Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks
Abstract
:1. Introduction
2. Results and Discussion
2.1. Gene Network of Hypoglycemia
2.2. Comparative Analysis of the Gene Networks of Hypoglycemia and Diabetic Vascular Disease
2.3. Comparative Analysis of the Gene Networks of Hypoglycemia, Cognitive Decline and AD
2.4. Study Limitations
3. Materials and Methods
3.1. The ANDSystem Tool and Network Analysis
3.2. The Gene Set Enrichment Analysis
3.3. The Databases AmiGO2 and GeneCards
3.4. Manual Classification of Links between Genes and Hypoglycemia
3.5. The Venn Diagram
4. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
AD | Alzheimer’s disease |
CTS | cross-talk specificity |
ERK | extracellular signal-regulated kinase |
GO | Gene Ontology |
SNP | single nucleotide polymorphism |
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Group of Molecules | Genes |
---|---|
Hormones | ADIPOQ, AVP, EPO, GCG, GH1, GIP, IAPP, INS, LEP, PRL, PTH, REN, SCT, and SST |
Cytokines and growth factors | ANGPTL4, CCL2, CSF3, EDN1, FGF2, FGF21, IGF1, IGF2, IL1B, IL6, TNF, and VEGFA |
Receptors | ADRB2, ADRB3, AGTR2, CD36, CD40, EGFR, GCGR, GHRHR, GLP1R, GPR142, IGF1R, IGF2R, INSR, LEPR, MC2R, NOTCH1, NR3C1, SORCS1, and SSTR2 |
Enzymes | ACE, AKT1, AKT2, CHAT, CPT1A, CYP2C9, CYP3A4, DNMT1, DPP4, EIF2AK3, FBP1, G6PC1, GCK, GPD1, GPD2, GPX3, GSR, GYS2, H6PD, HK1, MAP4K2, MBOAT4, METAP2, NAMPT, NOS1, PARK7, PDK4, PGM1, SERPINA1, SIAH2, SIRT1, SIRT6, SOD2, TGM1, TIGAR, UQCRC2, VHL, and WWOX |
Transporters | ABCC8, AQP4, AQP7, CACNA1C, KCNJ11, KCNH2, MPC2, RAMP1, SLC5A1, SLC5A2, SLC5A4, SLC16A1, SLC2A1, SLC2A2, SLC22A1, SLC30A8, SLC25A20, SLC30A10, and UCP2 |
Transcription factors | ARNTL, DDIT3, FOS, FOXO1, HNF1A, HNF4A, NFE2L2, NR3C1, PPARA, PROP1, SOX17, and TCF7L2 |
Neuropeptides | ADCYAP1, CHGA, GRP, HCRT, NPY, PPY, and UCN |
Structural proteins | CLDN5 and MAP2 |
Other proteins | ALB, CDKN1A, CISD1, CRP, IGFBP1, IGFBP2, IGFBP3, IGFBP6, NRP1, PRNP, PSMB9, PSMG1, SELE, SELP, SERPINE1, TRAF6, and VAMP8 |
MicroRNAs | MIR155 and MIR410 |
Link | Genes |
---|---|
Gene expression is up-regulated by hypoglycemia | ADIPOQ, ALB, ANGPTL4, AQP4, AVP, CCL2, CD40, CDKN1A, CHAT, CHGA, CRP, CYP3A4, DDIT3, EDN1, EIF2AK3, EPO, FOS, GIP, GH1, GPD1, GPX3, GRP, HCRT, IGFBP1, IGFBP2, IL6, LEPR, NOS1, NPY, PARK7, PDK4, PPY, PRL, PRNP, REN, SELE, SERPINE1, SLC2A1, SOD2, SOX17, TIGAR, VEGFA, and UCN |
Gene expression is down-regulated by hypoglycemia | CLDN5, CPT1A, DNMT1, FBP1, GPD2, GSR, MAP2, METAP2, NFE2L2, NRP1, PTH, RAMP1, SELP, SLC25A20, SLC2A1, SST, and VEGFA |
Molecules with hypoglycemic or antihyperglycemic activity | CSF3, GIP, GLP1R, IGF1, IGF2, IGF2R, IGFBP6, IL1B, INS, KCNH2, MIR155, NOTCH1, SCT, SLC16A1, SSTR2, and TRAF6 |
Protective effect against hypoglycemia and/or response to hypoglycemia | ADRB3, CD36, FOXO1, GCG, GCGR, DPP4, GH1, IAPP, IGFBP3, KCNH2, LEP, MBOAT4, MIR410, MPC2, PPARA, PRL, SLC2A2, SOD2, TNF, VHL, VAMP8, and UCN |
SNPs associated with the risk of hypoglycemia | ABCC8, ACE, ADRB2, AGTR2, AKT2, AQP7, CACNA1C, CYP2C9, G6PC, GCK, GHRHR, GYS2, HK1, HNF1A, HNF4A, IGF1R, INSR, KCNJ11, MAP4K2, MC2R, NR3C1, PGM1, PROP1, PSMB9, SERPINA1, SIRT6, SLC22A1, SLC2A2, SORCS1, TCF7L2, TGM1, UCP2, UQCRC2, and WWOX |
Other links | ADCYAP1, AKT1, ARNTL, CISD1, EGFR, FGF2, FGF21, GPR142, H6PD, NAMPT, PSMG1, SIAH2, SIRT1, SLC2A2, SLC30A10, SLC30A8, SLC5A1, SLC5A2, and SLC5A4 |
Gene Ontology Biological Process | Genes | p-Values with Bonferroni Correction |
---|---|---|
GO:0050796~regulation of insulin secretion | ABCC8, ARNTL, CACNA1C, CPT1A, GCG, GCK, GIP, GLP1R, HNF1A, HNF4A, IL1B, KCNJ11, LEP, SLC16A1, SLC2A1, SLC2A2, TNF | 2.66 × 10−16 |
GO:0042593~glucose homeostasis | ADIPOQ, AKT1, G6PC1, GCG, GCGR, GCK, HNF1A, HNF4A, IL6, INS, INSR, LEP, LEPR, PDK4, SIRT6, SLC16A1, SLC30A8, TCF7L2 | 2.16 × 10−13 |
GO:0045944~positive regulation of transcription from RNA polymerase II promoter | ADCYAP1, ADRB2, AKT1, ARNTL, CD40, CSF3, DDIT3, EDN1, EGFR, FGF2, FOS, FOXO1, HNF1A, HNF4A, IGF1, IL1B, IL6, NAMPT, NFE2L2, NOS1, NOTCH1, NR3C1, PARK7, PPARA, PROP1, PTH, SERPINE1, SIRT1, SOX17, TCF7L2, TNF, TRAF6, UCN, VEGFA, WWOX | 8.36 × 10−10 |
GO:1901215~negative regulation of neuron death | AKT1, CHGA, CSF3, EPO, FGF21, IL6, PARK7, PPARA, SIRT1, TIGAR, UCN | 1.35 × 10−09 |
GO:0015758~glucose transport | AKT1, EDN1, G6PC1, GCK, GH1, HK1, INS, SLC2A1, SLC2A2, SLC5A1 | 8.35 × 10−09 |
GO:0006006~glucose metabolic process | ADIPOQ, AKT1, AKT2, CPT1A, H6PD, IGF2, INS, KCNJ11, LEP, PDK4, PGM1, TNF | 1.30 × 10−08 |
GO:0045725~positive regulation of glycogen biosynthetic process | AKT1, AKT2, GCK, IGF1, IGF2, INS, INSR, PTH | 2.58 × 10−08 |
GO:0043066~negative regulation of apoptotic process | AKT1, ALB, ANGPTL4, AVP, CDKN1A, EGFR, FOXO1, GCG, IGF1, IGF1R, IL6, LEP, PARK7, PRNP, PROP1, SIAH2, SIRT1, SOD2, TRAF6, UCN, UCP2, VEGFA, VHL | 3.92 × 10−08 |
GO:0045429~positive regulation of nitric oxide biosynthetic process | AGTR2, AKT1, EDN1, EGFR, IL1B, IL6, INS, INSR, SOD2, TNF | 1.14 × 10−07 |
GO:0046326~positive regulation of glucose import | ADIPOQ, AKT1, AKT2, FGF21, IGF1, INS, INSR, NFE2L2, PTH | 1.66 × 10−07 |
Gene Ontology Biological Process | Enrichment Significance, p-Value with Bonferroni Correction | ||||
---|---|---|---|---|---|
Cardiovascular Disease | Diabetic Neuropathy | Diabetic Retinopathy | Diabetic Nephropathy | AD | |
GO:0045429~positive regulation of nitric oxide biosynthetic process | 2.05 × 10−08 | 1.29 × 10−06 | 3.63 × 10−08 | 3.29 × 10−09 | 2.21 × 10−08 |
GO:0008284~positive regulation of cell proliferation | 1.13 × 10−08 | 1.49 × 10−06 | 4.81 × 10−07 | 5.07 × 10−10 | 2.77 × 10−08 |
GO:0045944~positive regulation of transcription from RNA polymerase II promoter | 2.38 × 10−06 | 6.50 × 10−05 | 8.74 × 10−09 | 1.49 × 10−10 | 6.93 × 10−12 |
GO:0051897~positive regulation of protein kinase B signaling | 1.02 × 10−04 | 3.99 × 10−05 | 4.67 × 10−06 | 2.32 × 10−08 | 5.76 × 10−09 |
GO:0046326~positive regulation of glucose import | 1.67 × 10−07 | 3.65 × 10−05 | 2.74 × 10−07 | 1.37 × 10−06 | 3.24 × 10−04 |
GO:0045740~positive regulation of DNA replication | 9.77 × 10−05 | 1.47 × 10−04 | 1.49 × 10−04 | 5.77 × 10−04 | 4.78 × 10−05 |
GO:0048661~positive regulation of smooth muscle cell proliferation | 6.05 × 10−04 | 6.33 × 10−04 | 2.17 × 10−05 | 5.54 × 10−08 | 1.36 × 10−05 |
GO:0050731~positive regulation of peptidyl-tyrosine phosphorylation | 8.86 × 10−05 | 4.33 × 10−07 | 0.004386 | 2.44 × 10−05 | 4.72 × 10−06 |
GO:0045840~positive regulation of mitotic nuclear division | 7.25 × 10−04 | 2.00 × 10−05 | 0.001034 | 0.003167 | 1.52 × 10−04 |
GO:0042593~glucose homeostasis | 3.09 × 10−04 | 0.005116 | 1.71 × 10−05 | 1.26 × 10−07 | 1.04 × 10−06 |
GO:0070374~positive regulation of ERK1 and ERK2 cascade | 0.007662 | 9.15 × 10−07 | 1.72 × 10−06 | 3.86 × 10−08 | 0.001765 |
AD | Genes Up-Regulated by AD | Genes Down- Regulated by AD | Genes with SNPs Increasing AD Risk | Genes with Other Relations with AD | |
---|---|---|---|---|---|
Hypoglycemia | |||||
Genes up-regulated by hypoglycemia | CCL2, CD40, CDKN1A, CYP3A4, FOS, HCRT, IGFBP2, IL6, PARK7, SERPINA1, VEGFA | AVP, EDN1, LEPR, SLC2A1, VEGFA | CHAT, NPY, PRNP | ADIPOQ, ALB, AQP4, CHGA, CRP, DDIT3, EIF2AK3, EPO, GH1, GIP, NOS1, SERPINE1, SOD2 | |
Genes down-regulated by hypoglycemia | VEGFA | MAP2, METAP2, NFE2L2, SELP, SST, VEGFA | DNMT1 | ||
Genes with SNPs increasing hypoglycemia risk | CYP2C9 | HK1, IGF1R, INSR, NR3C1, SIRT6, WWOX | ADRB2, PSMB9 | ACE, IGF2R, PGM1, SORCS1, TCF7L2 | |
Genes with other relations with hypoglycemia | IGFBP3, IGF2, MIR155, NOTCH1, TNF | NAMPT, SIRT1, SLC30A10, SSTR2 | AKT1, ARNTL, CD36, IL1B, PPARA | ADCYAP1, CSF3, EGFR, FGF2, FOXO1, GLP1R, IAPP, IGF1, INS, KCNH2, LEP, SLC16A1 |
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Saik, O.V.; Klimontov, V.V. Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks. Int. J. Mol. Sci. 2021, 22, 12419. https://doi.org/10.3390/ijms222212419
Saik OV, Klimontov VV. Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks. International Journal of Molecular Sciences. 2021; 22(22):12419. https://doi.org/10.3390/ijms222212419
Chicago/Turabian StyleSaik, Olga V., and Vadim V. Klimontov. 2021. "Hypoglycemia, Vascular Disease and Cognitive Dysfunction in Diabetes: Insights from Text Mining-Based Reconstruction and Bioinformatics Analysis of the Gene Networks" International Journal of Molecular Sciences 22, no. 22: 12419. https://doi.org/10.3390/ijms222212419