Molecular and Cellular Biochemistry

, Volume 450, Issue 1–2, pp 105–112 | Cite as

The possible antidiabetic effects of vitamin D receptors agonist in rat model of type 2 diabetes

  • Wafaa M. Abdel-RehimEmail author
  • Rasha A. El-Tahan
  • Mennatullah A. El-Tarawy
  • Rowaida R. Shehata
  • Maher A. Kamel


Vitamin D3 deficiency was found to be tightly linked to many health problems including metabolic syndrome, cancer, cardiovascular diseases, and type 2 diabetes mellitus. In our study, we tested the possible antidiabetic effects of one of vitamin D3 analogs, alfacalcidol, solely or in a combination with metformin on type 2 diabetic rats. Type 2 diabetic model rats were induced by feeding high-fat diet for 4 weeks followed by intraperitoneal injection of streptozotocin. In addition to the control group, the diabetic rats were divided into four groups: untreated, metformin-treated, alfacalcidol-treated, and combination-treated group (metformin + alfacalcidol) for 4 weeks. The level of fasting blood glucose, fasting serum insulin, homeostatic model of insulin resistance, serum lipid profile, liver enzymes, calcium, phosphorus, and 25-hydroxyvitamin D3 were also determined. Besides, sterol regulatory element binding protein-1c (SREBP-1c) and vitamin D receptors (VDR) gene expression at mRNA and protein levels were evaluated. The level of significance was fixed at P ≤ 0.05 for all statistical tests. Alfacalcidol, solely or combined with metformin, significantly ameliorated glucose homeostasis and lipid profile parameters (P < 0.001) with a neutral effect on calcium and phosphorus levels. Significant downregulation of mRNA expression of SREBP-1c in the liver, white as well as brown adipose tissues (P < 0.001) and different patterns of mRNA expression of VDR gene in pancreas and white adipose tissue were observed in rats treated with alfacalcidol solely or in combination with metformin. Vitamin D3 analogs can modulate glucose parameters and lipid metabolism in a diabetic rat model and it provides additional protective effects when combined with metformin.


Alfacalcidol Diabetes SREBP-1c Vitamin D receptors 



This study has been carried out at Medical Research Institute, Alexandria, Egypt, and under the supervision of professors of Biochemistry.

Compliance with ethical standards

Conflict of interest

No potential conflict of interest was reported by the authors.


  1. 1.
    Altaf Q-A, Barnett A, Tahrani A (2014) Novel therapeutics for type 2 diabetes: insulin resistance. Diabetes Obes Metab 17:319–334CrossRefGoogle Scholar
  2. 2.
    Ismail-beigi F (2012) Glycemic management of type 2 diabetes mellitus. N Engl J Med 366:1319–1327CrossRefGoogle Scholar
  3. 3.
    Bird Y, Lemstra M, Rogers M et al (2015) The relationship between socioeconomic status/income and prevalence of diabetes and associated conditions: a cross-sectional population-based study in Saskatchewan, Canada. Int J Equity Health. Google Scholar
  4. 4.
    Forbes JM, Cooper ME (2013) Mechanisms of diabetic complications. Physiol Rev 93:137–188CrossRefGoogle Scholar
  5. 5.
    Dake AW, Sora ND (2016) Diabetic dyslipidemia review: an update on current concepts and management guidelines of diabetic dyslipidemia. Am J Med Sci 351:361–365CrossRefGoogle Scholar
  6. 6.
    Wu L, Parhofer KG (2014) Diabetic dyslipidemia. Metabolism 63:1469–1479CrossRefGoogle Scholar
  7. 7.
    Schofield JD, Liu Y, Rao-Balakrishna P et al (2016) Diabetes dyslipidemia Diabetes Ther 7:203–219CrossRefGoogle Scholar
  8. 8.
    Shao W, Espenshade PJ (2012) Expanding roles for SREBP in metabolism. Cell Metab 16:414–419CrossRefGoogle Scholar
  9. 9.
    Xiao X, Song B (2013) SREBP: a novel therapeutic target. Acta Biochim Biophys Sin 45:2–10CrossRefGoogle Scholar
  10. 10.
    Ferré P, Foufelle F (2007) SREBP-1c transcription factor and lipid homeostasis: clinical perspective. Horm Res 68:72–82Google Scholar
  11. 11.
    Spiro A, Buttriss JL (2014) Vitamin D: an overview of vitamin D status and intake in Europe. Nutr Bull 39:322–350CrossRefGoogle Scholar
  12. 12.
    Caprio M, Infante M, Calanchini M et al (2017) Vitamin D: not just the bone. Evidence for beneficial pleiotropic extraskeletal effects. Eat Weight Disord 22:27–41CrossRefGoogle Scholar
  13. 13.
    Sung C-C, Liao M-T, Lu K-C et al (2012) Role of Vitamin D in insulin resistance. J Biomed Biotechnol. Google Scholar
  14. 14.
    Bikle DD (2014) Vitamin D metabolism, mechanism of action, and clinical applications. Chem Biol 21:319–329CrossRefGoogle Scholar
  15. 15.
    Bid H, Manchanda P (2012) Vitamin D receptor and type 2 diabetes mellitus: growing therapeutic opportunities. Indian J Hum Genet 18:274–275CrossRefGoogle Scholar
  16. 16.
    Oh J-Y, Barrett-Connor E (2002) Association between vitamin D receptor polymorphism and type 2 diabetes or metabolic syndrome in community-dwelling older adults: the Rancho Bernardo Study. Metabolism 51:356–359CrossRefGoogle Scholar
  17. 17.
    Alvarez J, Ashraf A (2010) Role of vitamin D in insulin secretion and insulin sensitivity for glucose homeostasis. Int J Endocrinol. Google Scholar
  18. 18.
    Srinivasan K, Viswanad B, Asrat L et al (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320CrossRefGoogle Scholar
  19. 19.
    Young HC, Sang GK, Myung GL (2006) Dose-independent pharmacokinetics of metformin in rats: hepatic and gastrointestinal first-pass effects. J Pharm Sci 95:2543–2552CrossRefGoogle Scholar
  20. 20.
    Kawy HAS (2013) Alfacalcidol enhances the protective effects of lisinopril against nephrosclerosis in a rat model of hypertensive nephropathy. Egypt J Basic Clin Pharmacol 3:31–41Google Scholar
  21. 21.
    Feng X-T, Tang S-Y, Jiang Y-X et al (2017) Anti-diabetic effects of Zhuoduqing formula, a Chinese herbal decoction, on a rat model of type 2 diabetes. Afr J Tradit Complement Altern Med 14:42–50CrossRefGoogle Scholar
  22. 22.
    Friedewald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502Google Scholar
  23. 23.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408CrossRefGoogle Scholar
  24. 24.
    Harinarayan CV (2014) Vitamin D and diabetes mellitus. Hormones 13:163–181CrossRefGoogle Scholar
  25. 25.
    El-Desouki RAM (2016) New insights on the role of vitamin D in type 2 diabetes mellitus: review article. J Basic Appl Res 2:396–407Google Scholar
  26. 26.
    Wei Y, Sowers JR, Clark SE et al (2008) Angiotensin II-induced skeletal muscle insulin resistance mediated by NF-kappaB activation via NADPH oxidase. Am J Physiol Endocrinol Metab 294:E345–E351CrossRefGoogle Scholar
  27. 27.
    Norman AW, Frnakel BJ, Heldt AM et al (1980) Vitamin D deficiency inhibits pancreatic secretion of insulin. Science 209:823–825CrossRefGoogle Scholar
  28. 28.
    Nikooyeh B, Neyestani TR, Farvid M et al (2011) Daily consumption of vitamin D- or vitamin D+ calcium-fortified yogurt drink improved glycemic control in patients with type 2 diabetes: a randomized clinical trial. Am J Clin Nutr 93:764–771CrossRefGoogle Scholar
  29. 29.
    Cheng S, So WY, Zhang D et al (2016) Calcitriol reduces hepatic triglyceride accumulation and glucose output through Ca2+/CaMKKβ/AMPK activation under insulin-resistant conditions in type 2 diabetes mellitus. Curr Mol Med 16:747–758CrossRefGoogle Scholar
  30. 30.
    Carling D, Mayer FV, Sanders MJ et al (2011) AMP-activated protein kinase: nature’s energy sensor. Nat Chem Biol 7:512–518CrossRefGoogle Scholar
  31. 31.
    Asano L, Watanabe M, Ryoden Y et al (2017) Vitamin D metabolite, 25-hydroxyvitamin D, regulates lipid metabolism by inducing degradation of SREBP/SCAP. Cell Chem Biol 24:207–217CrossRefGoogle Scholar
  32. 32.
    Wang XX, Jiang T, Shen Y et al (2011) Vitamin D receptor agonist doxercalciferol modulates dietary fat-induced renal disease and renal lipid metabolism. Am J Physiol Renal Physiol 300:F801–F810Google Scholar
  33. 33.
    Zittermann A, Frisch S, Berthold HK et al (2009) Vitamin D supplementation enhances the beneficial effects of weight loss on cardiovascular disease risk markers. Am J Clin Nutr 89:1321–1327CrossRefGoogle Scholar
  34. 34.
    McCarthy AD, Cortizo AM, Sedlinsky C (2016) Metformin revisited: does this regulator of AMP-activated protein kinase secondarily affect bone metabolism and prevent diabetic osteopathy. World J Diabetes 7:122–133CrossRefGoogle Scholar
  35. 35.
    Leung PS (2016) The potential protective action of vitamin D in hepatic insulin resistance and pancreatic islet dysfunction in type 2 diabetes mellitus. Nutrients. Google Scholar
  36. 36.
    Johnson JA, Grande JP, Roche PC et al (1994) Immunohistochemical localization of the 1,25(OH)2D3 receptor and calbindin D28k in human and rat pancreas. Am J Physiol 267:E356–E360Google Scholar
  37. 37.
    Wolden-Kirk H, Overbergh L, Christesen HT et al (2011) Vitamin D and diabetes: its importance for beta cell and immune function. Mol Cell Endocrinol 347:106–120CrossRefGoogle Scholar
  38. 38.
    Kong J, Li YC (2006) Molecular mechanism of 1, 25-dihydroxyvitamin D3 inhibition of adipogenesis in 3T3-L1 cells. Am J Physiol Endocrinol Metab 290:916–924CrossRefGoogle Scholar
  39. 39.
    Ching S, Kashinkunti S, Niehaus MD et al (2011) Mammary adipocytes bioactivate 25-hydroxyvitamin D3 and signal via vitamin D3 receptor, modulating mammary epithelial cell growth. J Cell Biochem 112:3393–3405CrossRefGoogle Scholar
  40. 40.
    Ochs-balcom HM, Chennamaneni R, Millen AE et al (2011) Vitamin D receptor gene polymorphisms are associated with adiposity phenotypes. Am J Clin Nutr 93:5–10CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Wafaa M. Abdel-Rehim
    • 1
    Email author
  • Rasha A. El-Tahan
    • 1
  • Mennatullah A. El-Tarawy
    • 2
  • Rowaida R. Shehata
    • 3
  • Maher A. Kamel
    • 1
  1. 1.Department of Biochemistry, Medical Research InstituteAlexandria UniversityAlexandriaEgypt
  2. 2.Department of Pharmacology and TherapeuticsPharos UniversityAlexandriaEgypt
  3. 3.Department of Pharmacology, Medical Research InstituteAlexandria UniversityAlexandriaEgypt

Personalised recommendations