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Metformin protects against insulin resistance-related dementia risk involving restored microglial homeostasis
González Pérez N, Bellotto M, Porte Alcón S, Bentivegna M, Arcucci L, Vinuesa Á, Presa J, Brites F et al.. Life sciences, 2025-06-08
Topic: Brain proteins, microglia and lab models
Aims The rising prevalence of type 2 diabetes (T2D), obesity, and metabolic syndrome highlights the need for therapeutic strategies addressing both metabolic and neurological aspects of these conditions. This study evaluates the potential of metformin, a widely prescribed antidiabetic drug, to mitigate hippocampal changes induced by a moderate high-fat diet (HFD) and explores its mechanisms beyond glycemic regulation, including modulation of microglial autophagy, mitochondrial turnover, and neuroinflammation. Materials and methods We analyzed data from diabetic patients enrolled in the NACC study, a retrospective observational study, to assess cognitive outcomes associated with metformin use. Additionally, we examined the effects of metformin in HFD-treated mice, evaluating hippocampal insulin resistance, synaptic marker and microglial status. We also employed BV2 microglial cells exposed to palmitate as a lipotoxic stimulus to assess the potential of metformin in modulating microglial autophagy, mitochondrial status and inflammatory response. Key findings In diabetic patients, metformin use is associated with improved memory and executive function, independent of cardiovascular risk factor control. In HFD-treated mice, metformin reduced hippocampal insulin resistance, increased synaptophysin levels, and reversed microglial activation and autophagy impairment. In BV2 microglial cells, metformin reduced IL-1β and TNFα expression, restored autophagic flux, and regulated mitochondrial turnover, leading to decreased mitochondrial ROS production. Significance Our findings suggest that metformin exerts therapeutic effects beyond glycemic control in the context of T2D. By mitigating neuroinflammation and modulating microglial autophagy, metformin emerges as a promising therapeutic agent for cognitive decline associated with diabetes and potentially other neurological disorders.
Cite this study APA, Vancouver, BibTeX · download .bib or .ris
APA 7th
González Pérez, N., Bellotto, M., Porte Alcón, S., Bentivegna, M., Arcucci, L., Á, V., et al. (2025). Metformin protects against insulin resistance-related dementia risk involving restored microglial homeostasis. Life sciences. https://doi.org/10.1016/j.lfs.2025.123803
Vancouver
González Pérez N, Bellotto M, Porte Alcón S, Bentivegna M, Arcucci L, Á V, et al. Metformin protects against insulin resistance-related dementia risk involving restored microglial homeostasis. Life sciences. 2025. doi:10.1016/j.lfs.2025.123803. PMID: 40494433.
BibTeX
@article{gonzalezperez2025-40494433,
author = {González Pérez, N. and Bellotto, M. and Porte Alcón, S. and Bentivegna, M. and Arcucci, L. and Á, Vinuesa and Presa, J. and Brites, F. and others},
title = {{Metformin protects against insulin resistance-related dementia risk involving restored microglial homeostasis}},
journal = {Life sciences},
year = {2025},
doi = {10.1016/j.lfs.2025.123803},
pmid = {40494433},
url = {https://doi.org/10.1016/j.lfs.2025.123803}
}
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Key findings
- Materials and methods We analyzed data from diabetic patients enrolled in the NACC study, a retrospective observational study, to assess cognitive outcomes associated with metformin use.
- Key findings In diabetic patients, metformin use is associated with improved memory and executive function, independent of cardiovascular risk factor control.
- Significance Our findings suggest that metformin exerts therapeutic effects beyond glycemic control in the context of T2D.
- By mitigating neuroinflammation and modulating microglial autophagy, metformin emerges as a promising therapeutic agent for cognitive decline associated with diabetes and potentially other neurological disorders.
Why it matters
Among people with diabetes in the NACC records, metformin use was associated with better memory and executive function. In mice fed a high-fat diet, metformin reduced insulin resistance in the hippocampus (a memory area) and reversed changes in microglia, the brain's immune cells, and in cultured microglial cells it lowered inflammatory signals. The authors see metformin as a promising candidate against diabetes-related cognitive decline, though the human evidence here is observational and the mechanism work was done in mice and cells.
Study details
- Evidence strengthLow
How this study scored 39/100
Published in a peer-reviewed journal. Scored zero for study design, sample size, effect reported and randomized / blinded because the record does not state it.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (Life sciences) |
| Journal's citation record | 3 / 4 | Life Sciences: journal h-index 288 (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 | 4 / 5 | 2025 — within 3 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 | 3 / 3 | Studied in people (pubmed indexes it as a clinical or observational study) |
| Randomized / blinded | 0 / 2 | No randomization or blinding stated — scores zero (not stated in the record — scored 0) |
| Times cited | 2 / 7 | Cited 8 times (OpenAlex, 2026-10-10) |
| Citations per year | 1 / 5 | 2.7 citations a year over 3 year(s) since 2025 |
| Impact for its field and year | 2 / 6 | Cited 2.4× 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 | 1 / 4 | Cited 8 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 1 / 4 | Last-listed author Carlos Javier Pomilio: h-index 12 (OpenAlex, whole career) |
| Institution's track record | 0 / 3 | Consejo Nacional de Investigaciones Científicas y Técnicas: institution h-index 639 (OpenAlex) |
| Multicenter collaboration | 2 / 3 | OpenAlex lists 4 institution(s) in 1 country |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 40494433) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 39 / 100 | — |
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