20Jan 2017

VITAMIN D3 IMPROVES LIVER FUNCTIONS IN EXPERIMENTALLY INDUCED TYPE II DIABETES MELLITUS IN WISTAR RATS

  • Lecturer of Physiology, Faculty of Medicine, Ain Shams University.
  • Lecturer of Clinical Pathology, Faculty of Medicine, Ain Shams University Cairo, Egypt.
  • Abstract
  • Keywords
  • References
  • Cite This Article as
  • Corresponding Author

Background and Aim: Vitamin D3 could ameliorate the effects of type 2 diabetes mellitus; however, liver changes in diabetes needs more studies and to highlight changes in liver cell mitochondrial NAD+ and Stearoyl-CoA desaturase 1 (SCD1). Materials and Methods: Forty adult Wistar rats, of both sexes, were randomly allocated into equal groups of control, vitamin D3 non-diabetic, diabetic, type 2 diabetic and vitamin D3 treated diabetic groups. At the end of the study, all rats were anaesthetized by i.p. Pentoparbitone (40 mg/kg B.W). Fasting blood glucose level was measured by rat tail, then after aortic cannulation, the separated plasma was used for determination of lipid profile, liver functions and insulin level. HOMA-IR and atherogenic indices were calculated. Liver specimens were used for detection of SCD1 gene expression by Real time PCR and mitochondrial NAD+. Results: Glycemic parameters and plasma liver enzymes, liver mitochondrial NAD+ were significantly elevated in the diabetic group compared to the control group, and were significantly lowered in vitamin D3 treated diabetic group compared to the diabetic group. The diabetic group had dyslipidemia compared to the control group, while lipid profile was improved in vitamin D3 treated diabetic group compared to the diabetic group. SCD1 gene expression in liver cells was downregulated in both diabetic groups (untreated and treated) compared to the control group. Conclusion: Vitamin D3 reversed the damaging diabetic effects on liver functions efficiently, probably by ameliorating oxidative stress, however, it altered SCD1 gene expression and regulated its effect on diabetes to lesser extent.


  1. Ahmad H, Ahmed Z, Khan R. Effect of Chromium Picolinate Supplementation on Diabetic Profile and Nutritional Status of the Type-2 Diabetic Adult Population – A Randomized Controlled Trial. J. Food and Nutrition Research. 4(8): 535-542, 2016
  2. Alam MM, Meerza D, Naseem I. Protective effect of quercetin on hyperglycemia, oxidative stress and DNA damage in alloxan induced type 2 diabetic mice. Life Sci 109(1):8-14, 2014
  3. Al-Daghri N, Alkharfy K, Al-Othman A, El-Kholie E, Moharram O, Alokail M, Al-Saleh Y, Sabico S, Kumar S, Chrousos G. Vitamin D supplementation as an adjuvant therapy for patients with T2DM: an 18-month prospective interventional study. CardiovascDiabetol 11: 85, 2012.
  4. Behradmanesh S, Roudini K, Baradaran A. Effect of Supplementary Vitamin D on Improvement of Glycemic Parameters in Patients with Type 2 Diabetic. J Isfahan Med Sch 29(151):1098–1105, 2011.
  5. Bell NH, Epstein S, Greene A, Shary J, Oexmann MJ, Shaw S. Evidence for alteration of the vitamin D-endocrine system in obese subjects. J ClinInves 76: 370–373, 1985.
  6. Bland R, Markovic D, Hills CE, Hughes SV, Chan SL, Squires PE, Hewison M. Expression of 25-hydroxyvitamin D3-1alpha-hydroxylase in pancreatic islets. J Steroid BiochemMolBiol 89–90(1–5):121–125, 2004.
  7. BorissovaAM ,Tankova T , Kirilov G , Dakovska L , Kovacheva R. The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int. J. Clini. Pra. 57(4):258-261, 2003.
  8. Boucher BJ. Inadequate vitamin D status. Does it contribute to the disorders comprising syndrome “X”. Br J Nutr 79: 315–327, 1998.
  9. Boucher BJ, Mannan N, Noonan K, Hales CN, Evans SJ. Glucose intolerance and impairment of insulin secretion in relation to vitamin D deficiency in East London Asians.Diabetologia 38: 1239-1245, 1995.
  10. Breslavsky A, Frand J, Matas Z, Boaz M, Barnea, Z, Shargorodsky M. Effect of high doses of vitamin D on arterial properties, adiponectin, leptin and glucose homeostasis in type 2 diabetic patients. ClinNutr 32: 970-975, 2013.
  11. BruanJEA and Severson DL. Lipoprotein lipase released from myocytes is increased by decavandate but not insulin. Am. J. of Physiol 262(E): 663-E670, 1992.
  12. Busch AK, Gurisik E, Cordery DV, Michelle Sudlow, Gareth S, Denyer D, Labutt R, Hughes WE, Biden TJ. Increased fatty acid desaturation and enhanced expression of stearoyl coenzyme A desaturase protects pancreatic beta-cells from lipoapoptosis. Diabetes 54:2917–2924, 2005.
  13. Chang E and Kim Y. Vitamin D decreases adipocyte lipid storage and increases NAD-SIRT1 pathway in 3T3-L1 adipocytes. Nutrition 32: 702–708, 2016.
  14. Chiu KC, Chu A, Go VLW, Saad MF. Hypovitaminosis D is associated with insulin resistance and ? cell dysfunction. Am J ClinNutr 79: 820–825, 2004.
  15. Danaei G, Finucane MM, Lu Y, Singh GM, Cowan MJ, Paciorek CJ, Lin JK, Farzadfar F, Khang YH, Stevens GA, Rao M, Ali MK, Riley LM, Robinson CA, Ezzati M. National, regional, and global trends in fasting plasma glucose and diabetes prevalence since 1980: systematic analysis of health examination surveys and epidemiological studies with 370 country-years and 2·7 million participants. Lancet 378:3-40, 2011.
  16. DeLuca HF and Cantorna MT. Vitamin D: its role and uses in immunology. FASEB J 15:2579-2585, 2001.
  17. Dobrzyn P and Dobrzyn A. Stearoyl-CoA desaturase: a new therapeutic target of liver steatosis. Drug Development Research 67(8): 643-650, 2006.
  18. Droge W. Free radicals in the physiological control of cell function.Physiol. Rev. 82: 47-95, 2002.
  19. Flier JS, Khan CR, Roth J. Receptor, anti-receptor antibodies and mechanisms of insulin resistance. New Engl. J Med. 300: 413-419, 1979.
  20. Flowers MT, Groen AK, Oler AT, Keller M, Choi Y, Schueler KL, Richards OC, Lan H, Miyazaki CM, KuipersF, Kendziorski CM, Ntambi JM, Attie AD. Cholestasis and hypercholesterolemia in SCD1-deficient mice fed a low-fat, high carbohydrate diet. J Lipid Res 47:2668–2680, 2006.
  21. Foster DW. The Role of the Carnitine System in Human Metabolism Annals of the New York Academy of Sciences 1033:1-16, 2004.
  22. Fruchart JC. Separation of low density lipoproteins and determination of cholesterol and phospholipids bound to this fraction. Rev. Fr. Des laboratories 103: 7-17, 1982.
  23. George N, Kumar TP, Antony S, Jayanarayanan S. Effect of vitamin D3 in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats. British journal of Nutrition 108(8): 1410-1418, 2012.
  24. Giacco F and Brownlee M .Oxidative stress and diabetic complications Circ Res. 107(9): 1058-1070, 2010.
  25. Gregori S, Giarratana N, Smiroldo S, Uskokovic M, Adorini L. A 1alpha, 25-dihydroxyvitamin D(3) analog enhances regulatory T-cells and arrests autoimmune diabetes in NOD mice. Diabetes 51: 1367-1374, 2002.
  26. Grundy SM, Greenland P, Herd A, Huebsch JA, Jones RJ, Mitchell JH, Schlant RC.Cardiovascular and risk factor evaluation of healthy American adults.A statement for physicians by an Ad Hoc Committee appointed by the Steering Committee, American Heart Association. Circulation 75: 1340A-1362A, 1987.
  27. Hamadi N, Mansour A, Hassan MH, Khalifi-Touhami F, Badary O. Ameliorative effects of resveratrol on liver injury in streptozotocin-induced diabetic rats. J BiochemMolToxicol 26(10):384-92, 2012.
  28. Heshmat R, Tabatabaee O, Moradzade K, Abasszade S. The effect of parenteral vitamin D supplementation on insulin resistance and anthropometric factors in patients with diabetes type 2. Iran J Diabetes Lipid Disord 10(5):492–501, 2011.
  29. Holick MF. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J ClinNutr; 79: 362-371, 2004.
  30. Holland B and Welch A. Hormone in insulin resistance of abdominal obesity: cause or effect? The composition of food 5:115, 1992.
  31. Hossein-nezhad A and Holick M. Vitamin D for health: a global perspective. Mayo Clin Proc 88: 720-755, 2013.
  32. Huang Y, Li X, Wang M, Ning H, Lima A, Li Y, Sun C. Lipoprotein lipase links vitamin D, insulin resistance, and type 2 diabetes: a cross-sectional epidemiological study. CardiovascDiabetol 12:17, 2013.
  33. Jeppsson JO, Kobold U, Barr J, Finke A, Hoelzel W, Hoshino T, Miedema K, Mosca A, Mauri P, Paroni R, Thienpont L, Umemoto M, Weykamp C. Approved IFCC Reference Method for the Measurement of HbA1c in Human Bl. Cl. Chem and Lab Med. 40(1):78-89, 2002.
  34. Kakkar R, Mantha SV, Radhi J, Prasad K, Kalra J. Increased oxidative stress in rat liver and pancreas during progression of streptozotocin- induced diabetes. ClinSci 94:623-632, 1998.
  35. Koliaki C and Roden M. Alterations of mitochondrial function and insulin sensitivity in human obesity and diabetes mellitus. Annual Review of Nutrition 36: 337-367, 2016.
  36. Kudchodkar BJ, Lee JC, Lee SM, DiMarco NM, Lacko AG. Effect of cholesterol homeostasis in diabetic rats. Journal of Lipid Research 29: 1272-1287, 1988.
  37. Lopes-Virella MF, Stone P, Ellis S, ClowellJA.Cholesterol determination in high-density lipoproteins separated by three different methods. Clin. Chem. 23: 882, 1977.
  38. Luong K, Nguyen LTH, Nguyen DNP. The role of vitamin D in protecting type 1 diabetes mellitus. Diabetes Metab Res Rev 21: 338-346, 2005.
  39. Maestro B, Davila N, Carranza MC, Calle C: Identification of a Vitamin D response element in the human insulin receptor gene promoter. J Steroid BiochemMolBiol 2003, 84(2–3):223–230.
  40. Maestro B, Molero S, Bajo S. Transcriptional activation of the human insulin receptorgene by 1, 25-dihydroxyvitamin D(3). Cell bio-chemfunct 20:227–232, 2002.
  41. Mathieu C, Gysemans C, Guilietti A, Bouillon R. Vitamin D and diabetes. Diabetologia 48: 1247-1257, 2005.
  42. Maxwell SRJ, Thomason H, Sandler D, Leguen C, Baxter MA, Thorpe GHG, Jones AF, Barnett AH. Antioxidant status in patients with uncomplicated insulin-dependent and non-insulin-dependent diabetes mellitus. European J of ClinInves 27(6):484-490, 1997.
  43. Miyazaki M and Ntambi JM. Role of stearoyl-coenzyme A desaturase in lipid metabolism. Prostaglandins, Leukotrienes and Essential Fatty Acids 68(2) 113-121, 2003.
  44. Ntambi JM, Miyazaki M, Stoehr JP, Lan H, Kendziorski CM, Yandell BS, Song Y, Cohen P, Friedman JM, Attie AD. Loss of stearoyl- CoA desaturase-1 function protects mice against adiposity. Proc Natl AcadSci USA 99(17):11482–11486, 2002.
  45. Ogunkolade BW, Boucher BJ, Prahl JM, Bustin SA, Burrin JM, Noonan K, North BV, Mannan N, McDermott MF,Deluca HF, Hitman GA. Vitamin D receptor (VDR) mRNA and VDR protein levels in relation to vitamin D status, insulin secretory capacity, and VDR genotype in Bangladeshi Asians. Diabetes; 51: 2294-2300, 2002.
  46. Ortlepp JR, Metrikat J, Albrecht M, Von Korff A, Hanrath P, Hoffmann R. The vitamin D receptor gene variant and physical activity predicts fasting glucose levels in healthy young men. Diabet Med 20: 451-454, 2003.
  47. Palomer X, González-Clemente JM, Blanco-Vaca F, Mauricio D. Role of vitamin D in the pathogenesis of type 2 diabetes mellitus. Diabetes, Obesity and Metabolism 10(3):185–197, 2008.
  48. Popeijus HE, Saris WHM, Mensink RP. Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome. Int. J. of Obesity 32:1076–1082, 2008.
  49. Reitman S. and Frankel S.A colorimetric method for determining serum glutamic oxaloacetic and glutamic pyruvic transminases. Am. J. Clin. Pathol. 28: 56-63, 1957.
  50. Rifai N, Bachorik PS, and Albers JJ.Lipids, lipoproteins and apolipoproteins. In: Burtis CA, Ashwood ER, Tietz (3rd edn). W.B Saundes, Philadelphia, 809-861, 1999.
  51. Roden M. Mechanisms of disease: hepatic steatosis in type 2 diabetes pathogenesis and clinical relevance. Nat ClinPractEndocrinolMetab 2:335–348, 2006.
  52. Saleh NK, Saleh HA.Protective effects of vitamin E against myocardial ischemia/reperfusion injury in rats. Saudi Med J 31(2): 142-147, 2010.
  53. Salgado ALF, de Carvalho L, Oliveira AC, Nascimento VN, Vieira JG, Parise ER. Insulin resistance index (HOMA-IR) in the differentiation of patients with non-alcoholic fatty liver disease and healthy individuals, Arq. Gastroenterol. 47 (2):165-169, 2010.
  54. Shehab D, Al-Jarallah K, Mojiminiyi OA, Al Mohamedy H, Abdella NA. Does Vitamin D deficiency play a role in peripheral neuropathy in Type 2 diabetes? Diabet. Med. 29: 43-49, 2012.
  55. Shulman GI. Cellular mechanisms of insulin resistance. J. Clin. Invest. 106: 171-176, 2000.
  56. Simpson RU, Thomas GA, Arnold AJ.Identification of 1, 25-dihydroxyvitamin D3 receptors and activities in muscle. J Biological Chemistry 260(15):8882–8891, 1985.
  57. Srinivasan K., Viswanad B., Asrat L., Kaul C.L., and Ramarao P. (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(4):313-320.
  58. Stefan N, Hennige AM, Staiger H, Machann J, Schick F, Krober SM, Machicao F, Fritsche A, Haring H. Alpha2-Heremans-Schmid glycoprotein/fetuin-A is associated with insulin resistance and fat accumulation in the liver in humans. Diabetes Care 29:853-857, 2006.
  59. Stefan N, Peter A, Cegan A, Staiger H, Machann J, Schick F, Claussen CD, Fritsche A, Häring HU and Schleicher E. Low hepatic stearoyl-CoA desaturase 1 activity is associated with fatty liver and insulin resistance in obese humans. Diabetologia 51:648–656, 2008.
  60. Stene LC, Ulriksen J, Magnus P, Joner G. Use of cod liver oil during pregnancy is associated with lower risk of type 1 diabetes in the offspring. Diabetologia43: 1093-1098, 2000.
  61. Talaei A, Mohamadi M, Adgi Z. The effect of vitamin D on insulin resistance in patients with type 2 diabetes.Diabetology& Metabolic Syndrome 5:8, 2013.
  62. Tangvarasittichai S. Oxidative stress, insulin resistance, dyslipidemia and type 2 diabetes mellitus. World J Diabetes 6(3): 456-480, 2015.
  63. Tietz NW. Textbook of clinical chemistry, W.B. Saunders co London, 1986.
  64. Vassault A, Grafmeyer D, Naudin C, Dumont GR, Bailly M. Protocole de validation de techniques. Ann Bio Clin 44: 679-685, 1986.
  65. Wang J, Yu L, Schmidt RE, Su C, Huang X, Gould K, Cao G. Characterization of HSCD5, a novel human stearoyl-CoA desaturase unique to primates. BiochemBiophys Res Commun 332: 735, 2005.
  66. Wang J, Yu L, Wang H, Gao Y, SchrementiJP,Porter RK, Yurek DA, Kuo M, Suen C, Cao G, Bean JS, Kauffman RF, Qian Y. Identification and characterization of Hamster Stearoyl-Co a desaturase isoforms. Lipids 43: 197, 2008.
  67. Wortsman J, Matsuoka LY, Chen TC, Lu Z, Holick MF. Decreased bioavailability of vitamin D in obesity.Am J Clin Nut 72: 690-693, 2000.
  68. Yang Y, Liu B, Gao L, Wang D, Chen Q, Wang Q, Song M.Effect of 1, 25-Dihydroxyvitamin D3 on triglyceride content and expressions of protein tyrosine phosphatase-1B in liver of type 2 diabetes mellitus rat. Int J ClinExp Med 9(6):9425-9430, 2016.
  69. Yin Y, Yu Z, Xia M, Luo X, Lu X, Ling W. Vitamin D attenuates high fat diet-induced hepatic steatosis in rats by modulating lipid metabolism. Eur J Clin Invest 42: 1189-1196, 2012.
  70. 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 J 17:509-511, 2003.
  71. Zhang J, Huang Y, Hou T, Wang Y. Hypoglycemic effect of Artemisia sphaerocephalaKrasch seed polysaccharide in alloxan-induced diabetic rats. SWISS. MED. WKLY., 136: 529-532, 2006.
  72. Zhao XQ, Quan L, Du GL, Xiao S, Lü WK, Zhu J. Protective effects and mechanisms of 1, 25(OH)2D3 on diabetes-induced liver injury in a streptozotocin-diabetic rat model. Zho-nghuaGanZang Bing ZaZhi 21: 778-780, 2013.
  73. Zittermann A. Vitamin D and disease prevention with special reference to cardiovascular disease.ProgBiophysMolBiol 92:39-48, 2006.

[Noha N. Lasheen and Nashwa El-Khazragy. (2017); VITAMIN D3 IMPROVES LIVER FUNCTIONS IN EXPERIMENTALLY INDUCED TYPE II DIABETES MELLITUS IN WISTAR RATS Int. J. of Adv. Res. 5 (Jan). 1715-1726] (ISSN 2320-5407). www.journalijar.com


NOHA N. LASHEEN
Lecturer of Physiology, Faculty of Medicine, Ain Shams University

DOI:


Article DOI: 10.21474/IJAR01/2942      
DOI URL: https://dx.doi.org/10.21474/IJAR01/2942