ArticleThe Journal of biological chemistry2012
Insulin promotes neuronal survival via the alternatively spliced protein kinase CδII isoform.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 53 papers.
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Who cites it
53 citing papers in PubMed, 94 citations in OpenAlex.
- Intranasal insulin for improving cognitive function in multiple sclerosis.Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics · 2025Trial
- Chronic Fatty Acid Exposure Disrupts SH-SY5Y and Neuronal Differentiation and Is a Potential Link Between Type-2 Diabetes and Alzheimer's Disease.Molecular neurobiology · 2025Article
- The Dilemma of Insulin Delivery into the Brain: A Comprehensive Review.Current drug delivery · 2025Review
- Review
- Diabetes: a tipping point in neurodegenerative diseases.Trends in molecular medicine · 2023Review
- The function of alternative splicing in the proteome: rewiring protein interactomes to put old functions into new contexts.Nature structural & molecular biology · 2023Review
- Effect of insulin on IR and GLP1-R expressions in HT22 cells.Medical oncology (Northwood, London, England) · 2023Article
- Type 2 Diabetes (T2DM) and Parkinson's Disease (PD): a Mechanistic Approach.Molecular neurobiology · 2023Review
- Small molecule targeting long noncoding RNA GAS5 administered intranasally improves neuronal insulin signaling and decreases neuroinflammation in an aged mouse model.Scientific reports · 2023Article
- Structure-activity relationship of a peptide permeation enhancer.Tissue barriers · 2023Article
- Current Insights on the Use of Insulin and the Potential Use of Insulin Mimetics in Targeting Insulin Signalling in Alzheimer's Disease.International journal of molecular sciences · 2022Review
- The Role of Insulin Signaling in Hippocampal-Related Diseases: A Focus on Alzheimer's Disease.International journal of molecular sciences · 2022Review
- Falling Short: The Contribution of Central Insulin Receptors to Gait Dysregulation in Brain Aging.Biomedicines · 2022Review
- Role of Biliverdin Reductase A in the Regulation of Insulin Signaling in Metabolic and Neurodegenerative Diseases: An Update.International journal of molecular sciences · 2022Review
- Cognitive disorder and dementia in type 2 diabetes mellitus.World journal of diabetes · 2022Review
- Article
- Programming of cardiometabolic health: the role of maternal and fetal hyperinsulinaemia.The Journal of endocrinology · 2022Review
- Insulin sensitizes neural and vascular TRPV1 receptors in the trigeminovascular system.The journal of headache and pain · 2022Article
- Mechanisms mediating the impact of maternal obesity on offspring hypothalamic development and later function.Frontiers in endocrinology · 2022Review
- Insulin action in the brain regulates both central and peripheral functions.American journal of physiology. Endocrinology and metabolism · 2021Review
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
Abstract
Insulin signaling pathways in the brain regulate food uptake and memory and learning. Insulin and protein kinase C (PKC) pathways are integrated and function closely together. PKC activation in the brain is essential for learning and neuronal repair. Intranasal delivery of insulin to the central nervous system (CNS) has been shown to improve memory, reduce cerebral atrophy, and reverse neurodegeneration. However, the neuronal molecular mechanisms of these effects have not been studied in depth. PKCδ plays a central role in cell survival. Its splice variants, PKCδI and PKCδII, are switches that determine cell survival and fate. PKCδI promotes apoptosis, whereas PKCδII promotes survival. Here, we demonstrate that insulin promotes alternative splicing of PKCδII isoform in HT22 cells. The expression of PKCδI splice variant remains unchanged. Insulin increases PKCδII alternative splicing via the PI3K pathway. We further demonstrate that Akt kinase mediates phosphorylation of the splicing factor SC35 to promote PKCδII alternative splicing. Using overexpression and knockdown assays, we demonstrate that insulin increases expression of Bcl2 and bcl-xL via PKCδII. We demonstrate increased cell proliferation and increased BrdU incorporation in insulin-treated cells as well as in HT22 cells overexpressing PKCδII. Finally, we demonstrate in vivo that intranasal insulin promotes cognitive function in mice with concomitant increases in PKCδII expression in the hippocampus. This is the first report of insulin, generally considered a growth or metabolic hormone, regulating the alternative isoform expression of a key signaling kinase in neuronal cells such that it results in increased neuronal survival.
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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.