Iranian Journal of Medical Sciences

Document Type : Original Article(s)

Authors

1 Clinical Biomechanics and Ergonomics Center, Aja University of Medical Sciences, Tehran, Iran

2 Department of Exercise Physiology, Faculty of Sport Sciences and Health, University of Tehran, Tehran, Iran

3 Department of Exercise Physiology, Faculty of Sports Sciences, Shomal University, Amol, Iran

10.30476/ijms.2026.107912.4254

Abstract

Background: Diabetic Cardiomyopathy (DCM) is connected to prolonged systemic glucose metabolism and/or hyperinsulinemia-induced cardiac metaflammation. This study aims to investigate the effects of combined endurance and resistance training on the protein levels of nucleotide-binding domain, leucine-rich–containing family, pyrin domain–containing-3 (NLRP3), caspase-1, and interleukin -1β (IL-1β) in the myocardium of male rats with type 2 diabetes. 
Methods: In this experimental study, 24 male Wistar rats (8 weeks old, 260±20 g) were randomly divided into three groups: (n=8/groups): Normal Control (NC), Diabetes Control (DC), and Diabetes+Combined Training (DCT). After type 2 diabetes induction, the training group performed the combined training for 8 weeks, five sessions/week, in spring 2024 at AJA University of Medical Sciences. Approximately 48 hours following the end of the training protocol, blood samples and myocardium tissue were taken for subsequent assessment of inflammatory and biochemical markers. Group comparisons were achieved using one-way ANOVA, followed by the Tukey post hoc test using SPSS (version 22).
Results: Chronic implementation of combined training significantly downregulated final weight (P=0.033), protein levels of NLRP3, Caspase-1, and IL-1β (P=0.03, 0.001 and 0.019, respectively) in the cardiac tissue as well as modulation the homeostatic model assessment for insulin resistance (HOMA-IR: P=0.039) via attenuation of serum glucose and insulin levels (P=0.032 and 0.07) of the training group compared to the diabetic group. 
Conclusion: The modality of combined training (endurance+resistance) can reduce the risk factors associated with DCM in the myocardium of type 2 diabetic rats.

Highlights

Kambiz Pourfarzad (Google Scholar
Simin Riahy (Google Scholar)

Keywords

  1. Amanat S, Ghahri S, Dianatinasab A, Fararouei M, Dianatinasab M. Exercise and Type 2 Diabetes. Adv Exp Med Biol. 2020;1228:91-105. doi: 10.1007/978-981-15-1792-1_6. PubMed PMID: 32342452.
  2. Sampath Kumar A, Maiya AG, Shastry BA, Vaishali K, Ravishankar N, Hazari A, et al. Exercise and insulin resistance in type 2 diabetes mellitus: A systematic review and meta-analysis. Ann Phys Rehabil Med. 2019;62:98-103. doi: 10.1016/j.rehab.2018.11.001. PubMed PMID: 30553010.
  3. Sun Y, Ding S. NLRP3 Inflammasome in Diabetic Cardiomyopathy and Exercise Intervention. Int J Mol Sci. 2021;22. doi: 10.3390/ijms222413228. PubMed PMID: 34948026; PubMed Central PMCID: PMC8707657.
  4. Yu ZW, Zhang J, Li X, Wang Y, Fu YH, Gao XY. A new research hot spot: The role of NLRP3 inflammasome activation, a key step in pyroptosis, in diabetes and diabetic complications. Life Sci. 2020;240:117138. doi: 10.1016/j.lfs.2019.117138. PubMed PMID: 31809715.
  5. Satheesan A, Kumar J, Leela KV, Murugesan R, Chaithanya V, Angelin M. Review on the role of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome pathway in diabetes: mechanistic insights and therapeutic implications. Inflammopharmacology. 2024;32:2753-79. doi: 10.1007/s10787-024-01556-2. PubMed PMID: 39160391.
  6. Swanson KV, Deng M, Ting JP. The NLRP3 inflammasome: molecular activation and regulation to therapeutics. Nat Rev Immunol. 2019;19:477-89. doi: 10.1038/s41577-019-0165-0. PubMed PMID: 31036962; PubMed Central PMCID: PMC7807242.
  7. Luo B, Huang F, Liu Y, Liang Y, Wei Z, Ke H, et al. NLRP3 Inflammasome as a Molecular Marker in Diabetic Cardiomyopathy. Front Physiol. 2017;8:519. doi: 10.3389/fphys.2017.00519. PubMed PMID: 28790925; PubMed Central PMCID: PMC5524816.
  8. Milan KL, Megha B, Ramkumar KM. Role of inflammasomes in diabetes mellitus: mechanisms, complications, and therapeutic potential. Mol Biol Rep. 2025;52:621. doi: 10.1007/s11033-025-10719-5. PubMed PMID: 40544214.
  9. Schroeder EC, Franke WD, Sharp RL, Lee DC. Comparative effectiveness of aerobic, resistance, and combined training on cardiovascular disease risk factors: A randomized controlled trial. PLoS One. 2019;14:e0210292. doi: 10.1371/journal.pone.0210292. PubMed PMID: 30615666; PubMed Central PMCID: PMC6322789.
  10. Chen X, Li H, Wang K, Liang X, Wang W, Hu X, et al. Aerobic Exercise Ameliorates Myocardial Inflammation, Fibrosis and Apoptosis in High-Fat-Diet Rats by Inhibiting P2X7 Purinergic Receptors. Front Physiol. 2019;10:1286. doi: 10.3389/fphys.2019.01286. PubMed PMID: 31681001; PubMed Central PMCID: PMC6798156.
  11. Mardare C, Kruger K, Liebisch G, Seimetz M, Couturier A, Ringseis R, et al. Endurance and Resistance Training Affect High Fat Diet-Induced Increase of Ceramides, Inflammasome Expression, and Systemic Inflammation in Mice. J Diabetes Res. 2016;2016:4536470. doi: 10.1155/2016/4536470. PubMed PMID: 26788518; PubMed Central PMCID: PMC4691630.
  12. Quiroga R, Nistal E, Estebanez B, Porras D, Juarez-Fernandez M, Martinez-Florez S, et al. Exercise training modulates the gut microbiota profile and impairs inflammatory signaling pathways in obese children. Exp Mol Med. 2020;52:1048-61. doi: 10.1038/s12276-020-0459-0. PubMed PMID: 32624568; PubMed Central PMCID: PMC8080668.
  13. Liang F, Huang T, Li B, Zhao Y, Zhang X, Xu B. High-intensity interval training and moderate-intensity continuous training alleviate beta-amyloid deposition by inhibiting NLRP3 inflammasome activation in APPswe/PS1dE9 mice. Neuroreport. 2020;31:425-32. doi: 10.1097/WNR.0000000000001429. PubMed PMID: 32150150.
  14. ZhuGe DL, Javaid HMA, Sahar NE, Zhao YZ, Huh JY. Fibroblast growth factor 2 exacerbates inflammation in adipocytes through NLRP3 inflammasome activation. Arch Pharm Res. 2020;43:1311-24. doi: 10.1007/s12272-020-01295-2. PubMed PMID: 33245516.
  15. Guide for the Care and Use of Laboratory Animals. The National Academies Collection: Reports funded by National Institutes of Health. 8th ed. Washington (DC)2011. doi: 10.17226/12910. PubMed PMID: 21595115.
  16. Rashidpour A, Piralaiy E, Hamidian G, Ismael BR. Protective effects of aerobic exercise on cardiac histology and stereological parameters in a rat model of type 2 diabetes mellitus. J Diabetes Metab Disord. 2025;24:138. doi: 10.1007/s40200-025-01641-5. PubMed PMID: 40469910; PubMed Central PMCID: PMC12130402.
  17. Shaikh SA, Varatharajan R, Muthuraman A. Palm Oil Derived Tocotrienol-Rich Fraction Attenuates Vascular Dementia in Type 2 Diabetic Rats. Int J Mol Sci. 2022;23. doi: 10.3390/ijms232113531. PubMed PMID: 36362316; PubMed Central PMCID: PMC9653761.
  18. Parastesh M, Heidarianpour A, Sadegh M. Investigating the effects of endurance, resistance and combined training on reproductive hormones and sperm parameters of streptozotocin-nicotinamide diabetic male rats. J Diabetes Metab Disord. 2019;18:273-9. doi: 10.1007/s40200-018-0380-4. PubMed PMID: 31890651; PubMed Central PMCID: PMC6915199.
  19. Ghadiri N, Gorgin Karaji Z, Farsani ZH, Akbarzadeh H. The combined effects of resistance and endurance training with ursolic acid supplementation on some Alzheimer’s disease-related biomarkers in a rat model of type 2 diabetes. Bulletin of the National Research Centre. 2024;48:85. doi: 10.1186/s42269-024-01240-z.
  20. Galvan-Alvarez V, Martin-Rincon M, Gallego-Selles A, Martinez Canton M, HamedChaman N, Gelabert-Rebato M, et al. Determinants of the maximal functional reserve during repeated supramaximal exercise by humans: The roles of Nrf2/Keap1, antioxidant proteins, muscle phenotype and oxygenation. Redox Biol. 2023;66:102859. doi: 10.1016/j.redox.2023.102859. PubMed PMID: 37666117; PubMed Central PMCID: PMC10491831.
  21. Chen D, Sindone A, Huang MLH, Peter K, Jenkins AJ. Diabetic cardiomyopathy: insights into pathophysiology, diagnosis and clinical management. J Mol Cell Cardiol. 2025;206:55-69. doi: 10.1016/j.yjmcc.2025.06.013. PubMed PMID: 40623544.
  22. Rais N, Ved A, Ahmad R, Parveen K, Gautam GK, Bari DG, et al. Model of Streptozotocin-nicotinamide Induced Type 2 Diabetes: a Comparative Review. Curr Diabetes Rev. 2022;18:e171121198001. doi: 10.2174/1573399818666211117123358. PubMed PMID: 34789130.
  23. Stanford KI, Goodyear LJ. Exercise and type 2 diabetes: molecular mechanisms regulating glucose uptake in skeletal muscle. Adv Physiol Educ. 2014;38:308-14. doi: 10.1152/advan.00080.2014. PubMed PMID: 25434013; PubMed Central PMCID: PMC4315445.
  24. Petersen AM, Pedersen BK. The anti-inflammatory effect of exercise. J Appl Physiol (1985). 2005;98:1154-62. doi: 10.1152/japplphysiol.00164.2004. PubMed PMID: 15772055.
  25. Zhang Y, Ye T, Zhou P, Li R, Liu Z, Xie J, et al. Exercise ameliorates insulin resistance and improves ASK1-mediated insulin signalling in obese rats. J Cell Mol Med. 2021;25:10930-8. doi: 10.1111/jcmm.16994. PubMed PMID: 34734480; PubMed Central PMCID: PMC8642671.
  26. Ding S, Xu S, Ma Y, Liu G, Jang H, Fang J. Modulatory Mechanisms of the NLRP3 Inflammasomes in Diabetes. Biomolecules. 2019;9. doi: 10.3390/biom9120850. PubMed PMID: 31835423; PubMed Central PMCID: PMC6995523.
  27. Zhang X, Fu Y, Li H, Shen L, Chang Q, Pan L, et al. H3 relaxin inhibits the collagen synthesis via ROS- and P2X7R-mediated NLRP3 inflammasome activation in cardiac fibroblasts under high glucose. J Cell Mol Med. 2018;22:1816-25. doi: 10.1111/jcmm.13464. PubMed PMID: 29314607; PubMed Central PMCID: PMC5824385.
  28. Luo B, Li B, Wang W, Liu X, Liu X, Xia Y, et al. Rosuvastatin alleviates diabetic cardiomyopathy by inhibiting NLRP3 inflammasome and MAPK pathways in a type 2 diabetes rat model. Cardiovasc Drugs Ther. 2014;28:33-43. doi: 10.1007/s10557-013-6498-1. PubMed PMID: 24254031.
  29. Ye Y, Bajaj M, Yang HC, Perez-Polo JR, Birnbaum Y. SGLT-2 Inhibition with Dapagliflozin Reduces the Activation of the Nlrp3/ASC Inflammasome and Attenuates the Development of Diabetic Cardiomyopathy in Mice with Type 2 Diabetes. Further Augmentation of the Effects with Saxagliptin, a DPP4 Inhibitor. Cardiovasc Drugs Ther. 2017;31:119-32. doi: 10.1007/s10557-017-6725-2. PubMed PMID: 28447181.
  30. Zhang H, Chen X, Zong B, Yuan H, Wang Z, Wei Y, et al. Gypenosides improve diabetic cardiomyopathy by inhibiting ROS-mediated NLRP3 inflammasome activation. J Cell Mol Med. 2018;22:4437-48. doi: 10.1111/jcmm.13743. PubMed PMID: 29993180; PubMed Central PMCID: PMC6111804.
  31. Zhang T, Ding S, Wang R. Research Progress of Mitochondrial Mechanism in NLRP3 Inflammasome Activation and Exercise Regulation of NLRP3 Inflammasome. Int J Mol Sci. 2021;22. doi: 10.3390/ijms221910866. PubMed PMID: 34639204; PubMed Central PMCID: PMC8509472.
  32. Zaidi H, Byrkjeland R, Njerve IU, Akra S, Solheim S, Arnesen H, et al. Effects of exercise training on inflammasome-related mediators and their associations to glucometabolic variables in patients with combined coronary artery disease and type 2 diabetes mellitus: Sub-study of a randomized control trial. Diab Vasc Dis Res. 2019;16:360-8. doi: 10.1177/1479164119836922. PubMed PMID: 30939905.
  33. Lee J, Lee Y, LaVoy EC, Umetani M, Hong J, Park Y. Physical activity protects NLRP3 inflammasome-associated coronary vascular dysfunction in obese mice. Physiol Rep. 2018;6:e13738. doi: 10.14814/phy2.13738. PubMed PMID: 29932503; PubMed Central PMCID: PMC6014451.
  34. Hong J, Park E, Lee J, Lee Y, Rooney BV, Park Y. Exercise training mitigates ER stress and UCP2 deficiency-associated coronary vascular dysfunction in atherosclerosis. Sci Rep. 2021;11:15449. doi: 10.1038/s41598-021-94944-5. PubMed PMID: 34326395; PubMed Central PMCID: PMC8322067.
  35. Ma M, Chen W, Hua Y, Jia H, Song Y, Wang Y. Aerobic exercise ameliorates cardiac hypertrophy by regulating mitochondrial quality control and endoplasmic reticulum stress through M(2) AChR. J Cell Physiol. 2021;236:6581-96. doi: 10.1002/jcp.30342. PubMed PMID: 33615478.