Skip to main content
Top
Published in: BMC Endocrine Disorders 1/2020

01-12-2020 | Dyslipidemia | Research article

Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications

Authors: Lina H. M. Ahmed, Alexandra E. Butler, Soha R. Dargham, Aishah Latif, Omar M. Chidiac, Stephen L. Atkin, Charbel Abi Khalil

Published in: BMC Endocrine Disorders | Issue 1/2020

Login to get access

Abstract

Background

Vitamin D deficiency is diagnosed by total serum 25-hydroxyvitamin D (25(OH)D) concentration and is associated with poor health and increased mortality; however, some populations have low 25(OH) D concentrations without manifestations of vitamin D deficiency. The Vitamin D Metabolite Ratio (VMR) has been suggested as a superior indicator of vitamin D status. Therefore, VMR was determined in a population with type 2 diabetes at high risk for vitamin D deficiency and correlated with diabetic complications.

Research design and methods

Four hundred sisty patients with type 2 diabetes (T2D) were recruited, all were vitamin D3 supplement naive. Plasma concentration of 25-hydroxyvitamin D3 (25(OH)D3) and its metabolites 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) and 24,25-dihydroxyvitamin D3 (24,25(OH)2D3) and its epimer, 3-epi-25-hydroxyvitamin D3 (3-epi-25(OH)D3), were measured by LC-MS/MS analysis. VMR-1 was calculated as a ratio of 24,25(OH)2D3:25(OH)D3; VMR-2 as a ratio of 1,25(OH)2D3:25(OH)D3; VMR-3 was calculated as a ratio of 3-epi-25(OH)D3: 25(OH)D3.

Results

An association means that there were significant differences between the ratios found for those with versus those without the various diabetic complications studied. VMR-1 was associated with diabetic retinopathy (p = 0.001) and peripheral artery disease (p = 0.012); VMR-2 associated with hypertension (p < 0.001), dyslipidemia (p < 0.001), diabetic retinopathy (p < 0.001), diabetic neuropathy (p < 0.001), coronary artery disease (p = 0.001) and stroke (p < 0.05). VMR-3 associated with hypertension (p < 0.05), dyslipidemia (p < 0.001) and coronary artery disease (p < 0.05).

Conclusions

In this cross sectional study, whilst not causal, VMR-2 was shown to be the superior predictor of diabetic and cardiovascular complications though not demonstrative of causality in this cross-sectional study population over VMR-1, VMR-3 and the individual vitamin D concentration measurements; VMR-2 associated with both microvascular and cardiovascular indices and therefore may have utility in predicting the development of diabetic complications.
Appendix
Available only for authorised users
Literature
1.
go back to reference Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6 Suppl):1678S–88S.CrossRefPubMed Holick MF. Sunlight and vitamin D for bone health and prevention of autoimmune diseases, cancers, and cardiovascular disease. Am J Clin Nutr. 2004;80(6 Suppl):1678S–88S.CrossRefPubMed
2.
go back to reference Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 dietary reference intakes for calcium and vitamin D: what dietetics practitioners need to know. J Am Diet Assoc. 2011;111(4):524–7.CrossRefPubMed Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 dietary reference intakes for calcium and vitamin D: what dietetics practitioners need to know. J Am Diet Assoc. 2011;111(4):524–7.CrossRefPubMed
4.
go back to reference Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365–408.CrossRefPubMed Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, molecular mechanism of action, and pleiotropic effects. Physiol Rev. 2016;96(1):365–408.CrossRefPubMed
5.
go back to reference Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353–73.CrossRefPubMed Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc. 2006;81(3):353–73.CrossRefPubMed
6.
go back to reference el-Sonbaty MR, Abdul-Ghaffar NU. Vitamin D deficiency in veiled Kuwaiti women. Eur J Clin Nutr. 1996;50(5):315–8.PubMed el-Sonbaty MR, Abdul-Ghaffar NU. Vitamin D deficiency in veiled Kuwaiti women. Eur J Clin Nutr. 1996;50(5):315–8.PubMed
7.
go back to reference Mirsaeid Ghazi AA, Rais Zadeh F, Pezeshk P, Azizi F. Seasonal variation of serum 25 hydroxy D3 in residents of Tehran. J Endocrinol Investig. 2004;27(7):676–9.CrossRef Mirsaeid Ghazi AA, Rais Zadeh F, Pezeshk P, Azizi F. Seasonal variation of serum 25 hydroxy D3 in residents of Tehran. J Endocrinol Investig. 2004;27(7):676–9.CrossRef
8.
go back to reference Bassil D, Rahme M, Hoteit M, Fuleihan GH. Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes. Dermatoendocrinol. 2013;5(2):274–98.CrossRefPubMedPubMedCentral Bassil D, Rahme M, Hoteit M, Fuleihan GH. Hypovitaminosis D in the Middle East and North Africa: prevalence, risk factors and impact on outcomes. Dermatoendocrinol. 2013;5(2):274–98.CrossRefPubMedPubMedCentral
11.
go back to reference Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626–32.CrossRefPubMedPubMedCentral Ginde AA, Liu MC, Camargo CA Jr. Demographic differences and trends of vitamin D insufficiency in the US population, 1988-2004. Arch Intern Med. 2009;169(6):626–32.CrossRefPubMedPubMedCentral
12.
go back to reference Mitchell DM, Henao MP, Finkelstein JS, Burnett-Bowie SA. Prevalence and predictors of vitamin D deficiency in healthy adults. Endocr Pract. 2012;18(6):914–23.CrossRefPubMedPubMedCentral Mitchell DM, Henao MP, Finkelstein JS, Burnett-Bowie SA. Prevalence and predictors of vitamin D deficiency in healthy adults. Endocr Pract. 2012;18(6):914–23.CrossRefPubMedPubMedCentral
13.
go back to reference Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.CrossRefPubMed Mittelbrunn M, Gutierrez-Vazquez C, Villarroya-Beltri C, Gonzalez S, Sanchez-Cabo F, Gonzalez MA, et al. Unidirectional transfer of microRNA-loaded exosomes from T cells to antigen-presenting cells. Nat Commun. 2011;2:282.CrossRefPubMed
14.
go back to reference Zahiri Z, Sharami SH, Milani F, Mohammadi F, Kazemnejad E, Ebrahimi H, et al. Metabolic syndrome in patients with polycystic ovary syndrome in Iran. Int J Fertil Steril. 2016;9(4):490–6.PubMed Zahiri Z, Sharami SH, Milani F, Mohammadi F, Kazemnejad E, Ebrahimi H, et al. Metabolic syndrome in patients with polycystic ovary syndrome in Iran. Int J Fertil Steril. 2016;9(4):490–6.PubMed
15.
go back to reference Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004;116(9):634–9.CrossRefPubMed Bischoff-Ferrari HA, Dietrich T, Orav EJ, Dawson-Hughes B. Positive association between 25-hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004;116(9):634–9.CrossRefPubMed
16.
go back to reference Cauley JA, Danielson ME, Boudreau R, Barbour KE, Horwitz MJ, Bauer DC, et al. Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI). J Bone Miner Res. 2011;26(10):2378–88.CrossRefPubMed Cauley JA, Danielson ME, Boudreau R, Barbour KE, Horwitz MJ, Bauer DC, et al. Serum 25-hydroxyvitamin D and clinical fracture risk in a multiethnic cohort of women: the Women's Health Initiative (WHI). J Bone Miner Res. 2011;26(10):2378–88.CrossRefPubMed
17.
go back to reference Cauley JA, Lui LY, Ensrud KE, Zmuda JM, Stone KL, Hochberg MC, et al. Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA. 2005;293(17):2102–8.CrossRefPubMed Cauley JA, Lui LY, Ensrud KE, Zmuda JM, Stone KL, Hochberg MC, et al. Bone mineral density and the risk of incident nonspinal fractures in black and white women. JAMA. 2005;293(17):2102–8.CrossRefPubMed
18.
go back to reference Tieu EW, Tang EK, Tuckey RC. Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway. FEBS J. 2014;281(14):3280–96.CrossRefPubMed Tieu EW, Tang EK, Tuckey RC. Kinetic analysis of human CYP24A1 metabolism of vitamin D via the C24-oxidation pathway. FEBS J. 2014;281(14):3280–96.CrossRefPubMed
19.
go back to reference Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin N Am. 2014;43(1):205–32.CrossRef Mitri J, Pittas AG. Vitamin D and diabetes. Endocrinol Metab Clin N Am. 2014;43(1):205–32.CrossRef
20.
go back to reference Kamao M, Tatematsu S, Hatakeyama S, Sakaki T, Sawada N, Inouye K, et al. C-3 epimerization of vitamin D3 metabolites and further metabolism of C-3 epimers: 25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation. J Biol Chem. 2004;279(16):15897–907.CrossRefPubMed Kamao M, Tatematsu S, Hatakeyama S, Sakaki T, Sawada N, Inouye K, et al. C-3 epimerization of vitamin D3 metabolites and further metabolism of C-3 epimers: 25-hydroxyvitamin D3 is metabolized to 3-epi-25-hydroxyvitamin D3 and subsequently metabolized through C-1alpha or C-24 hydroxylation. J Biol Chem. 2004;279(16):15897–907.CrossRefPubMed
21.
go back to reference Schleicher RL, Encisco SE, Chaudhary-Webb M, Paliakov E, McCoy LF, Pfeiffer CM. Isotope dilution ultra performance liquid chromatography-tandem mass spectrometry method for simultaneous measurement of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 3-epi-25-hydroxyvitamin D3 in human serum. Clin Chim Acta. 2011;412(17–18):1594–9.CrossRefPubMed Schleicher RL, Encisco SE, Chaudhary-Webb M, Paliakov E, McCoy LF, Pfeiffer CM. Isotope dilution ultra performance liquid chromatography-tandem mass spectrometry method for simultaneous measurement of 25-hydroxyvitamin D2, 25-hydroxyvitamin D3 and 3-epi-25-hydroxyvitamin D3 in human serum. Clin Chim Acta. 2011;412(17–18):1594–9.CrossRefPubMed
22.
go back to reference Butler AE, Dargham SR, Latif A, Mokhtar HR, Robay A, Chidiac OM, Jayyousi A, Al Suwaidi J, Crystal RG, Abi Khalil C, Atkin SL. Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications. Ther Adv Chronic Dis. 2020;11:2040622320924159. PMID: 33062234; PMCID: PMC7534081.https://doi.org/10.1177/2040622320924159. Butler AE, Dargham SR, Latif A, Mokhtar HR, Robay A, Chidiac OM, Jayyousi A, Al Suwaidi J, Crystal RG, Abi Khalil C, Atkin SL. Association of vitamin D3 and its metabolites in patients with and without type 2 diabetes and their relationship to diabetes complications. Ther Adv Chronic Dis. 2020;11:2040622320924159. PMID: 33062234; PMCID: PMC7534081.https://​doi.​org/​10.​1177/​2040622320924159​.
23.
go back to reference Abbas S, Linseisen J, Rohrmann S, Beulens JW, Buijsse B, Amiano P, et al. Dietary vitamin D intake and risk of type 2 diabetes in the European prospective investigation into Cancer and nutrition: the EPIC-InterAct study. Eur J Clin Nutr. 2014;68(2):196–202.CrossRefPubMed Abbas S, Linseisen J, Rohrmann S, Beulens JW, Buijsse B, Amiano P, et al. Dietary vitamin D intake and risk of type 2 diabetes in the European prospective investigation into Cancer and nutrition: the EPIC-InterAct study. Eur J Clin Nutr. 2014;68(2):196–202.CrossRefPubMed
24.
go back to reference O'Beirne SL, Salit J, Rodriguez-Flores JL, Staudt MR, Abi Khalil C, Fakhro KA, et al. Type 2 diabetes risk allele loci in the Qatari population. PLoS One. 2016;11(7):e0156834.CrossRefPubMedPubMedCentral O'Beirne SL, Salit J, Rodriguez-Flores JL, Staudt MR, Abi Khalil C, Fakhro KA, et al. Type 2 diabetes risk allele loci in the Qatari population. PLoS One. 2016;11(7):e0156834.CrossRefPubMedPubMedCentral
25.
go back to reference Deckers JG, Schellevis FG, Fleming DM. WHO diagnostic criteria as a validation tool for the diagnosis of diabetes mellitus: a study in five European countries. Eur J Gen Pract. 2006;12(3):108–13.CrossRefPubMed Deckers JG, Schellevis FG, Fleming DM. WHO diagnostic criteria as a validation tool for the diagnosis of diabetes mellitus: a study in five European countries. Eur J Gen Pract. 2006;12(3):108–13.CrossRefPubMed
26.
go back to reference Souberbielle JC, Cavalier E, Delanaye P, Massart C, Brailly-Tabard S, Cormier C, et al. Serum calcitriol concentrations measured with a new direct automated assay in a large population of adult healthy subjects and in various clinical situations. Clin Chim Acta. 2015;451(Pt B):149–53.CrossRefPubMed Souberbielle JC, Cavalier E, Delanaye P, Massart C, Brailly-Tabard S, Cormier C, et al. Serum calcitriol concentrations measured with a new direct automated assay in a large population of adult healthy subjects and in various clinical situations. Clin Chim Acta. 2015;451(Pt B):149–53.CrossRefPubMed
27.
28.
go back to reference Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, et al. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol. 2007;103(3–5):316–21.CrossRefPubMed Hewison M, Burke F, Evans KN, Lammas DA, Sansom DM, Liu P, et al. Extra-renal 25-hydroxyvitamin D3-1alpha-hydroxylase in human health and disease. J Steroid Biochem Mol Biol. 2007;103(3–5):316–21.CrossRefPubMed
29.
go back to reference Wagner D, Hanwell HE, Schnabl K, Yazdanpanah M, Kimball S, Fu L, et al. The ratio of serum 24,25-dihydroxyvitamin D (3) to 25-hydroxyvitamin D (3) is predictive of 25-hydroxyvitamin D (3) response to vitamin D (3) supplementation. J Steroid Biochem Mol Biol. 2011;126(3–5):72–7.CrossRefPubMed Wagner D, Hanwell HE, Schnabl K, Yazdanpanah M, Kimball S, Fu L, et al. The ratio of serum 24,25-dihydroxyvitamin D (3) to 25-hydroxyvitamin D (3) is predictive of 25-hydroxyvitamin D (3) response to vitamin D (3) supplementation. J Steroid Biochem Mol Biol. 2011;126(3–5):72–7.CrossRefPubMed
30.
go back to reference Bosworth CR, Levin G, Robinson-Cohen C, Hoofnagle AN, Ruzinski J, Young B, et al. The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease. Kidney Int. 2012;82(6):693–700.CrossRefPubMedPubMedCentral Bosworth CR, Levin G, Robinson-Cohen C, Hoofnagle AN, Ruzinski J, Young B, et al. The serum 24,25-dihydroxyvitamin D concentration, a marker of vitamin D catabolism, is reduced in chronic kidney disease. Kidney Int. 2012;82(6):693–700.CrossRefPubMedPubMedCentral
31.
go back to reference Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22–31.CrossRefPubMed Crosby J, Peloso GM, Auer PL, Crosslin DR, Stitziel NO, Lange LA, et al. Loss-of-function mutations in APOC3, triglycerides, and coronary disease. N Engl J Med. 2014;371(1):22–31.CrossRefPubMed
33.
go back to reference Pike JW, Meyer MB. Regulation of mouse Cyp24a1 expression via promoter-proximal and downstream-distal enhancers highlights new concepts of 1,25-dihydroxyvitamin D (3) action. Arch Biochem Biophys. 2012;523(1):2–8.CrossRefPubMed Pike JW, Meyer MB. Regulation of mouse Cyp24a1 expression via promoter-proximal and downstream-distal enhancers highlights new concepts of 1,25-dihydroxyvitamin D (3) action. Arch Biochem Biophys. 2012;523(1):2–8.CrossRefPubMed
34.
go back to reference Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ. Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. Public Health Nutr. 2011;14(2):340–6.CrossRefPubMed Crowe FL, Steur M, Allen NE, Appleby PN, Travis RC, Key TJ. Plasma concentrations of 25-hydroxyvitamin D in meat eaters, fish eaters, vegetarians and vegans: results from the EPIC-Oxford study. Public Health Nutr. 2011;14(2):340–6.CrossRefPubMed
Metadata
Title
Vitamin D3 metabolite ratio as an indicator of vitamin D status and its association with diabetes complications
Authors
Lina H. M. Ahmed
Alexandra E. Butler
Soha R. Dargham
Aishah Latif
Omar M. Chidiac
Stephen L. Atkin
Charbel Abi Khalil
Publication date
01-12-2020
Publisher
BioMed Central
Published in
BMC Endocrine Disorders / Issue 1/2020
Electronic ISSN: 1472-6823
DOI
https://doi.org/10.1186/s12902-020-00641-1

Other articles of this Issue 1/2020

BMC Endocrine Disorders 1/2020 Go to the issue
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.