ArticleNature neuroscience2019
Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence.
Article in Nature neuroscience, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT05227820 (Anti-Inflammatory, Insulin-Sensitizing Agent for Treatment of Cognitive Decline Due to Degenerative Dementias), which is not on this map. Cited by 102 papers, 1 of them a synthesis that pooled it.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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.
Anti-Inflammatory, Insulin-Sensitizing Agent for Treatment of Cognitive Decline Due to Degenerative Dementias
Who cites it
102 citing papers in PubMed, 1 synthesis or guideline pooled it, 166 citations in OpenAlex.
- Rethinking Alzheimer's: novel miRNAs illuminate a disease beyond the brain.Molecular psychiatry · 2026Pooled it
- Prevention of type 2 diabetes through prediabetes remission without weight loss.Nature medicine · 2025Trial
- Distinct senescent β-cell senotypes differentially drive islet aging and dysfunction.bioRxiv : the preprint server for biology · 2026Article
- Longitudinal associations of cumulative and repeated-measure patterns of insulin resistance surrogate indices with biological age acceleration and incident cardiovascular disease across cardiovascular-kidney-metabolic syndrome stages 0-3: evidence from CHARLS 2011-2020.Cardiovascular diabetology · 2026Article
- Association of various insulin resistance surrogate indices with aging acceleration and future risk of cardiovascular disease in individuals with cardiovascular-kidney-metabolic syndrome stages 0-3: insights from CHARLS 2011-2020 data.Cardiovascular diabetology · 2026Article
- Senotherapeutics for metabolic disease and diabetic complications.Journal of internal medicine · 2026Review
- Comparative evaluation of insulin resistance indices for predicting adverse cardiovascular events in hyperuricemia: insights from UK biobank and Shanghai Pudong cohort.Frontiers in nutrition · 2026Article
- Exercise alone or combined with functional foods in aging and age-related diseases: targeting DNA damage, repair pathways, and genome integrity.Frontiers in aging neuroscience · 2026Review
- Single-Cell RNA-Seq Revealed the Immune Microenvironment Reprogramming by Dexmedetomidine Treatment in Ischemic Stroke.Molecular neurobiology · 2025Article
- Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer's risk via ERRα dysregulation and energy dyshomeostasis.Nature communications · 2025Article
- Targeting Neurodegeneration with SGLT2is: From Molecular Mechanisms to Clinical Implications.Molecular neurobiology · 2025Review
- Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia.Nature communications · 2025Article
- Gene expression composite scores of cellular senescence predict aging health outcomes in the Health and Retirement Study.Nature communications · 2025Article
- ATM deficiency drives phenotypic diversity and Purkinje cell degeneration in a macaque model of ataxia-telangiectasia.Cell reports. Medicine · 2025Article
- Targeting PGE2 mediated senescent neuron improves tumor therapy.Neuro-oncology · 2025Article
- Role of Peripheral NLRP3 Inflammasome in Cognitive Impairments: Insights of Non-central Factors.Molecular neurobiology · 2025Review
- Brain-derived exosomal hemoglobin transfer contributes to neuronal mitochondrial homeostasis under hypoxia.eLife · 2025Article
- Protein kinases in neurodegenerative diseases: current understandings and implications for drug discovery.Signal transduction and targeted therapy · 2025Review
- Genome-Wide Network Analysis of DRG-Sciatic Nerve Network-Inferred Cellular Senescence and Senescence Phenotype in Peripheral Sensory Neurons.Molecular neurobiology · 2025Article
- Age-related p53 SUMOylation accelerates senescence and tau pathology in Alzheimer's disease.Cell death and differentiation · 2025Article
42 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
9 authors at 4 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Prediabetes and Alzheimer's disease both increase in prevalence with age. The former is a risk factor for the latter, but a mechanistic linkage between them remains elusive. We show that prediabetic serum hyperinsulinemia is reflected in the cerebrospinal fluid and that this chronically elevated insulin renders neurons resistant to insulin. This leads to abnormal electrophysiological activity and other defects. In addition, neuronal insulin resistance reduces hexokinase 2, thus impairing glycolysis. This hampers the ubiquitination and degradation of p35, favoring its cleavage to p25, which hyperactivates CDK5 and interferes with the GSK3β-induced degradation of β-catenin. CDK5 contributes to neuronal cell death while β-catenin enters the neuronal nucleus and re-activates the cell cycle machinery. Unable to successfully divide, the neuron instead enters a senescent-like state. These findings offer a direct connection between peripheral hyperinsulinemia, as found in prediabetes, age-related neurodegeneration and cognitive decline. The implications for neurodegenerative conditions such as Alzheimer's disease are described.
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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.