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Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain
Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, Lucchinetti CF, Nair KS.. JCI insight, 2019-09-19
Topic: Brain proteins, microglia and lab models
Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined. As insulin resistance impairs mitochondrial oxidative metabolism and increases ROS in skeletal muscle, we considered whether similar events occur in the brain, which - like muscle - is rich in insulin receptors and mitochondria. We show that high-fat diet-induced (HFD-induced) brain insulin resistance in mice decreased mitochondrial ATP production rate and oxidative enzyme activities in brain regions rich in insulin receptors. HFD increased ROS emission and reduced antioxidant enzyme activities, with the concurrent accumulation of oxidatively damaged mitochondrial proteins and increased mitochondrial fission. Improvement of insulin sensitivity by both aerobic exercise and metformin ameliorated HFD-induced abnormalities. Moreover, insulin-induced enhancement of ATP production in primary cortical neurons and astrocytes was counteracted by the insulin receptor antagonist S961, demonstrating a direct effect of insulin resistance on brain mitochondria. Further, intranasal S961 administration prevented exercise-induced improvements in ATP production and ROS emission during HFD, supporting that exercise enhances brain mitochondrial function by improving insulin action. These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.
Key findings
- Insulin resistance associates with increased risk for cognitive decline and dementia; however, the underpinning mechanisms for this increased risk remain to be fully defined.
- These results support that insulin sensitizing by exercise and metformin restores brain mitochondrial function in insulin-resistant states.
Why it matters
In mice with high-fat diet-induced brain insulin resistance, mitochondrial ATP production and oxidative enzyme activities decreased, while oxidative stress increased. Improving insulin sensitivity with aerobic exercise and metformin restored brain mitochondrial function in these insulin-resistant states.
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Study details
- Evidence strengthLow
How this study scored 44/100
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.
| Component | Points | Why |
|---|---|---|
| Journal tier | 7 / 10 | Tier 3 — peer-reviewed journal (JCI insight) |
| Journal's citation record | 2 / 4 | JCI Insight: journal h-index 173 (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 | 2 / 5 | 2019 — within 10 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 | 5 / 7 | Cited 133 times (OpenAlex, 2026-10-10) |
| Citations per year | 3 / 5 | 14.8 citations a year over 9 year(s) since 2019 |
| Impact for its field and year | 3 / 6 | Cited 3.6× the average for papers of its field and year (OpenAlex FWCI) |
| Cited by studies here | 1 / 6 | Cited by 2 other studies in this library |
| Still being cited | 3 / 4 | Cited 63 times in 2024–2026 (2026 still in progress; OpenAlex) |
| Senior author's track record | 3 / 4 | Last-listed author K. Sreekumaran Nair: h-index 97 (OpenAlex, whole career) |
| Institution's track record | 2 / 3 | Mayo Clinic: institution h-index 1,606 (OpenAlex) |
| Multi-centre collaboration | 0 / 3 | OpenAlex lists 1 institution(s) in 1 country — scores zero (affiliation lists can be incomplete) |
| Indexed in PubMed | 2 / 2 | Indexed in PubMed (PMID 31534057) |
| Free to read | 0 / 2 | Behind a paywall — scores zero |
| Total | 44 / 100 | — |
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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 8 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
Ruegsegger, G. N., Vanderboom, P. M., Dasari, S., Klaus, K. A., Kabiraj, P., McCarthy, C. B., et al. (2019). Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI insight. https://doi.org/10.1172/jci.insight.130681
Vancouver
Ruegsegger GN, Vanderboom PM, Dasari S, Klaus KA, Kabiraj P, McCarthy CB, et al. Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain. JCI insight. 2019. doi:10.1172/jci.insight.130681. PMID: 31534057.
BibTeX
@article{ruegsegger2019-31534057,
author = {Ruegsegger, G. N. and Vanderboom, P. M. and Dasari, S. and Klaus, K. A. and Kabiraj, P. and McCarthy, C. B. and Lucchinetti, C. F. and Nair, K. S.},
title = {{Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain}},
journal = {JCI insight},
year = {2019},
doi = {10.1172/jci.insight.130681},
pmid = {31534057},
url = {https://doi.org/10.1172/jci.insight.130681}
}
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