ZINC POTENTIATES THE ANTIOXIDANT EFFECT OF DAPAGLIFLOZIN IN RATS WITH EXPERIMENTAL-INDUCED DIABETES
Abstract
Diabetes mellitus (DM) is a multifaceted disorder that disrupts the body’s overall metabolic equilibrium, giving rise to various organ-related complications such as cardiovascular, neuronal, and renal problems. In this research, we aimed to investigate the effects of zinc chloride (Zn), dapagliflozin (DAPA) and their combination on some biochemical parameters evaluating the liver function, lipid metabolism and cellular oxidative processes in rats with streptozotocin-induced diabetes. Material and methods: The rats were distributed into five groups (of five animals each): Control: citrate buffer; STZ and fat diet; STZ+Zn and fat diet; STZ+DAPA and fat diet; STZ+DAPA+Zn and fat diet. DM was induced in rats by intraperitoneal administration of a single daily dose of streptozotocin (STZ) of 20 mg/ kg body weight (kbw), for three consecutive days, and fat diet (10 g cholesterol/100 g diet) for 4 weeks. Citrate buffer (0.1 mL/100 g body) was intraperitoneal administered to the control rats. DAPA 1 mg/kbw, and Zn 5 mg/kbw were administered orally as a single daily dose for 4 weeks. Results: The treatment with Zn, DAPA and their combination resulted in weight loss and a decrease in blood glucose level, the higher effect being evidenced in STZ+Dapa+Zn group. The use of Zn, DAPA and Zn+DAPA in STZ-induced DM in rats with fat diet led to a decrease in blood values of transaminases, total cholesterol, triglycerides and in malondialdehyde activity, most substantially in the group treated with DAPA and Zn association. Conclusions: These outcomes suggest that the supplementation with Zn of DAPA treatment, enhanced the DAPA effect on decreasing the glycemia, restored the liver function, improved the lipid metabolism, and reduced the oxidative stress in STZ-induced DM in rats.
References
2. Mascolo A, Di Napoli R, Balzano N et al. Safety profile of sodium glucose co-transporter 2 (SGLT2) inhibitors: A brief summary. Front Cardiovasc Med 2022; 9: 1010693.
3. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393(10166): 31-39.
4. Minze MG, Will KJ, Terrell BT, Black RL, Irons BK. Benefits of SGLT2 inhibitors beyond glycemic control - a focus on metabolic, cardiovascular and renal outcomes. Curr Diabetes Rev 2018; 14(6): 509-517.
5. Shin H, Schneeweiss S, Glynn RJ, Patorno E. Evolving channeling in prescribing SGLT-2 inhibitors as first-line treatment for type 2 diabetes. Pharmacoepidemiol Drug Saf 2022; 31(5): 566-576.
6. Srinivas N, Sarnaik MK, Modi S, et al. Sodium-glucose cotransporter 2 (SGLT-2) inhibitors: delving into the potential benefits of cardiorenal protection beyond the treatment of type-2 diabetes mellitus. Cureus 2021;13(8):e16868.
7. Suga T, Kikuchi O, Kobayashi M, et al. SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels. Mol Metab 2019; 19: 1-12.
8. Duan S, Lu F, Song D, Zhang C, Zhang B, Xing C, Yuan Y. Current challenges and future perspectives of renal tubular dysfunction in diabetic kidney disease. Front Endocrinol (Lausanne) 2021; 12: 661185.
9. Granata A, Pesce F, Iacoviello M, et al. SGLT2 inhibitors: a broad impact therapeutic option for the nephrologist. Front Nephrol 2022; 2: 867075.
10. Vallon V, Nakagawa T. Renal tubular handling of glucose and fructose in health and disease. Compr Physiol 2021; 12(1): 2995-3044.
11. Zelniker TA, Wiviott SD, Raz I, et al. SGLT2 inhibitors for primary and secondary prevention of cardiovascular and renal outcomes in type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials. Lancet 2019; 393: 31.
12. Tuttle KR. Digging deep into cells to find mechanisms of kidney protection by SGLT2 inhibitors. J Clin Invest 2023; 133(5): e167700.
13. Jarosz M, Olbert M, Wyszogrodzka G, Młyniec K, Librowski T. Antioxidant and anti-inflammatory effects of zinc: zinc-dependent NF-κB signaling. Inflammopharmacology 2017; 25(1): 11–24.
14. Pompano LM, Boy E. Effects of dose and duration of zinc interventions on risk factors for type 2 diabetes and cardiovascular disease: a systematic review and meta-analysis. Adv Nutr 2021; 12(3): 1049.
15. Grădinaru D, Margină D, Ungurianu A, et al. Zinc status insulin resistance and glycoxidative stress in elderly subjects with type 2 diabetes mellitus. Exp Ther Med 2021; 22(6): 1393.
16. Choi S, Liu X, Pan Z. Zinc deficiency and cellular oxidative stress: prognostic implications in cardiovascular diseases. Acta Pharmacol Sin 2018; 39: 1120-1132.
17. Norouzi S, Adulcikas J, Sohal SS, Myers S. Zinc transporters and insulin resistance: therapeutic implications for type 2 diabetes and metabolic disease. J Biomed Sci 2017; 24: 87.
18. Fatehi M. Impact of zinc on insulin resistance and hepatic fat accumulation. Preprints 2023; 2023 010012.
19. Carmo de Carvalho e Martins M, da Silva Santos Oliveira AS, da Silva LAA, Primo MGS, de Carvalho Lira VB. Biological indicators of oxidative stress [malondialdehyde, catalase, glutathione peroxidase, and superoxide dismutase] and their application in nutrition. In: Patel VB, Preedy VR. (eds) Biomarkers in nutrition. Biomarkers in disease: methods, discoveries and applications. Springer, Cham. 2022.
20. Senthilkumar M, Amaresan N, Sankaranarayanan A. Estimation of malondialdehyde (MDA) by thiobarbituric acid (TBA) assay. In: Plant-microbe interactions. Springer Protocols Handbooks. Humana, New York, 2021.
21. Directive 2010/73/EU of the European Parliament and of the Council of 22 September 2010 on the protection of animals used for scientific purposes. http://eur-lex.europa.eu/legal-content/EN/TXT/?uri=CELEX:32010L0073.
22. Brawn P. Diabetes Distilled: More evidence that SGLT2 inhibitors slow CKD progression. Are we optimizing care? Diabetes & Primary Care 2023; 25: 19-20.
23. Liu AYL, Low S, Yeoh E, et al. A real-world study on SGLT2 inhibitors and diabetic kidney disease progression. Clin Kidney J 2022; 15(7): 1403-1414.
24. Lam D, Shaikh A. Real-life prescribing of SGLT2 inhibitors: How to handle the other medications, including glucose-lowering drugs and diuretics. Kidney360 2021; 2(4): 742-746.
25. George J, Lobkovich A, Nardolillo J, Farhat N, Kolander S, Thomas E. Real-world evaluation of insulin requirements after GLP1 agonist or SGLT2 inhibitor initiation and titration. Am J Health Syst Pharm 2022; 79(14): 1151-1157.
26. McGuire DK, Shih WJ, Cosentino F, et al. Association of SGLT2 inhibitors with cardio-vascular and kidney outcomes in patients with type 2 diabetes: a meta-analysis. JAMA Cardiol 2021; 6(2): 148-158.
27. Xu L, Li Y, Lang J, et al. Effects of sodium-glucose co-transporter 2 (SGLT2) inhibition on renal function and albuminuria in patients with type 2 diabetes: a systematic review and meta-analysis. PeerJ 2017; 5: e3405.
28. Heerspink HJL, Kosiborod M, Inzucchi SE, et al. Reno protective effects of sodium-glucose cotransporter-2 inhibitors. Kidney Int 2018, 94(1): 26-39.
29. Khanam S. Role of zinc supplementation on diabetes. Reports in Endocrine Disorders: Open Access 2018, 2(1): 2.
30. Olechnowicz J, Tinkov A, Skalny A, et al. Zinc status is associated with inflammation, oxidative stress, lipid, and glucose metabolism. J Physiol Sci 2018; 68: 19-31.
31. Oraby MA, El-Yamany MF, Safar MM, Assaf N, Ghoneim HA, Dapagliflozin attenuates early markers of diabetic nephropathy in fructose-streptozotocin-induced diabetes in rats. Biomed Pharmacother 2019; 109: 910-920
32. Yang H, Mei Z, Chen W, et al. Therapeutic efficacy of dapagliflozin on diabetic kidney disease in rats. Int Immunopharmacol 2022; 113(Part A): 109272.
33. Anton IC, Mititelu-Tartau L, Popa EG et al. Zinc chloride enhances the antioxidant status, improving the functional and structural organic disturbances in streptozotocin-induced diabetes in rats. Medicina 2022; 58(11): 1620.
34. Martins MDPSC, Oliveira ASDSS, Martins MDCCE, et al. Effects of zinc supplementation on glycemic control and oxidative stress in experimental diabetes: A systematic review. Clin Nutr ESPEN 2022; 51: 28-36.


This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
COPYRIGHT
Once an article is accepted for publication, MSJ requests a transfer of copyrights for published articles.
COPYRIGHT TRANSFER FORM FOR
REVISTA MEDICO-CHIRURGICALĂ A SOCIETĂȚII DE MEDICI ȘI NATURALIȘTI DIN IAȘI /
THE MEDICAL-SURGICAL JOURNAL OF THE SOCIETY OF PHYSICIANS AND NATURALISTS FROM IASI
We, the undersigned authors of the manuscript entitled
_____________________________________________________________________________________
_____________________________________________________________________________________
warrant that this manuscript, which is submitted for publication in the REVISTA MEDICO-CHIRURGICALĂ, has not been published and it is not under consideration for publication in another journal.
- we give the consent for publication in the REVISTA MEDICO-CHIRURGICALĂ, in printed and electronic format and we transfer unconditioned and complete the copyright of this manuscript to the REVISTA MEDICO-CHIRURGICALĂ, in the event of its acceptance.
- the manuscript does not break the intellectual property rights of any other person.
- we have read the submitted version of the manuscript and we are fully responsible for the content.
Names and signatures of authors / copyright owners (the following sequence is the authorship of the article):
- ______________________________/_________________________
- ______________________________/_________________________
- ______________________________/_________________________
N.B. All the authors must sign this form