ArticleThe Journal of biological chemistry2015
Dual Exosite-binding Inhibitors of Insulin-degrading Enzyme Challenge Its Role as the Primary Mediator of Insulin Clearance in Vivo.
Article in The Journal of biological chemistry, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 51 citations in OpenAlex.
- It Takes Two to Tango: Current Understanding of the Role of M16 Family of Proteases and Their Structural Properties.Biomolecules · 2025Review
- On electrostatic interactions of adenosine triphosphate-insulin-degrading enzyme revealed by quantum mechanics/molecular mechanics and molecular dynamics.Quantitative biology (Beijing, China) · 2024Article
- The Insulin-Degrading Enzyme from Structure to Allosteric Modulation: New Perspectives for Drug Design.Biomolecules · 2023Review
- Regulation of Insulin Clearance by Non-Esterified Fatty Acids.Biomedicines · 2022Review
- Inhibition of Insulin Degrading Enzyme to Control Diabetes Mellitus and its Applications on some Other Chronic Disease: a Critical Review.Pharmaceutical research · 2022Review
- Exploring the Structural Rearrangements of the Human Insulin-Degrading Enzyme through Molecular Dynamics Simulations.International journal of molecular sciences · 2022Article
- Article
- Hydroxypyridinethione Inhibitors of Human Insulin-Degrading Enzyme.ChemMedChem · 2021Article
- Targeting Insulin-Degrading Enzyme in Insulin Clearance.International journal of molecular sciences · 2021Review
- Modulation of Insulin Sensitivity by Insulin-Degrading Enzyme.Biomedicines · 2021Review
- Article
- Target Enzymes Considered for the Treatment of Alzheimer's Disease and Parkinson's Disease.BioMed research international · 2020Review
- Pancreatic β-cell-specific deletion of insulin-degrading enzyme leads to dysregulated insulin secretion and β-cell functional immaturity.American journal of physiology. Endocrinology and metabolism · 2019Article
- Identification of ebselen as a potent inhibitor of insulin degrading enzyme by a drug repurposing screening.European journal of medicinal chemistry · 2019Article
- Enzyme kinetics from circular dichroism of insulin reveals mechanistic insights into the regulation of insulin-degrading enzyme.Bioscience reports · 2018Article
- The Longest Amyloid-β Precursor Protein Intracellular Domain Produced with Aβ42 Forms β-Sheet-Containing Monomers That Self-Assemble and Are Proteolyzed by Insulin-Degrading Enzyme.ACS chemical neuroscience · 2018Article
- Liver-specific ablation of insulin-degrading enzyme causes hepatic insulin resistance and glucose intolerance, without affecting insulin clearance in mice.Metabolism: clinical and experimental · 2018Article
- Article
- The insulin-degrading enzyme is an allosteric modulator of the 20S proteasome and a potential competitor of the 19S.Cellular and molecular life sciences : CMLS · 2018Article
- Article
Corrections and comments
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Authors and funding
21 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE(-/-) mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using a structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Because one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50 times its IDE IC50 value, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese mice, NTE-1 treatment improved the glucose excursion. Yet in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not enhance insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Furthermore, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin metabolism in vivo and suggests IDE may be more important in helping regulate amylin clearance.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.