Type 2 Diabetes Mellitus, Insulin Resistance, and Vitamin D
Purpose of Review
There is a growing, largely inconsistent, literature on the role of vitamin D in association with type 2 diabetes, insulin resistance/insulin secretion, glycemic indices, and complications of type 2 diabetes. Pathophysiologic, bystander, preventive, and treatment roles of vitamin D have all been proposed. In this focused review, we attempt to organize and clarify our current information in this area.
Clinical study interpretation is difficult because of variability in dosage, dosage form, study duration, and populations studied, as well as recently reported normal human polymorphisms in vitamin D synthesis and catabolism, vitamin D-binding protein, and vitamin D receptors in addition to a host of potential epigenetic confounders. Low vitamin D status appears to be associated with type 2 diabetes and most other insulin resistance disorders reported to date. The extraskeletal benefits of supplementation/repletion in these disorders in our species, with a few highlighted exceptions, remain to be established.
This focused review attempts to summarize our current knowledge in this burgeoning area through a review of key meta-analyses, observational studies, randomized control trials, and Mendelian randomization studies and will hopefully serve as a guide to indicate future research directions and current best practice.
KeywordsVitamin D status T2DM Insulin resistance Diabetes complications Vitamin D deficiency Metabolic syndrome
AS is the corresponding author and reviewed about 65% of the articles cited. PD reviewed about 35% of the articles cited, chiefly those on gout, insulin resistance, and vitamin D, and she also prepared the 1st and 2nd drafts of the summary tables. GB, PD, VL, and AS all reviewed and edited the final presubmission draft.
Compliance with Ethical Standards
Conflict of Interest
Alan Sacerdote, Paulomi Dave, Vladimir Lokshin, and Gül Bahtiyar declare that they have no conflicts of interest.
Human and Animal Rights and Informed Consent
All reported studies/experiments with human or animal subjects performed by the authors have been previously published and complied with all applicable ethical standards (including the Helsinki declaration and its amendments, institutional/national research committee standards, and international/national institutional guidelines).
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
- 1.•• 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. A recent review summarizing reports showing significant positive correlation between serum 1,25-OH-vitamin D (the active form) and both insulin sensitivity and secretion, a negative association between vitamin D deficiency and glycemic control, and a positive association of VDD with incident T2DM.PubMedCrossRefGoogle Scholar
- 2.•• Gulseth HL, Wium C, Angel K, Eriksen EF, Birkeland KI. Effects of vitamin D supplementation on insulin sensitivity and insulin secretion in subjects with type 2 diabetes and vitamin D deficiency: a randomized controlled trial. Diabetes Care. 2017;40(7):872–8. A recent study of supplementation’s effects on insulin sensitivity and secretion and glycemic indicators in people with T2DM with replete baseline serum 25-OH-vitamin D.PubMedCrossRefGoogle Scholar
- 4.• Angellotti E, Pittas AG. The role of vitamin D in the prevention of type 2 diabetes: to D or not to D? Endocrinology. 2017;158(7):2013–21. In this recent focused review despite evidence for prevention from mechanistic and observational studies, a definitive answer regarding T2DM prevention with vitamin D is impossible because reverse causation cannot be excluded.PubMedPubMedCentralCrossRefGoogle Scholar
- 9.•• Santos RKF, Brandão-Lima PN, Tete RMDD, Freire ARS, Pires LV. Vitamin D ratio and glycaemic control in individuals with type 2 diabetes mellitus: a systematic review. Diabetes Metab Res Rev. 2018;34(3). A recent focused review of studies assessing the association of vitamin D status with glycemic indices in people with T2DM. CrossRefGoogle Scholar
- 10.•• Qu G, Wang L, Tang X, Wu W, Suna Y. The association between vitamin D level and diabetic peripheral neuropathy in patients with type 2 diabetes mellitus: an update systematic review and meta-analysis. J Clin Transl Endocrinol. 2017;9:25–31. A recent focused review and meta-analysis of studies exploring associations between vitamin D status and the common diabetic complication of peripheral neuropathy.PubMedPubMedCentralGoogle Scholar
- 11.•• Hansen CS, Fleischer J, Vistisen D, Ridderstråle M, Jensen JS, Jørgensen ME. High and low vitamin D level is associated with cardiovascular autonomic neuropathy in people with type 1 and type 2 diabetes. Diabet Med. 2017;34(3):364–71. A recent study of the association of vitamin D status with cardiac autonomic neuropathy in people with either T2DM or T1DM.PubMedCrossRefGoogle Scholar
- 13.•• Basat S, Sivritepe R, Ortaboz D, Sevim Çalık E, Küçük EV, Şimşek B, et al. The relationship between vitamin D level and erectile dysfunction in patients with type 2 diabetes mellitus. Aging Male. 2018;21(2):111–5. An important recent cross-sectional study of the association of erectile dysfunction with vitamin D status.PubMedCrossRefGoogle Scholar
- 14.•• Luo BA, Gao F, Qin LL. The association between vitamin D deficiency and diabetic retinopathy in type 2 diabetes: a meta-analysis of observational studies. Nutrients. 2017;9(3):307. An important recent study on the association of low vitamin D status and diabetic retinopathy.PubMedCentralCrossRefPubMedGoogle Scholar
- 19.•• Yu Y, Tian L, Xiao Y, Huang G, Zhang M. Effect of vitamin D supplementation on some inflammatory biomarkers in type 2 diabetes mellitus subjects: a systematic review and meta-analysis of randomized controlled trials. Ann Nutr Metab. 2018;73(1):62–73. A recent focused review and meta-analysis of interventional RCTs studying impact of vitamin D supplementation on surrogate markers for macrovascular complications.PubMedCrossRefGoogle Scholar
- 21.•• Li DM, Zhang Y, Li Q, Xu XH, Ding B, Ma JH. Low 25-hydroxyvitamin D level is associated with peripheral arterial disease in type 2 diabetes patients. Arch Med Res. 2016;47(1):49–54. A recent cross-sectional study exploring the association of low vitamin D status with peripheral arterial disease.PubMedCrossRefGoogle Scholar
- 23.•• Barchetta I, Cimini FA, Cavallo MG. Vitamin D supplementation and non-alcoholic fatty liver disease: present and future. Nutrients. 2017;9(9):1015. Recent focused review of observational studies on associations between low vitamin D status and NAFLD and intervention studies.PubMedCentralCrossRefPubMedGoogle Scholar
- 42.Wehr E, Pieber TR, Obermayer-Pietsch B. Effect of vitamin D3 treatment on glucose metabolism and menstrual frequency in polycystic ovary syndrome women: a pilot study. J Endocrinol Investig. 2011;34:757–63.Google Scholar
- 49.Mogili KD, Karuppusami R, Thomas S, Chandy A, Kamath MS, TKA. Prevalence of vitamin D deficiency in infertile women with polycystic ovarian syndrome and its association with metabolic syndrome - a prospective observational study. Eur J Obstet Gynecol Reprod Biol. 2018;229:15–9.PubMedCrossRefGoogle Scholar
- 54.Sacerdote A, Bahtiyar G “Treatment of congenital adrenal hyperplasia by reducing insulin resistance and cysticercosis induced polycystic ovarian syndrome,” in Darwish A editor Contemporary Gynecologic Practice, A. Darwish, Ed., InTech; 2015.Google Scholar
- 55.Bahtiyar G, Sacerdote A. “Management approaches to congenital adrenal hyperplasia in adolescents and adults; latest therapeutic developments,” in Chatterjee A editor Amenorrhea, InTech; 2011.Google Scholar
- 56.Thomas N, Kalani A, Vincent R, Luis Lam M, Bahtiyar G, Borensztein A, et al. Effect of vitamin D in a patient with classical adrenal hyperplasia due to 11-hydroxylase deficiency. J Med Cases. 2013;4(8):569–75.Google Scholar
- 57.Luis Lam M, Sacerdote AS, Bahtiyar G. Normalization of serum 11-deoxycortisol in a patient with non-classic adrenal hyperplasia due to 11-hydroxylase deficiency treated with vitamin D and a glucagon-like peptide(GLP)-1 agonist. Presented at The 96th Annual Meeting of The Endocrine Society, 6/21/2014, Chicago, IL. Presentation Number: SAT-0763.Google Scholar
- 59.Dono E, Inoue T, Ezeji G, Baby A, Bahtiyar G, Sacerdote AS. Amelioration of non-classic 11-hydroxylase deficiency in a vitamin D deficient patient with weight loss and ergocalciferol. press.endocrine.org/doi/abs/10.1210/endo-meetings.2015.AHPAA.7.THR-415.Google Scholar
- 60.Sacerdote, A.: Weight-dependent expression of non-classical aldosterone synthase deficiency. Program and Abstracts, Endo-2002, The Endocrine Society’s 84th Annual Meeting: 599, 2002.Google Scholar
- 61.Lundqvist J, Wikvall K, Norlin M. Vitamin D-mediated regulation of CYP21A2 transcription – a novel mechanism for vitamin D action. BiochimBiophysActa. 1820;2012:1553–9.Google Scholar
- 62.Fenteany G, Inoue T, Bahtiyar G, Sacerdote AS. Association of vitamin D repletion with normalization of elevated serum 17- OH-progesterone. Med Cas Rep. 2017;3:3.Google Scholar
- 69.International Diabetes Federation (IDF): The IDF consensus worldwide definition of the metabolic syndrome. https://www.idf.org/e-library/consensus-statements/60-idfconsensus-worldwide-definitionof-the-metabolic
- 82.•• Sipahi S, Acikgoz SB, Genc AB, Yildirim M, Solak Y, Tamer A. The association of vitamin D status and vitamin D replacement therapy with glycemic control, serum uric acid levels, and microalbuminuria in patients with type 2 diabetes and chronic kidney disease. Med Princ Pract. 2017;26:146–51. A recent study of associations between vitamin D status and glycemic indicators and renal function in people with T2DM and CKD.PubMedCrossRefGoogle Scholar
- 83.Hayashino Y, Okamura S, Tsujii S, Ishii H. Association of serum uric acid levels with the risk of development or progression of albuminuria among Japanese patients with type 2 diabetes: a prospective cohort study (Diabetes Distress and Care Registry at Tenri [DDCRT 10]). Acta Diabetol. 2016;53:599–607.PubMedCrossRefGoogle Scholar
- 86.•• Langer-Gould A, Lucas RM, Xiang AH, Wu J, Chen LH, Gonzales E, Haraszti S, Smith JB, Quach H, Barcellos LF. Vitamin D-binding protein polymorphisms, 25-hydroxyvitamin D, sunshine and multiple sclerosis. Nutrients. 2018;10(2). An important recent discussion about how VDBP polymorphisms affect the biologic expression of vitamin D. Google Scholar
- 93.•• Al-Daghri NM, Mohammed AK, Al-Attas OS, Ansari MGA, Wani K, Hussain SD, Sabico S, Tripathi G, Majed S, Alokail MS. Vitamin D receptor gene polymorphisms modify cardiometabolic response to vitamin D supplementation in T2DM patients. Sci Rep 2017, Article number: 8280. An important 1 year vitamin D intervention trial assessing cardiometabolic effects of vitamin D administration as a function of vitamin D receptor polymorphisms. Google Scholar
- 95.•• Bahrami A, Sadeghnia HR, Tabatabaeizadeh SA, Bahrami-Taghanaki H, Behboodi N, Esmaeili H, et al. Genetic and epigenetic factors influencing vitamin D status. J Cell Physiol. 2018;233(5):4033–43. A good recent review of genetic and epigenetic influences on vitamin D status.PubMedCrossRefGoogle Scholar
- 97.Lu L, Bennett DA, Millwood IY, Parish S, McCarthy MI, Mahajan A, et al. Mendelian randomization study in European and Chinese adults. PLoS Med. 2018;15(5):e1002566. A recent Mendelian randomization study in which only 2 SNPs associated with vitamin D synthesis, for which possible pleiotropic effects on incident T2DM risk had been excluded, from which the investigators were able to infer a causative, genetically instrumented protective effect of vitamin D against incident T2DM.PubMedPubMedCentralCrossRefGoogle Scholar
- 98.•• Pittas AG, Dawson-Hughes B, Patricia Sheehan P et al. for the D2d Research Group. Vitamin D supplementation and prevention of type 2 diabetes. June 7, 2019. https://doi.org/10.1056/NEJMoa1900906. The largest randomized, placebo-controlled vitamin D intervention study to date in people at high risk for incident T2DM not preselected for vitamin D deficiency. PubMedCrossRefGoogle Scholar
- 100.Kajbaf F, Mentaverri R, Diouf M, Fournier A, Kamel S, Lalau JD. The association between 25-hydroxyvitamin D and hemoglobin A1c levels in patients with type 2 diabetes and stage 1-5 chronic kidney disease. Int J Endocrinol. 2014;2014:142468–6. https://doi.org/10.1155/2014/142468.CrossRefPubMedPubMedCentralGoogle Scholar