Ivana Šarac
Marija Djekić-Ivanković
Jasmina Debeljak-Martačić- 1Institute for Medical Research, National Institute of Republic of Serbia, Centre of Research Excellence in Nutrition and Metabolism, University of Belgrade, Belgrade, Serbia
- 2School of Population and Global Health, McGill University, Montreal, QC, Canada
Editorial on the Research Topic
The role of vitamin D in metabolic and cardiovascular health
In the last few decades, interest in vitamin D (VitD) has grown significantly since numerous studies have suggested that besides its well-established roles in bone metabolism (1), it could have other important roles in organism, including roles in immunity, endocrine, cardiovascular, and reproductive system (2–7). Many studies indicated that VitD status is inversely associated with the incidence of several metabolic diseases and conditions, including obesity (8, 9), insulin resistance (10–14), metabolic syndrome (15–17), dyslipidemia (13, 18, 19), diabetes (10, 11, 20–22), non-alcoholic fatty liver disease (NAFLD) (23–25), and cardiovascular diseases (7, 26–28). However, the findings were often inconsistent, and the cause/effect relationships particularly remained to be confirmed, as well as the molecular pathways of these associations. Moreover, the relationship of VitD with metabolic and cardiovascular disorders seems to be bidirectional: e.g., obesity could worsen VitD deficiency (8), and vice versa, VitD deficiency could aggravate obesity and related metabolic and cardiovascular complications (insulin resistance, defects in insulin secretion, disordered metabolism of lipids, hepatic steatosis, and gut dysbiosis) (7, 9) by multiple mechanisms, many of which are still undiscovered and unclarified. Additionally, since in the above-mentioned disorders and diseases there is also chronic inflammation and increased oxidative stress, the role of VitD as immunomodulator and anti-oxidative agent has been proposed as one of the mechanisms by which VitD can influence these conditions (29–34).
This Frontiers Research Topic “The role of vitamin D in metabolic and cardiovascular health” focused on epidemiological research on associations of VitD with metabolic and cardiovascular health, particularly in specific population groups, and pathophysiological pathways of these associations, as well as possible confounding factors which modulate these associations. The Research Topic welcomed also articles on the role of VitD as one of supporting therapeutics in cardiovascular and metabolic diseases, as well as immunomodulator.
In this Research Topic there are 13 papers covering the above-mentioned aspects.
Chen Y. C. et al. compared the risk for VitD deficiency across different categories of metabolically healthy normal weight (MHNW) to metabolically unhealthy overweight/obese insulin resistant (MUO) subjects, by studding 6,655 Chinese adults. The study confirmed the highest risk for VitD deficiency among the MUO subjects, but also indicated some gender and age- related differences: among men, the increased risk was noted particularly in MUO men >50 years old, while in younger men, the risk was highest among metabolically healthy obese (MHO) men. In contrast, among women, in both age subgroups the highest risk was represented among MUO women, but the stronger association was noted among younger women. This study indicated possible gender-influenced associations of VitD status with obesity and adverse cardiometabolic and inflammatory profiles.
Similarly, Yin X. et al. analyzed the associations of VitD status with HOMA-IR (Homeostatic Model Assessment of Insulin Resistance), as a robust measure of insulin resistance, in 6,079 American adults without diabetes and other chronic diseases, by using the data from the National Health and Nutrition Examination Surveys (NHANES). The study also confirmed the negative associations between serum VitD concentrations and HOMA-IR, which remained significant after multiple adjustments for many possible confounders, including age, gender, race/ethnicity, and body mass index (BMI). Nevertheless, the further stratification analyses showed some racial/ethical differences: in people with Non-Hispanic Black origin this inverse association between VitD and HOMA-IR was not observed, which indicates the need for further studies focused on ethnic/racial disparities.
Song et al. examined the possible additive effects of obesity and VitD status on the all-cause, cardiovascular and cancer-related mortality, by using the data from the NHANES surveys. In the models adjusted for multiple confounders (including age, gender, race/ethnicity, smoking, and BMI), an independent effect of VitD both insufficiency and deficiency on all mortality rates was confirmed, with deficiency having stronger effect. Interestingly, the effect of VitD deficiency overcame the effect of obesity on all mortality rates. The highest risk for overall and cardiovascular mortality was observed among VitD deficient obese subjects, while for cancer mortality among VitD deficient normal weight subjects, indicating different mechanisms of associations of VitD with mortality in different conditions.
Similarly, Chen X. et al. examined the possible effects of VitD status on the all-cause, cardiovascular and cancer-related mortality among subjects with hyperlipidemia, by using the data from the NHANES surveys. In the models adjusted for multiple confounders (including age, gender, race/ethnicity, smoking, and BMI), serum VitD level was identified as an independent factor for all-cause and cardiovascular mortality, but no association was found with malignancy-specific mortality among these subjects. Particularly serum VitD levels <25 ng/ml were associated with a higher risk for all-cause and cardiovascular mortality, indicating the need for monitoring of VitD levels and correcting VitD insufficiency/deficiency among hyperlipidemic subjects.
Zheng et al. using the NHANES data found a significant negative correlation between serum VitD levels and the risk of frailty in older people.
Shree et al. performed a meta-analysis on the association of serum VitD levels and polymorphism in the VitD receptor (VDR) gene with celiac disease, showing that reduced serum level of 25(OH)D and rs2228570-T polymorphism of Fok1 T-allele of VDR gene could be implicated in pathophysiology of this autoimmune disease. Zhou et al. examined the association between serum VitD levels and plasma myeloperoxidase (MPO) levels, as a marker of oxidative stress, in 6,414 Chinese women and men. After adjusting for multiple confounders, the study found that circulating 25(OH)D was negatively associated with MPO levels.
Yin W. J. et al. examined 3,713 pregnant Chinese women in the second trimester of pregnancy, their serum VitD levels, biochemical and clinical indicators of cardiovascular risk and inflammation, and the inflammatory potential of their diet, using the empirical dietary inflammatory pattern (EDIP) score. The study revealed that serum VitD levels mediated significant proportion of the association between the dietary inflammatory potential (i.e., EDIP score) and cardiovascular risk in pregnant women. At the same time, the circulating marker of inflammation, high-sensitivity C-reactive protein (hs-CRP), mediated significant proportion of the association between serum VitD levels and cardiovascular risk, indicating significance of anti-inflammatory effect of VitD in the prevention of cardiometabolic disturbances related to pro-inflammatory diets.
Yang et al. performed a meta-analysis on the effects of VitD supplementation on the circulating lipid levels in subjects with prediabetes, and found that VitD supplementation might beneficially affect triglyceride levels in these subjects, while no significant effects on total cholesterol, HDL-cholesterol and LDL-cholesterol were found. The study revealed that particularly longer duration of treatment (more than 1 year), with doses which correct VitD deficiency/insufficiency, are required to improve triglyceride levels. However, just a few studies were included, and more research on that topic is necessary.
An interesting article by Lee et al. focused on the effect of VitD supplementation on hypercalciuria/urolithiasis prevention in 140 children with epilepsy undergoing ketogenic dietary therapy (KDT). It is known that ketogenic diets relate to increased risk for hypercalciuria/urolithiasis, while the role of VitD on this risk is less clear. Interestingly, the study showed an inverse association of serum VitD levels with the urinary calcium/urinary creatinine ratio, a marker of hypercalciuria. The study also pointed-out that the serum VitD levels >40 ng/mL and the vitamin D3 supplementation doses >50 IU/kg are probably needed for preventing hypercalciuria related to KDT.
Bernardo et al. studied the combined effect of obesity (induced by a high-fat diet) and VitD dietary depletion on metabolic profile and progression of kidney damage in an experimental model of ischemia/reperfusion kidney injury in rats. The study pointed out both independent and additive effects of obesity and VitD depletion on exacerbation of multiple metabolic and inflammatory changes, and progression of functional, hemodynamic, and morphological kidney alterations.
Gázquez et al. studied the effect of VitD supplementation during pregnancy in rats by using different VitD metabolites. The study showed that the monohydroxylated form of VitD, 25(OH)D3, given orally provided better VitD availability compared to vitamin D3: it doubled 25(OH)D3 concentrations in maternal and fetal blood. No adverse effects on pregnancy and fetus were shown. Moreover, 25(OH)D3 had an additional effect on the expression of VDR, fatty acid translocase (FAT), and scavenger-receptor class B type-1 (SR-B1) in maternal liver; and VDR and glutamate decarboxylase GAD67 in fetal brain, which requires further investigation.
Finally, Hanel et al. compared the gene-regulatory potential of three different VitD metabolites: 25(OH)D3, 25(OH)D2, and 1,25(OH)2D3 in human peripheral blood mononuclear cells (PBMCs), and found that although monohydroxylated metabolites can have similar effect on expression of 206 common target genes, their effective concentrations were in the range of supra-physiological concentrations and were 600-fold higher than effective concentrations for 1,25(OH)2D3, indicating 600-fold lower effectiveness.
In summary, the articles in this Research Topic confirm the independent and additive role of VitD in pathophysiology of cardiometabolic and autoimmune diseases, and emphasizes the need for further research in this field. Particularly studies in different population groups, studies on pathophysiological mechanisms, and well-controlled randomized trials with VitD as preventive and therapeutic agent, are needed.
Author contributions
IŠ wrote the manuscript. MD-I and JD-M revised, co-wrote, and edited the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.
Funding
The institutional financial support for this work is provided for IŠ and JD-M. from the Ministry of Education, Science, Technological development of the Republic of Serbia (contract number: 451-03-68/2022-14/200015) and Ministry of Science, Technological Development and Innovation of the Republic of Serbia (contract number: 451-03-47/2023-01/200015).
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1. Jones G. 100 years of vitamin D: Historical aspects of vitamin D. Endocr Connect. (2022) 11:594. doi: 10.1530/EC-21-0594
2. Silva ICJ, Lazaretti-Castro M. Vitamin D metabolism and extraskeletal outcomes: An update. Arch Endocrinol Metab. (2022) 66:748–55. doi: 10.20945/2359-3997000000565
3. Caprio M, Infante M, Calanchini M, Mammi C, Fabbri A. Vitamin D: Not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord. (2017) 22:27–41. doi: 10.1007/s40519-016-0312-6
4. Verstuyf A, Carmeliet G, Bouillon R, Mathieu C. Vitamin D: A pleiotropic hormone. Kidney Int. (2010) 78:140–5. doi: 10.1038/ki.2010.17
5. Lai Y-H, Fang T-C. The pleiotropic effect of vitamin D. ISRN Nephrol. (2013) 2013:898125. doi: 10.5402/2013/898125
6. Park JE, Pichiah PBT, Cha Y-S. Vitamin D and metabolic diseases: Growing roles of vitamin D. J Obes Metab Syndr. (2018) 27:223–32. doi: 10.7570/jomes.2018.27.4.223
7. Durgarao Y, Manjrekar PA, Adhikari P, Chakrapani M, Rukmini MS. Comprehensive review on diabetes associated cardiovascular complications—The vitamin D perspective. Cardiovasc Hematol Disord Drug Targets. (2019) 19:139–53. doi: 10.2174/1871529X19666190114155302
8. Vranić L, Mikolašević I, Milić S. Vitamin D deficiency: Consequence or cause of obesity? Medicina. (2019) 55:90541. doi: 10.3390/medicina55090541
9. Moukayed M, Grant WB. Linking the metabolic syndrome and obesity with vitamin D status: Risks and opportunities for improving cardiometabolic health and well-being. Diabetes Metab Syndr Obes. (2019) 12:1437–47. doi: 10.2147/DMSO.S176933
10. Pieńkowska A, Janicka J, Duda M, Dzwonnik K, Lip K, Medza A, et al. Controversial impact of vitamin D supplementation on reducing insulin resistance and prevention of type 2 diabetes in patients with prediabetes: A systematic review. Nutrients. (2023) 15:40983. doi: 10.3390/nu15040983
11. Sacerdote A, Dave P, Lokshin V, Bahtiyar G. Type 2 diabetes mellitus, insulin resistance, and vitamin D. Curr Diab Rep. (2019) 19:101. doi: 10.1007/s11892-019-1201-y
12. Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes. Diabetol Metab Syndr. (2013) 5:8. doi: 10.1186/1758-5996-5-8
13. Imga NN, Karci AC, Oztas D, Berker D, Guler S. Effects of vitamin D supplementation on insulin resistance and dyslipidemia in overweight and obese premenopausal women. Arch Med Sci. (2019) 15:598–606. doi: 10.5114/aoms.2018.75864
14. Lemieux P, Weisnagel SJ, Caron AZ, Julien A-S, Morisset A-S, Carreau A-M, et al. Effects of 6-month vitamin D supplementation on insulin sensitivity and secretion: A randomised, placebo-controlled trial. Eur J Endocrinol. (2019) 181:287–99. doi: 10.1530/EJE-19-0156
15. Melguizo-Rodríguez L, Costela-Ruiz VJ, García-Recio E, De Luna-Bertos E, Ruiz C, Illescas-Montes R. Role of vitamin D in the metabolic syndrome. Nutrients. (2021) 13:30830. doi: 10.3390/nu13030830
16. Prasad P, Kochhar A. Interplay of vitamin D and metabolic syndrome: A review. Diabetes Metab Syndr. (2016) 10:105–12. doi: 10.1016/j.dsx.2015.02.014
17. Schmitt EB, Nahas-Neto J, Bueloni-Dias F, Poloni PF, Orsatti CL, Petri Nahas EA. Vitamin D deficiency is associated with metabolic syndrome in postmenopausal women. Maturitas. (2018) 107:97–102. doi: 10.1016/j.maturitas.2017.10.011
18. Jiang X, Peng M, Chen S, Wu S, Zhang W. Vitamin D deficiency is associated with dyslipidemia: A cross-sectional study in 3788 subjects. Curr Med Res Opin. (2019) 35:1059–63. doi: 10.1080/03007995.2018.1552849
19. Wang Y, Si S, Liu J, Wang Z, Jia H, Feng K, et al. The associations of serum lipids with vitamin D status. PLoS ONE. (2016) 11:e0165157. doi: 10.1371/journal.pone.0165157
20. Lips P, Eekhoff M, van Schoor N, Oosterwerff M, de Jongh R, Krul-Poel Y, et al. Vitamin D and type 2 diabetes. J Steroid Biochem Mol Biol. (2017) 173:280–5. doi: 10.1016/j.jsbmb.2016.11.021
21. Pittas AG, Kawahara T, Jorde R, Dawson-Hughes B, Vickery EM, Angellotti E, et al. Vitamin D and risk for type 2 diabetes in people with prediabetes: A systematic review and meta-analysis of individual participant data from 3 randomized clinical trials. Ann Intern Med. (2023) 176:355–63. doi: 10.7326/M22-3018
22. Grammatiki M, Karras S, Kotsa K. The role of vitamin D in the pathogenesis and treatment of diabetes mellitus: A narrative review. Hormones. (2019) 18:37–48. doi: 10.1007/s42000-018-0063-z
23. Ravaioli F, Pivetti A, Di Marco L, Chrysanthi C, Frassanito G, Pambianco M, et al. Role of vitamin D in liver disease and complications of advanced chronic liver disease. Int J Mol Sci. (2022) 23:169016. doi: 10.3390/ijms23169016
24. Kitson MT, Roberts SK. D-livering the message: The importance of vitamin D status in chronic liver disease. J Hepatol. (2012) 57:897–909. doi: 10.1016/j.jhep.2012.04.033
25. Kwok RM, Torres DM, Harrison SA. Vitamin D and nonalcoholic fatty liver disease (NAFLD): Is it more than just an association? Hepatology. (2013) 58:1166–74. doi: 10.1002/hep.26390
26. Bouillon R. Vitamin D and cardiovascular disorders. Osteoporos Int. (2019) 30:2167–81. doi: 10.1007/s00198-019-05098-0
27. Saponaro F, Marcocci C, Zucchi R. Vitamin D status and cardiovascular outcome. J Endocrinol Invest. (2019) 42:1285–90. doi: 10.1007/s40618-019-01057-y
28. Franczyk A, Stolarz-Skrzypek K, Wesołowska A, Czarnecka D. Vitamin D and vitamin D receptor activators in treatment of hypertension and cardiovascular disease. Cardiovasc Hematol Disord Drug Targets. (2014) 14:34–44. doi: 10.2174/1871529X14666140228122836
29. Renke G, Starling-Soares B, Baesso T, Petronio R, Aguiar D, Paes R. Effects of vitamin D on cardiovascular risk and oxidative stress. Nutrients. (2023) 15:30769. doi: 10.3390/nu15030769
30. Berretta M, Quagliariello V, Bignucolo A, Facchini S, Maurea N, Di Francia R, et al. The multiple effects of vitamin D against chronic diseases: From reduction of lipid peroxidation to updated evidence from clinical studies. Antioxidants. (2022) 11:61090. doi: 10.3390/antiox11061090
31. Aggeletopoulou I, Thomopoulos K, Mouzaki A, Triantos C. Vitamin D-VDR novel anti-inflammatory molecules-new insights into their effects on liver diseases. Int J Mol Sci. (2022) 23:158465. doi: 10.3390/ijms23158465
32. Fassula AS, Gonzalez-Chica D, Giehl MC, Silva DAS, Cembranel F, Moreno YMF. Moderator role of vitamin D concentrations on the association between metabolic syndrome and C-reactive protein among adults. Arch Endocrinol Metab. (2021) 64:695–703. doi: 10.20945/2359-3997000000272
33. Garbossa SG, Folli F. Vitamin D, sub-inflammation and insulin resistance. A window on a potential role for the interaction between bone and glucose metabolism. Rev Endocr Metab Disord. (2017) 18:243–58. doi: 10.1007/s11154-017-9423-2
Keywords: vitamin D, obesity, diabetes, metabolic syndrome, dyslipidemia, NAFLD, cardiovascular disease, cardiometabolic health
Citation: Šarac I, Djekić-Ivanković M and Debeljak-Martačić J (2023) Editorial: The role of vitamin D in metabolic and cardiovascular health. Front. Nutr. 10:1193758. doi: 10.3389/fnut.2023.1193758
Received: 25 March 2023; Accepted: 07 April 2023;
Published: 24 April 2023.
Edited and reviewed by: Ellen E. Blaak, Maastricht University, Netherlands
Copyright © 2023 Šarac, Djekić-Ivanković and Debeljak-Martačić. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Ivana Šarac, ivanasarac@yahoo.com