey liver [30].
  • Surprisingly, IDE-mediated proteolysis of [(125)I]Abeta(1-40) in microglial cell-culture media was accompanied by the formation of (125)I-labelled peptides with higher apparent molecular masses, raising the possibility that the degradation products act as 'seeds' for Abeta oligomerization [31].


  1. Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo. Farris, W., Mansourian, S., Chang, Y., Lindsley, L., Eckman, E.A., Frosch, M.P., Eckman, C.B., Tanzi, R.E., Selkoe, D.J., Guenette, S. Proc. Natl. Acad. Sci. U.S.A. (2003) [Pubmed]
  2. Insulin-degrading enzyme in brain microvessels: proteolysis of amyloid {beta} vasculotropic variants and reduced activity in cerebral amyloid angiopathy. Morelli, L., Llovera, R.E., Mathov, I., Lue, L.F., Frangione, B., Ghiso, J., Castaño, E.M. J. Biol. Chem. (2004) [Pubmed]
  3. Sequence variation in the proximity of IDE may impact age at onset of both Parkinson disease and Alzheimer disease. Blomqvist, M.E., Silburn, P.A., Buchanan, D.D., Andreasen, N., Blennow, K., Pedersen, N.L., Brookes, A.J., Mellick, G.D., Prince, J.A. Neurogenetics (2004) [Pubmed]
  4. Regulation by retinoic acid of insulin-degrading enzyme and of a related endoprotease in human neuroblastoma cell lines. Melino, G., Draoui, M., Bernardini, S., Bellincampi, L., Reichert, U., Cohen, P. Cell Growth Differ. (1996) [Pubmed]
  5. Insulin-degrading enzyme, apolipoprotein E, and Alzheimer's disease. Edland, S.D. J. Mol. Neurosci. (2004) [Pubmed]
  6. Insulin-degrading enzyme haplotypes affect insulin levels but not dementia risk. Marlowe, L., Peila, R., Benke, K.S., Hardy, J., White, L.R., Launer, L.J., Myers, A. Neuro-degenerative diseases (2006) [Pubmed]
  7. Insulin Degrading Enzyme Is a Cellular Receptor Mediating Varicella-Zoster Virus Infection and Cell-to-Cell Spread. Li, Q., Ali, M.A., Cohen, J.I. Cell (2006) [Pubmed]
  8. Insulin degradation: progress and potential. Duckworth, W.C., Bennett, R.G., Hamel, F.G. Endocr. Rev. (1998) [Pubmed]
  9. Evidence for genetic linkage of Alzheimer's disease to chromosome 10q. Bertram, L., Blacker, D., Mullin, K., Keeney, D., Jones, J., Basu, S., Yhu, S., McInnis, M.G., Go, R.C., Vekrellis, K., Selkoe, D.J., Saunders, A.J., Tanzi, R.E. Science (2000) [Pubmed]
  10. Functional analysis of conserved residues in the active site of insulin-degrading enzyme. Perlman, R.K., Gehm, B.D., Kuo, W.L., Rosner, M.R. J. Biol. Chem. (1993) [Pubmed]
  11. Effect of nelfinavir on insulin metabolism, proteasome activity and protein degradation in HepG2 cells. Hamel, F.G., Fawcett, J., Tsui, B.T., Bennett, R.G., Duckworth, W.C. Diabetes, obesity & metabolism. (2006) [Pubmed]
  12. Links between Alzheimer's disease and diabetes. Sun, M.K., Alkon, D.L. Timely topics in medicine. Cardiovascular diseases [electronic resource]. (2006) [Pubmed]
  13. Androgen and glucocorticoid receptors interact with insulin degrading enzyme. Kupfer, S.R., Wilson, E.M., French, F.S. J. Biol. Chem. (1994) [Pubmed]
  14. Genetic variants in a haplotype block spanning IDE are significantly associated with plasma Abeta42 levels and risk for Alzheimer disease. Ertekin-Taner, N., Allen, M., Fadale, D., Scanlin, L., Younkin, L., Petersen, R.C., Graff-Radford, N., Younkin, S.G. Hum. Mutat. (2004) [Pubmed]
  15. Insulin-degrading enzyme and Alzheimer disease: a genetic association study in the Han Chinese. Bian, L., Yang, J.D., Guo, T.W., Sun, Y., Duan, S.W., Chen, W.Y., Pan, Y.X., Feng, G.Y., He, L. Neurology (2004) [Pubmed]
  16. Insulin-degrading enzyme regulates extracellular levels of amyloid beta-protein by degradation. Qiu, W.Q., Walsh, D.M., Ye, Z., Vekrellis, K., Zhang, J., Podlisny, M.B., Rosner, M.R., Safavi, A., Hersh, L.B., Selkoe, D.J. J. Biol. Chem. (1998) [Pubmed]
  17. Insulin degrading enzyme is localized predominantly at the cell surface of polarized and unpolarized human cerebrovascular endothelial cell cultures. Lynch, J.A., George, A.M., Eisenhauer, P.B., Conn, K., Gao, W., Carreras, I., Wells, J.M., McKee, A., Ullman, M.D., Fine, R.E. J. Neurosci. Res. (2006) [Pubmed]
  18. Degradation of the cleaved leader peptide of thiolase by a peroxisomal proteinase. Authier, F., Bergeron, J.J., Ou, W.J., Rachubinski, R.A., Posner, B.I., Walton, P.A. Proc. Natl. Acad. Sci. U.S.A. (1995) [Pubmed]
  19. High-density haplotype structure and association testing of the insulin-degrading enzyme (IDE) gene with type 2 diabetes in 4,206 people. Florez, J.C., Wiltshire, S., Agapakis, C.M., Burtt, N.P., de Bakker, P.I., Almgren, P., Bengtsson Boström, K., Tuomi, T., Gaudet, D., Daly, M.J., Hirschhorn, J.N., McCarthy, M.I., Altshuler, D., Groop, L. Diabetes (2006) [Pubmed]
  20. Differential effects of proteases involved in intracellular degradation of amyloid beta-protein between detergent-soluble and -insoluble pools in CHO-695 cells. Sudoh, S., Frosch, M.P., Wolf, B.A. Biochemistry (2002) [Pubmed]
  21. Identification of zinc ligands of the insulin-degrading enzyme. Perlman, R.K., Rosner, M.R. J. Biol. Chem. (1994) [Pubmed]
  22. Decreased catalytic activity of the insulin-degrading enzyme in chromosome 10-linked Alzheimer disease families. Kim, M., Hersh, L.B., Leissring, M.A., Ingelsson, M., Matsui, T., Farris, W., Lu, A., Hyman, B.T., Selkoe, D.J., Bertram, L., Tanzi, R.E. J. Biol. Chem. (2007) [Pubmed]
  23. Brain deposition of beta-amyloid is a common pathologic feature in HIV positive patients. Green, D.A., Masliah, E., Vinters, H.V., Beizai, P., Moore, D.J., Achim, C.L. AIDS (2005) [Pubmed]
  24. Differential degradation of amyloid beta genetic variants associated with hereditary dementia or stroke by insulin-degrading enzyme. Morelli, L., Llovera, R., Gonzalez, S.A., Affranchino, J.L., Prelli, F., Frangione, B., Ghiso, J., Castano, E.M. J. Biol. Chem. (2003) [Pubmed]
  25. Genetic variation in a haplotype block spanning IDE influences Alzheimer disease. Prince, J.A., Feuk, L., Gu, H.F., Johansson, B., Gatz, M., Blennow, K., Brookes, A.J. Hum. Mutat. (2003) [Pubmed]
  26. Insulin-degrading enzyme: stable expression of the human complementary DNA, characterization of its protein product, and chromosomal mapping of the human and mouse genes. Affholter, J.A., Hsieh, C.L., Francke, U., Roth, R.A. Mol. Endocrinol. (1990) [Pubmed]
  27. Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism. Shen, Y., Joachimiak, A., Rosner, M.R., Tang, W.J. Nature (2006) [Pubmed]
  28. Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele. Cook, D.G., Leverenz, J.B., McMillan, P.J., Kulstad, J.J., Ericksen, S., Roth, R.A., Schellenberg, G.D., Jin, L.W., Kovacina, K.S., Craft, S. Am. J. Pathol. (2003) [Pubmed]
  29. Alternative splicing of human insulin-degrading enzyme yields a novel isoform with a decreased ability to degrade insulin and amyloid beta-protein. Farris, W., Leissring, M.A., Hemming, M.L., Chang, A.Y., Selkoe, D.J. Biochemistry (2005) [Pubmed]
  30. Mechanisms involved in degradation of human insulin by cytosolic fractions of human, monkey, and rat liver. Wroblewski, V.J., Masnyk, M., Khambatta, S.S., Becker, G.W. Diabetes (1992) [Pubmed]
  31. Purified recombinant insulin-degrading enzyme degrades amyloid beta-protein but does not promote its oligomerization. Chesneau, V., Vekrellis, K., Rosner, M.R., Selkoe, D.J. Biochem. J. (2000) [Pubmed]
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