Obesity and carbohydrate metabolism disorders as factors modifying the toxic effect of xenobiotics

The influence of chemical factors of production and the environment on humans is increasingly realized against the background of an existing pathological condition: the prevalence of obesity, metabolic syndrome, insulin resistance and other disorders of carbohydrate metabolism is growing in the population, and in a number of occupational groups their share already reaches and even exceeds a third of workers.

The study aims to summarize experimental and epidemiological data on obesity, metabolic syndrome, insulin resistance, and other disorders of carbohydrate metabolism as factors modifying the toxic effects of xenobiotics in conditions of occupational and man-made exposure.

The search for original in vivo and human studies was conducted in Russian and international databases, taking into account the recommendations of PRISMA; the analysis included 27 sources from 1987–2024, where metabolic disorders were initiated or diagnosed before assessing the effects of chemical agents of various nature.

The results show that the metabolic dysregulations under consideration in most cases enhance the toxic effects of xenobiotics, altering their toxicokinetics and toxicodynamics and increasing the severity of hepatotoxicity, nephrotoxicity, and cardiotoxicity, oxidative stress, and inflammation. Data from epidemiological studies in the working cohort and in the general population, although extremely limited in the number of studies, generally confirm that obesity, metabolic syndrome, insulin resistance and other disorders of carbohydrate metabolism act not only as a background, but also as independent determinants of sensitivity to chemical stress. Given the high prevalence of these conditions among the working-age population, it is necessary to consider the possibility of taking them into account when assessing health risks and developing preventive measures.

Ethics. The study did not require the conclusion of a bioethical commission.

Funding. The study had no funding.

Conflict of interest. The author declares no conflict of interest.

Received: 23.12.2025 / Accepted: 11.02.2026 / Published: 27.03.2026

1. Shestakova E.A., Lunina E.Y., Galstyan G.R., Shestakova M.V., Dedov I.I. Type 2 diabetes and prediabetes prevalence in patients with different risk factor combinations in the NATION study. Sakharnyj diabet. 2020; 23(1): 4–11. https://doi.org/10.14341/DM12286 (in Russian).

2. Verbovoy A.F., Verbovaya N.I., Dolgikh Yu.A. Obesity is the basis of metabolic syndrome. Ozhirenie i metabolizm. 2021; 18(2): 142–149. https://doi.org/10.14341/omet12707 (in Russian).

3. Alferova V.I., Mustafina S.V. The prevalence of obesity in the adult population of the Russian Federation (literature review). Ozhirenie i metabolizm. 2022; 19(1): 96–105. https://doi.org/10.14341/omet12809 (in Russian).

4. Lavrenova E.A., Drapkina O.M. Insulin resistance in obesity: pathogenesis and effects. Ozhirenie i metabolizm. 2020; 17(1): 48–55. https://doi.org/10.14341/omet9759 (in Russian).

5. Dedov I.I., Shestakova M.V., Vikulova O.K., Zheleznyakova A.V., Isakov M.A., Sazonova D.V., Mokrysheva N.G. Diabetes mellitus in the Russian Federation: dynamics of epidemiological indicators according to the Federal Register of Diabetes Mellitus for the period 2010–2022. Sakharnyj diabet. 2023; 26(2): 104–123. https://doi.org/10.14341/DM13035 (in Russian).

6. Syurin S.A., Gorbanev S.A. Overweight and obesity in metallurgical workers of the Arctic: prevalence, causes of development, clinical significance. Zdorov'e naseleniya i sreda obitaniya – ZNiSO. 2019; (10): 11–15. https://doi.org/10.35627/2219-5238/2019-319-10-11-15 (in Russian).

7. Syurin S.A., Gorbanev S.A. Prevalence and correlates of obesity in industrial workers in arctic Russia. Ekologiya cheloveka. 2021; 28(5): 28–35. https://doi.org/10.33396/1728-0869-2021-5-28-35 (in Russian).

8. Dyagileva V.B., Bolotnova T.V. Metabolic syndrome in shift workers in a northern city of the Khanty-Mansiysk Okrug-Yugra. Meditsinskaya nauka i obrazovanie Urala. 2013; 2: 29–31. https://elibrary.ru/tabycn (in Russian).

9. Dyakovich O.A. Prevalence of metabolic syndrome in employees of various professional groups. Russian Journal of Occupational Health and Industrial Ecology [Med. truda i prom. ekol.]. 2020; 60(10): 674–680. https://doi.org/10.31089/1026-9428-2020-60-10-674-680 (in Russian).

10. Kang D., Lee E.S., Kim T.K., Kim Y.J., Lee S., Lee W., Sim H., Kim S.Y. Association with Combined Occupational Hazards Exposure and Risk of Metabolic Syndrome: A Workers' Health Examination Cohort 2012-2021. Saf Health Work. 2023; 14(3): 279–286. https://doi.org/10.1016/j.shaw.2023.08.006

11. Khamidulina Kh.Kh., Tarasova E.V., Zamkova I.V., Dorofeeva E.V., Araslanov I.N., Aniskova Yu.Yu., Proskurina A.S., Rabikova D.N., Lastovetskiy M.L., Nazarenko A.K. Scientific substantiation of the national list of chemicals affecting the endocrine system. Toksikologicheskiy vestnik. 2022; 30(2): 108–114. https://doi.org/10.47470/0869-7922-2022-30-2-108-114 (in Russian).

12. Khamidulina Kh.Kh., Tarasova E.V., Zamkova I.V., Dorofeeva E.V., Araslanov I.N., Aniskova Yu.Yu., Proskurina A.S., Rabikova D.N. International approaches to hazard assessment and classification of endocrine disruptors. Hygiene and Sanitation, Russian Journal [Gigiena i sanitariya]. 2021; 100(12): 1372–1376. https://doi.org/10.47470/0016-9900-2021-100-12-1372-1376 (in Russian).

13. Evteeva A.A., Sheremeta M.S., Pigarova E.A. Endocrine disruptors in the pathogenesis of socially significant diseases such as diabetes mellitus, malignant neoplasms, cardiovascular diseases, pathology of the reproductive system. Ozhirenie i metabolizm. 2021; 18(3): 327–335. https://doi.org/10.14341/omet12757 (in Russian).

14. Zheng X.Y., Tang S.L., Liu T., Wang Y., Xu X.J., Xiao N., Li C., Xu Y.J., He Z.X., Ma S.L., Chen Y.L., Meng R.L., Lin L.F. Effects of long-term PM2.5 exposure on metabolic syndrome among adults and elderly in Guangdong, China. Environ. Health. 2022; 21(1): 84. https://doi.org/10.1186/s12940-022-00888-2

15. Zemlyanova M.A., Koldibekova Yu.V. Modern approaches to assessment of metabolism disorders of xenobiotics during their administration into body from external environment. Ekologiya cheloveka. 2012; 8: 8–14. https://elibrary.ru/paijwp (in Russian).

16. Johnson C.H., Patterson A.D., Idle J.R., Gonzalez F.J. Xenobiotic metabolomics: major impact on the metabolome. Annu. Rev. Pharmacol. Toxicol. 2012; 52: 37–56. https://doi.org/10.1146/annurev-pharmtox-010611-134748

17. Sukhanov B.P., Gorshkov A.I., Kasyanov V.F., Korolev A.A. The influence of nutrition on the metabolism of drugs and xenobiotics: mechanisms of biotransformation, the influence of proteins, fats and carbohydrates (review). Hygiene and Sanitation, Russian Journal [Gigiena i sanitariya]. 1994; (5): 44–49. https://elibrary.ru/kdpeen

18. Piccinin E., Ducheix S., Peres C., Arconzo M., Vegliante M.C., Ferretta A., Bellafante E., Villani G., Moschetta A. PGC-1β Induces Susceptibility to Acetaminophen-Driven Acute Liver Failure. Sci. Rep. 2019; 9(1): 16821. https://doi.org/10.1038/s41598-019-53015-6

19. Kon K., Ikejima K., Okumura K., Arai K., Aoyama T., Watanabe S. Diabetic KK-A(y) mice are highly susceptible to oxidative hepatocellular damage induced by acetaminophen. Am. J. Physiol. Gastrointest. Liver Physiol. 2010; 299(2): G329–37. https://doi.org/10.1152/ajpgi.00361.2009

20. Aubert J., Begriche K., Delannoy M., Morel I., Pajaud J., Ribault C., Lepage S., McGill M.R., Lucas-Clerc C., Turlin B., Robin M.A., Jaeschke H., Fromenty B. Differences in early acetaminophen hepatotoxicity between obese ob/ob and db/db mice. J. Pharmacol. Exp. Ther. 2012; 342(3): 676–87. https://doi.org/10.1124/jpet.112.193813

21. Donthamsetty S., Bhave V.S., Mitra M.S., Latendresse J.R., Mehendale H.M. Nonalcoholic steatohepatitic (NASH) mice are protected from higher hepatotoxicity of acetaminophen upon induction of PPARalpha with clofibrate. Toxicol. Appl. Pharmacol. 2008; 230(3): 327–37. https://doi.org/10.1016/j.taap.2008.02.031

22. Ghanayem B.I., Bai R., Kissling G.E., Travlos G., Hoffler U. Diet-induced obesity in male mice is associated with reduced fertility and potentiation of acrylamide-induced reproductive toxicity. Biol. Reprod. 2010; 82(1): 96–104. https://doi.org/10.1095/biolreprod.109.078915

23. Tan X., Xie G., Sun X., Li Q., Zhong W., Qiao P., Sun X., Jia W., Zhou Z. High Fat Diet Feeding Exaggerates Perfluorooctanoic Acid-Induced Liver Injury in Mice via Modulating Multiple Metabolic Pathways. PLoS One. 2013; 8(4): e61409. https://doi.org/10.1371/journal.pone.0061409

24. Xu J., Lai K.K.Y., Verlinsky A., Lugea A., French S.W., Cooper M.P., Ji C., Tsukamoto H. Synergistic steatohepatitis by moderate obesity and alcohol in mice despite increased adiponectin and p-AMPK. J. Hepatol. 2011; 55(3): 673–682. https://doi.org/10.1016/j.jhep.2010.12.034

25. Liu T., Liang X., Lei C., Huang Q., Song W., Fang R., Li C., Li X., Mo H., Sun N., Lv H., Liu Z. High-Fat Diet Affects Heavy Metal Accumulation and Toxicity to Mice Liver and Kidney Probably via Gut Microbiota. Front Microbiol. 2020; 11: 1604. https://doi.org/10.3389/fmicb.2020.01604

26. Zhang X., Jackson S., Liu J., Li J., Yang Z., Sun D., Zhang W. Arsenic aggravates the progression of diabetic nephropathy through miRNA-mRNA-autophagy axis. Food Chem. Toxicol. 2024; 187: 114628. https://doi.org/10.1016/j.fct.2024.114628

27. Harvey I., Stephenson E.J., Redd J.R., Tran Q.T., Hochberg I., Qi N., Bridges D. Glucocorticoid-Induced Metabolic Disturbances Are Exacerbated in Obese Male Mice. Endocrinology. 2018; 159(6): 2275–2287. https://doi.org/10.1210/en.2018-00147

28. García-Ruiz I., Rodríguez-Juan C., Díaz-Sanjuán T., Martínez M.Á., Muñoz-Yagüe T., Solís-Herruzo J.A. Effects of Rosiglitazone on the Liver Histology and Mitochondrial Function in Ob/Ob Mice. Hepatology. 2007; 46: 414–423. https://doi.org/10.1002/hep.21687

29. Rull A., Geeraert B., Aragonès G., Beltrán-Debón R., Rodríguez-Gallego E., García-Heredia A., Pedro-Botet J., Joven J., Holvoet P., Camps J. Rosiglitazone and fenofibrate exacerbate liver steatosis in a mouse model of obesity and hyperlipidemia. A transcriptomic and metabolomic study. J. Proteome Res. 2014; 13(3): 1731–43. https://doi.org/10.1021/pr401230s

30. Sadler N.C., Webb-Robertson B.M., Clauss T.R., Pounds J.G., Corley R., Wright A.T. High-Fat Diets Alter the Modulatory Effects of Xenobiotics on Cytochrome P450 Activities. Chem. Res. Toxicol. 2018; 31(5): 308–318. https://doi.org/10.1021/acs.chemrestox.8b00008

31. Li X., Wang Z., Klaunig J.E. The effects of perfluorooctanoate on high fat diet induced non-alcoholic fatty liver disease in mice. Toxicology. 2019; 416: 1–14. https://doi.org/10.1016/j.tox.2019.01.017

32. Sawant S.P., Dnyanmote A.V., Shankar K., Limaye P.B., Latendresse J.R., Mehendale H.M. Potentiation of carbon tetrachloride hepatotoxicity and lethality in type 2 diabetic rats. J. Pharmacol. Exp. Ther. 2004; 308(2): 694–704. https://doi.org/10.1124/jpet.103.058834

33. Donthamsetty S., Bhave V.S., Mitra M.S., Latendresse J.R., Mehendale H.M. Nonalcoholic fatty liver sensitizes rats to carbon tetrachloride hepatotoxicity. Hepatology. 2007; 45(2): 391–403. https://doi.org/10.1002/hep.21530

34. Kučera O., Roušar T., Staňková P., Haňáčková L., Lotková H., Podhola M., Cervinková Z. Susceptibility of rat non-alcoholic fatty liver to the acute toxic effect of acetaminophen. J. Gastroenterol. Hepatol. 2012; 27(2): 323–30. https://doi.org/10.1111/j.1440-1746.2011.06807.x

35. Corcoran G.B., Wong B.K. Obesity as a risk factor in drug-induced organ injury: increased liver and kidney damage by acetaminophen in the obese overfed rat. J. Pharmacol. Exp. Ther. 1987; 241(3): 921–927. https://pubmed.ncbi.nlm.nih.gov/3598908/

36. Li X., Li H., Lu N., Feng Y., Huang Y., Gao Z. Iron increases liver injury through oxidative/nitrative stress in diabetic rats: Involvement of nitrotyrosination of glucokinase. Biochimie. 2012; 94(12): 2620–7. https://doi.org/10.1016/j.biochi.2012.07.019

37. Gao W., Li X., Gao Z., Li H. Iron increases diabetes-induced kidney injury and oxidative stress in rats. Biol. Trace Elem. Res. 2014; 160(3): 368-75. https://doi.org/10.1007/s12011-014-0021-9

38. Ma Y., Yue C., Sun Q., Wang Y., Gong Z., Zhang K., Da J., Zou H., Zhu J., Zhao H., Song R., Liu Z. Cadmium exposure exacerbates kidney damage by inhibiting autophagy in diabetic rats. Ecotoxicol. Environ. Saf. 2023; 267: 115674. https://doi.org/10.1016/j.ecoenv.2023.115674

39. Wagner J.G., Allen K., Yang H.Y., Nan B., Morishita M., Mukherjee B., Dvonch J.T., Spino C., Fink G.D., Rajagopalan S., Sun Q., Brook R.D., Harkema J.R. Cardiovascular depression in rats exposed to inhaled particulate matter and ozone: effects of diet-induced metabolic syndrome. Environ. Health Perspect. 2014; 122(1): 27–33. https://pmc.ncbi.nlm.nih.gov/articles/PMC3888573/

40. D'souza A.M., Beaudry J.L., Szigiato A.A., Trumble S.J., Snook L.A., Bonen A., Giacca A., Riddell M.C. Consumption of a high-fat diet rapidly exacerbates the development of fatty liver disease that occurs with chronically elevated glucocorticoids. Am. J. Physiol. Gastrointest. Liver Physiol. 2012; 302(8): G850–63. https://doi.org/10.1152/ajpgi.00378.2011

41. Wang Y., Seitz H.K., Wang X.D. Moderate alcohol consumption aggravates high-fat diet induced steatohepatitis in rats. Alcohol Clin. Exp. Res. 2010; 34(3): 567–573. https://doi.org/10.1111/j.1530-0277.2009.01122.x

42. Zhang X., Deng Q., He Z., Li J., Ma X., Zhang Z., Wu D., Xing X., Peng J., Guo H., Huang M., Chen L., Dang S., Zhu Y., Zhang Z., Yang B., Wang H., Chen W., Xiao Y. Influence of benzene exposure, fat content, and their interactions on erythroid-related hematologic parameters in petrochemical workers: a cross-sectional study. BMC Public Health. 2020; 20(1): 382. https://doi.org/10.1186/s12889-020-08493-z

43. Han Y., Wang Y., Li W., Chen X., Xue T., Chen W., Fan Y., Qiu X., Zhu T. Susceptibility of prediabetes to the health effect of air pollution: a community-based panel study with a nested case-control design. Environ. Health. 2019; 18(1): 65. https://doi.org/10.1186/s12940-019-0502-6

44. Shi X., Wang X., Zhang J., Dang Y., Ouyang C., Pan J., Yang A., Hu X. Associations of mixed metal exposure with chronic kidney disease from NHANES 2011-2018. Sci. Rep. 2024; 14(1): 13062. https://doi.org/10.1038/s41598-024-63858-3

45. Park S.K., Auchincloss A.H., O'Neill M.S., Prineas R., Correa J.C., Keeler J., Barr R.G., Kaufman J.D., Diez Roux A.V. Particulate air pollution, metabolic syndrome, and heart rate variability: the multi-ethnic study of atherosclerosis (MESA). Environ. Health Perspect. 2010; 118(10): 1406–11. https://pubmed.ncbi.nlm.nih.gov/20529761/

46. Valentovic M.A., Alejandro N., Betts Carpenter A., Brown P.I., Ramos K. Streptozotocin (STZ) diabetes enhances benzo(alpha)pyrene induced renal injury in Sprague Dawley rats. Toxicol. Lett. 2006; 164(3): 214–20. https://doi.org/10.1016/j.toxlet.2005.12.009

47. Costa C., Pupo C., Viscomi G., Catania S., Salemi M., Imperatore C. Modifications in the metabolic pathways of benzene in streptozotocin-induced diabetic rat. Arch. Toxicol. 1999; 73(6): 301–6. https://doi.org/10.1007/s002040050622

48. Apaydin F.G., Kalender S., Bas H., Demir F., Kalender Y. Lead Nitrate Induced Testicular Toxicity in Diabetic and Non-Diabetic Rats: Protective Role of Sodium Selenite. Arch. Biol. Technol. 2015; 58(1): 68–74. https://doi.org/10.1590/S1516-8913201400025

49. Hosseini S.A., Ahmadipour A., Soltani M. et al. Malathion-increased Hepatotoxicity in Diabetic Rats. Pharmaceutical and Biomedical Research. 2020; 6(1): 53–60. https://doi.org/10.18502/pbr.v6i1.3428

50. Blouin R.A., Dickson P., McNamara P.J., Cibull M., McClain C. Phenobarbital induction and acetaminophen hepatotoxicity: resistance in the obese Zucker rodent. J. Pharmacol. Exp. Ther. 1987; 243(2): 565–70.

51. Cao Z., Bakulski K.M., Paulson H.L., Wang X. Exposure to Heavy Metals, Obesity, and Stroke Mortality in the United States. medRxiv [Preprint]. 2023; 18: 2023.09.18.23295722. https://doi.org/10.1101/2023.09.18.23295722