Diabetes, immune system and Vitamin D – book chapter – 2019

Vitamin D in immune regulation

and diabetes mellitus – Chapter 22
Ihor Shymanskyi, Olha Lisakovska, Dmytro Labudzinskyi, Anna Mazanova and Mykola Veliky
Department of Biochemistry of Vitamins and Coenzymes, Palladin Institute of Biochemistry of National
Academy of Sciences of Ukraine, Kyiv, Ukraine

22.1 Introduction	428
22.2 Vitamin D synthesis and activation	428
22.3 Role of vitamin D in immune regulation and inflammatory responses	432
22.3.1 Vitamin D and innate immunity	432
22.3.2 Vitamin D and adaptive immunity	433
22.3.3 Cytokines in regulation of vitamin D-metabolizing enzymes	434
22.4 Vitamin D and diabetes mellitus	435
22.4.1 Vitamin D modulates β-cell function	435
22.4.2 Vitamin Dauto/paracrine system in diabetes mellitus	437
22.4.3 Antiinflammatory effect of vitamin D in diabetes mellitus	438
22.5 Conclusions	442
References (at bottom of VitaminDWiki page)	443

 Download the PDF from Sci-Hub via VitaminDWiki

Diabetes increases the expression (2) of CPY24A1
which destroys Vitamin D after it is seen by Vit D blood test
Thus preventing Vitamin D from benefiting tissues
(3) Addition of Vitamin D decreases the CYP24A1 expression

---

References

• Akiyama, T., Shinzawa, M., Akiyama, N., 2012. RANKL—RANK interaction in immune regulatory systems. WorldJ. Orthop. 3, 142—150.
• Alfonso, B., Liao, E., Busta, A., Poretsky, L., 2009. Vitamin D in diabetes mellitus—a new field of knowledge poised for D-velopment. Diabetes Metabol. Res. Rev. 25, 417—419.
• Ali, T., El Esawy, B., Elaskary, A., 2018. Effect of paricalcitol on pancreatic oxidative stress, inflammatory markers, and glycemic status in diabetic rats. Ir. J. Med. Sci. 187, 75—84.
• Barragan, M., Good, M., Kolls, J., 2015. Regulation of dendritic cell function by vitamin D. Nutrients 7, 8127—8151.
• Barrat, F., Cua, D., Boonstra, A., Richards, D., Crain, C., Savelkoul, H., et al., 2002. In vitro generation of interleukin 10-producing regulatory CD4 1 T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J.Exp. Med. 195, 603—616.
• Bhalla, A.K., Paavonen, T., Williams, M., Delves, P., Lydyard, P., 1991. Regulation of interleukin-1 and tumour necrosis factor gene expression in myelomonocytic cell lines by 1,25-dihydroxyvitamin D3. Immunology 72, 61 — 64.
• Bikle, D., 2014. Vitamin D metabolism, mechanism of action, and clinical applications. Chem. Biol. 21, 319—329.
• Bikle, D., 2016. Extraskeletal actions of vitamin D. Ann. N. Y. Acad. Sci. 1376, 29—52.
• Bivona, G., Agnello, L., Ciaccio, M., 2017. Vitamin D and immunomodulation: is it time to change the reference values? Ann. Clin. Lab. Sci. 47, 508—510.
• Bourlon, P., Billaudel, B., Faure-Dussert, A., 1999. 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. 160, 87—95.
• Brosbol-Ravnborg, A., Bundgaard, B., Hollsberg, P., 2013. Synergy between vitamin D3 and Toll-like receptor agonists regulates human dendritic cell response during maturation. Clin. Dev. Immunol. 2013, 807971.
• Chambers, E., Suwannasaen, D., Mann, E., Urry, Z., Richards, D., Lertmemongkolchai, G., et al., 2014. 1 a,25-Dihydroxyvitamin D3 in combination with transforming growth factor- increases the frequency of Foxp3 1 regulatory T cells through preferential expansion and usage of interleukin-2. Immunology 143, 52—60.
• Chen, J., Bruce, D., Cantorna, M., 2014. Vitamin D receptor expression controls proliferation of naive CD81 T cells and development of CD8 mediated gastrointestinal inflammation. BMC Immunol. 15, 6.
• Christakos, S., Dhawan, P., Verstuyf, A., Verlinden, L., Carmeliet, G., 2016. Vitamin D: metabolism, molecular mechanism of action, and pleiotropic effects. Physiol. Rev. 96, 365—408.
• Corripio-Miyar, Y., Mellanby, R., Morrison, K., McNeilly, T., 2017. 1,25-Dihydroxyvitamin D3 modulates the phenotype and function of monocyte derived dendritic cells in cattle. BMC Vet. Res. 13, 390.
• Di Rosa, M., Malaguarnera, G., De Gregorio, C., Palumbo, M., Nunnari, G., Malaguarnera, L., 2012. Immuno-modulatory effects of vitamin D3 in human monocyte and macrophages. Cell. Immunol. 280, 36—43.
• Fleet, J., 2017. The role of vitamin D in the endocrinology controlling calcium homeostasis. Mol. Cell. Endocrinol. 453, 36—45.
• Giarratana, N., Penna, G., Amuchastegui, S., Mariani, R., Daniel, K., Adorini, L., 2004. A vitamin D analog down-regulates proinflammatory chemokine production by pancreatic islets inhibiting T cell recruitment and type 1 diabetes development. J. Immunol. 173, 2280—2287.
• Grammatiki, M., Rapti, E., Karras, S., Ajjan, R., Kotsa, K., 2017. Vitamin D and diabetes mellitus: causal or casual association? Rev. Endocr. Metab. Disord. 18, 227—241.
• Gregoriou, E., Mamais, I., Tzanetakou, I., Lavranos, G., Chrysostomou, S., 2017. The effects of vitamin D supplementation in newly diagnosed type 1 dabetes patients: systematic review of randomized controlled trials. Rev. Diabet. Stud. 14, 260—268.
• Gysemans, C., Cardozo, A., Callewaert, H., Giulietti, A., Hulshagen, L., Bouillon, R., et al., 2005. 1,25-Dihydroxyvitamin D3 modulates expression of chemokines and cytokines in pancreatic islets: implications for prevention of diabetes in nonobese diabetic mice. Endocrinology 146, 1956—1964.
• Han, F., Lv, Y., Gong, L., Liu, H., Wan, Z., Liu, L., 2017. VDR Gene variation and insulin resistance related diseases. Lipids Health Dis. 16, 157.
• Hoseinzadeh, E., Taha, P., Wei, C., Godini, H., Ashraf, G.M., Taghavi, M., et al., 2018. The impact of air pollutants, UV exposure and geographic location on vitamin D deficiency. Food Chem. Toxicol. 113, 241—254.
• Hypponen, E., Laara, E., Reunanen, A., Jarvelin, M., Virtanen, S., 2001. Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 358, 1500—1503.
• Jeffery, L., Burke, F., Mura, M., Zheng, Y., Qureshi, O., Hewison, M., et al., 2009. 1,25- Dihydroxyvitamin D3 and IL-2 combine to inhibit T cell production of inflammatory cytokines and promote development of regulatory T cells expressing CTLA-4 and FoxP3. J. Immunol. 183, 5458—5467.
• Kagi, L., Bettoni, C., Pastor-Arroyo, E., Schnitzbauer, U., Hernando, N., Wagner, C., 2018. Regulation of vitamin D metabolizing enzymes in murine renal and extrarenal tissues by dietary phosphate, FGF23, and 1,25(OH)2D3. PLoS One 13, e0195427.
• Karonova, T., Grineva, E., Belyaeva, O., Bystrova, A., Jude, E., Andreeva, A., et al., 2018. Relationship between vitamin D status and vitamin D receptor gene polymorphisms with markers of metabolic syndrome among adults. Front. Endocrinol. (Lausanne) 9, 448.
• Kjalarsdottir, L., Tersey, S., Vishwanath, M., Chuang, J., Posner, B., Mirmira, R., et al., 2018. 1,25-Dihydroxyvitamin D3 enhances glucose-stimulated insulin secretion in mouse and human islets: a role for transcriptional regulation of voltage-gated calcium channels by the vitamin D receptor. J. Steroid Biochem. Mol. Biol. 185, 17—26 (ahead of print).
• Labudzynskyi, D., Manoylov, K., Shymansky, I., Veliky, M., 2016a. Immunoregulatory effects of vitamin D3 in experimentally induced type 1 diabetes. Cytol. Genet. 50, 231—240.
• Labudzynskyi, D., Shymanskyy, I., Veliky, M., 2016b. Role of vitamin D3 in regulation of interleukin-6 and osteopontin expression in liver of diabetic mice. Eur. Rev. Med. Pharmacol. Sci. 20, 2916—2919.
• Liu, C., Feng, X., Li, Q., Wang, Y., Li, Q., Hua, M., 2016. Adiponectin, TNF-a and inflammatory cytokines and risk of type 2 diabetes: a systematic review and metaanalysis. Cytokine 86, 100—109.
• Lu, M., Taylor, B., Korner, H., 2018. Genomic effects of the vitamin D receptor: potentially the link between vitamin D, immune cells, and multiple sclerosis. Front. Immunol. 9, 477.
• Mahon, B., Wittke, A., Weaver, V., Cantorna, M., 2003. The targets of vitamin D depend on the differentiation and activation status of CD4 positive T cells. J. Cell. Biochem. 89, 922—932.
• Mao, L., Ji, F., Liu, Y., Zhang, W., Ma, X., 2014. Calcitriol plays a protective role in diabetic nephropathy through anti-inflammatory effects. Int. J. Clin. Exp. Med. 7, 5437—5444.
• Mazanova, A., Shymanskyi, I., Lisakovska, O., Hajiyeva, L., Komisarenko, Y., Veliky, M., 2018. Effects of cholecalciferol on key components of vitamin D-endo/para/autocrine system in experimental type 1 diabetes. Int. J. Endocrinol. 2018, 2494016.
• Moran-Auth, Y., Penna-Martinez, M., Badenhoop, K., 2015. VDR FokI polymorphism is associated with a reduced T-helper cell population under vitamin D stimulation in type 1 diabetes patients. J. Steroid Biochem. Mol. Biol. 148, 184—186.
• Mousa, A., Naderpoor, N., Teede, H., Scragg, R., de Courten, B., 2018. Vitamin D supplementation for improvement of chronic low-grade inflammation in patients with type 2 diabetes: a systematic review and meta-analysis of randomized controlled trials. Nutr. Rev. 76, 380—394.
• Neelankal John, A., Iqbal, Z., Colley, S., Morahan, G., Makishima, M., Jiang, F., 2018. Vitamin D receptor-targeted treatment to prevent pathological dedifferentiation of pancreatic 3 cells under hyperglycaemic stress. Diabetes Metab. 44, 269—280.
• Overbergh, L., Stoffels, K., Waer, M., Verstuyf, A., Bouillon, R., Mathieu, C., 2006. Immune regulation of 25-hydroxyvitamin D-1alpha-hydroxylase in human monocytic THP1 cells: mechanisms of interferon-gamma-mediated induction. J. Clin.Endocrinol. Metab. 91, 3566-3374.
• Penna, G., Adorini, L., 2000. 1-alpha-25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164, 2405—2411.
• Penna-Martinez, M., Badenhoop, K., 2017. Inherited variation in vitamin D genes and type 1 diabetes predisposition, Genes (Basel), 8. p. E125.
• Pramyothin, P., Holick, M., 2012. Vitamin D supplementation: guidelines and evidence for subclinical deficiency. Curr. Opin. Gastroenterol. 28, 139—150.
• Sato, E., Imafuku, S., Ishii, K., Itoh, R., Chou, B., Soejima, T., et al., 2013. Vitamin D-dependent cathelicidin inhibits mycobacterium marinum infection in human monocytic cells. J. Dermatol. Sci. 70, 166—172.
• Sharp, S., Weedon, M., Hagopian, W., Oram, R., 2018. Clinical and research uses of genetic risk scores in type 1 diabetes. Curr. Opin. Genet. Dev. 50, 96—102.
• Shih, E., Mittelman, S., Pitukcheewanont, P., Azen, C., Monzavi, R., 2016. Effects of vitamin D repletion on glycemic control and inflammatory cytokines in adolescents with type 1 diabetes. Pediatr. Diabetes 17, 36—43.
• Skrobot, A., Demkow, U., Wachowska, M., 2018. Immunomodulatory role of vitamin D: a review. Adv. Exp. Med. Biol. 1108, 13—23.
• Sun, D., Luo, F., Xing, J., Zhang, F., Xu, J., Zhang, Z., 2018. 1,25(OH)2D3 inhibited Th17 cells differentiation via regulating the NF-kB activity and expression of IL-17. Cell Prolif. 51, e12461.
• Szymczak, I., Pawliczak, R., 2016. The active metabolite of vitamin D3 as a potential immunomodulator. Scand. J. Immunol. 83, 83—91.
• Takiishi, T., Ding, L., Baeke, F., Spagnuolo, I., Sebastiani, G., Laureys, J., et al., 2014. Dietary supplementation with high doses of regular vitamin D3 safely reduces diabetes incidence in NOD mice when given early and long term. Diabetes 63, 2026—2036.
• Treiber, G., Prietl, B., Frohlich-Reiterer, E., Lechner, E., Ribitsch, A., Fritsch, M., et al., 2015. Cholecalciferol supplementation improves suppressive capacity of regulatory T-cells in young patients with new-onset type 1 diabetes mellitus—a randomized clinical trial. Clin. Immunol. 161, 217—224.
• Wagner, H., Alvarsson, M., Mannheimer, B., Degerblad, M., Ostenson, C., 2016. No effect of high-dose vitamin D treatment on |3-cell function, insulin sensitivity, or glucose homeostasis in subjects with abnormal glucose tolerance: a randomized clinical trial. Diabetes Care 39, 345—352.
• Wolden-Kirk, H., Overbergh, L., Gysemans, C., Brusgaard, K., Naamane, N., Van Lommel, L., et al., 2013. Unraveling the effects of 1,25OH2D3 on global gene expression in pancreatic islets. J. Steroid Biochem. Mol. Biol. 136, 68—79.
• Xie, Z., Munson, S., Huang, N., Portale, A., Miller, W., Bikle, D., 2002. The mechanism of 1,25-dihydroxyvitamin D3 autoregulation in keratinocytes. J. Biol. Chem. 277, 36987—36990.
• Ysmail-Dahlouk, L., Nouari, W., Aribi, M., 2016. 1,25-Dihydroxyvitamin D3 down-modulates the production of proinflammatory cytokines and nitric oxide and enhances the phosphorylation of monocyte-expressed STAT6 at the recent-onset type 1 diabetes. Immunol. Lett. 179, 122—130.