Role of Vitamin D in Management of Diabetes and Unresolved Cardiovascular
Diseases

Prabhat   Kumar   Upadhyay; Navneet      Thakur; Vishal   Kumar   Vishwakarma; Ritesh   Kumar   Srivastav; Tarique   Mahmood   Ansari
Abstract

Background: Vitamin D deficiency is becoming a widely recognized global health issue. Serum values of 25-(OH) vitamin D (<20 ng/ml) are used to identify vitamin D deficiency. By prompting vascular endothelial cells to activate their nuclear receptor in cardio-myocytes, Vitamin D regulates obesity, Renin-angiotensin system (RAS), energy consumption, and pancreatic cell function. Vitamin D deficiency has been associated with diabetes, asthma, hyperlipidaemia, and pulmonary hypertension in humans.
Methods: PubMed and Google Scholar databases were utilised to search the literature on vitamin D and related diseases.
Result: It is also linked to an elevated risk of death and heart disease. On the other hand, metaanalyses of vitamin D intervention and trials have found no substantial changes in insulin sensitivity, lipid markers, or blood pressure, which result in the association between deficiency of vitamin D and cardiovascular disease.
Conclusion: In this review, we present the most recent research on the effects of Vitamin D therapy on various cardiovascular diseases and diabetes, and explain the underlying mechanisms.
Keywords: Vitamin D, hypertension, hyperlipidaemia, diabetes, pulmonary hypertension, cardiovascular disease, blood pressure.
[1]
Danik JS, Manson JE. Vitamin d and cardiovascular disease. Curr Treat Options Cardiovasc Med  2012; 14(4): 414-24.
 [http://dx.doi.org/10.1007/s11936-012-0183-8] [PMID: 22689009]

[2]
Khazai N, Judd SE, Tangpricha V. Calcium and vitamin D: Skeletal and extraskeletal health. Curr Rheumatol Rep  2008; 10(2): 110-7.
 [http://dx.doi.org/10.1007/s11926-008-0020-y] [PMID: 18460265]

[3]
Nibbelink KA, Tishkoff DX, Hershey SD, Rahman A, Simpson RU. 1,25(OH)2-vitamin D3 actions on cell proliferation, size, gene expression, and receptor localization, in the HL-1 cardiac myocyte. J Steroid Biochem Mol Biol  2007; 103(3-5): 533-7.
 [http://dx.doi.org/10.1016/j.jsbmb.2006.12.099] [PMID: 17276054]

[4]
Wu-Wong JR, Nakane M, Ma J, Ruan X, Kroeger PE. Effects of Vitamin D analogs on gene expression profiling in human coronary artery smooth muscle cells. Atherosclerosis  2006; 186(1): 20-8.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2005.06.046] [PMID: 16095599]

[5]
Demir M, Uyan U, Keçeoçlu S, Demir C. The relationship between vitamin D deficiency and pulmonary hypertension. Prague Med Rep  2013; 114(3): 154-61.
 [http://dx.doi.org/10.14712/23362936.2014.17] [PMID: 24093815]

[6]
Merke J, Milde P, Lewicka S, et al. Identification and regulation of 1,25-dihydroxyvitamin D3 receptor activity and biosynthesis of 1,25-dihydroxyvitamin D3. Studies in cultured bovine aortic endothelial cells and human dermal capillaries. J Clin Invest  1989; 83(6): 1903-15.
 [http://dx.doi.org/10.1172/JCI114097] [PMID: 2542376]

[7]
Holick MF. Vitamin D deficiency. N Engl J Med  2007; 357(3): 266-81.
 [http://dx.doi.org/10.1056/NEJMra070553] [PMID: 17634462]

[8]
Rowling MJ, Kemmis CM, Taffany DA, Welsh J. Megalin-mediated endocytosis of vitamin D binding protein correlates with 25-hydroxycholecalciferol actions in human mammary cells. J Nutr  2006; 136(11): 2754-9.
 [http://dx.doi.org/10.1093/jn/136.11.2754] [PMID: 17056796]

[9]
Pike JW, Zella LA, Meyer MB, Fretz JA, Kim S. Molecular actions of 1,25-dihydroxyvitamin D3 on genes involved in calcium homeostasis. J Bone Miner Res  2007; 22(S2) (Suppl. 2): V16-9.
 [http://dx.doi.org/10.1359/jbmr.07s207] [PMID: 18290714]

[10]
Alshahrani F, Aljohani N, Vitamin D. Deficiency, sufficiency and toxicity. Nutrients  2013; 5(9): 3605-16.
 [http://dx.doi.org/10.3390/nu5093605] [PMID: 24067388]

[11]
Fleck A. Latitude and ischaemic heart disease. Lancet  1989; 333(8638): 613.
 [http://dx.doi.org/10.1016/S0140-6736(89)91634-6] [PMID: 2564129]

[12]
Grimes DS, Hindle E, Dyer T. Sunlight, cholesterol and coronary heart disease. QJM  1996; 89(8): 579-90.
 [http://dx.doi.org/10.1093/qjmed/89.8.579] [PMID: 8935479]

[13]
Douglas AS, Dunnigan MG, Allan TM, Rawles JM. Seasonal variation in coronary heart disease in Scotland. J Epidemiol Community Health  1995; 49(6): 575-82.
 [http://dx.doi.org/10.1136/jech.49.6.575] [PMID: 8596091]

[14]
Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension  1997; 30(2): 150-6.
 [http://dx.doi.org/10.1161/01.HYP.30.2.150] [PMID: 9260973]

[15]
Kendrick J, Targher G, Smits G, Chonchol M. 25-Hydroxyvitamin D deficiency is independently associated with cardiovascular disease in the third national health and nutrition examination survey. Atherosclerosis  2009; 205(1): 255-60.
 [http://dx.doi.org/10.1016/j.atherosclerosis.2008.10.033] [PMID: 19091317]

[16]
Kim DH, Sabour S, Sagar UN, Adams S, Whellan DJ. Prevalence of hypovitaminosis D in cardiovascular diseases (from the National Health and Nutrition Examination Survey 2001 to 2004). Am J Cardiol  2008; 102(11): 1540-4.
 [http://dx.doi.org/10.1016/j.amjcard.2008.06.067] [PMID: 19026311]

[17]
Martins D, Wolf M, Pan D, et al. Prevalence of cardiovascular risk factors and the serum levels of 25-hydroxyvitamin D in the United States: Data from the third national health and nutrition examination survey. Arch Intern Med  2007; 167(11): 1159-65.
 [http://dx.doi.org/10.1001/archinte.167.11.1159] [PMID: 17563024]

[18]
Scragg R, Sowers M, Bell C. Serum 25-hydroxyvitamin D, ethnicity, and blood pressure in the third national health and nutrition examination survey. Am J Hypertens  2007; 20(7): 713-9.
 [http://dx.doi.org/10.1016/j.amjhyper.2007.01.017] [PMID: 17586404]

[19]
Chen S, Law CS, Grigsby CL, et al. Cardiomyocyte-specific deletion of the vitamin D receptor gene results in cardiac hypertrophy. Circulation  2011; 124(17): 1838-47.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.111.032680] [PMID: 21947295]

[20]
Raymond MA, Désormeaux A, Labelle A, et al. Endothelial stress induces the release of vitamin D-binding protein, a novel growth factor. Biochem Biophys Res Commun  2005; 338(3): 1374-82.
 [http://dx.doi.org/10.1016/j.bbrc.2005.10.105] [PMID: 16269129]

[21]
Martinesi M, Bruni S, Stio M, Treves C. 1,25-Dihydroxyvitamin D3 inhibits tumor necrosis factor-α-induced adhesion molecule expression in endothelial cells. Cell Biol Int  2006; 30(4): 365-75.
 [http://dx.doi.org/10.1016/j.cellbi.2006.01.004] [PMID: 16549374]

[22]
Simpson RU. Selective knockout of the vitamin d receptor in the heart results in cardiac hypertrophy: Is the heart a drugable target for vitamin D receptor agonists? Circulation  2011; 124(17): 1808-10.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.111.061234] [PMID: 22025636]

[23]
Weishaar RE, Kim SN, Saunders DE, Simpson RU. Involvement of vitamin D3 with cardiovascular function. III. Effects on physical and morphological properties. Am J Physiol  1990; 258(1 Pt 1): E134-42.
 [PMID: 2154115]

[24]
Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol  1995; 15(8): 1145-51.
 [http://dx.doi.org/10.1161/01.ATV.15.8.1145] [PMID: 7627708]

[25]
Boonstra A, Barrat FJ, Crain C, Heath VL, Savelkoul HFJ, O’Garra A. 1alpha,25-Dihydroxy vitamin D3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells. J Immunol  2001; 167(9): 4974-80.
 [http://dx.doi.org/10.4049/jimmunol.167.9.4974] [PMID: 11673504]

[26]
Li YY, Feldman AM, Sun Y, McTiernan CF. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Circulation  1998; 98(17): 1728-34.
 [http://dx.doi.org/10.1161/01.CIR.98.17.1728] [PMID: 9788826]

[27]
López-López N, González-Curiel I, Treviño-Santa Cruz MB, et al. Expression and vitamin D-mediated regulation of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in healthy skin and in diabetic foot ulcers. Arch Dermatol Res  2014; 306(9): 809-21.
 [http://dx.doi.org/10.1007/s00403-014-1494-2] [PMID: 25168880]

[28]
Timms PM, Mannan N, Hitman GA, et al. Circulating MMP9, vitamin D and variation in the TIMP-1 response with VDR genotype: Mechanisms for inflammatory damage in chronic disorders? QJM  2002; 95(12): 787-96.
 [http://dx.doi.org/10.1093/qjmed/95.12.787] [PMID: 12454321]

[29]
Wang TJ, Pencina MJ, Booth SL, et al. Vitamin D deficiency and risk of cardiovascular disease. Circulation  2008; 117(4): 503-11.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.107.706127] [PMID: 18180395]

[30]
Razzaque MS. The dualistic role of vitamin D in vascular calcifications. Kidney Int  2011; 79(7): 708-14.
 [http://dx.doi.org/10.1038/ki.2010.432] [PMID: 20962746]

[31]
Zittermann A, Schleithoff SS, Koerfer R. Vitamin D and vascular calcification. Curr Opin Lipidol  2007; 18(1): 41-6.
 [http://dx.doi.org/10.1097/MOL.0b013e328011c6fc] [PMID: 17218831]

[32]
Kassi E, Adamopoulos C, Basdra EK, Papavassiliou AG. Role of vitamin D in atherosclerosis. Circulation  2013; 128(23): 2517-31.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.113.002654] [PMID: 24297817]

[33]
Manolagas SC, Provvedini DM, Murry EJ, Tsoukas CD, Deftos LJ. The antiproliferative effect of calcitriol on human peripheral blood mononuclear cells. J Clin Endocrinol Metab  1986; 63(2): 394-400.
 [http://dx.doi.org/10.1210/jcem-63-2-394] [PMID: 3013918]

[34]
Pradhan AD, Manson JE. Update on the Vitamin D and OmegA-3 trial (VITAL). J Steroid Biochem Mol Biol  2016; 155(Pt B): 252-6.
 [http://dx.doi.org/10.1016/j.jsbmb.2015.04.006] [PMID: 25864623]

[35]
Norman PE, Powell JT. Vitamin D and cardiovascular disease. Circ Res  2014; 114(2): 379-93.
 [http://dx.doi.org/10.1161/CIRCRESAHA.113.301241] [PMID: 24436433]

[36]
Karhapää P, Pihlajamäki J, Pörsti I, et al. Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias. J Intern Med  2010; 268(6): 604-10.
 [http://dx.doi.org/10.1111/j.1365-2796.2010.02279.x] [PMID: 20831628]

[37]
Wang H, Xia N, Yang Y, Peng DQ. Influence of vitamin D supplementation on plasma lipid profiles: A meta-analysis of randomized controlled trials. Lipids Health Dis  2012; 11(1): 42.
 [http://dx.doi.org/10.1186/1476-511X-11-42] [PMID: 22433171]

[38]
Oosterwerff MM, Eekhoff EMW, Heymans MW, Lips P, van Schoor NM. Serum 25-hydroxyvitamin D levels and the metabolic syndrome in older persons: A population-based study. Clin Endocrinol (Oxf)  2011; 75(5): 608-13.
 [http://dx.doi.org/10.1111/j.1365-2265.2011.04110.x] [PMID: 21595731]

[39]
Pittas AG, Dawson-Hughes B, Li T, et al. Vitamin D and calcium intake in relation to type 2 diabetes in women. Diabetes Care  2006; 29(3): 650-6.
 [http://dx.doi.org/10.2337/diacare.29.03.06.dc05-1961] [PMID: 16505521]

[40]
Giovannucci E, Liu Y, Hollis BW, Rimm EB. 25-hydroxyvitamin D and risk of myocardial infarction in men: A prospective study. Arch Intern Med  2008; 168(11): 1174-80.
 [http://dx.doi.org/10.1001/archinte.168.11.1174] [PMID: 18541825]

[41]
Schottker B, Jorde R, Peasey A, et al. Network of Cohorts in Europe and the United States: Vitamin D and mortality: Meta-analysis of individual participant data from a large consortium of cohort studies from Europe and the United States. BMJ  2014; 348: g3656.
 [http://dx.doi.org/10.1136/bmj.g3656] [PMID: 24938302]

[42]
Brøndum-Jacobsen P, Benn M, Jensen GB, Nordestgaard BG. 25-hydroxyvitamin d levels and risk of ischemic heart disease, myocardial infarction, and early death: Population-based study and meta-analyses of 18 and 17 studies. Arterioscler Thromb Vasc Biol  2012; 32(11): 2794-802.
 [http://dx.doi.org/10.1161/ATVBAHA.112.248039] [PMID: 22936341]

[43]
Brøndum-Jacobsen P, Nordestgaard BG, Schnohr P, Benn M. 25-hydroxyvitamin D and symptomatic ischemic stroke: An original study and meta-analysis. Ann Neurol  2013; 73(1): 38-47.
 [http://dx.doi.org/10.1002/ana.23738] [PMID: 23225498]

[44]
Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: Reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ  2011; 342(apr19 1): d2040.
 [http://dx.doi.org/10.1136/bmj.d2040] [PMID: 21505219]

[45]
Parker J, Hashmi O, Dutton D, et al. Levels of vitamin D and cardiometabolic disorders: Systematic review and meta-analysis. Maturitas  2010; 65(3): 225-36.
 [http://dx.doi.org/10.1016/j.maturitas.2009.12.013] [PMID: 20031348]

[46]
Degerud E, Nygård O, de Vogel S, et al. Plasma 25-hydroxyvitamin d and mortality in patients with suspected stable angina pectoris. J Clin Endocrinol Metab  2018; 103(3): 1161-70.
 [http://dx.doi.org/10.1210/jc.2017-02328] [PMID: 29325121]

[47]
Lind L, Wengle B, Ljunghall S. Blood pressure is lowered by vitamin D (alphacalcidol) during long-term treatment of patients with intermittent hypercalcaemia. A double-blind, placebo-controlled study. Acta Med Scand  1987; 222(5): 423-7.
 [http://dx.doi.org/10.1111/j.0954-6820.1987.tb10959.x] [PMID: 3321926]

[48]
Lind L, Wengle B, Wide L, Sörensen OH, Ljunghall S. Hypertension in primary hyperparathyroidism--reduction of blood pressure by long-term treatment with vitamin D (alphacalcidol). A double-blind, placebo-controlled study. Am J Hypertens  1988; 1(4 Pt 1): 397-402.
 [http://dx.doi.org/10.1093/ajh/1.4.397] [PMID: 3063290]

[49]
Lind L, Pollare T, Hvarfner A, Lithell H, Sørensen OH, Ljunghall S. Long-term treatment with active vitamin D (alphacalcidol) in middle-aged men with impaired glucose tolerance. Effects on insulin secretion and sensitivity, glucose tolerance and blood pressure. Diabetes Res  1989; 11(3): 141-7.
 [PMID: 2697485]

[50]
Krause R, Bühring M, Hopfenmüller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet  1998; 352(9129): 709-10.
 [http://dx.doi.org/10.1016/S0140-6736(05)60827-6] [PMID: 9728997]

[51]
Witham MD, Dove FJ, Dryburgh M, Sugden JA, Morris AD, Struthers AD. The effect of different doses of vitamin D3 on markers of vascular health in patients with type 2 diabetes: A randomised controlled trial. Diabetologia  2010; 53(10): 2112-9.
 [http://dx.doi.org/10.1007/s00125-010-1838-1] [PMID: 20596692]

[52]
Heshmat R, Tabatabaei-Malazy O, Abbaszadeh-Ahranjani S, et al. Effect of vitamin D on insulin resistance and anthropometric parameters in Type 2 diabetes; a randomized double-blind clinical trial. Daru  2012; 20(1): 10.
 [http://dx.doi.org/10.1186/2008-2231-20-10] [PMID: 23351271]

[53]
Strobel F, Reusch J, Penna-Martinez M, et al. Effect of a randomised controlled vitamin D trial on insulin resistance and glucose metabolism in patients with type 2 diabetes mellitus. Horm Metab Res  2014; 46(1): 54-8.
 [PMID: 24198221]

[54]
Shab-Bidar S, Neyestani TR, Djazayery A, et al. Regular consumption of vitamin D-fortified yogurt drink (Doogh) improved endothelial biomarkers in subjects with type 2 diabetes: A randomized double-blind clinical trial. BMC Med  2011; 9(1): 125.
 [http://dx.doi.org/10.1186/1741-7015-9-125] [PMID: 22114787]

[55]
Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C. Effects of a short-term vitamin D3 and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab  2001; 86(4): 1633-7.
 [PMID: 11297596]

[56]
Margolis KL, Ray RM, Van Horn L, et al. Effect of calcium and vitamin D supplementation on blood pressure: The Women’s Health Initiative Randomized Trial. Hypertension  2008; 52(5): 847-55.
 [http://dx.doi.org/10.1161/HYPERTENSIONAHA.108.114991] [PMID: 18824662]

[57]
Khan H, Kunutsor S, Franco OH, Chowdhury R. Vitamin D, type 2 diabetes and other metabolic outcomes: A systematic review and meta-analysis of prospective studies. Proc Nutr Soc  2013; 72(1): 89-97.
 [http://dx.doi.org/10.1017/S0029665112002765] [PMID: 23107484]

[58]
Laway B, Kotwal S, Shah Z. Pattern of 25 hydroxy vitamin D status in North Indian people with newly detected type 2 diabetes: A prospective case control study. Indian J Endocrinol Metab  2014; 18(5): 726-30.
 [http://dx.doi.org/10.4103/2230-8210.139242] [PMID: 25285294]

[59]
Harinarayan CV. Vitamin D and diabetes mellitus. Hormones (Athens)  2014; 13(2): 163-81.
 [http://dx.doi.org/10.1007/BF03401332] [PMID: 24776618]

[60]
Forouhi NG, Ye Z, Rickard AP, et al. Circulating 25-hydroxyvitamin D concentration and the risk of type 2 diabetes: Results from the European Prospective Investigation into cancer (EPIC)-Norfolk cohort and updated meta-analysis of prospective studies. Diabetologia  2012; 55(8): 2173-82.
 [http://dx.doi.org/10.1007/s00125-012-2544-y] [PMID: 22526608]

[61]
Chung SJ, Lee YA, Hong H, et al. Inverse relationship between vitamin D status and insulin resistance and the risk of impaired fasting glucose in Korean children and adolescents: The Korean National Health and Nutrition Examination Survey (KNHANES) 2009–2010. Public Health Nutr  2014; 17(4): 795-802.
 [http://dx.doi.org/10.1017/S1368980013002334] [PMID: 24050711]

[62]
Serra-Planas E, Aguilera E, Granada ML, et al. High prevalence of vitamin D deficiency and lack of association with subclinical atherosclerosis in asymptomatic patients with type 1 Diabetes Mellitus from a Mediterranean area. Acta Diabetol  2015; 52(4): 773-9.
 [http://dx.doi.org/10.1007/s00592-014-0699-3] [PMID: 25572333]

[63]
Shih EM, Mittelman S, Pitukcheewanont P, Azen CG, Monzavi R. Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes. Pediatr Diabetes  2016; 17(1): 36-43.
 [http://dx.doi.org/10.1111/pedi.12238] [PMID: 25524404]

[64]
Nigil Haroon N, Anton A, John J, Mittal M. Effect of vitamin D supplementation on glycemic control in patients with type 2 diabetes: A systematic review of interventional studies. J Diabetes Metab Disord  2015; 14(1): 3.
 [http://dx.doi.org/10.1186/s40200-015-0130-9] [PMID: 25722966]

[65]
Gordon DJ, Hyde J, Trost DC, et al. Cyclic seasonal variation in plasma lipid and lipoprotein levels: The lipid research clinics coronary primary prevention trial placebo group. J Clin Epidemiol  1988; 41(7): 679-89.
 [http://dx.doi.org/10.1016/0895-4356(88)90120-5] [PMID: 3294350]

[66]
Ponda MP, Huang X, Odeh MA, Breslow JL, Kaufman HW. Vitamin D may not improve lipid levels: A serial clinical laboratory data study. Circulation  2012; 126(3): 270-7.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.111.077875] [PMID: 22718799]

[67]
Ponda MP, Dowd K, Finkielstein D, Holt PR, Breslow JL. The short-term effects of vitamin D repletion on cholesterol: A randomized, placebo-controlled trial. Arterioscler Thromb Vasc Biol  2012; 32(10): 2510-5.
 [http://dx.doi.org/10.1161/ATVBAHA.112.254110] [PMID: 22947589]

[68]
Vaidya A, Brown JM, Williams JS. The renin–angiotensin–aldosterone system and calcium-regulatory hormones. J Hum Hypertens  2015; 29(9): 515-21.
 [http://dx.doi.org/10.1038/jhh.2014.125] [PMID: 25631218]

[69]
Boxer RS, Dauser DA, Walsh SJ, Hager WD, Kenny AM. The association between vitamin D and inflammation with the 6-minute walk and frailty in patients with heart failure. J Am Geriatr Soc  2008; 56(3): 454-61.
 [http://dx.doi.org/10.1111/j.1532-5415.2007.01601.x] [PMID: 18194227]

[70]
Witham MD, Crighton LJ, Gillespie ND, et al. The effects of vitamin D supplementation on physical function and quality of life in older heart failure patients: A randomised controlled trial. Circ Heart Fail  2010; 3: 195-201.
 [http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.907899] [PMID: 20103775]

[71]
Witte KKA, Nikitin NP, Parker AC, et al. The effect of micronutrient supplementation on quality-of-life and left ventricular function in elderly patients with chronic heart failure. Eur Heart J  2005; 26(21): 2238-44.
 [http://dx.doi.org/10.1093/eurheartj/ehi442] [PMID: 16081469]
Cite As
Current Diabetes Reviews

Role of Vitamin D in Management of Diabetes and Unresolved Cardiovascular Diseases

Abstract
