ArticleJCI insight2022
Recurrent moderate hypoglycemia accelerates the progression of Alzheimer's disease through impairment of the TRPC6/GLUT3 pathway.
Article in JCI insight, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 2 of them syntheses that pooled it.
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Who cites it
18 citing papers in PubMed, 2 syntheses or guidelines pooled it, 33 citations in OpenAlex.
- Effect of hypoglycemic events on cognitive function in individuals with type 2 diabetes mellitus: a dose-response meta-analysis.Frontiers in neurology · 2024Pooled it
- Relationship between acute glucose variability and cognitive decline in type 2 diabetes: A systematic review and meta-analysis.PloS one · 2023Pooled it
- Solute carrier membrane transporters: emerging targets in CNS disorders.Nature reviews. Drug discovery · 2026Review
- The cognitive consequences of hypoglycemia in diabetes.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026Review
- TRPC6 governs brown adipose thermogenesis via a BMPR2-p38 MAPK signaling axis.Molecular metabolism · 2026Article
- Activation of AMPK by GLP-1R agonists mitigates Alzheimer-related phenotypes in transgenic mice.Nature aging · 2025Article
- Molecular landscape of the overlap between Alzheimer's disease and somatic insulin-related diseases.Alzheimer's research & therapy · 2024Article
- Elevated HbA1c Levels Are Associated with a Risk of Pancreatic Cancer: A Case-Control Study.Journal of clinical medicine · 2024Article
- Naringenin ameliorates amyloid-β pathology and neuroinflammation in Alzheimer's disease.Communications biology · 2024Article
- Essential New Complexity-Based Themes for Patient-Centered Diagnosis and Treatment of Dementia and Predementia in Older People: Multimorbidity and Multilevel Phenomenology.Journal of clinical medicine · 2024Review
- Hypoglycemia and Alzheimer Disease Risk: The Possible Role of Dasiglucagon.Cellular and molecular neurobiology · 2024Review
- Acute severe hypoglycemia alters mouse brain microvascular proteome.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2024Article
- Intermittent Theta Burst Stimulation Attenuates Cognitive Deficits and Alzheimer's Disease-Type Pathologies via ISCA1-Mediated Mitochondrial Modulation in APP/PS1 Mice.Neuroscience bulletin · 2024Article
- Metabolic Profile of Alzheimer's Disease: Is 10-Hydroxy-2-decenoic Acid a Pertinent Metabolic Adjuster?Metabolites · 2023Review
- Dementia in Diabetes: The Role of Hypoglycemia.International journal of molecular sciences · 2023Review
- From Determining Brain Insulin Resistance in a Sporadic Alzheimer's Disease Model to Exploring the Region-Dependent Effect of Intranasal Insulin.Molecular neurobiology · 2023Article
- Metabolic regulation of forkhead box P3 alternative splicing isoforms and their impact on health and disease.Frontiers in immunology · 2023Review
- Hypoglycemic medicines in the treatment of Alzheimer's disease: Pathophysiological links between AD and glucose metabolism.Frontiers in pharmacology · 2023Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Currently, the most effective strategy for dealing with Alzheimer's disease (AD) is delaying the onset of dementia. Severe hypoglycemia is strongly associated with dementia; however, the effects of recurrent moderate hypoglycemia (RH) on the progression of cognitive deficits in patients with diabetes with genetic susceptibility to AD remain unclear. Here, we report that insulin-controlled hyperglycemia slightly aggravated AD-type pathologies and cognitive impairment; however, RH significantly increased neuronal hyperactivity and accelerated the progression of cognitive deficits in streptozotocin-induced (STZ-induced) diabetic APP/PS1 mice. Glucose transporter 3-mediated (GLUT3-mediated) neuronal glucose uptake was not significantly altered under hyperglycemia but was markedly reduced by RH, which induced excessive mitochondrial fission in the hippocampus. Overexpression of GLUT3, specifically in the dentate gyrus (DG) area of the hippocampus, enhanced mitochondrial function and improved cognitive deficits. Activation of the transient receptor potential channel 6 (TRPC6) increased GLUT3-mediated glucose uptake in the brain and alleviated RH-induced cognitive deficits, and inactivation of the Ca2+/AMPK pathway was responsible for TRPC6-induced GLUT3 inhibition. Taken together, RH impairs brain GLUT3-mediated glucose uptake and further provokes neuronal mitochondrial dysfunction by inhibiting TRPC6 expression, which then accelerates progression of cognitive deficits in diabetic APP/PS1 mice. Avoiding RH is essential for glycemic control in patients with diabetes, and TRPC6/GLUT3 represents potent targets for delaying the onset of dementia in patients with diabetes.
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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 Socratic graph.