Hypoxic mesenchymal stem cell-derived secretome and alkaline water synergistically reduce apoptosis and insulin resistance in type 2 diabetes mellitus rat model
Main Article Content
Abstract
BACKGROUND
Type 2 Diabetes Mellitus (T2DM) is characterized by chronic inflammation and insulin resistance. These factors contribute to pancreatic β-cell apoptosis, reducing insulin production and impairing glucose homeostasis. This study aims to evaluate the protective effects of hypoxic mesenchymal stem cell-derived secretome (HMSCS) and alkaline water on inflammation, apoptosis, and insulin resistance in a T2DM rat model.
METHODS
An experimental study was conducted involving 24 male Wistar T2DM model rats (aged 6-8 weeks, 200-250g). They were randomized into four groups: T2DM rats only as negative control (K-), T2DM rats with metformin as positive control (K+), HMSCS treatment (P1), and HMSCS plus alkaline water group (P2). Caspase-3 expression was measured to assess apoptosis levels using RT-PCR, while homeostatic model assessment for insulin resistance (HOMA-IR) was measured using ELISA. One way ANOVA followed by a post hoc LSD test were used to analyse the data.
RESULTS
The P1 group (3.03 ± 1.26 a.u) and P2 group (2.93 ± 0.52 a.u.) had significantly lower caspase-3 expression compared to K- group (6.66 ± 2.76 a.u.) (p<0.05), but were not significantly different from K+ group (3.83 ± 1.61 a.u.) (p>0.05). Additionally, P2 group (6.76 ± 0.96) had a significantly lower HOMA-IR than K- group (18.92 ± 2.63) and K+ group (10.85 ± 1.39) (p<0.05), and similarly the P1 (7.71 ± 0.53) group also showed significant difference from K- and K+ groups (p<0.05).
CONCLUSION
Higher doses of HMSCS and alkaline water are associated with reduced pancreatic β-cell apoptosis and improved insulin sensitivity, highlighting its potential as a novel therapeutic approach for T2DM.
Article Details
Section
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.
The journal allows the authors to hold the copyright without restrictions and allow the authors to retain publishing rights without restrictions.
How to Cite
References
1. Galicia-Garcia U, Benito-Vicente A, Jebari S, et al. Pathophysiology of type 2 diabetes mellitus. Int J Mol Sci 2020; 21:6275. doi: 10.3390/ijms21176275.
2. Liu L, Du X, Zhang Z, Zhou J. Trigonelline inhibits caspase 3 to protect β cells apoptosis in streptozotocin-induced type 1 diabetic mice. Eur J Pharmacol 2018;836:115–21. doi: 10.1016/j.ejphar.2018.08.025.
3. Magliano DJ, Boyko EJ, Co-chair; IDF diabetes atlas 10th ed. scientific committee. Brussels: International Diabetes Federation; 2021.
4. Teratani T, Kasahara N, Fujimoto Y, et al. Mesenchymal stem cells secretions enhanced ATP generation on isolated islets during transplantation. Islets 2022;14:69–81. doi: 10.1080/19382014.2021.2022423.
5. Sun F, Sun Y, Wu F, Xu W, Qian H. Mesenchymal stem cell-derived extracellular vesicles: a potential therapy for diabetes mellitus and diabetic complications. Pharmaceutics 2022;14:2208. doi: 10.3390/pharmaceutics14102208.
6. Lee M, Fadriquela A, Antonio JM, et al. Effects of alkaline-reduced water on exercise-induced oxidative stress and fatigue in young male healthy adults. Processes 2022;10:1543. doi: 10.3390/pr10081543.
7. Rias YA, Kurniawan AL, Chang CW, Gordon CJ, Tsai HT. Synergistic effects of regular walking and alkaline electrolyzed water on decreasing inflammation and oxidative stress, and increasing quality of life in individuals with type 2 diabetes: A community-based randomized controlled trial. Antioxidants 2020;9:1–17. doi: 10.3390/antiox9100946.
8. Nasution I, Putra A, Setiawan E. Synergistic effects of hypoxia-preconditioned mesenchymal stem cells secretome and alkaline water in alleviating oxidative stress and inflammation in type 2 diabetic rats. Mater Socio-Medica 2025;37:4–10. doi: 10.5455/msm.2024.37.4-10.
9. Al-Azzawi B, McGuigan DH, Koivula FNM, et al. The secretome of mesenchymal stem cells prevents islet beta cell apoptosis via an IL-10-dependent mechanism. Open Stem Cell J 2020;6:1–12. doi: 10.2174/1876893802006010001.
10. Mayasari YI, Subchan P, Putra A. Secretome hypoxia mesenchymal stem cells inhibited ultraviolet radiation by inhibiting interleukin-6 through nuclear factor-kappa beta pathway in hyperpigmentation animal models. Open Access Maced J Med Sci 2023;11:188–94. doi: 10.3889/oamjms.2023.11222.
11. Pouriayevali F, Tavalaee M, Kazeminasab F, Dattilo M, Nasr-Esfahani MH. Effects of streptozotocin induced diabetes on one-carbon cycle and sperm function. Cell J 2024;26:81-90. doi: 10.22074/cellj.2023.2010652.1399.
12. Fardhani IM, Firdaus J, Febianti Z, Hairrudin H, Abrori C, Sakinah EN. The effect of neem gum on the reductionin rat blood glucose levels induced by streptozotocin. Bul Vet Udayana 2023;982–90. doi: 10.24843/bulvet.2023.v15.i05.p35.
13. Masoodian SM, Omidifar A, Moradkhani S, Asiabanha M, Khoshmirsafa M. HOMA-IR mean values in healthy individuals: a population-based study in Iranian subjects. J Diabetes Metab Disord 2022;22;219-24. doi: 10.1007/s40200-022-01099-9.
14. Liu YY, Chiang CH, Hung SC, et al. Hypoxia-preconditioned mesenchymal stem cells ameliorate ischemia/reperfusion-induced lung injury. PLoS One 2017;12:e018763. doi: 10.1371/journal.pone.0187637.
15. Sharma S, Lee KJ, Bajgai J, et al. Anti-oxidative and anti-diabetic effects of electrolyzed weakly alkaline reduced water on renal proximal tubular epithelial cells. Processes 2022;10:2025. doi: 10.3390/pr10102025.
16. Trigo CM, Rodrigues JS, Camões SP, Solá S, Miranda JP. Mesenchymal stem cell secretome for regenerative medicine: where do we stand? J Adv Res 2024;70:103–24. doi: 10.1016/j.jare.2024.05.004.
17. Sadeghi S, Mosaffa N, Huang B, Tehrani FR. Protective role of stem cells in POI: current status and mechanism of action, a review article. Heliyon 2024;10:e23271. doi: 10.1016/j.heliyon.2023.e23271.
18. Hu D, Kabayama S, Watanabe Y, et al. Health benefits of electrolyzed hydrogen water: antioxidant and anti-inflammatory effects in living organisms. Antioxidants 2024;13:313. doi: 10.3390/antiox13030313.
19. Delos Reyes FSLG, Mamaril ACC, Matias TJP, et al. The search for the elixir of life: on the therapeutic potential of alkaline reduced water in metabolic syndromes. Processes 2021;9:1876. doi: 10.3390/pr9111876.
20. Eguchi N, Vaziri ND, Dafoe DC, Ichii H. The role of oxidative stress in pancreatic β cell dysfunction in diabetes. Int J Mol Sci 2021;22:1509. doi: 10.3390/ijms22041509.
21. Chen J, Fei S, Chan LWC, et al. Inflammatory signaling pathways in pancreatic β-cell: new insights into type 2 diabetes pathogenesis. Pharmacol Res 2025;216:107776. doi: 10.1016/j.phrs.2025.107776.
22. Venkatesan K, Paulsamy P, Alqahtani S, et al. An update on the role of inflammation in insulin resistance and islet β cell failure: a crosstalk between immune cells, adipose tissue, cytokines, and oxidative stress. Lett Drug Des Discov 2025;22:100023. doi: 10.1016/j.lddd.2025.100023.
23. Wang C, Wu Y, Jiang J. The role and mechanism of mesenchymal stem cells in immunomodulation of type 1 diabetes mellitus and its complications: recent research progress and challenges: a review. Stem Cell Res Ther 2025;16:308. doi: 10.1186/s13287-025-04431-1.
24. Abdelmawgoud H, Saleh A. Anti-inflammatory and antioxidant effects of mesenchymal and hematopoietic stem cells in a rheumatoid arthritis rat model. Adv Clin Exp Med 2018;27:873–80. doi: 10.17219/acem/73720.
25. Zhang Y, Pan Y, Liu Y, et al. Exosomes derived from human umbilical cord blood mesenchymal stem cells stimulate regenerative wound healing via transforming growth factor-β receptor inhibition. Stem Cell Res Ther 2021;12:434. doi: 10.1186/s13287-021-02517-0.
26. Sun X, Hao H, Han Q, et al. Human mesenchymal stem cell derived secretome alleviates type 2 diabetes mellitus by reversing peripheral insulin resistance and relieving β-cell destruction. Stem Cell Res Ther 2018;9:1–13.
27. Donzelli E, Scuteri A. Mesenchymal stem cells: a trump card for the treatment of diabetes? Biomedicines 2020;8:112. doi: 10.3390/biomedicines8050112.
28. Huang CH, Chao YC, Chiang MT. Influence of alkaline reduced water supplementation on glucose and lipid metabolism in non-diabetic and diabetic rats. Nutrients 2024;16:4082. doi: 10.3390/nu16234082.