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Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo
Wesley Farris, Stefan Mansourian, Yang Chang, Loren D. Lindsley, Elizabeth A. Eckman, Matthew P. Frosch, Christopher B. Eckman, Rudolph E. Tanzi, Dennis J. Selkoe, Suzanne Y. Guénette. Proceedings of the National Academy of Sciences, 2003-03-12
Topic: Brain proteins, microglia and lab models
Two substrates of insulin-degrading enzyme (IDE), amyloid beta-protein (Abeta) and insulin, are critically important in the pathogenesis of Alzheimer's disease (AD) and type 2 diabetes mellitus (DM2), respectively. We previously identified IDE as a principal regulator of Abeta levels in neuronal and microglial cells. A small chromosomal region containing a mutant IDE allele has been associated with hyperinsulinemia and glucose intolerance in a rat model of DM2. Human genetic studies have implicated the IDE region of chromosome 10 in both AD and DM2. To establish whether IDE hypofunction decreases Abeta and insulin degradation in vivo and chronically increases their levels, we characterized mice with homozygous deletions of the IDE gene (IDE --). IDE deficiency resulted in a >50% decrease in Abeta degradation in both brain membrane fractions and primary neuronal cultures and a similar deficit in insulin degradation in liver. The IDE -- mice showed increased cerebral accumulation of endogenous Abeta, a hallmark of AD, and had hyperinsulinemia and glucose intolerance, hallmarks of DM2. Moreover, the mice had elevated levels of the intracellular signaling domain of the beta-amyloid precursor protein, which was recently found to be degraded by IDE in vitro. 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.
Why it matters
Mice lacking the insulin-degrading enzyme (IDE) gene broke down less amyloid-beta and insulin, built up more amyloid-beta in the brain, and had high insulin levels and glucose intolerance. The authors suggest reduced IDE function may underlie or contribute to some forms of Alzheimer's disease and type 2 diabetes.
How this study scored 56/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported, studied in people and randomised / blinded because the record does not state it. We have no data on strength of evidence, so that was left out: it earned 53 of the 95 points we could judge it on, which is 56 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Proceedings of the National Academy of Sciences) |
| Journal's citation record | 4 / 4 | Proceedings of the National Academy of Sciences: journal h-index 1,167 (OpenAlex, 2026-10-29) |
| Study design | 0 / 12 | No study design recorded — scores zero, not guessed (not stated in the record — scored 0) |
| Strength of evidence | — / 5 | No evidence rating recorded — left out of this score |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2003 — older than 20 years, still counted |
| Sample size | 0 / 4 | Participant count not stated — scores zero (not stated in the record — scored 0) |
| Effect reported | 0 / 3 | No effect size reported — scores zero (not stated in the record — scored 0) |
| Studied in people | 0 / 3 | Not stated whether this was studied in people — scores zero (not stated in the record — scored 0) |
| Randomised / blinded | 0 / 2 | No randomisation or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 7 / 7 | Cited 1,488 times (OpenAlex, 2026-10-10) |
| Citations per year | 5 / 5 | 59.5 citations a year over 25 year(s) since 2003 |
| Impact for its field and year | 5 / 6 | Cited 35.7× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 0 / 6 | No other study in this library cites it |
| Still being cited | 3 / 4 | Cited 137 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 2 / 4 | Last-listed author Suzanne Y. Guénette: h-index 23 (OpenAlex, whole career) |
| Institution's track record | 3 / 3 | Harvard University: institution h-index 3,235 (OpenAlex) |
| Multi-centre collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 12634421) |
| Free to read | 2 / 2 | Free to read |
| Points | 53 / 95 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 53 of the 95 points we could judge it on is 56 out of 100. |
| Total | 56 / 100 | — |
What each of these 20 components measures, and what this score is not →
Read the original
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Cite this study APA, Vancouver, BibTeX · download .bib or .ris
Built from the record alzhub holds for this paper, not looked up. Volume, issue and page numbers are not held in the record. The record names 10 authors; APA and Vancouver show the first six, BibTeX and the downloads carry all of them. Check the citation against the original before you use it.
APA 7th
Farris, W., Mansourian, S., Chang, Y., Lindsley, L. D., Eckman, E. A., Frosch, M. P., et al. (2003). Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences. https://doi.org/10.1073/pnas.0230450100
Vancouver
Farris W, Mansourian S, Chang Y, Lindsley LD, Eckman EA, Frosch MP, et al. Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo. Proceedings of the National Academy of Sciences. 2003. doi:10.1073/pnas.0230450100. PMID: 12634421.
BibTeX
@article{farris2003-12634421,
author = {Farris, Wesley and Mansourian, Stefan and Chang, Yang and Lindsley, Loren D. and Eckman, Elizabeth A. and Frosch, Matthew P. and Eckman, Christopher B. and Tanzi, Rudolph E. and Selkoe, Dennis J. and Guénette, Suzanne Y.},
title = {{Insulin-degrading enzyme regulates the levels of insulin, amyloid β-protein, and the β-amyloid precursor protein intracellular domain in vivo}},
journal = {Proceedings of the National Academy of Sciences},
year = {2003},
doi = {10.1073/pnas.0230450100},
pmid = {12634421},
url = {https://doi.org/10.1073/pnas.0230450100}
}
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