Tracking hepcidin level in induced type 2 diabetic rats and how Empagliflozin affects its level
Main Article Content
Keywords
Hepcidin, peripheral insulin resistance, SGLT2 inhibitor, high-fat diet/high-sugar diet, insulin
Abstract
Background: Hepcidin is a hormone that contributes in iron homeostasis, produced either through hepatic or extrahepatic pathways. Its production may be affected by proinflammatory mediators released by macrophages, which play a role in development of peripheral insulin resistance. Insulin itself may increase the production of hepcidin hormone from pancreatic β-cells.
Objectives: To evaluate the impact of induction type 2 diabetes mellitus (T2DM) in albino wister rat on the level of hepcidin. Also, to examine the role of two-week use of Empagliflozin, a sodium-glucose cotransporter-2 inhibitor (SGLT2 Inhibitor), on the hepcidin level comparing to control.
Method: An interventional study includes randomization of 36 rats into three groups (A: negative control, B: positive control, and C: Empagliflozin group). Two rats were excluded from the study for different reasons. T2DM was induced using high-fat diet/high-sugar diet (HFD/HSD) for 8 weeks. Empagliflozin then given to group C for two weeks in a dose of 35 mg/kg/day. Hepcidin level determined at the baseline, week 8, and week 10 intervals. Hepcidin was determined using enzyme-linked immunosorbent assay (ELISA).
Results: Hepcidin level significantly increased following induction of T2DM in both B and C groups. Hepcidin level in Group B insignificantly reduced two weeks after discontinuation of HFD/HSD and significantly reduced in group C. Group A experienced no statistical difference in hepcidin level at week 10 in compare to baseline.
Conclusion: Induction of T2DM associates with significant increase of Hepcidin level. Empagliflozin significantly reduced hepcidin level in newly induced diabetic rats.
References
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17. Hattori S. Anti-inflammatory effects of empagli-flozin in patients with type 2 diabetes and insu-lin resistance. Diabetol Metab Syndr. 2018 Dec 18;10:93. https://doi.org/10.1186/s13098-018-0395-5
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19. Miyachi Y, Tsuchiya K, Shiba K, et al. A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibi-tion. Sci Rep. 2018 Oct 31;8(1):16113. https://doi.org/10.1038/s41598-018-34305-x
20. Bjornstad P, Greasley PJ, Wheeler DC, et al. The potential roles of osmotic and nonosmotic sodium handling in mediating the effects of sodium- glucose cotransporter 2 inhibitors on heart failure. J Card Fail. 2021 Dec;27(12):1447–1455. https://doi.org/10.1016/j.cardfail.2021.07.003
21. Ghanim H, Abuaysheh S, Hejna J, et al. Dapagliflozin suppresses hepcidin and increases erythro-poiesis. J Clin Endocrinol Metab. 2020 Apr 1; 105(4):dgaa057. https://doi.org/10.1210/clinem/dgaa057
22. Han Y, Huang W, Meng H, et al. Pro-inflammatory cytokine interleukin-6-induced hepcidin, a key mediator of periodontitis-related anemia of inflam-mation. J Periodontal Res. 2021 Aug;56(4):690–701. https://doi.org/10.1111/jre.12865
23. Jiang F, Sun ZZ, Tang YT, et al. Hepcidin expres-sion and iron parameters change in type 2 diabetic patients. Diabetes Res Clin Pract. 2011 Jul;93(1):43–48. https://doi.org/10.1016/j.diabres.2011.03.028
24. Nikolakopoulou P, Chatzigeorgiou A, Kourtzelis I, et al. Streptozotocin-induced β-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain. Sci Rep. 2018 Jul 27;8(1):11335. https://doi.org/10.1038/s41598-018-29434-2
25. Hayashi K, Kojima R, and Ito M. Strain differ-ences in the diabetogenic activity of streptozotocin in mice. Biol Pharm Bull. 2006 Jun;29(6):1110–1119. https://doi.org/10.1248/bpb.29.1110
26. Furman BL. Streptozotocin-induced diabetic mod-els in mice and rats. Curr Protoc Pharmacol. 2015 Sep 1;70:5.47.1–5.47.20. https://doi.org/10.1002/0471141755.ph0547s70
27. Nedosugova LV, Markina YV, Bochkareva LA, et al. Inflammatory mechanisms of diabetes and its vascular complications. Biomedicines. 2022 May 18;10(5):1168. https://doi.org/10.3390/biomedicines10051168
28. Bekri S, Gual P, Anty R, et al. Increased adi-pose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006 Sep;131(3):788–796. https://doi.org/10.1053/j.gastro.2006.07.007
29. Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al. STAT3 mediates hepatic hepcidin expres-sion and its inflammatory stimulation. Blood. 2007 Jan 1;109(1):353–358. https://doi.org/10.1182/blood-2006-07-033969
30. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007 Jan; 132(1):294–300. https://doi.org/10.1053/j.gastro.2006.10.018
31. Altamura S, Kopf S, Schmidt J, Müdder K, et al. Uncoupled iron homeostasis in type 2 diabetes mellitus. J Mol Med (Berl). 2017 Dec;95(12):1387–1398. https://doi.org/10.1007/s00109-017-1596-3
32. Sam AH, Busbridge M, Amin A, et al. Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. Diabet Med. 2013 Dec;30(12):1495–1499. https://doi.org/10.1111/dme.12262
33. Suárez-Ortegón MF, Moreno M, Arbeláez A, et al. Circulating hepcidin in type 2 diabetes: a multivariate analysis and double blind evaluation of metformin effects. Mol Nutr Food Res. 2015 Dec;59(12):2460–2470. https://doi.org/10.1002/mnfr.201500310
34. Ndevahoma F, Mukesi M, Dludla PV, et al. Body weight and its influence on hepcidin levels in patients with type 2 diabetes: a systematic review and meta-analysis of clinical studies. Heliyon. 2021 Mar 11;7(3):e06429. https://doi.org/10.1016/j.heliyon.2021.e06429
35. Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling path-ways. J Immunol Res. 2021 Jun 2;2021:9944880. https://doi.org/10.1155/2021/9944880
36. Qu W, Yao L, Liu X, et al. Effects of sodium- glucose co-transporter 2 inhibitors on hemoglobin levels: a meta-analysis of randomized controlled trials. Front Pharmacol. 2021 Mar 12;12:630820. https://doi.org/10.3389/fphar.2021.630820
2. Bek SG, Üstüner B, Eren N, et al. The effect of hepcidin on components of metabolic syndrome in chronic kidney disease: a cross-sectional study. Rev Assoc Med Bras (1992). 2020 Aug;66(8):1100–1107. https://doi.org/10.1590/1806-9282.66.8.1100
3. Kwapisz J, Slomka A, and Zekanowska E. Hepcidin and its role in iron homeostasis. EJIFCC. 2009 Aug 25;20(2):124–128.
4. Zhang AS, Davies PS, Carlson HL, et al Mechanisms of HFE-induced regulation of iron homeostasis: insights from the W81A HFE mutation. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9500–9505. https://doi.org/10.1073/pnas.1233675100
5. D’Angelo G. Role of hepcidin in the pathophys-iology and diagnosis of anemia. Blood Res. 2013 Mar;48(1):10–15. https://doi.org/10.5045/br.2013.48.1.10
6. Rishi G, Wallace DF, and Subramaniam VN. Hepcidin: regulation of the master iron regulator. Biosci Rep. 2015 Mar 31;35(3):e00192. https://doi.org/10.1042/BSR20150014
7. Charlebois E, and Pantopoulos K. Iron overload inhibits BMP/SMAD and IL-6/STAT3 signaling to hepcidin in cultured hepatocytes. PLoS One. 2021 Jun 23;16(6):e0253475. https://doi.org/10.1371/journal.pone.0253475
8. Kemna EH, Tjalsma H, Willems HL, et al. Hepcidin: from discovery to differential diagnosis. Haematologica. 2008 Jan;93(1):90–97. https://doi.org/10.3324/haematol.11705
9. Zhao N, Zhang AS, and Enns CA. Iron regulation by hepcidin. J Clin Invest. 2013 Jun;123(6):2337–2343. https://doi.org/10.1172/JCI67225
10. Mashili F, Chibalin AV, Krook A, et al. Constitutive STAT3 phosphorylation contributes to skele-tal muscle insulin resistance in type 2 diabetes. Diabetes. 2013 Feb;62(2):457–465. https://doi.org/10.2337/db12-0337
11. Wang H, Li H, Jiang X, et al. Hepcidin is directly regulated by insulin and plays an important role in iron overload in streptozotocin-induced diabetic rats. Diabetes. 2014 May;63(5):1506–1518. https://doi.org/10.2337/db13-1195
12. Aregbesola A, Voutilainen S, Virtanen JK, et al. Serum hepcidin concentrations and type 2 diabetes. World J Diabetes. 2015 Jul 10;6(7):978–982. https://doi.org/10.4239/wjd.v6.i7.978
13. Nnodimy J, Chidozie NJ, Eberechi N, et al. Alterations of hepcidin and interleukin in dia-betics. Clinic Res Urol. 2020;3(1):1–3. https://doi.org/10.33309/2638-7670.030105
14. Kulaksiz H, Theilig F, Bachmann S, et al. The iron-regulatory peptide hormone hepcidin: expres-sion and cellular localization in the mammalian kidney. J Endocrinol. 2005 Feb;184(2):361–370. https://doi.org/10.1677/joe.1.05729
15. Atyia FTF, Gawaly AM, and Abd El-Bar ES. Hepcidin level changes in type 2 diabetes. Med J Cairo Univ. 2018 Sep; 86(6):3077–3082. https://doi.org/10.21608/mjcu.2018.59877
16. Fernández-Real JM, McClain D, and Manco M. Mechanisms linking glucose homeostasis and iron metabolism toward the onset and progression of type 2 diabetes. Diabetes Care. 2015 Nov;38(11):2169–2176. https://doi.org/10.2337/dc14-3082
17. Hattori S. Anti-inflammatory effects of empagli-flozin in patients with type 2 diabetes and insu-lin resistance. Diabetol Metab Syndr. 2018 Dec 18;10:93. https://doi.org/10.1186/s13098-018-0395-5
18. Singh RB, Fatima G, Kumar P, et al. Effects of empagliflozin on proinflammatory cytokines and other coronary risk factors in patients with type 2 diabetes mellitus: a single-arm real-world observa-tion. Int J Clin Pharmacol Ther. 2021 Jan;59(1):17–25.https://doi.org/10.5414/CP203787
19. Miyachi Y, Tsuchiya K, Shiba K, et al. A reduced M1-like/M2-like ratio of macrophages in healthy adipose tissue expansion during SGLT2 inhibi-tion. Sci Rep. 2018 Oct 31;8(1):16113. https://doi.org/10.1038/s41598-018-34305-x
20. Bjornstad P, Greasley PJ, Wheeler DC, et al. The potential roles of osmotic and nonosmotic sodium handling in mediating the effects of sodium- glucose cotransporter 2 inhibitors on heart failure. J Card Fail. 2021 Dec;27(12):1447–1455. https://doi.org/10.1016/j.cardfail.2021.07.003
21. Ghanim H, Abuaysheh S, Hejna J, et al. Dapagliflozin suppresses hepcidin and increases erythro-poiesis. J Clin Endocrinol Metab. 2020 Apr 1; 105(4):dgaa057. https://doi.org/10.1210/clinem/dgaa057
22. Han Y, Huang W, Meng H, et al. Pro-inflammatory cytokine interleukin-6-induced hepcidin, a key mediator of periodontitis-related anemia of inflam-mation. J Periodontal Res. 2021 Aug;56(4):690–701. https://doi.org/10.1111/jre.12865
23. Jiang F, Sun ZZ, Tang YT, et al. Hepcidin expres-sion and iron parameters change in type 2 diabetic patients. Diabetes Res Clin Pract. 2011 Jul;93(1):43–48. https://doi.org/10.1016/j.diabres.2011.03.028
24. Nikolakopoulou P, Chatzigeorgiou A, Kourtzelis I, et al. Streptozotocin-induced β-cell damage, high fat diet, and metformin administration regulate Hes3 expression in the adult mouse brain. Sci Rep. 2018 Jul 27;8(1):11335. https://doi.org/10.1038/s41598-018-29434-2
25. Hayashi K, Kojima R, and Ito M. Strain differ-ences in the diabetogenic activity of streptozotocin in mice. Biol Pharm Bull. 2006 Jun;29(6):1110–1119. https://doi.org/10.1248/bpb.29.1110
26. Furman BL. Streptozotocin-induced diabetic mod-els in mice and rats. Curr Protoc Pharmacol. 2015 Sep 1;70:5.47.1–5.47.20. https://doi.org/10.1002/0471141755.ph0547s70
27. Nedosugova LV, Markina YV, Bochkareva LA, et al. Inflammatory mechanisms of diabetes and its vascular complications. Biomedicines. 2022 May 18;10(5):1168. https://doi.org/10.3390/biomedicines10051168
28. Bekri S, Gual P, Anty R, et al. Increased adi-pose tissue expression of hepcidin in severe obesity is independent from diabetes and NASH. Gastroenterology. 2006 Sep;131(3):788–796. https://doi.org/10.1053/j.gastro.2006.07.007
29. Verga Falzacappa MV, Vujic Spasic M, Kessler R, et al. STAT3 mediates hepatic hepcidin expres-sion and its inflammatory stimulation. Blood. 2007 Jan 1;109(1):353–358. https://doi.org/10.1182/blood-2006-07-033969
30. Pietrangelo A, Dierssen U, Valli L, et al. STAT3 is required for IL-6-gp130-dependent activation of hepcidin in vivo. Gastroenterology. 2007 Jan; 132(1):294–300. https://doi.org/10.1053/j.gastro.2006.10.018
31. Altamura S, Kopf S, Schmidt J, Müdder K, et al. Uncoupled iron homeostasis in type 2 diabetes mellitus. J Mol Med (Berl). 2017 Dec;95(12):1387–1398. https://doi.org/10.1007/s00109-017-1596-3
32. Sam AH, Busbridge M, Amin A, et al. Hepcidin levels in diabetes mellitus and polycystic ovary syndrome. Diabet Med. 2013 Dec;30(12):1495–1499. https://doi.org/10.1111/dme.12262
33. Suárez-Ortegón MF, Moreno M, Arbeláez A, et al. Circulating hepcidin in type 2 diabetes: a multivariate analysis and double blind evaluation of metformin effects. Mol Nutr Food Res. 2015 Dec;59(12):2460–2470. https://doi.org/10.1002/mnfr.201500310
34. Ndevahoma F, Mukesi M, Dludla PV, et al. Body weight and its influence on hepcidin levels in patients with type 2 diabetes: a systematic review and meta-analysis of clinical studies. Heliyon. 2021 Mar 11;7(3):e06429. https://doi.org/10.1016/j.heliyon.2021.e06429
35. Lee N, Heo YJ, Choi SE, et al. Anti-inflammatory effects of empagliflozin and gemigliptin on LPS-stimulated macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 signalling path-ways. J Immunol Res. 2021 Jun 2;2021:9944880. https://doi.org/10.1155/2021/9944880
36. Qu W, Yao L, Liu X, et al. Effects of sodium- glucose co-transporter 2 inhibitors on hemoglobin levels: a meta-analysis of randomized controlled trials. Front Pharmacol. 2021 Mar 12;12:630820. https://doi.org/10.3389/fphar.2021.630820
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Dec 09, 2022
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Riyam Bassil Ali, Ahmed, M. H., Haidar K. Ibrahim, & Hasanain Sh. Mahmood. (2022). Tracking hepcidin level in induced type 2 diabetic rats and how Empagliflozin affects its level. Journal of Population Therapeutics and Clinical Pharmacology, 29(04), 158-166. https://doi.org/10.47750/jptcp.2022.965
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All articles published in JPTCP are licensed under Copyright Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Riyam Bassil Ali, Ahmed, M. H., Haidar K. Ibrahim, & Hasanain Sh. Mahmood. (2022). Tracking hepcidin level in induced type 2 diabetic rats and how Empagliflozin affects its level. Journal of Population Therapeutics and Clinical Pharmacology, 29(04), 158-166. https://doi.org/10.47750/jptcp.2022.965