Vitamin D and Magnesium Combination Lowers High-Sensitivity C-Reactive Protein, Interleukin-12, Renin, and Carotid Vessel in Diabetic Rats
Abstract
BACKGROUND: Diabetes mellitus induces oxidative stress, inflammation, and endothelial dysfunction, accelerating atherosclerosis development marked by elevated high-sensitivity C-reactive protein (hs-CRP) and interleukin-12 (IL-12). Diabetes often causes significant vascular changes, which can be represented by carotid tunica intima thickening and elevated renin level. Metformin, which remains as the standard therapy, has limited vascular effects. Vitamin D and magnesium exhibit vasoprotective and anti-inflammatory properties; however, their combined effects on diabetic vascular injury remain unclear. This study evaluated the effects of vitamin D and magnesium combination on serum hs-CRP, IL-12, renin, and carotid tunica intima thickness in diabetic rats.
METHODS: Wistar rats were diabetic-induced by 45 mg/kg streptozotocin and 110 mg/kg nicotinamide. Following the induction, the rats were subsequently assigned to receive no treatment, metformin, or a combination of vitamin D and magnesium. Healthy rats were also included as control. Blood sample was collected after 21 days of treatment. Serum hs-CRP, IL-12, and renin were measured using enzyme-linked immunosorbent assay (ELISA), while the carotid tunica intima thickness was assessed by Doppler ultrasound.
RESULTS: Diabetic rats showed significant increases hs-CRP, IL-12, renin level, and intima thickness (p<0.001) compared to control. Both metformin and combination of Vitamin D and magnesium reduced these parameters, with combination of Vitamin D and magnesium showing the greatest improvement. Carotid intima thickness in the combination of Vitamin D and magnesium group was comparable to normal controls, indicating marked vascular protection.
CONCLUSION: Vitamin D and magnesium combination provided superior glycemic, anti-inflammatory, and vascular protective effects compared to metformin alone. This adjunctive strategy might have potential in preventing vascular complications in diabetes.
KEYWORDS: diabetes mellitus, oxidative stress, endothelial dysfunction, hs-CRP, IL-12, atherosclerosis
References
Liu Z, Gong J, Huang W, Lu F, Dong H. The effect of Momordica charantia in the treatment of diabetes mellitus: A review. Evid Based Complement Alternat Med. 2021; 2021: 3796265, CrossRef.
Perhimpunan Dokter Spesialis Kardiovaskular Indonesia. Panduan Prevensi Penyakit Kardiovaskular Aterosklerosis. 1st Ed. Jakarta: Perhimpunan Dokter Spesialis Kardiovaskular Indonesia; 2022, article.
Soelistijo S, Lindarto D, Decroli E, Permana H, Sucipto KW, Kusnadi Y, et al. Pedoman Pengelolaan dan Pencegahan Diabetes Melitus Tipe 2 Dewasa di Indonesia 2021. Jakarta: PB Perkeni; 2021, article.
Poznyak A, Grechko A V, Poggio P, Myasoedova VA, Alfieri V, Orekhov AN. The diabetes mellitus-atherosclerosis connection: The role of lipid and glucose metabolism and chronic inflammation. Int J Mol Sci. 2020; 21(5): 1835, CrossRef.
Hasheminasabgorji E, Jha JC. Dyslipidemia, diabetes and atherosclerosis: Role of inflammation and ROS-redox-sensitive factors. Biomedicines. 2021; 9(11): 1602, CrossRef.
Ngwa DN, Pathak A, Agrawal A. IL-6 regulates induction of C-reactive protein gene expression by activating STAT3 isoforms. Mol Immunol. 2022; 146: 50-6, CrossRef.
Pathak A, Singh SK, Thewke DP, Agrawal A. Conformationally altered C-reactive protein capable of binding to atherogenic lipoproteins reduces atherosclerosis. Front Immunol. 2020: 11: 1780, CrossRef.
Theofilis P, Oikonomou E, Lazaros G, Vogiatzi G, Anastasiou M, Mystakidi VC, et al. The association of diabetes mellitus with carotid atherosclerosis and arterial stiffness in the Corinthia study. Nutr Metab Cardiovasc Dis. 2022; 32(3): 567-76, CrossRef.
Ma X, Ma J, Leng T, Yuan Z, Hu T, Liu Q, et al. Advances in oxidative stress in pathogenesis of diabetic kidney disease and efficacy of TCM intervention. Ren Fail. 2023; 45(1): 2146512, CrossRef.
Nabi AHMN, Ebihara A. Diabetes and renin-angiotensin-aldosterone system: Pathophysiology and genetics. In: Renin-Angiotensin Aldosterone System. London: IntechOpen; 2021. p. 1-31, CrossRef.
Kim DH, Meza CA, Clarke H, Kim JS, Hickner RC. Vitamin D and endothelial function. Nutrients. 2020; 12(2): 575, CrossRef.
Pramesthi ADED, Ardana M, Indriyanti N. Drug-herb interaction between metformin and momordica charantia in diabetic mice. Mol Cell Biomed Sci. 2019; 3(2): 81-7, CrossRef.
Ahmad MF, Haidar MA, Naseem N, Ahsan H, Siddiqui WA. Hypoglycaemic, hypolipidaemic and antioxidant properties of Celastrus paniculatus seed extract in STZ-induced diabetic rats. Mol Cell Biomed Sci. 2023; 7(1): 10-7, CrossRef.
Laurence DR, Bacharach AL. Evaluation of Drug Activities: Pharmacometrics. Vol. 2. Amsterdam: Elsevier; 2013, NLMID.
Fernández-Alvarez V, Linares Sánchez M, López Alvarez F, Suárez Nieto C, Mäkitie AA, Olsen KD, et al. Evaluation of intima-media thickness and arterial stiffness as early ultrasound biomarkers of carotid artery atherosclerosis. Cardiol Ther. 2022; 11(2): 231-47, CrossRef.
Khanolkar S, Hirani S, Mishra A, Vardhan S, Hirani S, Prasad R, et al. Exploring the role of vitamin D in atherosclerosis and its impact on cardiovascular events: A comprehensive review. Cureus. 2023; 15(7): e42470, CrossRef.
Abugoukh TM, Al Sharaby A, Elshaikh AO, Joda M, Madni A, Ahmed I, et al. Does vitamin D have a role in diabetes? Cureus. 2022; 14(10): e30432, CrossRef.
Liu M, Dudley SC. Magnesium, oxidative stress, inflammation, and cardiovascular disease. Antioxidants. 2020; 9(10): 907, CrossRef.
Shah N, Sethi R, Shah S, Jafri K, Duran J, Chang Y, et al. The roles of platelet-activating factor and magnesium in pathophysiology of hypertension, atherogenesis, cardiovascular disease, stroke and aging. Cardiogenetics. 2022; 12(1): 49-62, CrossRef.
Ter Braake AD, Shanahan CM, de Baaij JHF. Magnesium counteracts vascular calcification. Arterioscler Thromb Vasc Biol. 2017; 37(8): 1431-45, CrossRef.
Jebari-Benslaiman S, Galicia-García U, Larrea-Sebal A, Olaetxea JR, Alloza I, Vandenbroeck K, et al. Pathophysiology of atherosclerosis. Int J Mol Sci. 2022; 23(6): 3346, CrossRef.
Yurekli I, Gokalp O, Kiray M, Bademci M, Yetkin U, Ergunes K, et al. Experimental research Effect of 1α-25-dihydroxyvitamin D 3 on intimal hyperplasia developing in vascular anastomoses: A rabbit model. Arch Med Sci. 2013; 3: 404-8, CrossRef.
Ismail N, Zaghloul DAM, Mubarak W, Amer A. Potential protective effect of vitamin D on aortic tissue of Streptozotocin-induced diabetic vascular damage in adult male rats. SVU Int J Med Sci. 2020; 4(2): 185-95, CrossRef.
Morrissey C, Amiot MJ, Goncalves A, Raverdy C, Masson D, Tardivel C, et al. Vitamin D supplementation on carotid remodeling and stiffness in obese adolescents. Nutrients. 2022; 14(11): 2296, CrossRef.
Fitriana Y, Tjahjono HA. Associations between 25-hydroxy-Vitamin D Levels to Carotid Intima-Media Thickness (CIMT) and Flow- Mediated Dilation (FMD) as Parameters of Subclinical Atherosclerosis in Children with Type 1 Diabetes Mellitus. Malang: Faculty of Medicine, Universitas Brawijaya; 2019, article.
Chen CY, Lin MW, Xie XY, Lin CH, Yang CW, Wu PC, et al. Studying the roles of the renin-angiotensin system in accelerating the disease of high-fat-diet-induced diabetic nephropathy in a db/db and ACE2 double-gene-knockout mouse model. Int J Mol Sci. 2024; 25(1): 329, CrossRef.
Khodadadiyan A, Rahmanian M, Shekouh D, Golmohammadi M, Ghaedi A, Bazrgar A, et al. Evaluating the effect of vitamin D supplementation on serum levels of 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D, parathyroid hormone and renin-angiotensin-aldosterone system: a systematic review and meta-analysis of clinical trials. BMC Nutr. 2023; 9: 132, CrossRef.
Talari HR, Zakizade M, Soleimani A, Bahmani F, Ghaderi A, Mirhosseini N, et al. Effects of magnesium supplementation on carotid intima-media thickness and metabolic profiles in diabetic haemodialysis patients: A randomised, double-blind, placebo-controlled trial. Br J Nutr. 2019; 121(7): 809-17, CrossRef.
Guo G, Zhou J, Xu T, Sheng Z, Huang A, Sun L, et al. Effect of magnesium supplementation on chronic kidney disease-mineral and bone disorder in hemodialysis patients: A meta-analysis of randomized controlled trials. J Ren Nutr. 2022; 32(1): 102-11, CrossRef.
Rahayu RF, Prayitno A, Purwanto B, Soewondo W, Nurwati I, Pamungkasari EP, et al. Combination of metformin and magnesium citrate reduces TNF-α, NF-κB p65, IL-6, CD4, and MMP-9 expressions in diabetic model rats. Indones Biomed J. 2024; 16(6): 546-52, CrossRef.
Hariri Z, Kord-Varkaneh H, Alyahya N, Prabahar K, Găman MA, Abu-Zaid A. Higher dietary vitamin D intake influences the lipid profile and hs-CRP concentrations: Cross-sectional assessment based on the national health and nutrition examination survey. 2023; 13(2): 581, CrossRef.
Mazidi M, Rezaie P, Vatanparast H. Impact of vitamin D supplementation on C-reactive protein; A systematic review and meta-analysis of randomized controlled trials. BMC Nutr. 2018; 4(1): 1, CrossRef.
Heidari H, Amani R, Feizi A, Askari G, Kohan S, Tavasoli P. Vitamin D supplementation for premenstrual syndrome-related inflammation and antioxidant markers in students with vitamin D deficient: A randomized clinical trial. Sci Rep. 2019; 9(1): 14939, CrossRef.
Arabi SM, Bahrami LS, Ranjbar G, Tabesh H, Norouzy A. The effect of vitamin D supplementation on inflammation in critically ill patients: A systematic review. PharmaNutrition. 2020; 13: 100196, CrossRef.
Barker T, Rogers VE, Henriksen VT, Levy M, Schneider ED, Templeton J, et al. Circulating cytokine concentrations are not altered by supplemental vitamin D in knee osteoarthritis: A pilot study. J Nutr Intermed Metab. 2019; 18: 100103, CrossRef.
Azzahra BF, Yueniwati Y, Permatasari HK, Rahayu RF, Tifani AS, Fauzi A. Combined vitamin D and magnesium supplementation improves insulin, HOMA indices, blood glucose, and oxidative stress markers in diabetic rats. Indones Biomed J. 2026; 18(1): 20-7, CrossRef.
DOI: https://doi.org/10.18585/inabj.v18i2.4061
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