The incidence of both type 2 and type 1 diabetes mellitus has been increasing worldwide. Vitamin D deficiency, or the awareness of its prevalence, has also been increasing. Vitamin D may have a role in the pathogenic mechanisms predisposing to type 2 diabetes by modulating insulin resistance and/or pancreatic β-cell function. Vitamin D status or elements involved in its activation or transport may also be involved in the development of type 1 diabetes mellitus through immunomodulatory role . Based on these observations a potential association between vitamin D and diabetes has been hypothesized. In this review we discuss up to date evidence linking vitamin D with the development of diabetes. Moreover, the role of vitamin D supplementation in the prevention of both types of diabetes is analysed together with its role in improving glycemic control in diabetic patients. We also address the potential role of vitamin D deficiency in the development of macro- and microvascular complications in diabetes. Finally, we provide recommendation for Vitamin D therapy in diabetes in view of current evidence and highlight areas for potential future research in this area.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Price excludes VAT (USA)
Tax calculation will be finalised during checkout.
Type 2 diabetes mellitus
Type 1 diabetes mellitus
Vitamin D receptor
Peroxisome proliferator-activated receptor
Oral glucose tolerance test
Vitamin D binding protein
- NOD mice:
Non obese diabetic mice
Chronic renal failure
Glomerular filtration rate
Coronary heart disease
Leahy JL. Pathogenesis of type 2 diabetes mellitus. Arch Med Res. 2005;36(3):197–209.
Atkinson MA, Maclaren NK. The pathogenesis of insulin-dependent diabetes mellitus. Engl J Med. 1995;331:1428–36.
Harinarayan CV. Vitamin D, and diabetes mellitus. Hormones. 2014;13(2):163–81.
Takiishi T, Gysemans C, Bouillon R, Mathieu C. Vitamin D and diabetes. Rheum Dis Clin North Am. 2012;38(1):179–206.
Chuang JC, Cha JY, Garmey JC, Mirmira RG, Repa JJ. Research resource: nuclear hormone receptor expression in the endocrine pancreas. Molecular endocrinology. 2008;22(10):2353–63.
Pludowski P, Holick MF, Pilz S, et al. Vitamin D effects on musculoskeletal health, immunity, autoimmunity, cardiovascular disease, cancer, fertility, pregnancy, dementia and mortality-a review of recent evidence. Autoimmunity reviews. 2013;12(10):976–89.
Fan Y, Futawaka K, Koyama R, et al. Vitamin D3/VDR resists diet-induced obesity by modulating UCP3 expression in muscles. J Biomed Sci. 2016;23(1):56.
Zostautiene I, Jorde R, Schirmer H, et al. Genetic Variations in the Vitamin D Receptor Predict Type 2 Diabetes and Myocardial Infarction in a Community-Based Population: The Tromsø Study. PLoS One. 2015;10(12), e0145359.
Li L, Wu B, Liu JY, Yang LB. Vitamin D receptor gene polymorphisms and type 2 diabetes: a meta-analysis. Archives Med Res. 2013;44(3):235–41.
Pilz S, Kienreich K, Rutters F, et al. Role of vitamin D in the development of insulin resistance and type 2 diabetes. Curr Diab Rep. 2013;13(2):261–70.
Zhukouskaya VV, Eller-Vainicher C, Shepelkevich AP, Dydyshko Y, Cairoli E, Chiodini I. Bone health in type 1 diabetes: focus on evaluation and treatment in clinical practice. J Endocrinol Invest. 2015;38(9):941–50.
Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ. Chapter 1: Epidemiology of Type 1 Diabetes. Endocrinol Metab Clin North Am. 2010;39(3):481–97.
Chagas CE, Borges MC, Martini LA, Rogero MM. Focus on vitamin D, inflammation and type 2 diabetes. Nutrients. 2012;4:52–67.
Norman AW. Minireview: vitamin D receptor: new assignments for an already busy receptor. Endocrinology. 2006;147(12):5542–8.
Maestro B, Campion J, Davila N, Calle C. Stimulation by 1,25-dihydroxyvitamin D3 of insulin receptor expression and insulin responsiveness for glucose transport in U-937 human promonocytic cells. Endocr J. 2000;47:383–91.
Wright DC, Hucker KA, Holloszy JO, Han DH. Ca2+ and AMPK both mediate stimulation of glucose transport by muscle contractions. Diabetes. 2004;53:330–5.
Draznin B, Sussman K, Kao M, Lewis D, Sherman N. The existence of an optimal range of cytosolic free calcium for insulin-stimulated glucose transport in rat adipocytes. J Biol Chem. 1987;262:14385–8.
Draznin B. Cytosolic calcium and insulin resistance. Am J Kidney Dis. 1993;21:32–8.
Reusch JE, Begum N, Sussman KE, Draznin B. Regulation of GLUT-4 phosphorylation by intracellular calcium in adipocytes. Endocrinology. 1991;129:3269–73.
Dunlop TW, Väisänen S, Frank C, Molnár F, Sinkkonen L, Carl-berg C. The human peroxisome proliferator-activated receptor delta gene is a primary target of 1alpha,25-dihydroxyvitamin D3 and its nuclear receptor. J Mol Biol. 2005;349:248–60.
Cade C, Norman AW. Rapid normalization/stimulation by 1,25-dihydroxyvitamin D3 of insulin secretion and glucose tolerance in the Vitamin D-deficient rat. Endocrinology. 1987;120:1490–7.
Johnson JA, Grande JP, Roche PC, Kumar R. Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas. Am J Physiol. 1994;267:E356–60.
Bland R, Markovic D, Hills CE, et al. Expression of 25- hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid Biochem Mol Biol. 2004;89–90:121–5.
Maestro B, Davila N, Carranza MC, Calle C. Identification of a Vitamin D response element in the human insulin receptor gene promoter. J Steroid Biochem Mol Biol. 2003;84:223–30.
Maestro B, Molero S, Bajo S, Davila N, Calle C. Transcriptional activation of the human insulin receptor gene by 1,25-dihydroxyvitamin D(3). Cell Biochem Funct. 2002;20:227–32.
Bourlon PM, Billaudel B, Faure-Dussert A. Influence of vitamin D3 deficiency and 1,25 dihydroxyvitamin D3 on de novo insulin biosynthesis in the islets of the rat endocrine pancreas. J Endocrinol. 1999;160:87–95.
Zeitz U, Weber K, Soegiarto DW, Wolf E, Balling R, Erben RG. Impaired insulin secretory capacity in mice lacking a functional vitamin D receptor. Faseb J. 2003;17:509–51.
Pittas AG, Lau J, Hu FB, Dawson-Hughes B. The role of vitamin D and calcium in type 2 diabetes. A systematic review and meta- analysis. J Clin Endocrinol Metab. 2007;92:2017–29.
Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM. C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus. JAMA. 2001;286:327–34.
Hu FB, Meigs JB, Li TY, Rifai N, Manson JE. Inflammatory markers and risk of developing type 2 diabetes in women. Diabetes. 2004;53:693–700.
Chih-Chien S, Min-Tser L, Kuo-Cheng L, Chia-Chao W. Role of Vitamin D in Insulin Resistance. J Biomed Biotechnol. 2012;2012:634195.
Pittas AG, Joseph NA, Greenberg AS. Adipocytokines and insulin resistance. J Clin Endocrinol Metab. 2004;89:447–52.
Christakos S, Liu Y. Biological actions and mechanism of action of calbindin in the process of apoptosis. J Steroid Biochem Mol Biol. 2004;89-90(1–5):401–4.
Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science. 1980;209(4458):823–5.
Chiu KC, Chu A, Go VL, Saad MF. Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr. 2004;79(5):820–5.
Hyppönen E, Boucher BJ, Berry DJ, Power C. 25-hydroxyvitamin D, IGF-1, and metabolic syndrome at 45 years of age: a cross-sectional study in the 1958 British Birth Cohort. Diabetes. 2008;57(2):298–305.
Lu L, Yu Z, Pan A, et al. Plasma 25-hydroxyvitamin D concentration and metabolic syndrome among middle-aged and elderly Chinese individuals. Diabetes Care. 2009;32(7):1278–83.
Scragg R, Sowers M. Bell C; Third National Health and Nutrition Examination Survey. Serum 25-hydroxyvitamin D, diabetes, and ethnicity in the Third National Health and Nutrition Examination Survey. Diabetes Care. 2004;27(12):2813–8.
Reis JP, von Muhlen D, Kritz-Silverstein D, et al. Vitamin D, parathyroid hormone levels, and the prevalence of metabolic syndrome in community-dwelling older adults. Diabetes Care. 2007;30:1549–55.
Afzal S, Bojesen SE, Nordestgaard BG. Low 25-hydroxyvitamin D and risk of type 2 diabetes: a prospective cohort study and metaanalysis. Clin Chem. 2013;52(2):381–91.
Anderson JL, May HT, Horne BD, et al. Relation of vitamin D deficiency to cardiovascular risk factors, disease status, and incident events in a general healthcare population. Am J Cardiol. 2010;106:963–8.
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;55:2173–82.
Gagnon C, Lu ZX, Magliano DJ, et al. Serum 25- hydroxyvitamin D, calcium intake, and risk of type 2 diabetes after 5 years: results from a national, population-based prospective study (the Australian Diabetes, Obesity and Lifestyle study). Diabetes Care. 2011;34:1133–8.
Gonzalez-MoleroI R-MG, Morcillo S, et al. Vitamin D and incidence of diabetes: a prospective cohort study. Clin Nutr. 2012;31:571–3.
Grimnes G, Emaus N, Joakimsen RM, et al. Baseline serum 25-hydroxyvitamin D concentrations in the Tromso Study 1994–95 and risk of developing type 2 diabetes mellitus during 11 years of follow-up. Diabet Med. 2010;27:1107–15.
Hurskainen AR, Virtanen JK, Tuomainen TP, Nurmi T, Voutilainen S. Association of serum 25-hydroxyvitamin D with type 2 diabetes and markers of insulin resistance in a general older population in Finland. Diabetes Metab Res Rev. 2012;28:418–23.
Husemoen LL, Thuesen BH. Fenger M, Jørgensen T, Glu ̈mer C, Svensson J, et al. Serum 25(OH)D and type 2 diabetes association in a general population. Diabetes Care. 2012;35:1695–700.
Knekt P, Laaksonen M, Mattila C, et al. Serum vitamin D and subsequent occurrence of type 2 diabetes. Epidemiology. 2008;19:666–71.
Pilz S, van den Hurk K, Nijpels G, et al. Vitamin D status, incident diabetes and prospective changes in glucose metabolism in older subjects: the Hoorn study. Nutr Metab Cardiovasc Dis. 2012;22:883–9.
Pittas AG, Sun Q, Manson JE, Dawson-Hughes B, Hu FB. Plasma 25-hydroxyvitamin D concentration and risk of incident type 2 diabetes in women. Diabetes Care. 2010;33:2021–3.
Robinson JG, Manson JE, Larson J, et al. Lack of association between 25(OH)D levels and incident type 2 diabetes in older women. Diabetes Care. 2011;34:628–34.
Thorand B, Zierer A, Huth C, et al. Effect of serum 25- hydroxyvitamin D on risk for type 2 diabetes may be partially mediated by subclinical inflammation: results from the MONICA/KORA Augsburg study. Diabetes Care. 2011;34:2320–2.
Deleskog A, Hilding A, Brismar K, Hamsten A, Efendic S, Ostenson CG. Low serum 25- hydroxyvitamin D level predicts progression to type 2 diabetes in individuals with prediabetes but not with normal glucose tolerance. Diabetologia. 2012;55:1668–78.
Pittas AG, Harris SS, Stark PC, et al. The effects of calcium and vitamin D supplementation on blood glucose and markers of inflammation in nondiabetic adults. Diabetes Care. 2007;30:980–6.
de Boer IH, Tinker LF, Connelly S, et al. Calcium plus vitamin D supplementation and the risk of incident diabetes in the Women’s Health Initiative. Diabetes Care. 2008;31:701–7.
Avenell A, Cook JA, MacLennan GS, et al. Vitamin D supplementation and type 2 diabetes: a substudy of a randomised placebo-controlled trial in older people (RECORD trial, ISRCTN 51647438). Age Ageing. 2009;38:606–9.
Zittermann A, Frisch S, Berthold HK, et al. Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr. 2009;89:1321–7.
von Hurst PR, Stonehouse W, Coad J. Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. Br J Nutr. 2010;103:549–55.
Jorde R, Sneve M, Torjesen P, et al. No improvement in cardiovascular risk factors in overweight and obese subjects after supplementation with vitamin D3 for 1 year. J Intern Med. 2010;267:462–72.
Wood AD, Secombes KR, Thies F, et al. Vitamin D3 Supplementation Has No Effect on Conventional Cardiovascular Risk Factors: A Parallel-Group, Double-Blind, Placebo-Controlled RCT. J Clin Endocrinol Metab. 2012;97:3557–68.
Nagpal J, Pande JN, Bhartia A. A double-blind, randomized, placebo-controlled trial of the short-term effect of vitamin D3 supplementation on insulin sensitivity in apparently healthy, middle-aged, centrally obese men. Diabet Med. 2009;26:19–27.
Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.
Mitri J, Dawson-Hughes B, Hu FB, et al. Effects of vitamin D and calcium supplementation on pancreatic beta cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94:486–94.
Nazarian S, St Peter JV, Boston RC, et al. Vitamin D3 supplementation improves insulin sensitivity in subjects with impaired fasting glucose. Transl Res. 2011;158:276–81.
Jorde R, Sollid ST, Svartberg J, et al. Vitamin D 20,000 IU per Week for Five Years Does Not Prevent Progression From Prediabetes to Diabetes. J Clin Endocrinol Metab. 2016;101(4):1647–55.
Tuomainen TP, Virtanen JK, Voutilainen S, Nurmi T, Mursu J, de Mello VD, et al. Glucose Metabolism Effects of Vitamin D in Prediabetes: The VitDmet Randomized Placebo-Controlled Supplementation Study. J Diabetes Res. 2015;2015:672653.
Barengolts E, Manickam B, Eisenberg Y, Akbar A, Kukreja S, Ciubotaru I. Effect of high-dose vitamin D repletion on glycemic control in African-American males with prediabetes and hypovitaminosis D. Endocr Pract. 2015;21(6):604–12.
Oosterwerff MM, Eekhoff EM, Van Schoor NM, et al. Effect of moderate-dose vitamin D supplementation on insulin sensitivity in vitamin D–deficient non-Western immigrants in the Netherlands: a randomized placebo-controlled trial. Am J Clin Nutr. 2014;100(1):152–60.
Davidson MB, Duran P, Lee ML, Friedman TC. High-dose vitamin D supplementation in people with prediabetes and hypovitaminosis D. Diabetes Care. 2013;36(2):260–6.
Poolspup N, Suksomboon N, Plordplong N. Effect of vitamin D supplementation on insulin resistance and glycaemic control in prediabetes: a systematic review and meta-analysis. Diabet Med. 2016;33(3):290–9.
Seida JC, Mitri J, Colmers IN, et al. Clinical review: Effect of vitamin D3 supplementation on improving glucose homeostasis and preventing diabetes: a systematic review and meta-analysis. J Clin Endocrinol Metab. 2014;99(10):3551–60.
Sorkin JD, Vasaitis TS, Streeten E, Ryan AS, Goldberg AP. Evidence for threshold effects of 25-hydroxyvitamin D on glucose tolerance and insulin resistance in black and white obese postmenopausal women. J Nutr. 2014;144:734–42.
Pittas AG, Dawson-Hughes B, Sheehan PR, et al. D2d Research Group. Rationale and design of the Vitamin D and Type 2 Diabetes (D2d) study: a diabetes prevention trial. Diabetes Care. 2014;37(12):3227–34.
Krul-Poel YH, Westra S, ten Boekel E, et al. Effect of Vitamin D Supplementation on Glycemic Control in Patients With Type 2 Diabetes (SUNNY Trial): A Randomized Placebo-Controlled Trial. Diabetes Care. 2015;38(8):1420–6.
Hewison M. An update on vitaminDandhuman immunity. Clin Endocrinol. 2012;76:315–25.
Olt S. Relationship between vitamin D and glycemic control in patients with type 2 diabetes mellitus. Int J Clin Exp Med. 2015;8(10):19180–3.
Kostoglou-Athanassiou I, Athanassiou P, Gkountouvas A, Kaldrymides P. Vitamin D and glycemic control in diabetes mellitus type 2. Ther Adv Endocrinol Metab. 2013;4(4):122–8.
Orwoll E, Riddle M, Prince M. Effects of vitamin D on insulin and glucagon secretion in non-insulin-dependent diabetes mellitus. Am J Clin Nutr. 1994;59(5):1083–7.
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.
George PS, Pearson ER, Witham MD. Effect of vitamin D supplementation on glycaemic control and insulin resistance: a systematic review and meta-analysis. Diabet Med. 2012;29(8):e142–50.
Krul-Poel YH, Ter Wee M, Lips P, Simsek S. MANAGEMENT OF ENDOCRINE DISEASE: The effect of vitamin D supplementation on glycaemic control in patients with Type 2 Diabetes Mellitus: a systematic review and meta-analysis. Eur J Endocrinol. 2016.
Bellastella G, Maiorino MI, Olita L, et al. Vitamin D deficiency in type 2 diabetic patients with hypogonadism. J Sex Med. 2014;11:536–42.
Ibrahim MA, Sarhan II, Halawa MR, et al. Study of the effect of vitamin D supplementation on glycemic control in type 2 diabetic prevalent hemodialysis patients. Hemodial Int. 2015;19 Suppl 3:S11–9.
Perez-Diaz I, Sebastian-Barajas G, Hernandez-Flores ZG, Rivera-Moscoso R, Osorio-Landa HK, Flores-Rebollar A. The impact of vitamin D levels on glycemic control and bone mineral density in postmenopausal women with type 2 diabetes. J Endocrinol Invest. 2015;38(12):1365–72.
Shaseb E, Tohidi M, Abbasinazari M, et al. The effect of a single dose of vitamin D on glycemic status and C-reactive protein levels in type 2 diabetic patients with ischemic heart disease: a randomized clinical trial. Acta Diabetol. 2016;53(4):575–82.
Steck AK, Rewers MJ. Genetics of type 1 diabetes. Clin Chem. 2011;57(2):176–85.
Ogunkolade BW, Boucher BJ, Prahl JM, et al. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes. 2002;51(7):2294–300.
Garcia D, Angel B, Carrasco E, et al. VDR polymorphisms influence the immune response in type 1 diabetic children from Santiago. Chile Diabetes Res Clin Pract. 2007;77(1):134–40.
Pani MA, Knapp M, Donner H, et al. Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans. Diabetes. 2000;49(3):504–7.
Chang TJ, Lei HH, Yeh JI, et al. Vitamin D receptor gene polymorphisms influence susceptibility to type 1 diabetes mellitus in the Taiwanese population. Clin Endocrinol (Oxf). 2000;52(5):575–80.
Lemos MC, Fagulha A, Coutinho E, et al. Lack of association of vitamin D receptor gene polymorphisms with susceptibility to type 1 diabetes mellitus in the Portuguese population. Hum Immunol. 2008;69(2):134–8.
Turpeinen H, Hermann R, Vaara S, et al. Vitamin D receptor polymorphisms: no association with type 1 diabetes in the Finnish population. Eur J Endocrinol. 2003;149(6):591–6.
Tizaoui K, Kaabachi W, Hamzaoui A, Hamzaoui K. Contribution of VDR polymorphisms to type 1 diabetes susceptibility: Systematic review of case–control studies and meta-analysis. J Steroid Biochem Mol Biol. 2014;143:240–9.
Ongagna JC, Pinget M, Belcourt A. Vitamin D-binding protein gene polymorphism association with IA-2 autoantibodies in type 1 diabetes. Clin Biochem. 2005;38(5):415–9.
Ongagna JC, Kaltenbacher MC, Sapin R, Pinget M, Belcourt A. The HLA-DQB alleles and amino acid variants of the vitamin Dbinding protein in diabetic patients in Alsace. Clin Biochem. 2001;34:59–63.
Thorsen SU, Mortensen HB, Carstensen B, et al. No association between type 1 diabetes and genetic variation in vitamin D metabolism genes: a Danish study. Pediatr Diabetes. 2014;15(6):416–21.
Blanton D, Han Z, Bierschenk L, et al. Reduced serum vitamin D binding protein levels are associated with type 1 diabetes. Diabetes. 2011;60:2566–70.
Hussein AG, Mohamed RH, Alghobashy AA. Synergism of CYP2R1 and CYP27B1 polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Cell Immunol. 2012;279(1):42–5.
Cooper JD, Smyth DJ, Walker NM, et al. Inherited variation in vitamin D genes is associated with predisposition to autoimmune disease type 1 diabetes. Diabetes. 2011;60(5):1624–31.
Ramos-Lopez E, Brück P, Jansen T, Herwig J, Badenhoop K. CYP2R1 (vitamin D 25-hydroxylase) gene is associated with susceptibility to type 1 diabetes and vitamin D levels in Germans. Diabetes Metab Res Rev. 2007;23(8):631–6.
Bailey R, Cooper JD, Zeitels L, et al. Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes. Diabetes. 2007;56(10):2616–21.
Frederiksen BN, Kroehl M, Fingerlin TE, Steck AK, Rewers M, Norris JM. Association between vitamin D metabolism gene polymorphisms and risk of islet autoimmunity and progression to type 1 diabetes: the diabetes autoimmunity study in the young (DAISY). J Clin Endocrinol Metab. 2013;98(11):E1845–51.
Pociot F, McDermott MF. Genetics of type 1 diabetes mellitus. Genes Immun. 2002;3(5):235–49.
Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005;23:275–306.
Guery JC, Adorini L. Dendritic cells are the most efficient in presenting endogenous naturally processed self-epitopes to class II-restricted T cells. J Immunol. 1995;54:536–44.
Yang CY, Leung PS, Adamopoulos IE, Gershwin ME. The implication of vitamin D and autoimmunity: a comprehensive review. Clin Rev Allergy Immunol. 2013;45:217–26.
Overbergh L, Decallonne B, Waer M, et al. 1alpha,25-dihydroxyvitamin D3 induces an autoantigen specific T-helper 1/T-helper 2 immune shift in NOD mice immunized with GAD65 (p524-543). Diabetes. 2009;49:1301–7.
Riachy R, Vandewalle B, Moerman E, et al. 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis. 2006;11:151–9.
Casteels K, Waer M, Laureys J, et al. Prevention of autoimmune destruction of syngeneic islet grafts in spontaneously diabetic nonobese diabetic mice by a combination of a vitamin D3 analog and cyclosporine. Diabetes. 1998;51:1367–74.
Del Pino-Montes J, Benito GE, Fernandez-Salazar MP, et al. Calcitriol improves streptozotocin-induced diabetes and recovers bone mineral density in diabetic rats. Calcif Tissue Int. 2004;75:526–32.
Takiishi T, Belle TV, Gysemans C, Mathieu C. Effects of vitamin D on antigen-specific and non-antigen-specific immune modulation: relevance for type 1 diabetes. Pediat Diabetes. 2013;14:81–9.
Luong KVQ, Hoang Nguyen LT, Pham Nguyen DN. The role of vitamin D in protecting type 1 diabetes mellitus. Diabetes Metab Res Rev. 2005;21:338–46.
Keen H, Ekoe JM. The geography of diabetes mellitus. Br Med Bull. 1984;40:359–65.
Mathieu C, Waer M, Laureys J, et al. Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3. Diabetologia. 1994;37:552–8.
Hyppönen E, Läärä E, Reunanen A, Järvelin MR, Virtanen SM. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet. 2001;358(9292):1500–3.
Dong JY, Zhang WG, Chen JJ, Zhang ZL, Han SF, Qin LQ. Vitamin D intake and risk of type 1 diabetes: a meta-analysis of observational studies. Nutrients. 2013;5(9):3551–62.
Mutlu A, Mutlu GY, Ozsu E, Cizmecioglu FM, Hatun S. Vitamin D deficiency in children and adolescents with type 1 diabetes. J Clin Res Pediatr Endocrinol. 2011;3:179–83.
Shen L, Zhuang QS, Ji HF. Assessment of vitamin D levels in type 1 and type 2 diabetes patients: Results from metaanalysis. Mol Nutr Food Res. 2016;60(5):1059–67.
Rasoul MA, Al-Mahdi M, Al-Kandari H, Dhaunsi GS, Haider MZ. Low serum vitamin-D status is associated with high prevalence and early onset of type-1 diabetes mellitus in Kuwaiti children. BMC Pediatr. 2016;16(1):95.
Raab J, Giannopoulou EZ, Schneider S, et al. Prevalence of vitamin D deficiency in pre-type 1 diabetes and its association with disease progression. Diabetologia. 2014;57(5):902–8.
Al-Daghri NM, Al-Attas OS, Alokail MS, et al. Lower vitamin D status is more common among Saudi adults with diabetes mellitus type 1 than in non-diabetics. BMC Public Health. 2014;14:153.
Abd-Allah SH, Pasha HF, Hagrass HA, Alghobashy AA. Vitamin D status and vitamin D receptor gene polymorphisms and susceptibility to type 1 diabetes in Egyptian children. Gene. 2014;536(2):430–4.
Greer RM, Portelli SL, Hung BS, et al. Serum vitamin D levels are lower in Australian children and adolescents with type 1 diabetes than in children without diabetes. Pediatr Diabetes. 2013;14(1):31–41.
Thorsen SU, Mortensen HB, Carstensen B, et al. No difference in vitamin D levels between children newly diagnosed with type 1 diabetes and their healthy siblings: a 13-year nationwide Danish study. Diabetes Care. 2013;36(9):e157–8.
Sørensen IM, Joner G, Jenum PA, Eskild A, Torjesen PA, Stene LC. Maternal serum levels of 25-hydroxy-vitamin D during pregnancy and risk of type 1 diabetes in the offspring. Diabetes. 2012;61(1):175–8.
Sørensen IM, Joner G, Jenum PA, et al. Vitamin D-binding protein and 25-hydroxyvitamin D during pregnancy in mothers whose children later developed type 1 diabetes. Diabetes Metab Res Rev. 2016. doi:10.1002/dmrr.2812.
Miettinen ME, Reinert L, Kinnunen L, et al. Serum 25-hydroxyvitamin D level during early pregnancy and type 1 diabetes risk in the offspring. Diabetologia. 2012;55(5):1291–4.
Jia-Yi D, Weiguo Z, Jiong Jack C, Zeng-Li Z, Shu-Fen H, Li-Qiang Q. Vitamin D Intake and Risk of Type 1 Diabetes: A Meta-Analysis of Observational Studies. Nutrients. 2013;5:3551–62.
The EURODIAB Substudy 2 Study Group. Vitamin D supplement in early childhood and risk fortype I (insulin-dependent) diabetes mellitus. Diabetologia. 1999;42:51–4.
Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy associated with lower risk of type I diabetes in the offspring. Diabetologia. 2000;43:1093–8.
Stene LC, Joner G. Use of cod liver oil during the first year of life is associated with lower risk of childhood-onset type 1 diabetes: A large, population-based, case–control study. Am J Clin Nutr. 2003;78:1128–34.
Visalli N, Sebastiani L, Adorisio E, et al. IMDIAB Group. Environmental risk factors for type 1 diabetes in Rome and province. Arch. Dis. Child. 2003;88:695–8.
Tenconi MT, Devoti G, Comelli M, et al. Pavia T1DM Registry Group. Major childhood infectious diseases and other determinants associated with type 1 diabetes: A case–control study. Acta Diabetol. 2007;44:14–9.
Ahadi M, Tabatabaeiyan M, Moazzami K. Association between environmental factors and risk of type 1 diabetes—A case–control study. Endokrynol Pol. 2011;62:134–7.
Simpson M, Brady H, Yin X, et al. No association of vitamin D intake or 25-hydroxyvitamin D levels in childhood with risk of islet autoimmunity and type 1 diabetes: The Diabetes Autoimmunity Study in the Young (DAISY). Diabetologia. 2011;54:2779–88.
Marjamaki L, Niinisto S, Kenward MG, et al. Maternal intake of vitamin D during pregnancy and risk of advanced β cell autoimmunity and type 1 diabetes in offspring. Diabetologia. 2010;53:1599–607.
Al Sawah S, Compher CW, Hanlon AL, Lipman TH. 25-Hydroxyvitamin D and glycemic control: A cross-sectional study of children and adolescents with type 1 diabetes. Diabetes Res Clin Pract. 2016;115:54–9.
Lamichhane AP, Crandell JL, Jaacks LM, Couch SC, Lawrence JM, Mayer-Davis EJ. Longitudinal associations of nutritional factors with glycated hemoglobin in youth with type 1 diabetes: the SEARCH Nutrition Ancillary Study. Am J Clin Nutr. 2015;101(6):1278–85.
Aljabri KS, Bokhari SA, Khan MJ. Glycemic changes after vitamin D supplementation in patients with type 1 diabetes mellitus and vitamin D deficiency. Ann Saudi Med. 2010;30(6):454–8.
Mohammadian S, Fatahi N, Zaeri H, Vakili MA. Effect of Vitamin D3 Supplement in Glycemic Control of Pediatrics with Type 1 Diabetes Mellitus and Vitamin D Deficiency. J Clin Diagn Res. 2015;9(3):SC05–7.
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. Pediat Diabetes. 2016;17:36–43.
Nwosu BU, Maranda L. The effects of vitamin D supplementation on hepatic dysfunction, vitamin D status, and glycemic control in children and adolescents with vitamin D deficiency and either type 1 or type 2 diabetes mellitus. PLoS One. 2014;9(6), e99646.
Herrmann M, Sullivan DR, Veillard AS, et al. The FIELD Study Investigators. Serum 25-Hydroxyvitamin D: A Predictor of Macrovascular and Microvascular Complications in Patients With Type 2 Diabetes. Diabetes Care. 2015;38:521–8.
Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002;346:1145–51.
Deng X, Cheng J, Shen M. Vitamin D improves diabetic nephropathy in rats by inhibiting renin and relieving oxidative stress. J Endocrinol Invest. 2016;39(6):657–66.
Izquierdo MJ, Cavia M, Muρiz P, et al. Paricalcitol reduces oxidative stress and inflammation in hemodialysis patients. BMC Nephrol. 2012;13:159.
Li YC. Podocytes as target of vitamin D. Curr Diabetes Rev. 2011;7:35–40.
Yuan W, Pan W, Kong J, et al. 1,25-Dihydroxyvitamin D3 Suppresses renin gene transcription by blocking the activity of the cyclic AMP response element in the renin gene promoter. J Biol Chem. 2007;282:29821–30.
Parving HH, Lehnert H, Brφchner-Mortensen J, et al. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. N Engl J Med. 2001;345:870–8.
Agarwal R, Acharya M, Tian J, et al. Antiproteinuric effect of oral paricalcitol in chronic kidney disease. Kidney Int. 2005;68:2823–8.
Alborzi P, Patel NA, Peterson C, et al. Paricalcitol reduces albuminuria and inflammation in chronic kidney disease: a randomized double-blind pilot trial. Hypertension. 2008;52:249–55.
de Boer IH, Sachs MC, Cleary PA, et al. Diabetes Control and Complication Trial/Epidemiology of Diabetes Interventions and Complications Study Research Group. Circulating vitamin D metabolites and kidney disease in type 1 diabetes. J Clin Endocrinol Metab. 2012;97(12):4780–8.
Joergensen C, Tarnow L, Goetze JP. Vitamin D analogue therapy, cardiovascular risk and kidney function in people with Type 1 diabetes mellitus and diabetic nephropathy: a randomized trial. Diabet Med. 2015;32(3):374–81.
de Zeeuw D, Agarwal R, Amdahl M, et al. Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet. 2010;376:1543–51.
Derakhshanian H, Shab-Bidar S, Speakman JR, Nadimi H, Djafarian K. Vitamin D and diabetic nephropathy: a systematic review and meta-analysis. Nutrition. 2015;31:1189–94.
National Institute of Diabetes and Digestive Kidney Diseases, National Institutes of Health. Diabetic neuropathies: the nerve damage of diabetes Bethesda. National Institutes of Health, The U.S. Department of Health and Human Services; 2009, Available from: hhttp://diabetes.niddk.nih.gov/dm/pubs/neuropathies/index.aspxi [updated June 25, 2012].
Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–93.
Esyeghamati A, Fotouhi A, Faghihi-Kashani S, et al. Non-linear contribution of serum vitamin D to symptomatic diabetic neuropathy: A case–control study. Diabetes Res Clin Pract. 2016;111:44–50.
Eyles DW, Smith S, Kinobe R, Hewison M, McGrath JJ. Distribution of the vitamin D receptor and 1 alpha-hydroxylase in human brain. J Chem Neuroanat. 2005;29:21–30.
Naveilhan P, Neveu I, Wion D, Brachet P. 1,25- Dihydroxyvitamin D3, an inducer of glial cell line-derived neurotrophic factor. NeuroReport. 1996;7(13):2171–5. v1996.
Ahmadieh H, Azar ST, Lakkis N, Arabi A. Hypovitaminosis d in patients with type 2 diabetes mellitus: a relation to disease control and complications. ISRN Endocrinol. 2013;2013:641098.
Shehab D, Al-Jarallah K, Mojiminiyi OA, Al Mohamedy H, Abdella NA. Does Vitamin D deficiency play a role in peripheral neuropathy in Type 2 diabetes? Diabet Med. 2012;29:43–9.
Soderstrom LH, Johnson SP, Diaz VA, Mainous 3rd AG. Association between vitamin D and diabetic neuropathy in a nationally representative sample: results from 2001–2004 NHANES. Diabet Med. 2012;29:50–5.
Shehab D, Al-Jarallah K, Abdella N, Mojiminiyi OA, Al Mohamedy H. Prospective evaluation of the effect of short-term oral vitamin d supplementation on peripheral neuropathy in type 2 diabetes mellitus. Med Princ Pract. 2015;24:250–6.
Lee P, Chen R. Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Arch Intern Med. 2008;168(7):171–2.
Van Belle TL, Gysemans C, Mathieu C. Vitamin D and diabetes: the odd couple. Trends Endocrinol Metab. 2013;24:561–8.
Verrotti A, Loiacono G, Mohn A, Chiarelli F. New insights in diabetic autonomic neuropathy in children and adolescents. Eur J Endocrinol. 2009;161:811–8.
Lv WS, Zhao WJ, Gong SL, et al. Serum 25-hydroxyvitamin D levels and peripheral neuropathy in patients with type 2 diabetes: a systematic review and meta-analysis. J Endocrinol Invest. 2015;38(5):513–8.
Bell DS. Reversal of the Symptoms of Diabetic Neuropathy through Correction of Vitamin D Deficiency in a Type 1 Diabetic Patient. Case Rep Endocrinol. 2012;2012:165056.
Yau JW, Rogers SL, Kawasaki R, et al. Meta-analysis for Eye Disease (META-EYE) Study Group. Global prevalence and major risk factors ofdiabetic retinopathy. Diabetes Care. 2012;35(3):556–64.
Bonakdaran S, Shoeibi N. Is there any correlation between vitamin D insufficiency and diabetic retinopathy? Int J Ophthalmol. 2015;8(2):326–31.
Albert DM, Scheef EA, Wang S, et al. Calcitriol is a potent inhibitor of retinal neovascularization. Invest Ophthalmol Vis Sci. 2007;48:2327–34.
Ren Z, Li W, Zhao Q, Ma L, Zhu J. The impact of 1,25- dihydroxy vitamin D3 on the expressions of vascular endothelial growth factor and transforming growth factor-b1 in the retinas of rats with diabetes. Diabetes Res Clin Pract. 2012;98:474–80.
Shokravi MT, Marcus DM, Alroy J, Egan K, Saornil MA, Albert DM. Vitamin D inhibits angiogenesis in transgenic murineretinoblastoma. Invest Ophthalmol Vis Sci. 1995;36:83–7.
Kaur H, Donaghue KC, Chan AK, et al. Vitamin D deficiency is associated with retinopathy in children and adolescents with type 1 diabetes. Diabetes Care. 2011;34(6):1400–2.
Shimo N, Yasuda T, Kaneto H, et al. Vitamin D deficiency is significantly associated with retinopathy in young Japanese type 1 diabetic patients. Diabetes Res Clin Pract. 2014;106(2):e41–3.
Alcubierre N, Valls J, Rubinat E, et al. Vitamin D Deficiency Is Associated with the Presence and Severity of Diabetic Retinopathy in Type 2 Diabetes Mellitus. J Diabetes Res. 2015;2015:374178.
Alam U, Amjad Y, Chan AW, Asghar O, Petropoulos IN, Malik RA. Vitamin D Deficiency Is Not Associated with Diabetic Retinopathy or Maculopathy. J Diabetes Res. 2016;2016:6156217.
Taverna MJ, Selam JL, Slama G. Association between a protein polymorphism in the start codon of the vitamin D receptor gene and severe diabetic retinopathy in C-peptide- negative type 1 diabetes. J Clin Endocrinol Metab. 2005;90:4803–8.
Taverna MJ, Sola A, Guyot-Argenton C, et al. Taq I polymorphism of the vitamin D receptor and risk of severe diabetic retinopathy. Diabetologia. 2002;45:436–42.
Reddy GB, Sivaprasad M, Shalini T, et al. Plasma vitamin D status in patients with type 2 diabetes with and without retinopathy. Nutrition. 2015;31(7–8):959–63.
Zoppini G, Galletti A, Targher G, et al. Lower levels of 25-hydroxyvitamin D3 are associated with a higher prevalence of microvascular complications in patients with type 2 diabetes. BMJ Open Diabetes Res Care. 2015;3(1), e000058.
He R, Shen J, Liu F, et al. Vitamin D deficiency increases the risk of retinopathy in Chinese patients with type 2 diabetes. Diabet Med. 2014;31(12):1657–64.
Patrick PA, Visintainer PF, Shi Q, Weiss IA, Brand DA. Vitamin D and retinopathy in adults with diabetes mellitus. Arch Ophthalmol. 2012;130(6):756–60.
Aksoy H, AkcΈay F, Kurtul N, Baykal O, Avci B. Serum 1,25 dihydroxy vitamin D (1,25(OH)2D3), 25 hydroxy vitamin D(25(OH)D) and parathormone levels in diabetic retinopathy. Clin Biochem. 2000;33(1):47–51.
Suzuki A, Kotake M, Ono Y, et al. Hypovitaminosis D in type 2 diabetesmellitus: associationwith microvascular complications and type of treatment. Endocr J. 2006;53(4):503–10.
Payne JF, Ray R, Watson DG, et al. Vitamin D insufficiency in diabetic retinopathy. Endocr Pract. 2012;18(2):185–93.
Zhong X, Du Y, Lei Y, Liu N, Guo Y, Pan T. Effects of vitamin D receptor gene polymorphism and clinical characteristics on risk of diabetic retinopathy in Han Chinese type 2 diabetes patients. Gene. 2015;566(2):212–6.
Hong YJ, Kang ES, Ji MJ, et al. Association between Bsm1 Polymorphism in Vitamin D Receptor Gene and Diabetic Retinopathy of Type 2 Diabetes in Korean Population. Endocrinol Metab (Seoul). 2015;30(4):469–74.
Cyganek K, Mirkiewicz-Sieradzka B, Malecki MT, et al. Clinical risk factors and the role of VDR gene polymorphisms in diabetic retinopathy in Polish type 2 diabetes patients. Acta Diabetol. 2006;43:114–9.
Hao Y, Ma X, Luo Y, et al. Additional role of serum 25- hydroxyvitamin D3 levels in atherosclerosis in Chinese middleaged and elderly men. Clin Exp Pharmacol Physiol. 2014;41(3):174–9.
Papandreou D, Hamid ZT. The Role of Vitamin D in Diabetes and Cardiovascular Disease: An Updated Review of the Literature. Dis Markers. 2015;2015:580474.
Heidari B, Nargesi AA, Hafezi-Nejad N, et al. Assessment of serum 25 hydroxy vitamin D improves coronary heart disease risk stratification in patients withtype 2 diabetes. Am Heart J. 2015;170(3):573–9.e5.
Kunadian V, Ford GA, Bawamia B, et al. Vitamin D deficiency and coronary artery disease: a review of the evidence. Am Heart J. 2014;167(3):283–91.
Lee JH, Gadi R, Spertus JA, et al. Prevalence of vitamin D deficiency in patients with acute myocardial infarction. Am J Cardiol. 2011;107(11):1636–8.
Schneider L, Lutsey PL, Selvin E, et al. Vitamin D, vitamin D binding protein gene polymorphisms, race and risk of incident stroke: the Atherosclerosis Risk in Communities (ARIC) study. Eur J Neurol. 2015;22(8):1220–7.
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;205:255–60.
Giovannucci E, Liu Y, Hollis BW. RimmEB. 25- hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med. 2008;168:1174–80.
Hsia J, Heiss G, Ren H, et al. Women’s Health Initiative Investigators. Calcium/vitamin D supplementation and cardiovascular events. Circulation. 2007;115:846–54.
Avenell A, MacLennan GS, Jenkinson DJ, et al. RECORD Trial Group. Long-term follow-up for mortality and cancer in a randomized placebo-controlled trial of vitamin D(3) and/or calcium(RECORD trial). J Clin Endocrinol Metab. 2012;97:614–22.
Zagami RM, Di Pino A, Urbano F, Piro S, Purrello F, Rabuazzo AM. Low circulating vitamin D levels are associated with increased arterial stiffness in prediabetic subjects identified according to HbA1c. Atherosclerosis. 2015;243(2):395–401.
Lee JI, Oh SJ, Ha WC, et al. Serum 25-hydroxyvitamin D concentration and arterial stiffness among type 2 diabetes. Diabetes Res Clin Pract. 2012;95:42–7.
Lieberman R, Wadwa RP, Nguyen N, et al. The association between vitamin D and vascular stiffness in adolescents with and without type 1 diabetes. PloS ONE. 2013;8, e77272.
van Schooten FJ, Hirvonen A, Maas LM, et al. Putative susceptibility markers of coronary artery disease: association between VDR genotype, smoking and aromatic DNA adduct levels in human right atrial tissue. FASEB J. 1998;12:1409–17.
Ortlepp JR, von Korff A, Hanrath P, et al. Vitamin D receptor gene polymorphism Bsml is not associated with the prevalence and severity of CAD in a large-scale angiographic cohort of 3441 patients. Eur J Clin Invest. 2003;33:106–9.
Shanker J, Maitra A, Arvind P, et al. Role of vitamin D levels and vitamin D receptor polymorphisms in relation to coronary artery disease: the Indian atherosclerosis research study. Coron Art Disease. 2011;22:324–32.
Pan XM, Li DR, Yang L, et al. No association between vitamin D receptor polymorphisms and coronary artery disease in a Chinese population. DNA Cell Biol. 2009;28:521–5.
Maia J, da Silva AS, do Camo RF, et al. The association between vitamin D receptor gene polymorphisms (Taq1 and FokI), type 2 diabetes and micro-macrovascular complications in postmenopausal women. Appl Clin Genet. 2016;9:131–6.
Engelen L, Schalkwijk CG, Eussen SJ, et al. Low 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 levels are independently associated with macroalbuminuria, but not with retinopathy and macrovascular disease in type 1 diabetes: the EURODIAB prospective complications study. Cardiovasc Diabetol. 2015;14:67.
Sugden JA, Davies JI, Witham MD, et al. Vitamin D improves endothelial function in patients with type 2 diabetes mellitus and low vitamin D levels. Diabet Med. 2008;25(3):320–5.
Joergensen C, Reinhard H, Schmedes A, et al. Vitamin D levels and asymptomatic coronary artery disease in type 2 diabetic patients with elevated urinary albumin excretion rate. Diabetes Care. 2012;35(1):168–72.
Muscogiuri G, Altieri B, Annweiler C, et al. Vitamin D and chronic diseases: the current state of the art. Arch Toxicol. 2016;18 [Epub ahead of print].
Conflict of interest
The authors declare no conflict of interest.
Rights and permissions
About this article
Cite this article
Grammatiki, M., Rapti, E., Karras, S. et al. Vitamin D and diabetes mellitus: Causal or casual association?. Rev Endocr Metab Disord 18, 227–241 (2017). https://doi.org/10.1007/s11154-016-9403-y
- Vitamin D
- 25-hydroxyvitamin D
- Diabetes mellitus
- Type 1 diabetes
- Type 2 diabetes
- Diabetes complications