Ukr.Biochem.J. 2024; Volume 96, Issue 2, Mar-Apr, pp. 38-50


Vitamin D(3) auto-/paracrine system in rat brain relating to vitamin D(3) status in experimental type 2 diabetes mellitus

I. Shymanskyi1*, O. Lisakovska1, A. Khomenko1,
L. Yanitska2, M. Veliky1

1Palladin Institute of Biochemistry, National Academy of Sciences of Ukraine, Kyiv, Ukraine;
2Bogomolets National Medical University, Kyiv, Ukraine;

Received: 29 January 2024; Revised: 08 March 2024;
Accepted: 11 March 2024; Available on-line: 30 April 2024

Growing evidence suggests that vitamin D3 (D3, cholecalciferol) deficiency and impaired signaling of the hormonally active form of D3, 1α,25(OH)2D3 (1,25D3), through its cellular receptor (VDR) can be significant risk factors for the development of numerous multifactorial diseases, including diabetes. Our investigation was aimed at researching the D3 status in relation to the state of the D3 auto-/paracrine system in the brain and clarifying the effectiveness of the therapeutic use of D3 as a neuroprotective agent in experimental type 2 diabetes mellitus (T2DM). T2DM was induced in male Wistar rats by a combination of a high fat diet and a low dose of streptozotocin (25 mg/kg BW). Diabetic animals were treated with or without cholecalciferol (1,000 IU/kg BW, 30 days). The content of 25-hydroxyvitamin D3 (25D3) in blood serum and brain tissue was determined by ELISA. Analysis of mRNA expression of CYP24A1 and CYP27B1 genes was performed by RT-PCR. Protein levels of VDR, vitamin D3 binding protein (VDBP), CYP27B1 and CYP24A1 were investigated by Western blotting. A significant T2DM-associated decrease in the content of 25D3 in the blood serum was revealed, which correlated with a reduced content of this metabolite in the brain tissue. Impaired D3 status in animals with T2DM was accompanied by an increase in the levels of mRNA and protein of both 25D3 lα-hydroxylase (CYP27B1) and 1,25-hydroxyvitamin D3-24-hydroxylase (CYP24A1), which, respectively, provide local formation and degradation in the nervous tissue of the hormonally active form of D3 – 1,25D3. At the same time, a significant T2DM-induced down-regulation of the brain content of VDBP was shown. In addition, diabetes caused a slight increase in the protein expression of the VDR, through which the auto-/paracrine effects of 1,25D3 are realized in the brain. We have established a complete or partial corrective effect of cholecalciferol on D3 status, its bioavailability in the CNS and the level of protein expression of CYP27B1 and CYP24A1 in the brain of rats with T2DM. Abnormal D3 status in animals with T2DM was accompanied by compensatory changes in the expression of key components of the auto-/paracrine vitamin D3 system. Cholecalciferol was demonstrated to be partially effective in counteracting the impairments caused by T2DM.

Keywords: , , , ,


  1. Eizirik DL, Pasquali L, Cnop M. Pancreatic β-cells in type 1 and type 2 diabetes mellitus: different pathways to failure. Nat Rev Endocrinol. 2020;16(7):349-362. PubMed, CrossRef
  2. Sanaye MM, Kavishwar SA. Diabetic Neuropathy: Review on Molecular Mechanisms. Curr Mol Med. 2023;23(2):97-110. PubMed, CrossRef
  3. Pickering J, Wong R, Al-Salami H, Lam V, Takechi R. Cognitive Deficits in Type-1 Diabetes: Aspects of Glucose, Cerebrovascular and Amyloid Involvement. Pharm Res. 2021;38(9):1477-1484. PubMed, CrossRef
  4. Hamzé R, Delangre E, Tolu S, Moreau M, Janel N, Bailbé D, Movassat J. Type 2 Diabetes Mellitus and Alzheimer’s Disease: Shared Molecular Mechanisms and Potential Common Therapeutic Targets. Int J Mol Sci. 2022;23(23):15287. PubMed, PubMedCentral, CrossRef
  5. An Y, Xu BT, Wan SR, Ma XM, Long Y, Xu Y, Jiang ZZ. The role of oxidative stress in diabetes mellitus-induced vascular endothelial dysfunction. Cardiovasc Diabetol. 2023;22(1):237. PubMed, PubMedCentral, CrossRef
  6. Batista TM, Haider N, Kahn CR. Defining the underlying defect in insulin action in type 2 diabetes. Diabetologia. 2021;64(5):994-1006. PubMed, PubMedCentral, CrossRef
  7. Gholamhosseinian A, Abbasalipourkabir R, Ziamajidi N, Sayadi M, Sayadi K. The anti-inflammatory effect of omega-3 polyunsaturated fatty acids dramatically decreases by iron in the hippocampus of diabetic rats. Life Sci. 2020;245:117393. PubMed, CrossRef
  8. Khaleghi-Mehr M, Delshad AA, Shafie-Damavandi S, Roghani M. Metformin mitigates amyloid β1-40-induced cognitive decline via attenuation of oxidative/nitrosative stress and neuroinflammation. Metab Brain Dis. 2023;38(4):1127-1142. PubMed, CrossRef
  9. Muriach M, Flores-Bellver M, Romero FJ, Barcia JM. Diabetes and the brain: oxidative stress, inflammation, and autophagy. Oxid Med Cell Longev. 2014;2014:102158. PubMed, PubMedCentral, CrossRef
  10. Luo JS, Ning JQ, Chen ZY, Li WJ, Zhou RL, Yan RY, Chen MJ, Ding LL. The role of mitochondrial quality control in cognitive dysfunction in diabetes. Neurochem Res. 2022;47(8):2158-2172. PubMed, PubMedCentral, CrossRef
  11. Saha D, Paul S, Gaharwar U, Priya A, Neog A, Singh A, Bk B. Cdk5-mediated brain unfolded protein response upregulation associated with cognitive impairments in type 2 diabetes and ameliorative action of NAC. ACS Chem Neurosci. 2023; 14(15): 2761-2774.
  12. Anirudhan A, Ahmad SF, Emran TB, Angulo-Bejarano PI, Sharma A, Ahmed SSSJ. Comparative Efficacy of Metformin and Glimepiride in Modulating Pharmacological Network to Increase BDNF Levels and Benefit Type 2 Diabetes-Related Cognitive Impairment. Biomedicines. 2023;11(11):2939. PubMed, PubMedCentral, CrossRef
  13. Saponaro F, Saba A, Zucchi R. An Update on Vitamin D Metabolism. Int J Mol Sci. 2020;21(18):6573. PubMed, PubMedCentral, CrossRef
  14. Shymanskyi IO, Lisakovska OO, Mazanova AO, Veliky MM. Vitamin D in transcriptional regulation of immune response and inflammation. Adv Med Biol. 2021;183:1-83.
  15. Mesinovic J, Mousa A, Wilson K, Scragg R, Plebanski M, de Courten M, Scott D, Naderpoor N, de Courten B. Effect of 16-weeks vitamin D replacement on calcium-phosphate homeostasis in overweight and obese adults. J Steroid Biochem Mol Biol. 2019;186:169-175. PubMed, CrossRef
  16. Martens PJ, Gysemans C, Verstuyf A, Mathieu AC. Vitamin D’s effect on immune function. Nutrients. 2020;12(5):1248. PubMed, PubMedCentral, CrossRef
  17. Christakos S, Dhawan P, Verstuyf A, Verlinden L, Carmeliet G. Vitamin D: Metabolism, Molecular Mechanism of Action, and Pleiotropic Effects. Physiol Rev. 2016;96(1):365-408. PubMed, PubMedCentral, CrossRef
  18. Plantone D, Primiano G, Manco C, Locci S, Servidei S, De Stefano N. Vitamin D in neurological diseases. Int J Mol Sci. 2022;24(1):87. PubMed, PubMedCentral, CrossRef
  19. Pertile RAN, Brigden R, Raman V, Cui X, Du Z, Eyles D. Vitamin D: A potent regulator of dopaminergic neuron differentiation and function. J Neurochem. 2023;166(5):779-789. PubMed, CrossRef
  20. Alqudah M, Khanfar M, Alfaqih MA, Al-Shboul O, Ghazi Al-U’Datt D, Al-Dwairi A, Allouh M. Correlation between vitamin D and serum brain derived neurotropic factor levels in type 2 diabetes mellitus patients. Biomed Rep. 2022;16(6):54. PubMed, PubMedCentral, CrossRef
  21. Moretti R, Morelli ME, Caruso P. Vitamin D in neurological diseases: a rationale for a pathogenic impact. Int J Mol Sci. 2018;19(8):2245. PubMed, PubMedCentral, CrossRef
  22. Peeyush KT, Savitha B, Sherin A, Anju TR, Jes P, Paulose CS. Cholinergic, dopaminergic and insulin receptors gene expression in the cerebellum of streptozotocin-induced diabetic rats: functional regulation with Vitamin D3 supplementation. Pharmacol Biochem Behav. 2010;95(2):216-222. PubMed, CrossRef
  23. Cui C, Cui J, Jin F, Cui Y, Li R, Jiang X, Tian Y, Wang K, Jiang P, Gao J. Induction of the Vitamin D Receptor Attenuates Autophagy Dysfunction-Mediated Cell Death Following Traumatic Brain Injury. Cell Physiol Biochem. 2017;42(5):1888-1896. PubMed, CrossRef
  24. Farhangi MA, Mesgari-Abbasi M, Nameni G, Hajiluian G, Shahabi P. The effects of vitamin D administration on brain inflammatory markers in high fat diet induced obese rats. BMC Neurosci. 2017;18(1):81. PubMed, PubMedCentral, CrossRef
  25. Gooch H, Cui X, Anggono V, Trzaskowski M, Tan MC, Eyles DW, Burne THJ, Jang SE, Mattheisen M, Hougaard DM, Pedersen BN, Cohen A, Mortensen PB, Sah P, McGrath JJ. 1,25-Dihydroxyvitamin D modulates L-type voltage-gated calcium channels in a subset of neurons in the developing mouse prefrontal cortex. Transl Psychiatry. 2019;9(1):281. PubMed, PubMedCentral, CrossRef
  26. Almeida Moreira Leal LK, Lima LA, Alexandre de Aquino PE, Costa de Sousa JA, Jataí Gadelha CV, Felício Calou IB, Pereira Lopes MJ, Viana Lima FA, Tavares Neves KR, Matos de Andrade G, Socorro de Barros Viana G. Vitamin D (VD3) antioxidative and anti-inflammatory activities: Peripheral and central effects. Eur J Pharmacol. 2020;879:173099. PubMed, CrossRef
  27. Sui A, Xu Y, Pan B, Guo T, Wu J, Shen Y, Yang J, Guo X. Histone demethylase KDM6B regulates 1,25-dihydroxyvitamin D3-induced senescence in glioma cells. J Cell Physiol. 2019;234(10):17990-17998. PubMed, CrossRef
  28. Grygorieva N, Tronko M, Kovalenko V, Komisarenko S, Tatarchuk T, Dedukh N, Veliky M, Strafun S, Komisarenko Y, Kalashnikov A, Orlenko V, Pankiv V, Shvets O, Gogunska I, Regeda S. Ukrainian Consensus on Diagnosis and Management of Vitamin D Deficiency in Adults. Nutrients. 2024;16(2):270. PubMed, PubMedCentral, CrossRef
  29. Mazanova A, Shymanskyi I, Lisakovska O, Hajiyeva L, Komisarenko Y, Veliky M. Effects of Cholecalciferol on Key Components of Vitamin D-Endo/Para/Autocrine System in Experimental Type 1 Diabetes. Int J Endocrinol. 2018;2018:2494016. PubMed, PubMedCentral, CrossRef
  30. Shymanskyi I, Mazanova A, Lisakovska O, Labudzynskyi D, Makarova O, Komisarenko Yu, Veliky М. The role of vitamin D auto /paracrine system in the development of metabolic inflammation of liver tissue in experimental type 2 diabetes. Endokrynologia. 2021;26(3):271-280. CrossRef
  31. Natrus LV, Osadchuk YuS, Lisakovska OO, Labudzinskyi DO, Klys YuG, Chaikovsky YuB. Effect of Propionic Acid on Diabetes-Induced Impairment of Unfolded Protein Response Signaling and Astrocyte/Microglia Crosstalk in Rat Ventromedial Nucleus of the Hypothalamus. Neural Plast. 2022;2022:6404964. PubMed, PubMedCentral, CrossRef
  32. Mazanova AO, Shymanskyy IO, Veliky MM. Development and validation of immunoenzyme test-system for determination of 25-hydroxyvitamin D in blood serum. Biotechnol Acta. 2016;9(2):28-36. CrossRef
  33. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(−ΔΔC(T)) method. Methods. 2001; 25(4): 402-408. PubMed, CrossRef
  34. Bivona G, Gambino CM, Lo Sasso B, Scazzone C, Giglio RV, Agnello L, Ciaccio M. Serum Vitamin D as a Biomarker in Autoimmune, Psychiatric and Neurodegenerative Diseases. Diagnostics (Basel). 2022;12(1):130. PubMed, PubMedCentral, CrossRef
  35. Pop TL, Sîrbe C, Benţa G, Mititelu A, Grama A. The Role of Vitamin D and Vitamin D Binding Protein in Chronic Liver Diseases. Int J Mol Sci. 2022;23(18):10705. PubMed, PubMedCentral, CrossRef
  36. 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):184. PubMed, PubMedCentral, CrossRef
  37. Bikle DD, Schwartz J. Vitamin D Binding Protein, Total and Free Vitamin D Levels in Different Physiological and Pathophysiological Conditions. Front Endocrinol (Lausanne). 2019;10:317. PubMed, PubMedCentral, CrossRef
  38. Nykjaer A, Fyfe JC, Kozyraki R, Leheste JR. Jacobsen C, Nielsen MS, Verroust PJ, Aminoff M, de la Chapelle A, Moestrup SK, Ray R, Gliemann J, Willnow TE, Christensen EI. Cubilin dysfunction causes abnormal metabolism of the steroid hormone 25(OH) vitamin D(3). Proc Natl Acad Sci USA. 2001;98(24):13895-13900. PubMed, PubMedCentral, CrossRef
  39. Meyer MB, Pike JW. Mechanistic homeostasis of vitamin D metabolism in the kidney through reciprocal modulation of Cyp27b1 and Cyp24a1 expression. J Steroid Biochem Mol Biol. 2020;196:105500. PubMed, PubMedCentral, CrossRef
  40. Garcion E, Sindji L, Leblondel G, Brachet P, Darcy F. 1,25-dihydroxyvitamin D3 regulates the synthesis of gamma-glutamyl transpeptidase and glutathione levels in rat primary astrocytes. J Neurochem. 1999;73(2):859-866. PubMed, PubMedCentral, CrossRef
  41. Beeraka NM, Avila-Rodriguez MF, Aliev G. Recent Reports on Redox Stress-Induced Mitochondrial DNA Variations, Neuroglial Interactions, and NMDA Receptor System in Pathophysiology of Schizophrenia. Mol Neurobiol. 2022;59(4):2472-2496. PubMed, PubMedCentral, CrossRef
  42. Said MA. Vitamin D attenuates endothelial dysfunction in streptozotocin induced diabetic rats by reducing oxidative stress. Arch Physiol Biochem. 2022;128(4):959-963. PubMed, CrossRef
  43. Liang Y, Yu H, Ke X, Eyles D, Sun R, Wang Z, Huang S, Lin L, McGrath JJ, Lu J, Guo X, Yao P. Vitamin D deficiency worsens maternal diabetes induced neurodevelopmental disorder by potentiating hyperglycemia-mediated epigenetic changes. Ann N Y Acad Sci. 2021;1491(1):74-88. PubMedCrossRef
  44. Wang Q, He Y, Shen Y, Zhang Q, Chen D, Zuo C, Qin J, Wang H, Wang J, Yu Y. Vitamin D inhibits COX-2 expression and inflammatory response by targeting thioesterase superfamily member 4. J Biol Chem. 2014;289(17):11681-11694. PubMed, PubMedCentral, CrossRef

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