IDE Gene

Name	insulin-degrading enzyme
Description	This gene encodes a zinc metallopeptidase that degrades intracellular insulin, and thereby terminates insulins activity, as well as participating in intercellular peptide signalling by degrading diverse peptides such as glucagon, amylin, bradykinin, and kallidin. The preferential affinity of this enzyme for insulin results in insulin-mediated inhibition of the degradation of other peptides such as beta-amyloid. Deficiencies in this protein's function are associated with Alzheimer's disease and type 2 diabetes mellitus but mutations in this gene have not been shown to be causitive for these diseases. This protein localizes primarily to the cytoplasm but in some cell types localizes to the extracellular space, cell membrane, peroxisome, and mitochondrion. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants have been described but have not been experimentally verified.[provided by RefSeq, Sep 2009]
Summary	{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Insulin‐degrading enzyme (IDE) is a multifunctional zinc metallopeptidase that plays a central role in maintaining peptide homeostasis by degrading key substrates such as amyloid‐β (Aβ) monomers and insulin, thereby functionally linking Alzheimer’s disease (AD) and type 2 diabetes mellitus (T2DM)."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " IDE efficiently clears soluble Aβ, yet its proteolytic activity is selective: it degrades monomeric Aβ while sparing oligomers and fibrils, a specificity that may underlie synaptic dysfunction when monomer clearance is insufficient (see also"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "and."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In fact, impaired IDE function or reduced expression—as observed in certain genetic contexts such as APOE ε4 carriers—correlates with increased Aβ accumulation and accentuated risk for AD."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}, {"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Structural analyses have revealed that IDE’s activity depends on a unique enclosed catalytic chamber formed by two domains whose repositioning enables selective substrate entry; this architectural arrangement allows IDE to accommodate a variety of peptides including insulin, Aβ, amylin, and glucagon."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Moreover, IDE expression is modulated by insulin receptor signaling—insulin treatment enhances IDE levels via a phosphatidylinositol-3 kinase–dependent pathway—suggesting a feedback mechanism that regulates both insulin and Aβ turnover."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Consistent with its in vivo importance, mouse models with reduced IDE activity show elevated brain Aβ levels, reinforcing its role in Aβ clearance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Adding a new dimension to IDE biology, a mitochondrial isoform generated from an upstream translation initiation site has been identified; this variant is imported into mitochondria where it participates in degrading cleaved mitochondrial targeting sequences, hinting at additional intracellular functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Furthermore, in studies of Aβ toxicity, selective removal of monomeric Aβ using IDE was shown to reverse protofibril-induced neurotoxicity, emphasizing that IDE’s actions are critical for mitigating toxic peptide aggregation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": " Finally, in comparative analyses of Aβ-degrading enzymes in AD brain, IDE mRNA expression may be upregulated as a compensatory response even when its overall activity does not change, and reduced IDE expression has also been linked to altered clearance of other bioactive peptides such as chemokines."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Dominic M Walsh, Igor Klyubin, Julia V Fadeeva, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Naturally secreted oligomers of amyloid beta protein potently inhibit hippocampal long-term potentiation in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2002)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/416535a"}], "href": "https://doi.org/10.1038/416535a"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "11932745"}], "href": "https://pubmed.ncbi.nlm.nih.gov/11932745"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Wesley Farris, Stefan Mansourian, Yang Chang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin-degrading enzyme regulates the levels of insulin, amyloid beta-protein, and the beta-amyloid precursor protein intracellular domain in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.0230450100"}], "href": "https://doi.org/10.1073/pnas.0230450100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12634421"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12634421"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Yan Ling, Kevin Morgan, Noor Kalsheker "}, {"type": "b", "children": [{"type": "t", "text": "Amyloid precursor protein (APP) and the biology of proteolytic processing: relevance to Alzheimer's disease."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Int J Biochem Cell Biol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s1357-2725(03)00133-x"}], "href": "https://doi.org/10.1016/s1357-2725(03"}, {"type": "t", "text": "00133-x) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12824062"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12824062"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Bonnie C Miller, Elizabeth A Eckman, Kumar Sambamurti, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Proc Natl Acad Sci U S A (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1073/pnas.1031520100"}], "href": "https://doi.org/10.1073/pnas.1031520100"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12732730"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12732730"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "David G Cook, James B Leverenz, Pamela J McMillan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Reduced hippocampal insulin-degrading enzyme in late-onset Alzheimer's disease is associated with the apolipoprotein E-epsilon4 allele."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Am J Pathol (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/s0002-9440(10)63822-9"}], "href": "https://doi.org/10.1016/s0002-9440(10"}, {"type": "t", "text": "63822-9) PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12507914"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12507914"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yuequan Shen, Andrzej Joachimiak, Marsha Rich Rosner, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Structures of human insulin-degrading enzyme reveal a new substrate recognition mechanism."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/nature05143"}], "href": "https://doi.org/10.1038/nature05143"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17051221"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17051221"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "Lixia Zhao, Bruce Teter, Takashi Morihara, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Insulin-degrading enzyme as a downstream target of insulin receptor signaling cascade: implications for Alzheimer's disease intervention."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurosci (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1523/JNEUROSCI.2860-04.2004"}], "href": "https://doi.org/10.1523/JNEUROSCI.2860-04.2004"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15590928"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15590928"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Malcolm A Leissring, Wesley Farris, Xining Wu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Alternative translation initiation generates a novel isoform of insulin-degrading enzyme targeted to mitochondria."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2004)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20041081"}], "href": "https://doi.org/10.1042/BJ20041081"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15285718"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15285718"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Asad Jan, Oskar Adolfsson, Igor Allaman, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Abeta42 neurotoxicity is mediated by ongoing nucleated polymerization process rather than by discrete Abeta42 species."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2011)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M110.172411"}], "href": "https://doi.org/10.1074/jbc.M110.172411"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "21156804"}], "href": "https://pubmed.ncbi.nlm.nih.gov/21156804"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Suqing Wang, Rui Wang, Lang Chen, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Expression and functional profiling of neprilysin, insulin-degrading enzyme, and endothelin-converting enzyme in prospectively studied elderly and Alzheimer's brain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Neurochem (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1111/j.1471-4159.2010.06899.x"}], "href": "https://doi.org/10.1111/j.1471-4159.2010.06899.x"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20663017"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20663017"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Min Ren, Qing Guo, Liang Guo, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Polymerization of MIP-1 chemokine (CCL3 and CCL4) and clearance of MIP-1 by insulin-degrading enzyme."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO J (2010)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/emboj.2010.256"}], "href": "https://doi.org/10.1038/emboj.2010.256"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "20959807"}], "href": "https://pubmed.ncbi.nlm.nih.gov/20959807"}]}]}]}
Synonyms	INSULYSIN
Proteins	IDE_HUMAN
NCBI Gene ID	3416
API
Download Associations
Predicted Functions
Co-expressed Genes
Expression in Tissues and Cell Lines

Functional Associations

IDE has 8,943 functional associations with biological entities spanning 8 categories (molecular profile, organism, chemical, functional term, phrase or reference, disease, phenotype or trait, structural feature, cell line, cell type or tissue, gene, protein or microRNA) extracted from 125 datasets.

Click the + buttons to view associations for IDE from the datasets below.

If available, associations are ranked by standardized value

Harmonizome 3.0

IDE Gene

Functional Associations

Please acknowledge the Harmonizome in your publications by citing the following reference(s):

	Dataset	Summary
	Achilles Cell Line Gene Essentiality Profiles	cell lines with fitness changed by IDE gene knockdown relative to other cell lines from the Achilles Cell Line Gene Essentiality Profiles dataset.
	Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of IDE gene relative to other tissues from the Allen Brain Atlas Adult Human Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles	tissues with high or low expression of IDE gene relative to other tissues from the Allen Brain Atlas Adult Mouse Brain Tissue Gene Expression Profiles dataset.
	Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles	tissue samples with high or low expression of IDE gene relative to other tissue samples from the Allen Brain Atlas Aging Dementia and Traumatic Brain Injury Tissue Sample Gene Expression Profiles dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray	tissue samples with high or low expression of IDE gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by Microarray dataset.
	Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq	tissue samples with high or low expression of IDE gene relative to other tissue samples from the Allen Brain Atlas Developing Human Brain Tissue Gene Expression Profiles by RNA-seq dataset.
	Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles	tissues with high or low expression of IDE gene relative to other tissues from the Allen Brain Atlas Prenatal Human Brain Tissue Gene Expression Profiles dataset.
	BioGPS Cell Line Gene Expression Profiles	cell lines with high or low expression of IDE gene relative to other cell lines from the BioGPS Cell Line Gene Expression Profiles dataset.
	BioGPS Human Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of IDE gene relative to other cell types and tissues from the BioGPS Human Cell Type and Tissue Gene Expression Profiles dataset.
	BioGPS Mouse Cell Type and Tissue Gene Expression Profiles	cell types and tissues with high or low expression of IDE gene relative to other cell types and tissues from the BioGPS Mouse Cell Type and Tissue Gene Expression Profiles dataset.
	Carcinogenome Chemical Perturbation Carcinogenicity Signatures	small molecule perturbations changing expression of IDE gene from the Carcinogenome Chemical Perturbation Carcinogenicity Signatures dataset.
	CCLE Cell Line Gene CNV Profiles	cell lines with high or low copy number of IDE gene relative to other cell lines from the CCLE Cell Line Gene CNV Profiles dataset.
	CCLE Cell Line Gene Expression Profiles	cell lines with high or low expression of IDE gene relative to other cell lines from the CCLE Cell Line Gene Expression Profiles dataset.
	CCLE Cell Line Proteomics	Cell lines associated with IDE protein from the CCLE Cell Line Proteomics dataset.
	ChEA Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of IDE gene from the CHEA Transcription Factor Binding Site Profiles dataset.
	ChEA Transcription Factor Targets	transcription factors binding the promoter of IDE gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets dataset.
	ChEA Transcription Factor Targets 2022	transcription factors binding the promoter of IDE gene in low- or high-throughput transcription factor functional studies from the CHEA Transcription Factor Targets 2022 dataset.
	CMAP Signatures of Differentially Expressed Genes for Small Molecules	small molecule perturbations changing expression of IDE gene from the CMAP Signatures of Differentially Expressed Genes for Small Molecules dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores	cellular components containing IDE protein from the COMPARTMENTS Curated Protein Localization Evidence Scores dataset.
	COMPARTMENTS Curated Protein Localization Evidence Scores 2025	cellular components containing IDE protein from the COMPARTMENTS Curated Protein Localization Evidence Scores 2025 dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores	cellular components co-occuring with IDE protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores dataset.
	COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025	cellular components co-occuring with IDE protein in abstracts of biomedical publications from the COMPARTMENTS Text-mining Protein Localization Evidence Scores 2025 dataset.
	COSMIC Cell Line Gene CNV Profiles	cell lines with high or low copy number of IDE gene relative to other cell lines from the COSMIC Cell Line Gene CNV Profiles dataset.
	COSMIC Cell Line Gene Mutation Profiles	cell lines with IDE gene mutations from the COSMIC Cell Line Gene Mutation Profiles dataset.
	CTD Gene-Chemical Interactions	chemicals interacting with IDE gene/protein from the curated CTD Gene-Chemical Interactions dataset.
	CTD Gene-Disease Associations	diseases associated with IDE gene/protein from the curated CTD Gene-Disease Associations dataset.
	DepMap CRISPR Gene Dependency	cell lines with fitness changed by IDE gene knockdown relative to other cell lines from the DepMap CRISPR Gene Dependency dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores	diseases associated with IDE gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Experimental Gene-Disease Association Evidence Scores 2025	diseases associated with IDE gene in GWAS datasets from the DISEASES Experimental Gene-Disease Assocation Evidence Scores 2025 dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores	diseases co-occuring with IDE gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores dataset.
	DISEASES Text-mining Gene-Disease Association Evidence Scores 2025	diseases co-occuring with IDE gene in abstracts of biomedical publications from the DISEASES Text-mining Gene-Disease Assocation Evidence Scores 2025 dataset.
	DisGeNET Gene-Disease Associations	diseases associated with IDE gene in GWAS and other genetic association datasets from the DisGeNET Gene-Disease Associations dataset.
	DisGeNET Gene-Phenotype Associations	phenotypes associated with IDE gene in GWAS and other genetic association datasets from the DisGeNET Gene-Phenoptype Associations dataset.
	DrugBank Drug Targets	interacting drugs for IDE protein from the curated DrugBank Drug Targets dataset.
	ENCODE Histone Modification Site Profiles	histone modification site profiles with high histone modification abundance at IDE gene from the ENCODE Histone Modification Site Profiles dataset.
	ENCODE Transcription Factor Binding Site Profiles	transcription factor binding site profiles with transcription factor binding evidence at the promoter of IDE gene from the ENCODE Transcription Factor Binding Site Profiles dataset.
	ENCODE Transcription Factor Targets	transcription factors binding the promoter of IDE gene in ChIP-seq datasets from the ENCODE Transcription Factor Targets dataset.
	ESCAPE Omics Signatures of Genes and Proteins for Stem Cells	PubMedIDs of publications reporting gene signatures containing IDE from the ESCAPE Omics Signatures of Genes and Proteins for Stem Cells dataset.
	GAD Gene-Disease Associations	diseases associated with IDE gene in GWAS and other genetic association datasets from the GAD Gene-Disease Associations dataset.
	GAD High Level Gene-Disease Associations	diseases associated with IDE gene in GWAS and other genetic association datasets from the GAD High Level Gene-Disease Associations dataset.