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Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX.. The Journal of pathology, 2011-05-19
Topic: Amyloid, tau and blood-test diagnosis
Brain glucose metabolism is impaired in Alzheimer's disease (AD), the most common form of dementia. Type 2 diabetes mellitus (T2DM) is reported to increase the risk for dementia, including AD, but the underlying mechanism is not understood. Here, we investigated the brain insulin-PI3K-AKT signalling pathway in the autopsied frontal cortices from nine AD, 10 T2DM, eight T2DM-AD and seven control cases. We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases. The deficiency of insulin-PI3K-AKT signalling was more severe in individuals with both T2DM and AD (T2DM-AD). This decrease in insulin-PI3K-AKT signalling could lead to activation of glycogen synthase kinase-3β, the major tau kinase. The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration. The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation. Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.
Key findings
- We found decreases in the levels and activities of several components of the insulin-PI3K-AKT signalling pathway in AD and T2DM cases.
- The levels and the activation of the insulin-PI3K-AKT signalling components correlated negatively with the level of tau phosphorylation and positively with protein O-GlcNAcylation, suggesting that impaired insulin-PI3K-AKT signalling might contribute to neurodegeneration in AD through down-regulation of O-GlcNAcylation and the consequent promotion of abnormal tau hyperphosphorylation and neurodegeneration.
- The decrease in brain insulin-PI3K-AKT signalling also correlated with the activation of calpain I in the brain, suggesting that the decrease might be caused by calpain over-activation.
- Our findings provide novel insight into the molecular mechanism by which type 2 diabetes mellitus increases the risk for developing cognitive impairment and dementia in Alzheimer's disease.
Why it matters
In autopsied frontal cortex from nine Alzheimer's disease, 10 type 2 diabetes, eight T2DM-AD and seven control cases, this study found decreased levels and activities of components of the insulin-PI3K-AKT signalling pathway. It suggests impaired insulin signalling might contribute to neurodegeneration, but this is tissue-based work and not a treatment, cure or prevention.
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Study details
- Evidence strengthLow
How this study scored 49/100
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 institution's track record, so that was left out: it earned 48 of the 97 points we could judge it on, which is 49 out of 100.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (The Journal of pathology) |
| Journal's citation record | 3 / 4 | The Journal of Pathology: journal h-index 254 (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 | 1 / 5 | Rated “low” in our summary |
| Peer-review validation | 10 / 10 | Peer-reviewed. Published as an article in a named peer-reviewed journal. |
| How recent | 1 / 5 | 2011 — within 20 year(s) of the newest study here |
| 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 | 6 / 7 | Cited 502 times (OpenAlex, 2026-10-10) |
| Citations per year | 4 / 5 | 29.5 citations a year over 17 year(s) since 2011 |
| Impact for its field and year | 5 / 6 | Cited 22.4× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 3 / 6 | Cited by 13 other studies in this library |
| Still being cited | 3 / 4 | Cited 68 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author Cheng‐Xin Gong: h-index 81 (OpenAlex, whole career) |
| Institution's track record | — / 3 | No institution listed in OpenAlex — left out of this score |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 0 institution(s) in 0 countries — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 21598254) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Points | 48 / 97 | Scored on 19 of 20 parts. We have no data for the rest, so they are left out: 48 of the 97 points we could judge it on is 49 out of 100. |
| Total | 49 / 100 | — |
What each of these 20 components measures, and what this score is not →
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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. Check the citation against the original before you use it.
APA 7th
Liu, Y., Liu, F., Grundke-Iqbal, I., Iqbal, K., & Gong, C. X. (2011). Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. The Journal of pathology. https://doi.org/10.1002/path.2912
Vancouver
Liu Y, Liu F, Grundke-Iqbal I, Iqbal K, Gong CX. Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes. The Journal of pathology. 2011. doi:10.1002/path.2912. PMID: 21598254.
BibTeX
@article{liu2011-21598254,
author = {Liu, Y. and Liu, F. and Grundke-Iqbal, I. and Iqbal, K. and Gong, C. X.},
title = {{Deficient brain insulin signalling pathway in Alzheimer's disease and diabetes}},
journal = {The Journal of pathology},
year = {2011},
doi = {10.1002/path.2912},
pmid = {21598254},
url = {https://doi.org/10.1002/path.2912}
}
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