Evaluation of the Relationship Between Vitamin D and Inflammation in Type 2 Diabetes and Diabetic Complications

Authors

  • Tuba Taslamacioglu Duman Department of Internal Medicine, Bolu Abant İzzet Baysal University Faculty of Medicine, Bolu, Turkiye

DOI:

https://doi.org/10.63623/6epkqc16

Keywords:

Inflammation, Vitamin D, Type 2 diabetes mellitus, Diabetic complications

Abstract

Type 2 diabetes mellitus (T2DM) and its microvascular complications are characterized by chronic inflammation, which arises as a consequence of persistent hyperglycemia and insulin resistance. In obese patients with T2DM, abdominal adiposity further contributes to metabolic imbalance and an increased inflammatory burden. During the inflammatory process in adipose tissue, proinflammatory cytokine levels rise, while anti-inflammatory cytokines decrease. Vitamin D has been increasingly recognized for its role in modulating inflammation, a key factor in the progression of T2DM and its associated complications. This review examines the relationship between vitamin D status and inflammatory markers in individuals with T2DM, highlighting the potential mechanisms through which vitamin D influences immune responses and metabolic pathways. Recent clinical and experimental studies investigating the impact of vitamin D deficiency on chronic inflammation (such as via tumor necrosis factor alpha, interleukins, and C-reactive protein), insulin resistance, and the development of diabetic complications including cardiovascular disease, nephropathy, and neuropathy are discussed. Furthermore, the review elaborates on the potential benefits of vitamin D supplementation in managing inflammation and mitigating disease progression. Although existing evidence suggests a strong link between vitamin D and inflammatory processes in T2DM, further well-designed clinical trials are needed to establish causality and determine optimal supplementation strategies.

References

[1]Rohm TV, Meier DT, Olefsky JM, Donath MY. Inflammation in obesity, diabetes, and related disorders. Immunity, 2022, 55(1), 31-55. DOI: 10.1016/j.immuni.2021.12.013

[2]Chawla A, Nguyen KD, Goh YP. Macrophage-mediated inflammation in metabolic disease. Nature Reviews Immunology, 2011, 11(11), 738-749. DOI: 10.1038/nri3071

[3]Prietl B, Treiber G, Pieber TR, Amrein K. Vitamin D and immune function. Nutrients, 2013, 5(7), 2502-2521. DOI: 10.3390/nu5072502

[4]Holick MF. Vitamin D deficiency. The New England Journal of Medicine, 2007, 357(3), 266-281. DOI: 10.1056/NEJMra070553

[5]Erkus E, Aktas G, Kocak MZ, Duman TT, Atak BM, Savli H. Diabetic regulation of subjects with type 2 diabetes mellitus is associated with serum vitamin D levels. Revista da Associacao Medica Brasileira (1992), 2019, 65(1), 51-55. DOI: 10.1590/1806-9282.65.1.51

[6]Chokhandre MK, Mahmoud MI, Hakami T, Jafer M, Inamdar AS. Vitamin D & its analogues in type 2 diabetic nephropathy: a systematic review. Journal of Diabetes and Metabolic Disorders, 2015, 14, 58. DOI: 10.1186/s40200-015-0186-6

[7]Delrue C, Speeckaert R, Delanghe JR, Speeckaert MM. The role of vitamin D in diabetic nephropathy: A translational approach. International Journal of Molecular Sciences, 2022, 23(2), 807. DOI: 10.3390/ijms23020807

[8]Penna-Martinez M, Badenhoop K. Inherited variation in vitamin D Genes and type 1 diabetes predisposition. Genes, 2017, 8(4), 125. DOI: 10.3390/genes8040125

[9]Pike JW, Meyer MB, Lee SM, Onal M, Benkusky NA. The vitamin D receptor: contemporary genomic approaches reveal new basic and translational insights. The Journal of Clinical Investigation, 2017, 127(4), 1146-1154. DOI: 10.1172/jci88887

[10]Song Z, Xiao C, Jia X, Luo C, Shi L, Xia R, et al. Vitamin D/VDR Protects Against Diabetic Kidney Disease by Restoring Podocytes Autophagy. Diabetes, Metabolic Syndrome and Obesity : Targets and Therapy, 2021, 14, 1681-1693. DOI: 10.2147/dmso.s303018

[11]Uitterlinden AG, Fang Y, Van Meurs JB, Pols HA, Van Leeuwen JP. Genetics and biology of vitamin D receptor polymorphisms. Gene, 2004, 338(2), 143-156. DOI: 10.1016/j.gene.2004.05.014

[12]Wang H, Wang J, Qu H, Wei H, Ji B, Yang Z, et al. In vitro and in vivo inhibition of mTOR by 1,25-dihydroxyvitamin D(3) to improve early diabetic nephropathy via the DDIT4/TSC2/mTOR pathway. Endocrine, 2016, 54(2), 348-359. DOI: 10.1007/s12020-016-0999-1

[13]Shoelson SE, Lee J, Goldfine AB. Inflammation and insulin resistance. The Journal of Clinical Investigation, 2006, 116(7), 1793-1801. DOI: 10.1172/jci29069

[14]Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nature reviews Immunology, 2011, 11(2), 85-97. DOI: 10.1038/nri2921

[15]O'Rourke RW, White AE, Metcalf MD, Olivas AS, Mitra P, Larison WG, et al. Hypoxia-induced inflammatory cytokine secretion in human adipose tissue stromovascular cells. Diabetologia, 2011, 54(6), 1480-1490. DOI: 10.1007/s00125-011-2103-y

[16]Weisberg SP, McCann D, Desai M, Rosenbaum M, Leibel RL, Ferrante AW Jr. Obesity is associated with macrophage accumulation in adipose tissue. The Journal of Clinical Investigation, 2003, 112(12), 1796-1808. DOI: 10.1172/jci19246

[17]Skurk T, Alberti-Huber C, Herder C, Hauner H. Relationship between adipocyte size and adipokine expression and secretion. The Journal of Clinical Endocrinology and Metabolism, 2007, 92(3), 1023-1033. DOI: 10.1210/jc.2006-1055

[18]Park HS, Park JY, Yu R. Relationship of obesity and visceral adiposity with serum concentrations of CRP, TNF-alpha and IL-6. Diabetes Research and Clinical Practice, 2005, 69(1), 29-35. DOI: 10.1016/j.diabres.2004.11.007

[19]Chadt A, Scherneck S, Joost HG, Al-Hasani H. Molecular links between Obesity and Diabetes: “Diabesity”. Endotext. South Dartmouth (MA): MDText.com, Inc. 2000.

[20]Dula SB, Jecmenica M, Wu R, Jahanshahi P, Verrilli GM, Carter JD, et al. Evidence that low-grade systemic inflammation can induce islet dysfunction as measured by impaired calcium handling. Cell Calcium, 2010, 48(2-3), 133-142. DOI: 10.1016/j.ceca.2010.07.007

[21]Ramadan JW, Steiner SR, O'Neill CM, Nunemaker CS. The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes. Cell Calcium, 2011, 50(6), 481-490. DOI: 10.1016/j.ceca.2011.08.005

[22]Osborn O, Brownell SE, Sanchez-Alavez M, Salomon D, Gram H, Bartfai T. Treatment with an Interleukin 1 beta antibody improves glycemic control in diet-induced obesity. Cytokine, 2008, 44(1), 141-148. DOI: 10.1016/j.cyto.2008.07.004

[23]Westermark P, Andersson A, Westermark GT. Islet amyloid polypeptide, islet amyloid, and diabetes mellitus. Physiological Reviews, 2011, 91(3), 795-826. DOI: 10.1152/physrev.00042.2009

[24]Cesari M, Penninx BW, Newman AB, Kritchevsky SB, Nicklas BJ, Sutton-Tyrrell K, et al. Inflammatory markers and onset of cardiovascular events: results from the Health ABC study. Circulation, 2003, 108(19), 2317-2322. DOI: 10.1161/01.cir.0000097109.90783.FC

[25]Koukkunen H, Penttilä K, Kemppainen A, Halinen M, Penttila I, Rantanen T, et al. C-reactive protein, fibrinogen, interleukin-6 and tumour necrosis factor-alpha in the prognostic classification of unstable angina pectoris. Annals of Medicine, 2001, 33(1), 37-47. DOI: 10.3109/07853890109002058

[26]Blake GJ, Ridker PM. High sensitivity C-reactive protein for predicting cardiovascular disease: an inflammatory hypothesis. European Heart Journal, 2001, 22(5), 349-352. DOI: 10.1053/euhj.2000.2280

[27]Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. The New England journal of medicine, 2002, 347(20), 1557-1565. DOI: 10.1056/NEJMoa021993

[28]Rifai N, Ridker PM. High-sensitivity C-reactive protein: a novel and promising marker of coronary heart disease. Clinical Chemistry, 2001, 47(3), 403-411.

[29]Iademarco MF, McQuillan JJ, Dean DC. Vascular cell adhesion molecule 1: contrasting transcriptional control mechanisms in muscle and endothelium. Proceedings of the National Academy of Sciences of the United States of America, 1993, 90(9), 3943-3947. DOI: 10.1073/pnas.90.9.3943

[30]Landry DB, Couper LL, Bryant SR, Lindner V. Activation of the NF-kappa B and I kappa B system in smooth muscle cells after rat arterial injury. Induction of vascular cell adhesion molecule-1 and monocyte chemoattractant protein-1. The American Journal of Pathology, 1997, 151(4), 1085-1095.

[31]Yudkin JS, Kumari M, Humphries SE, Mohamed-Ali V. Inflammation, obesity, stress and coronary heart disease: is interleukin-6 the link? Atherosclerosis, 2000, 148(2), 209-214. DOI: 10.1016/s0021-9150(99)00463-3

[32]Deiuliis J, Shah Z, Shah N, Needleman B, Mikami D, Narula V, et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PloS one, 2011, 6(1), e16376. DOI: 10.1371/journal.pone.0016376

[33]Nishimura S, Manabe I, Nagasaki M, Eto K, Yamashita H, Ohsugi M, et al. CD8+ effector T cells contribute to macrophage recruitment and adipose tissue inflammation in obesity. Nature Medicine, 2009, 15(8), 914-920. DOI: 10.1038/nm.1964

[34]Winer S, Chan Y, Paltser G, Truong D, Tsui H, Bahrami J, et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nature Medicine, 2009, 15(8), 921-929. DOI: 10.1038/nm.2001

[35]Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nature medicine, 2009, 15(8), 930-939. DOI: 10.1038/nm.2002

[36]Esser N, L'Homme L, De Roover A, Kohnen L, Scheen AJ, Moutschen M, et al. Obesity phenotype is related to NLRP3 inflammasome activity and immunological profile of visceral adipose tissue. Diabetologia, 2013, 56(11), 2487-2497. DOI: 10.1007/s00125-013-3023-9

[37]Fujisaka S, Usui I, Bukhari A, Ikutani M, Oya T, Kanatani Y, et al. Regulatory mechanisms for adipose tissue M1 and M2 macrophages in diet-induced obese mice. Diabetes, 2009, 58(11), 2574-2582. DOI: 10.2337/db08-1475

[38]Niewczas MA, Pavkov ME, Skupien J, Smiles A, Md Dom ZI, Wilson JM, et al. A signature of circulating inflammatory proteins and development of end-stage renal disease in diabetes. Nature medicine, 2019, 25(5), 805-813. DOI: 10.1038/s41591-019-0415-5

[39]Schena FP, Gesualdo L. Pathogenetic mechanisms of diabetic nephropathy. Journal of the American Society of Nephrology, 2005, 16 Suppl 1, S30-33. DOI: 10.1681/asn.2004110970

[40]Wada J, Makino H. Innate immunity in diabetes and diabetic nephropathy. Nature Reviews Nephrology, 2016, 12(1), 13-26. DOI: 10.1038/nrneph.2015.175

[41]Chow F, Ozols E, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in mouse type 2 diabetic nephropathy: correlation with diabetic state and progressive renal injury. Kidney international, 2004, 65(1), 116-128. DOI: 10.1111/j.1523-1755.2004.00367.x

[42]Chow FY, Nikolic-Paterson DJ, Atkins RC, Tesch GH. Macrophages in streptozotocin-induced diabetic nephropathy: potential role in renal fibrosis. Nephrology, Dialysis, Transplantation, 2004, 19(12), 2987-2996. DOI: 10.1093/ndt/gfh441

[43]Galkina E, Ley K. Leukocyte recruitment and vascular injury in diabetic nephropathy. Journal of the American Society of Nephrology, 2006, 17(2), 368-377. DOI: 10.1681/asn.2005080859

[44]Nguyen D, Ping F, Mu W, Hill P, Atkins RC, Chadban SJ. Macrophage accumulation in human progressive diabetic nephropathy. Nephrology (Carlton), 2006, 11(3), 226-231. DOI: 10.1111/j.1440-1797.2006.00576.x

[45]Shikata K, Makino H. Role of macrophages in the pathogenesis of diabetic nephropathy. Contributions to Nephrology, 2001, (134), 46-54. DOI: 10.1159/000060147

[46]Catalán V, Gómez-Ambrosi J, Ramirez B, Rotellar F, Pastor C, Silva C, et al. Proinflammatory cytokines in obesity: impact of type 2 diabetes mellitus and gastric bypass. Obesity Surgery, 2007, 17(11), 1464-1474. DOI: 10.1007/s11695-008-9424-z

[47]Kim CS, Park HS, Kawada T, Kim JH, Lim D, Hubbard NE, et al. Circulating levels of MCP-1 and IL-8 are elevated in human obese subjects and associated with obesity-related parameters. International Journal of Obesity (Lond), 2006, 30(9), 1347-1355. DOI: 10.1038/sj.ijo.0803259

[48]King GL. The role of inflammatory cytokines in diabetes and its complications. Journal of Periodontology, 2008, 79(8 Suppl), 1527-1534. DOI: 10.1902/jop.2008.080246

[49]McCarty MF. Adjuvant strategies for prevention of glomerulosclerosis. Medical Hypotheses, 2006, 67(6), 1277-1296. DOI: 10.1016/j.mehy.2004.11.048

[50]Soto I, Krebs MP, Reagan AM, Howell GR. Vascular Inflammation Risk Factors in Retinal Disease. Annual Review of Vision Science, 2019, 5, 99-122. DOI: 10.1146/annurev-vision-091517-034416

[51]Dai Y, Wu Z, Wang F, Zhang Z, Yu M. Identification of chemokines and growth factors in proliferative diabetic retinopathy vitreous. Biomed Research International, 2014, 2014, 486386. DOI: 10.1155/2014/486386

[52]Olson JA, Whitelaw CM, McHardy KC, Pearson DW, Forrester JV. Soluble leucocyte adhesion molecules in diabetic retinopathy stimulate retinal capillary endothelial cell migration. Diabetologia, 1997, 40(10), 1166-1171. DOI: 10.1007/s001250050802

[53]Baum P, Toyka KV, Blüher M, Kosacka J, Nowicki M. Inflammatory Mechanisms in the Pathophysiology of Diabetic Peripheral Neuropathy (DN)-New Aspects. International Journal of Molecular Sciences, 2021, 22(19), 10835. DOI: 10.3390/ijms221910835

[54]Dattola A, Silvestri M, Bennardo L, Passante M, Scali E, Patruno C, et al. Role of vitamins in skin health: A systematic review. Current Nutrition Reports, 2020, 9(3), 226-235. DOI: 10.1007/s13668-020-00322-4

[55]Pieńkowska A, Janicka J, Duda M, Dzwonnik K, Lip K, Mędza A, et al. Controversial impact of vitamin D supplementation on reducing insulin resistance and prevention of type 2 diabetes in patients with prediabetes: A systematic review. Nutrients, 2023, 15(4), 983. DOI: 10.3390/nu15040983

[56]Adams JS, Rafison B, Witzel S, Reyes RE, Shieh A, Chun R, et al. Regulation of the extrarenal CYP27B1-hydroxylase. The Journal of Steroid Biochemistry and Molecular Biology, 2014, 144 Pt A, 22-27. DOI: 10.1016/j.jsbmb.2013.12.009

[57]Haussler MR, Haussler CA, Jurutka PW, Thompson PD, Hsieh JC, Remus LS, et al. The vitamin D hormone and its nuclear receptor: molecular actions and disease states. The Journal of Endocrinology, 1997, 154 Suppl, S57-73.

[58]Klopot A, Hance KW, Peleg S, Barsony J, Fleet JC. Nucleo-cytoplasmic cycling of the vitamin D receptor in the enterocyte-like cell line, Caco-2. Journal of Cellular Biochemistry, 2007, 100(3), 617-628. DOI: 10.1002/jcb.21087

[59]Argano C, Natoli G, Mularo S, Nobili A, Monaco ML, Mannucci PM, et al. Impact of diabetes mellitus and its comorbidities on elderly patients hospitalized in internal medicine wards: data from the RePoSi registry. Healthcare (Basel), 2022, 10(1), 86 DOI: 10.3390/healthcare10010086

[60]Helming L, Böse J, Ehrchen J, Schiebe S, Frahm T, Geffers R, et al. 1alpha,25-Dihydroxyvitamin D3 is a potent suppressor of interferon gamma-mediated macrophage activation. Blood, 2005, 106(13), 4351-4358. DOI: 10.1182/blood-2005-03-1029

[61]Bikle DD. Vitamin D Regulation of Immune Function. Current Osteoporosis Reports, 2022, 20(3), 186-193. DOI: 10.1007/s11914-022-00732-z

[62]Saponaro F, Saba A, Zucchi R. An Update on Vitamin D Metabolism. International Journal of Molecular Sciences, 2020, 21(18), 6573. DOI: 10.3390/ijms21186573

[63]Cantorna MT, Arora J. Two lineages of immune cells that differentially express the vitamin D receptor. The Journal of Steroid Biochemistry and Molecular Biology, 2023, 228, 106253. DOI: 10.1016/j.jsbmb.2023.106253

[64]Ao T, Kikuta J, Ishii M. The Effects of vitamin D on immune system and inflammatory diseases. Biomolecules, 2021, 11(11). DOI: 10.3390/biom11111624

[65]Chen Y, Zhang J, Ge X, Du J, Deb DK, Li YC. Vitamin D receptor inhibits nuclear factor κB activation by interacting with IκB kinase β protein. The Journal of Biological Chemistry, 2013, 288(27), 19450-19458. DOI: 10.1074/jbc.M113.467670

[66]Zhang Y, Leung DY, Richers BN, Liu Y, Remigio LK, Riches DW, et al. Vitamin D inhibits monocyte/macrophage proinflammatory cytokine production by targeting MAPK phosphatase-1. Journal of Immunology, 2012, 188(5), 2127-2135. DOI: 10.4049/jimmunol.1102412

[67]Chen X, Zhou M, Yan H, Chen J, Wang Y, Mo X. Association of serum total 25-hydroxy-vitamin D concentration and risk of all-cause, cardiovascular and malignancies-specific mortality in patients with hyperlipidemia in the United States. Frontiers in Nutrition, 2022, 9, 971720. DOI: 10.3389/fnut.2022.971720

[68]Khademi Z, Hamedi-Shahraki S, Amirkhizi F. Vitamin D insufficiency is associated with inflammation and deregulation of adipokines in patients with metabolic syndrome. BMC Endocrine Disorders, 2022, 22(1), 223. DOI: 10.1186/s12902-022-01141-0

[69]Maddaloni E, Cavallari I, Napoli N, Conte C. Vitamin D and Diabetes Mellitus. Frontiers of Hormone research, 2018, 50, 161-176. DOI: 10.1159/000486083

[70]Mitri J, Muraru MD, Pittas AG. Vitamin D and type 2 diabetes: a systematic review. European Journal of Clinical Nutrition, 2011, 65(9), 1005-1015. DOI: 10.1038/ejcn.2011.118

[71]Targher G, Bertolini L, Scala L, Cigolini M, Zenari L, Falezza G, et al. Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease. Nutrition, Metabolism, and Cardiovascular Diseases, 2007, 17(7), 517-524. DOI: 10.1016/j.numecd.2006.04.002

[72]Teleni L, Baker J, Koczwara B, Kimlin MG, Walpole E, Tsai K, et al. Clinical outcomes of vitamin D deficiency and supplementation in cancer patients. Nutrition Reviews, 2013, 71(9), 611-621. DOI: 10.1111/nure.12047

[73]Umar M, Sastry KS, Chouchane AI. Role of Vitamin D Beyond the Skeletal Function: A Review of the Molecular and Clinical Studies. International Journal of Molecular Sciences, 2018, 19(6), 1618. DOI: 10.3390/ijms19061618

[74]Wimalawansa SJ. Non-musculoskeletal benefits of vitamin D. The Journal of Steroid Biochemistry and Molecular Biology, 2018, 175, 60-81. DOI: 10.1016/j.jsbmb.2016.09.016

[75]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(4), 1490-1497. DOI: 10.1210/endo-120-4-1490

[76]Chertow BS, Sivitz WI, Baranetsky NG, Clark SA, Waite A, Deluca HF. Cellular mechanisms of insulin release: the effects of vitamin D deficiency and repletion on rat insulin secretion. Endocrinology, 1983, 113(4), 1511-1518. DOI: 10.1210/endo-113-4-1511

[77]Kadowaki S, Norman AW. Dietary vitamin D is essential for normal insulin secretion from the perfused rat pancreas. The Journal of Clinical Investigation, 1984, 73(3), 759-766. DOI: 10.1172/jci111269

[78]Norman AW, Frankel JB, Heldt AM, Grodsky GM. Vitamin D deficiency inhibits pancreatic secretion of insulin. Science, 1980, 209(4458), 823-825. DOI: 10.1126/science.6250216

[79]Tanaka Y, Seino Y, Ishida M, Yamaoka K, Yabuuchi H, Ishida H, et al. Effect of vitamin D3 on the pancreatic secretion of insulin and somatostatin. Acta endocrinologica, 1984, 105(4), 528-533. DOI: 10.1530/acta.0.1050528

[80]Bourlon PM, Faure-Dussert A, Billaudel B. The de novo synthesis of numerous proteins is decreased during vitamin D3 deficiency and is gradually restored by 1, 25-dihydroxyvitamin D3 repletion in the islets of langerhans of rats. The Journal of Endocrinology, 1999, 162(1), 101-109. DOI: 10.1677/joe.0.1620101

[81]Cade C, Norman AW. Vitamin D3 improves impaired glucose tolerance and insulin secretion in the vitamin D-deficient rat in vivo. Endocrinology, 1986, 119(1), 84-90. DOI: 10.1210/endo-119-1-84

[82]Clark SA, Stumpf WE, Sar M. Effect of 1,25 dihydroxyvitamin D3 on insulin secretion. Diabetes, 1981, 30(5), 382-386. DOI: 10.2337/diab.30.5.382

[83]Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, et al. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. The Journal of steroid biochemistry and molecular biology, 2004, 89-90(1-5), 121-125. DOI: 10.1016/j.jsbmb.2004.03.115

[84]Sergeev IN, Rhoten WB. 1,25-Dihydroxyvitamin D3 evokes oscillations of intracellular calcium in a pancreatic beta-cell line. Endocrinology, 1995, 136(7), 2852-2861. DOI: 10.1210/endo.136.7.7789310

[85]Milner RD, Hales CN. The role of calcium and magnesium in insulin secretion from rabbit pancreas studied in vitro. Diabetologia, 1967, 3(1), 47-49. DOI: 10.1007/bf01269910

[86]Fujita T, Sakagami Y, Tomita T, Okamoto Y, Oku H. Insulin secretion after oral calcium load. Endocrinologia japonica, 1978, 25(6), 645-648. DOI: 10.1507/endocrj1954.25.645

[87]Gedik O, Zileli MS. Effects of hypocalcemia and theophylline on glucose tolerance and insulin release in human beings. Diabetes, 1977, 26(9), 813-819. DOI: 10.2337/diab.26.9.813

[88]Yasuda K, Hurukawa Y, Okuyama M, Kikuchi M, Yoshinaga K. Glucose tolerance and insulin secretion in patients with parathyroid disorders. Effect of serum calcium on insulin release. The New England Journal of Medicine, 1975, 292(10), 501-504. DOI: 10.1056/nejm197503062921003

[89]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. The American Journal of Physiology, 1994, 267(3 Pt 1), E356-360. DOI: 10.1152/ajpendo.1994.267.3.E356

[90]Kadowaki S, Norman AW. Pancreatic vitamin D-dependent calcium binding protein: biochemical properties and response to vitamin D. Archives of Biochemistry and Biophysics, 1984, 233(1), 228-236. DOI: 10.1016/0003-9861(84)90621-0

[91]Sooy K, Schermerhorn T, Noda M, Surana M, Rhoten WB, Meyer M, et al. Calbindin-D(28k) controls [Ca(2+)](i) and insulin release. Evidence obtained from calbindin-d(28k) knockout mice and beta cell lines. Journal of Biological Chemistry, 1999, 274(48), 34343-34349. DOI: 10.1074/jbc.274.48.34343

[92]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 Journal, 2003, 17(3), 509-511. DOI: 10.1096/fj.02-0424fje

[93]Giulietti A, van Etten E, Overbergh L, Stoffels K, Bouillon R, Mathieu C. Monocytes from type 2 diabetic patients have a pro-inflammatory profile. 1,25-Dihydroxyvitamin D(3) works as anti-inflammatory. Diabetes Research and Clinical Practice, 2007, 77(1), 47-57. DOI: 10.1016/j.diabres.2006.10.007

[94]Gysemans CA, Cardozo AK, Callewaert H, Giulietti A, Hulshagen L, Bouillon R, et al. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology, 2005, 146(4), 1956-1964. DOI: 10.1210/en.2004-1322

[95]Riachy R, Vandewalle B, Kerr Conte J, Moerman E, Sacchetti P, Lukowiak B, et al. 1,25-dihydroxyvitamin D3 protects RINm5F and human islet cells against cytokine-induced apoptosis: implication of the antiapoptotic protein A20. Endocrinology, 2002, 143(12), 4809-4819. DOI: 10.1210/en.2002-220449

[96]van Etten E, Mathieu C. Immunoregulation by 1,25-dihydroxyvitamin D3: basic concepts. The Journal of Steroid Biochemistry and Molecular Biology, 2005, 97(1-2), 93-101. DOI: 10.1016/j.jsbmb.2005.06.002

[97]Riachy R, Vandewalle B, Moerman E, Belaich S, Lukowiak B, Gmyr V, et al. 1,25-Dihydroxyvitamin D3 protects human pancreatic islets against cytokine-induced apoptosis via down-regulation of the Fas receptor. Apoptosis, 2006, 11(2), 151-159. DOI: 10.1007/s10495-006-3558-z

[98]Oh J, Weng S, Felton SK, Bhandare S, Riek A, Butler B, et al. 1,25(OH)2 vitamin d inhibits foam cell formation and suppresses macrophage cholesterol uptake in patients with type 2 diabetes mellitus. Circulation, 2009, 120(8), 687-698. DOI: 10.1161/circulationaha.109.856070

[99]Song Y, Wang L, Pittas AG, Del Gobbo LC, Zhang C, Manson JE, et al. Blood 25-hydroxy vitamin D levels and incident type 2 diabetes: a meta-analysis of prospective studies. Diabetes Care, 2013, 36(5), 1422-1428. DOI: 10.2337/dc12-0962

[100]Pittas AG, Dawson-Hughes B, Sheehan P, Ware JH, Knowler WC, Aroda VR, et al. Vitamin D supplementation and prevention of type 2 diabetes. The New England Journal of Medicine, 2019, 381(6), 520-530. DOI: 10.1056/NEJMoa1900906

[101]LeBlanc ES, Pratley RE, Dawson-Hughes B, Staten MA, Sheehan PR, Lewis MR, et al. Baseline characteristics of the vitamin D and type 2 diabetes (D2d) study: A contemporary prediabetes cohort that will inform diabetes prevention efforts. Diabetes Care, 2018, 41(8), 1590-1599. DOI: 10.2337/dc18-0240

[102]Farahmand MA, Daneshzad E, Fung TT, Zahidi F, Muhammadi M, Bellissimo N, et al. What is the impact of vitamin D supplementation on glycemic control in people with type-2 diabetes: a systematic review and meta-analysis of randomized controlled trails. BMC Endocrine Disorders, 2023, 23(1), 15. DOI: 10.1186/s12902-022-01209-x

[103]Pittas AG, Jorde R, Kawahara T, Dawson-Hughes B. Vitamin D Supplementation for Prevention of Type 2 Diabetes Mellitus: To D or Not to D? The Journal of Clinical Endocrinology and Metabolism, 2020, 105(12), 3721-3733. DOI: 10.1210/clinem/dgaa594

[104]Dawson-Hughes B, Staten MA, Knowler WC, Nelson J, Vickery EM, LeBlanc ES, et al. intratrial exposure to vitamin D and new-onset diabetes among adults with prediabetes: A secondary analysis from the vitamin D and type 2 diabetes (D2d) study. Diabetes Care, 2020, 43(12), 2916-2922. DOI: 10.2337/dc20-1765

[105]Rani P, Koulmane Laxminarayana SL, Swaminathan SM, Nagaraju SP, Bhojaraja MV, Shetty S, et al. TGF-β: elusive target in diabetic kidney disease. Renal Failure, 2025, 47(1), 2483990. DOI: 10.1080/0886022x.2025.2483990

[106]Deb DK, Chen Y, Zhang Z, Zhang Y, Szeto FL, Wong KE, et al. 1,25-Dihydroxyvitamin D3 suppresses high glucose-induced angiotensinogen expression in kidney cells by blocking the NF-{kappa}B pathway. American Journal of Physiology Renal Physiology, 2009, 296(5), F1212-1218. DOI: 10.1152/ajprenal.00002.2009

[107]Huang HY, Lin TW, Hong ZX, Lim LM. Vitamin D and Diabetic Kidney Disease. International Journal of Molecular Sciences, 2023, 24(4), 3751. DOI: 10.3390/ijms24043751

[108]Wang Y, Deb DK, Zhang Z, Sun T, Liu W, Yoon D, et al. Vitamin D receptor signaling in podocytes protects against diabetic nephropathy. Journal of the American Society of Nephrology, 2012, 23(12), 1977-1986. DOI: 10.1681/asn.2012040383

[109]Wang Y, Yang S, Zhou Q, Zhang H, Yi B. Effects of Vitamin D Supplementation on Renal Function, Inflammation and Glycemic Control in Patients with Diabetic Nephropathy: a Systematic Review and Meta-Analysis. Kidney and Blood Pressure Research, 2019, 44(1), 72-87. DOI: 10.1159/000498838

[110]Lu L, Lu Q, Chen W, Li J, Li C, Zheng Z. Vitamin D(3) Protects against Diabetic Retinopathy by Inhibiting High-Glucose-Induced Activation of the ROS/TXNIP/NLRP3 Inflammasome Pathway. Journal of Diabetes Research, 2018, 2018, 8193523. DOI: 10.1155/2018/8193523

[111]Tecilazich F, Formenti AM, Giustina A. Role of vitamin D in diabetic retinopathy: Pathophysiological and clinical aspects. Reviews in Endocrine & Metabolic Disorders, 2021, 22(4), 715-727. DOI: 10.1007/s11154-020-09575-4

[112]Dervis N, Jurja S, Chisnoiu T, Mihai CM, Stoica AM. Serum Vitamin D Levels as Predictors of Response to Intravitreal Anti-VEGF Therapy in Diabetic Macular Edema: A Clinical Correlation Study. International Journal of Molecular Sciences, 2025, 26(17), 8481. DOI: 10.3390/ijms26178481

[113]Cheng Y, Chen Y, Li K, Liu S, Pang C, Gao L, et al. How inflammation dictates diabetic peripheral neuropathy: An enlightening review. CNS Neuroscience & Therapeutics, 2024, 30(4), e14477. DOI: 10.1111/cns.14477

[114]Hao W, Tashiro S, Hasegawa T, Sato Y, Kobayashi T, Tando T, et al. Hyperglycemia Promotes Schwann Cell De-differentiation and De-myelination via Sorbitol Accumulation and Igf1 Protein Down-regulation. Journal of Biological Chemistry, 2015, 290(28), 17106-17115. DOI: 10.1074/jbc.M114.631291

[115]Román-Pintos LM, Villegas-Rivera G, Rodríguez-Carrizalez AD, Miranda-Díaz AG, Cardona-Muñoz EG. Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function. Journal of Diabetes Research, 2016, 2016, 3425617. DOI: 10.1155/2016/3425617

Downloads

Published

2025-11-26

Issue

Section

Articles