ArticleDiabetes2016
Brain Insulin Signaling Is Increased in Insulin-Resistant States and Decreases in FOXOs and PGC-1α and Increases in Aβ1-40/42 and Phospho-Tau May Abet Alzheimer Development.
Article in Diabetes, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 82 citations in OpenAlex.
- Brain insulin resistance as a driver of proteinopathy in neurodegeneration: from cell-type-specific mechanisms to targeted therapeutics.Translational neurodegeneration · 2026Review
- FOXO transcription factors in Alzheimer's Disease: balancing neuroprotection and neuronal degeneration.Molecular biology reports · 2026Review
- Progranulin deficiency in the brain activates an insulin signaling pathway that may promote neurodegeneration.iScience · 2026Article
- Up regulated hippocampal insulin pathway and oxidative stress are related to opposite changes in olfaction and episodic memory in a compensatory metabolic syndrome model in rats.Frontiers in cellular neuroscience · 2026Article
- Discovery of a brain penetrant SGK1 inhibitor using a ligand- and structure-based virtual screening methodology.Journal of enzyme inhibition and medicinal chemistry · 2025Article
- Type 2 Diabetes Mellitus Exacerbates Pathological Processes of Parkinson's Disease: Insights from Signaling Pathways Mediated by Insulin Receptors.Neuroscience bulletin · 2025Review
- Ferroptosis in Cognitive Impairment Associated with Diabetes and Alzheimer's Disease: Mechanistic Insights and New Therapeutic Opportunities.Molecular neurobiology · 2025Review
- Multi-target-directed therapeutic strategies for Alzheimer's disease: controlling amyloid-β aggregation, metal ion homeostasis, and enzyme inhibition.Chemical science · 2025Review
- Sarcopenia and cognitive impairment: a multidimensional study of clinical associations, shared genetics, and causal links.Frontiers in aging neuroscience · 2025Article
- Exercise-mediated IL-6 downstream effects modulate brain pathology-can exercise training protocols influence the downstream effects?Frontiers in neurology · 2025Review
- State of the Science on Brain Insulin Resistance and Cognitive Decline Due to Alzheimer's Disease.Aging and disease · 2024Review
- Bezafibrate confers neuroprotection in the 5xFAD mouse model of Alzheimer's disease.Biochimica et biophysica acta. Molecular basis of disease · 2023Article
- Astragaloside IV-mediated inhibition of oxidative stress by upregulation of ghrelin in type 2 diabetes-induced cognitive impairment.Naunyn-Schmiedeberg's archives of pharmacology · 2023Article
- The Role of PGC-1α-Mediated Mitochondrial Biogenesis in Neurons.Neurochemical research · 2023Review
- Review
- Linking Diabetes to Alzheimer's Disease: Potential Roles of Glucose Metabolism and Alpha-Glucosidase.Current neuropharmacology · 2023Review
- FoxO1 as a tissue-specific therapeutic target for type 2 diabetes.Frontiers in endocrinology · 2023Review
- Insulin and aging - a disappointing relationship.Frontiers in endocrinology · 2023Review
- FOXO transcription factors as therapeutic targets in human diseases.Trends in pharmacological sciences · 2022Review
- The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer's Disease: Therapeutic Implications and Future Perspectives.Antioxidants (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Increased coexistence of Alzheimer disease (AD) and type 2 diabetes mellitus (T2DM) suggests that insulin resistance abets neurodegenerative processes, but linkage mechanisms are obscure. Here, we examined insulin signaling factors in brains of insulin-resistant high-fat-fed mice, ob/ob mice, mice with genetically impaired muscle glucose transport, and monkeys with diet-dependent long-standing obesity/T2DM. In each model, the resting/basal activities of insulin-regulated brain protein kinases, Akt and atypical protein kinase C (aPKC), were maximally increased. Moreover, Akt hyperactivation was accompanied by hyperphosphorylation of substrates glycogen synthase kinase-3β and mammalian target of rapamycin and FOXO proteins FOXO1, FOXO3A, and FOXO4 and decreased peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) expression. Akt hyperactivation was confirmed in individual neurons of anterocortical and hippocampal regions that house cognition/memory centers. Remarkably, β-amyloid (Aβ1-40/42) peptide levels were as follows: increased in the short term by insulin in normal mice, increased basally in insulin-resistant mice and monkeys, and accompanied by diminished amyloid precursor protein in monkeys. Phosphorylated tau levels were increased in ob/ob mice and T2DM monkeys. Importantly, with correction of hyperinsulinemia by inhibition of hepatic aPKC and improvement in systemic insulin resistance, brain insulin signaling normalized. As FOXOs and PGC-1α are essential for memory and long-term neuronal function and regeneration and as Aβ1-40/42 and phospho-tau may increase interneuronal plaques and intraneuronal tangles, presently observed aberrations in hyperinsulinemic states may participate in linking insulin resistance to AD.
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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.