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.


Egon Willighagen , Alex Pico , Denise Slenter , Eric Weitz , and Daniela Digles


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Homo sapiens



Disease Ontology

diabetic neuropathy brain small vessel disease hyperglycemia

Pathway Ontology

disease pathway

Cell Type Ontology



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
O2- radical Metabolite chebi:61073
Glucose Metabolite wikidata:Q37525
Glucose Metabolite wikidata:Q37525
Glucose Metabolite wikidata:Q37525
ROS Metabolite chebi:26523
Ca2+ Metabolite chebi:29108
K+ Metabolite chebi:29103
K+ Metabolite chebi:29103
Na+ Metabolite wikidata:Q31541104
Na+ Metabolite wikidata:Q31541104
K+ Metabolite chebi:29103
ROS Metabolite chebi:26523
e- Metabolite chebi:10545
NO Metabolite chebi:16480
AGE Metabolite chebi:84123
ROS Metabolite chebi:26523
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: Assumed to represent Protein kinase C, a family of protein kinases.
Na⁺/K⁺-ATPase Protein eccode: 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. The role of glycation in the pathogenesis of diabetic polyneuropathy. King RH. Mol Pathol. 2001 Dec;54(6):400–8. PubMed Europe PMC Scholia
  2. 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
  3. 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
  4. 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