Chronic hyperglycemia impairment of neuron function (WP5283)
Homo sapiens
Chronic excess of glucose (chronic hyperglycemia) impairs neuron function via the polyol pathway, causing ROS and RNS eventually. These activate nuclear transcription factors that increase the expression of ion channel transducers TRP and NaV and impairs their capacity to self-repair. Meanwhile, microglia-released cytokines, ATP, BDNF, and NO stimulate GPCR and tyrosine kinase receptors. This causes a signaling cascade leading to the phosphorylation of TRP and NaV channels, further distorting normal biology.
Authors
Egon Willighagen , Alex Pico , Denise Slenter , Eric Weitz , and Daniela DiglesActivity
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Cited In
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Organisms
Homo sapiensCommunities
Annotations
Disease Ontology
diabetic neuropathy brain small vessel disease hyperglycemiaPathway Ontology
disease pathwayCell Type Ontology
neuron| Label | Type | Compact URI | Comment |
|---|---|---|---|
| NAD | Metabolite | wikidata:Q12499775 | |
| NADP | Metabolite | wikidata:Q26987754 | |
| PGE2 | Metabolite | wikidata:Q416554 | |
| O2- radical | Metabolite | chebi:61073 | |
| Sorbitol | Metabolite | wikidata:Q245280 | |
| ADP | Metabolite | wikidata:Q185253 | |
| NADPH | Metabolite | wikidata:Q26841327 | |
| Na+ | Metabolite | wikidata:Q31541104 | |
| AGE | Metabolite | chebi:84123 | |
| ATP | Metabolite | wikidata:Q80863 | |
| NADH | Metabolite | wikidata:Q26987453 | |
| Fructose | Metabolite | wikidata:Q61738075 | |
| Glucose | Metabolite | wikidata:Q37525 | |
| ROS | Metabolite | chebi:26523 | |
| Ca2+ | Metabolite | chebi:29108 | |
| K+ | Metabolite | chebi:29103 | |
| e- | Metabolite | chebi:10545 | |
| NO | Metabolite | chebi:16480 | |
| PRKCQ | GeneProduct | ncbigene:5588 | |
| PRKCZ | GeneProduct | ncbigene:5590 | |
| MMP7 | GeneProduct | ncbigene:4316 | |
| MMP28 | GeneProduct | ncbigene:79148 | |
| PRKCD | GeneProduct | ncbigene:5580 | |
| MMP15 | GeneProduct | ncbigene:4324 | |
| MMP16 | GeneProduct | ncbigene:4325 | |
| PRKCH | GeneProduct | ncbigene:5583 | |
| PRKCI | GeneProduct | ncbigene:5584 | |
| PRKCE | GeneProduct | ncbigene:5581 | |
| MMP3 | GeneProduct | ncbigene:4314 | |
| MMP23B | GeneProduct | ncbigene:8510 | |
| MMP20 | GeneProduct | ncbigene:9313 | |
| PRKCG | GeneProduct | ncbigene:5582 | |
| MMP1 | GeneProduct | ncbigene:4312 | |
| MMP2 | GeneProduct | ncbigene:4313 | |
| SNAP25 | GeneProduct | ncbigene:6616 | |
| MMP10 | GeneProduct | ncbigene:4319 | |
| MMP11 | GeneProduct | ncbigene:4320 | |
| PRKD3 | GeneProduct | ncbigene:23683 | |
| PRKCA | GeneProduct | ncbigene:5578 | |
| MMP8 | GeneProduct | ncbigene:4317 | |
| MMP9 | GeneProduct | ncbigene:4318 | |
| MMP13 | GeneProduct | ncbigene:4322 | |
| PRKCB | GeneProduct | ncbigene:5579 | |
| MMP12 | GeneProduct | ncbigene:4321 | |
| MMP24 | GeneProduct | ncbigene:10893 | |
| MMP21 | GeneProduct | ncbigene:118856 | |
| MMP14 | GeneProduct | ncbigene:4323 | |
| MMP25 | GeneProduct | ncbigene:64386 | |
| MMP19 | GeneProduct | ncbigene:4327 | |
| MMP27 | GeneProduct | ncbigene:64066 | |
| MMP17 | GeneProduct | ncbigene:4326 | |
| PKC | Protein | eccode:2.7.11.13 | Assumed to represent Protein kinase C, a family of protein kinases. |
| Na⁺/K⁺-ATPase | Protein | eccode:7.2.2.13 | aka sodium–potassium pump |
| NADPHoxidase | Protein | wikidata:Q97651124 | |
| TKR | Protein | ensembl:ENSG00000007350 | Also known as TKTL1 |
| Sorbitol dehydrogenase | Protein | uniprot:Q00796 | |
| GPCR | Protein | wikidata:Q38173 | |
| RAGE | Protein | ncbigene:177 | Also AGER |
| C3 | Protein | ncbigene:718 | |
| Cytokines | Protein | wikidata:Q212354 | |
| Glut-1 | Protein | ncbigene:6513 | |
| TRPV1 | Protein | uniprot:Q8NER1 | AKA transient receptor potential vannilloid-1 |
| BDNF | Protein | ncbigene:627 | |
| Glut-3 | Protein | ncbigene:6515 | |
| INOS | Protein | uniprot:P35228 | Assumed to represent one of the nitric oxide sunthases (due to connection to NO metabolite); the xNOS family of enzymes catalyzes the production of nitric oxide from L-arginine. Publication [PMID: 30766472] states :'Nitric oxide (NO) is a potent vasoactive gas formed by three nitric oxide synthase (NOS) isoenzymes: neuronal (nNOS), endothelial (eNOS), and inducible (iNOS)' |
| TRPA1 | Protein | uniprot:O75762 | AKA transient receptor potential ankyrin-1 |
| NMDA | Protein | interpro:IPR018882 | 'increasing N-Methyl-D-Aspartate receptor (NMDAR) phosphorylation reduces its endogenous blockade by magnesium, thereby enhancing calcium (Ca+2) and sodium (Na+) influx' [PMID: 30766472]. Receptor exist in 8 variants. |
| Nav1.6 | Protein | ensembl:ENSG00000196876 | |
| Nav1.7 | Protein | ensembl:ENSG00000169432 | |
| Nav1.8 | Protein | ensembl:ENSG00000185313 | |
| Aldose reductase | Protein | eccode:1.1.1.21 |
References
- The role of glycation in the pathogenesis of diabetic polyneuropathy. King RH. Mol Pathol. 2001 Dec;54(6):400–8. PubMed Europe PMC Scholia
- Advanced glycation end-products: a biological consequence of lifestyle contributing to cancer disparity. Turner DP. Cancer Res. 2015 May 15;75(10):1925–9. PubMed Europe PMC Scholia
- Neurons and Microglia; A Sickly-Sweet Duo in Diabetic Pain Neuropathy. Rajchgot T, Thomas SC, Wang JC, Ahmadi M, Balood M, Crosson T, et al. Front Neurosci. 2019 Jan 31;13:25. PubMed Europe PMC Scholia
- Advanced Glycation End Products (AGEs): Biochemistry, Signaling, Analytical Methods, and Epigenetic Effects. Perrone A, Giovino A, Benny J, Martinelli F. Oxid Med Cell Longev. 2020 Mar 18;2020:3818196. PubMed Europe PMC Scholia