ArticleJCI insight2019
Exercise and metformin counteract altered mitochondrial function in the insulin-resistant brain.
Article in JCI insight, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 80 papers, 3 of them syntheses that pooled it.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
80 citing papers in PubMed, 3 syntheses or guidelines pooled it, 126 citations in OpenAlex.
- Effect of antidiabetic drugs in Alzheimer´s disease: a systematic review of preclinical and clinical studies.Molecular neurodegeneration · 2025Pooled it
- The Impact of Exercise Training on the Brain and Cognition in Type 2 Diabetes, and its Physiological Mediators: A Systematic Review.Sports medicine - open · 2025Pooled it
- Metformin for neurocognitive dysfunction in schizophrenia: a systematic review.Frontiers in psychiatry · 2024Pooled it
- Two weeks of exercise alters neuronal extracellular vesicle insulin signaling proteins and pro-BDNF in older adults with prediabetes.Aging cell · 2025Trial
- Exercise restores brain insulin sensitivity in sedentary adults who are overweight and obese.JCI insight · 2022Trial
- Brain functions and cognition on transient insulin deprivation in type 1 diabetes.JCI insight · 2021Trial
- The Interplay of Metabolic Dysfunction, Neuroinflammation, and Mitochondrial Dysfunction in Balance Impairment: Insights from Type 2 Diabetes Mellitus and Alzheimer's Disease.Molecular neurobiology · 2026Review
- The Interaction Between Insulin Resistance and Neuroinflammation in the Brain and Its Impact on Diabetic Encephalopathy.Biology · 2026Review
- Exercise Increases the Sensitivity of Cerebral Glucose Metabolism to Intranasal Insulin in Young, Healthy Adults.Journal of neurochemistry · 2026Article
- Elevation of Mitochondrial CaCells · 2026Article
- Effect of a single exercise bout on fasting cerebral blood flow and brain insulin sensitivity in middle-aged to older adults.Experimental physiology · 2026Article
- The impact of exercise on brain mitochondrial health and its relevance to Alzheimer's disease.Brain and environment · 2026Article
- Antidepressant Effects of L-Arginine and Its Role in Brain Energy MetabolismIranian biomedical journal · 2026Article
- Acute peripheral versus central inhibition of insulin receptors differentially alters cytokine and blood-brain barrier responses to an inflammatory stimulus.Brain, behavior, and immunity · 2026Article
- From Metabolism to Mind: The Cardio-Metabolic-Brain Axis and the Role of Insulin Resistance-A Review.Biomedicines · 2026Review
- Molecular pathways, tissue-specific roles, and therapeutic opportunities in mitochondrial resilience-based strategies for insulin resistance.Frontiers in clinical diabetes and healthcare · 2026Review
- Beyond muscle weakness: pathogenesis of sepsis-induced myopathy and its management.Open medicine (Warsaw, Poland) · 2026Review
- Pharmacological modulation of the PI3K/AKT/GSK3β axis: a new frontier in Alzheimer's disease treatment.Inflammopharmacology · 2026Review
- Brain insulin resistance: a key pathological hub linking metabolic and neuropsychiatric comorbidities.Frontiers in aging neuroscience · 2026Review
- Diet supplementation with the macroalgaeFrontiers in nutrition · 2026Article
20 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
8 authors at 2 institutions in 2 countries.
Funding
Abstract
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.
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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.