Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance
Abstract
1. Introduction
2. Materials and Methods
2.1. Animal Experiments
2.2. Glucose Tolerance Test
2.3. Enzyme-Linked Immunosorbent Assay (ELISA) for Insulin
2.4. Calculation of the Homeostatic Model Assessment (HOMA) Index
2.5. Hematoxylin-Eosin (H&E) Staining
2.6. Measurement of Liver Metabolism Indicators
2.7. Liver Glycogen Quantification
2.8. Immunohistochemical (IHC) Staining
2.9. Central Carbon Metabolite Analysis
2.10. Diseases Search
2.11. Quantitative Real-Time PCR (qPCR)
2.12. Cell Culture
2.13. Measurement of Cell Apoptosis
2.14. Glucose Consumption Experiment
2.15. Glucose Tolerance Test of Min6 Cells
2.16. Statistical Analysis
3. Results
3.1. Exposure to O3 Leads to Impaired Glucose Tolerance and Insulin Resistance
3.2. The Pathways Through Which O3 Exposure Affects Blood Glucose Levels
3.3. O3 Exposure Induces Intensified Hepatocyte Apoptosis and Lipid Metabolism Disorders
3.4. O3 Exposure Reduces Liver Glycogen Content and Abnormal Metabolic Products
3.5. In Vitro Experiments to Verify the Damage Mechanism of O3 Exposure
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
Abbreviation | Definition |
AUC | Area under the curve |
CHO | Cholesterol |
CTD | Comparative Toxicogenomics Database |
DAB | Diaminobenzidine |
ELISA | Enzyme-linked immunosorbent assay |
FINS | Fasting insulin |
FPG | Fasting plasma glucose |
Gapdh | Glyceraldehyde-3-phosphate dehydrogenase |
HOMA | Homeostatic Model Assessment |
H&E | Hematoxylin & Eosin |
IHC | Immunohistochemical |
LC-MS | Liquid Chromatography-Mass Spectrometry |
LDH | Lactate dehydrogenase |
LDL-C | Low-density lipoprotein cholesterol |
OPLS-DA | Orthogonal Partial Least Squares Discriminant Analysis |
qPCR | Quantitative real-time PCR |
SI | Stimulation index |
TG | Triglyceride |
VIP | Variable important in projection |
Appendix A
Appendix A.1. Exposure Concentration Basis
Appendix A.2. Real-Time Quantitative PCR Experimental Method
Appendix A.3. Gene Primers
Gene | Sequence (5′ → 3′) | |
---|---|---|
Gs3kβ | sense: | GGCTGTGTGTTGGCTGAATTGTTG |
antisense: | TTTGCTCCCTTGTTGGTGTTCCTAG | |
Glut2 | sense: | ACAGTCACACCAGCATACACAACAC |
antisense: | CCGAGCCACCCACCAAAGAATG | |
G6pc | sense: | GACTGTGGGCATCAATCTCCTCTG |
antisense: | GCTGTTGCTGTAGTAGTCGGTGTC | |
Fbp1 | sense: | GCTCTATGGTATCGCTGGCTCAAC |
antisense: | GACACAAGAACACAGGTAGCGTAGG | |
Pygl | sense: | GTCATTCCAGCCACAGACCTATCG |
antisense: | GCTTCCTCTGCCATCTCCACATTG | |
Gys2 | sense: | GCCCTCCTCAGTACCACCTTCTC |
antisense: | CCTCTCAGCCTCCTCTTCCTCATC | |
Agtr1a | sense: | GGACACTGCCATGCCCATAACC |
antisense: | GTAGACAGGCTTGAGTGCGACTTG | |
Pik3r1 | sense: | GGGAAGCGAGACGGCACTTTC |
antisense: | TCTACCACTACGGAGCAGGCATAG | |
Insr | sense: | ATCCGCCGCTCCTATGCTCTG |
antisense: | GAGTTGCCTCAGGTTCTGGTTGTC | |
Egfr | sense: | TCCTGATTGGTGCTGTGCGATTC |
antisense: | CTGGCAGTTCTCCTCTCCTCCTC | |
Tnf | sense: | CGCTCTTCTGTCTACTGAACTTCGG |
antisense: | GTGGTTTGTGAGTGTGAGGGTCTG | |
Cd40 | sense: | TGTGATTTGTGCCAGCCAGGAAG |
antisense: | TTCTTAACCCGAAGCCCTTGATTGG | |
Irs1 | sense: | GACGGGTTGCAGGAGGTGTTTG |
antisense: | TGGCAGGAGAGTGGTGGAGTTG | |
antisense: | AGAAGAAGAGGCTGTGGAGGATGG | |
Irs2 | sense: | TGTGATTTGTGCCAGCCAGGAAG |
antisense: | TTCTTAACCCGAAGCCCTTGATTGG |
Appendix A.4
Disease | Gene |
---|---|
Diabetes Mellitus | A|ADIPOQ|ADRB1|ALPK1|AOC3|CAT|CP|CPT1A|CYBB|FN1|IRS1|LEPR|MAP3K5|MT2A|NCF1|PON1|PPARG|PTGS2|RAC1|SOD1 |
Glucose Intolerance | AGT|AGTR1A|AHR|CD36|CNR1|CYP1B1|FRK|GPX4|IKBKB|INSR|LEP|LEPR|METRNL|NFE2L2|NONO|NR5A2|PIK3R1|PRDX4|PRKAA1|RAPGEF3|SCD1|SQSTM1|TLR4|XBP1 |
Insulin Resistance | ACACB|ADIPOQ|ADM|ADRB2|AHR|AR|C3|CASP1|CCL2|CD163|CD36|CD40|CD68|CPE|EGFR|GNAS|GPX3|HMGA1|HMOX1|HSD11B1|IGFALS|IGFBP2|IKBKB|INS1|INSR|IRS1|IRS2|ITGAM|LEP|LEPR|LIPC|MC4R|METRNL|NFE2L2|NLRP3|NOS3|NR4A1|NR4A3|PIK3R1|PLTP|PPARA|PPARG|PRKAA1|PRKAR1A|PTPN1|RETN|SCD1|SELENOP|SLC2A4|SOD2|SQSTM1|SREBF1|SREBF2|TNF|XBP1|ZC3H10 |
Hyperglycemia | A|ADIPOQ|ADM|AGER|CCL2|CD163|CD40|CNR2|COL3A1|FBN1|FCGR3B|GCK|GPX1|HMGA1|HNF1A|HSD11B1|IL6|INS1|INSR|IRS2|ITGAM|LEP|LEPR|NFE2L2|NOS3|NQO1|PRDX4|PRKAR1A|PRKCB|PTGS2|SP1|TERT|ZC3H10 |
Diabetes Mellitus, Type 2 | A|ADAMTS9|ADCY5|ADIPOQ|AKT1|AKT2|ATF3|ATP2A2|ATP2A3|AUTS2|BAX|BCL2|BCL2L1|BCL2L11|BRAF|C2CD4B|C3|CAPN10|CASP3|CASP8|CAT|CBS|CCND2|CD36|CDKAL1|CDO1|CMIP|CPT1A|CYP1A2|ECE1|EDN1|EDNRA|EDNRB|EGFR|ENPP1|ETS1|FAS|FTO|GCK|GCLC|GCLM|GLP1R|GP2|GPD2|GPX1|GSTM1|HBA1|HHEX|HK1|HMG20A|HMGA1|HMOX1|HNF1A|HNF1B|HNF4A|HP|HPX|ICAM1|ID1|IL13RA1|IL6|INPPL1|INS1|IRS1|IRS2|ITGA1|JADE2|KCNQ1|LEP|LEPR|LIPC|MAEA|MAT1A|MIR130B|MIR144|MIR17HG|MIR222|MIR409|MIR744|NFKB1|NOS2|NOS3|NOTCH2|OGG1|PAM|PEPD|PPARA|PPARG|PPARGC1A|PRKCB|PTPN1|RETN|S100A6|SCTR|SLC22A3|SLC2A1|SLC2A4|SMAD5|SNAP25|SOD1|SOD2|TCF7L2|TIMP1|TMEM18|TNF|TNFRSF1A|TNFRSF1B|UBE2E2|WFS1|ZC3HC1|ZFAND3 |
Appendix A.5
Differential Metabolites | Mean Value of Control Group (ng/mL) | Mean Value of 1.0 ppm Group (ng/mL) | Fold Change | VIP |
---|---|---|---|---|
3-Phosphoglyceric acid | 1.999034 | 3.052333 | 1.526904 | 1.262554 |
Fructose | 144.1563 | 88.70745 | 0.615356 | 1.651555 |
Methylmalonic acid | 2.684819 | 1.786713 | 0.665487 | 1.033505 |
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Tian, Y.; Wu, X.; Gong, Z.; Liang, X.; Zhu, H.; Zhang, J.; Hu, Y.; Li, B.; Xu, P.; Guo, K.; et al. Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance. Toxics 2025, 13, 652. https://doi.org/10.3390/toxics13080652
Tian Y, Wu X, Gong Z, Liang X, Zhu H, Zhang J, Hu Y, Li B, Xu P, Guo K, et al. Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance. Toxics. 2025; 13(8):652. https://doi.org/10.3390/toxics13080652
Chicago/Turabian StyleTian, Yuchai, Xiaoyun Wu, Zhihua Gong, Xiaomin Liang, Huizhen Zhu, Jiyue Zhang, Yangcheng Hu, Bin Li, Pengchong Xu, Kaiyue Guo, and et al. 2025. "Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance" Toxics 13, no. 8: 652. https://doi.org/10.3390/toxics13080652
APA StyleTian, Y., Wu, X., Gong, Z., Liang, X., Zhu, H., Zhang, J., Hu, Y., Li, B., Xu, P., Guo, K., & Yue, H. (2025). Ozone Exposure Induces Prediabetic Symptoms Through Hepatic Glycogen Metabolism and Insulin Resistance. Toxics, 13(8), 652. https://doi.org/10.3390/toxics13080652