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Vitamin D3 prevents the increase in ectonucleotidase activities and ameliorates lipid profile in type 1 diabetic rats

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Abstract

This study was designed to assess the potential effect of vitamin D3 (VD3) in avoiding atherothrombosis by modulation of lipid metabolism and platelet activation in type 1 diabetic rats. Male wistar rats were divided into eight groups (n = 5–10): Control/Saline (Sal); Control/Metformin 500 mg/kg (Metf); Control/Vitamin D3 90 µg/kg (VD3); Control/Metformin 500 mg/kg + VD3 90 µg/kg (Metf + VD3); Diabetic/Saline (Sal); Diabetic/Metformin 500 mg/kg (Metf); Diabetic/Vitamin D3 90 µg/kg (VD3); Diabetic/Metformin 500 mg/kg + VD3 90 µg/kg (Metf + VD3). Treatments were administered during 30 days after diabetes induction with streptozotocin (STZ). After 31 days, the rats were euthanized and blood was collected and separated into serum and platelets, both used for lipid profile and ectonucleotidase activity assays, respectively. Ectonucleoside triphosphate phosphohydrolase (E-NTPDase), ectonucleotide pyrophosphatase/phosphodiesterase (E-NPP), and 5′-nucleotidase and adenosine deaminase (E-ADA) were significantly higher in the Diabetic than in Control group. Treatment with Metf and/or VD3 prevented the increase in NTPDase and E-NPP activities in diabetic rats. Only Metf + VD3 significantly prevented the increase in 5′-nucleotidase. VD3 alone, but not Metf, prevented the increase in ADA activity when compared to saline-treated diabetic rats. Treatment of rats with VD3, Metf, and Metf + VD3 was also effective in the prevention of lipid metabolism disorder in diabetic and was able to ameliorate lipid metabolism in non-diabetic rats. These results provide evidence for the potential of Metf and VD3 in the treatment of platelet dysfunction and lipid metabolism impairment in T1D, which may be important in the control and prevention of atherothrombosis in diabetes.

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Abbreviations

25(OH)D3 :

25-Hydroxyvitamin D3

T1D:

Type 1 Diabetes

VD3 :

Vitamin D3

Metf:

Metformin

Metf + VD3 :

Metformin plus Vitamin D3

CVD:

Cardiovascular Disease

TG:

Triglycerides

LDL-c:

Low Density Lipid Cholesterol

VLDL-c:

Very Low Density Lipid Cholesterol

HDL-c:

High Density Lipid Cholesterol

VDR:

Vitamin D Receptor

PGI2:

Prostacyclin

ADA:

Adenosine desaminase

NTPDase:

Ectonucleoside Triphosphate Phosphoydrolase

E-NPP:

Ectonucleotide pyrophosphatase/phosphodiesterase

Sal:

Saline

STZ:

Streptozotocin

References

  1. Lambert P, Bingley PJ (2002) What is type 1 diabetes? Medicine 30:1–5. doi:10.1383/medc.30.1.1.28264

    Article  Google Scholar 

  2. Junod A, Lambert AE, Stauffacher W et al (1969) Diabetogenic action of streptozotocin: relationship of dose to metabolic response. J Clin Invest 48:2129–2139. doi:10.1172/JCI106180

    PubMed Central  CAS  PubMed  Google Scholar 

  3. Gawaz M, Langer H, May AE (2005) Platelets in inflammation and atherogenesis. J Clin Invest 115:3378–3384. doi:10.1172/JCI27196

    PubMed Central  CAS  PubMed  Google Scholar 

  4. Birk AV, Broekman MJ, Gladek EM et al (2002) Role of extracellular ATP metabolism in regulation of platelet reactivity. J Lab Clin Med 140:166–175

    CAS  PubMed  Google Scholar 

  5. Lunkes GI, Lunkes DS, Morsch VM et al (2004) NTPDase and 5′-nucleotidase activities in rats with alloxan-induced diabetes. Diabetes Res Clin Pract 65:1–6. doi:10.1016/j.diabres.2003.11.016S0168822703003164

    CAS  PubMed  Google Scholar 

  6. Lunkes GI, Lunkes DS, Leal D et al (2008) Effect of high glucose levels in human platelet NTPDase and 5′-nucleotidase activities. Diabetes Res Clin Pract 81:351–357. doi:10.1016/j.diabres.2008.06.001

    CAS  PubMed  Google Scholar 

  7. Lunkes GI, Lunkes D, Stefanello F et al (2003) Enzymes that hydrolyze adenine nucleotides in diabetes and associated pathologies. Thromb Res 109:189–194

    CAS  PubMed  Google Scholar 

  8. Schmatz R, Schetinger MR, Spanevello RM et al (2009) Effects of resveratrol on nucleotide degrading enzymes in streptozotocin-induced diabetic rats. Life Sci 84:345–350. doi:10.1016/j.lfs.2008.12.019

    CAS  PubMed  Google Scholar 

  9. Berthezène F (2002) Diabetic dyslipidaemia. Br J Diabetes Vasc Dis 2:S12–S17

    Google Scholar 

  10. Gargiulo P, Caccese D, Pignatelli P et al (2002) Metformin decreases platelet superoxide anion production in diabetic patients. Diabetes Metab Res Rev 18:156–159. doi:10.1002/dmrr.282

    CAS  PubMed  Google Scholar 

  11. Chan NN (2001) Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol 38:2131–2132

    CAS  PubMed  Google Scholar 

  12. El-Batran SA, Abdel-Salam OM, Nofal SM et al (2006) Effect of rosiglitazone and nateglinide on serum glucose and lipid profile alone or in combination with the biguanide metformin in diabetic rats. Pharmacol Res 53:69–74. doi:10.1016/j.phrs.2005.08.008

    CAS  PubMed  Google Scholar 

  13. Ghatak SB, Dhamecha PS, Bhadada SV et al (2011) Investigation of the potential effects of metformin on atherothrombotic risk factors in hyperlipidemic rats. Eur J Pharmacol 659:213–223. doi:10.1016/j.ejphar.2011.03.029

    CAS  PubMed  Google Scholar 

  14. Kassi E, Adamopoulos C, Basdra EK et al (2013) Role of vitamin D in atherosclerosis. Circulation 128:2517–2531. doi:10.1161/CIRCULATIONAHA.113.002654

    Article  PubMed  Google Scholar 

  15. Peeyush KT, Savitha B, Sherin A et al (2010) Cholinergic, dopaminergic and insulin receptors gene expression in the cerebellum of streptozotocin-induced diabetic rats: functional regulation with Vitamin D3 supplementation. Pharmacol Biochem Behav 95:216–222. doi:10.1016/j.pbb.2010.01.008

    CAS  PubMed  Google Scholar 

  16. George N, Kumar TP, Antony S et al (2012) Effect of vitamin D3 in reducing metabolic and oxidative stress in the liver of streptozotocin-induced diabetic rats. Br J Nutr 108:1410–1418. doi:10.1017/S0007114511006830

    CAS  PubMed  Google Scholar 

  17. Rudnicki PM, Molsted-Pedersen L (1997) Effect of 1,25-dihydroxycholecalciferol on glucose metabolism in gestational diabetes mellitus. Diabetologia 40:40–44. doi:10.1007/s001250050640

    Article  CAS  PubMed  Google Scholar 

  18. Borissova AM, Tankova T, Kirilov G et al (2003) The effect of vitamin D3 on insulin secretion and peripheral insulin sensitivity in type 2 diabetic patients. Int J Clin Pract 57:258–261

    CAS  PubMed  Google Scholar 

  19. Clark SA, Stumpf WE, Sar M (1981) Effect of 1,25 dihydroxyvitamin D3 on insulin secretion. Diabetes 30:382–386

    Article  CAS  PubMed  Google Scholar 

  20. Chiu KC, Chu A, Go VL et al (2004) Hypovitaminosis D is associated with insulin resistance and beta cell dysfunction. Am J Clin Nutr 79:820–825

    CAS  PubMed  Google Scholar 

  21. Chan KM, Delfert D, Junger KD (1986) A direct colorimetric assay for Ca2+-stimulated ATPase activity. Anal Biochem 157:375–380

    CAS  PubMed  Google Scholar 

  22. Furstenau CR, Trentin Dda S, Barreto-Chaves ML et al (2006) Ecto-nucleotide pyrophosphatase/phosphodiesterase as part of a multiple system for nucleotide hydrolysis by platelets from rats: kinetic characterization and biochemical properties. Platelets 17:84–91. doi:10.1080/09537100500246641

    Article  PubMed  Google Scholar 

  23. Guisti G, Galanti B (1984) Colorimetric method. Bergmeyer HU. Verlag Chemie, Weinheim, pp 315–323

    Google Scholar 

  24. Bachorik PS, Albers JJ (1986) Precipitation methods for quantification of lipoproteins. Methods Enzymol 129:78–100

    CAS  PubMed  Google Scholar 

  25. Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    CAS  PubMed  Google Scholar 

  26. Calgaroto NS, Thome GR, da Costa P et al (2014) Effect of vitamin D3 on behavioural and biochemical parameters in diabetes type 1-induced rats. Cell Biochem Funct 32:502–510. doi:10.1002/cbf.3044

    CAS  PubMed  Google Scholar 

  27. Del Pino-Montes J, Benito GE, Fernandez-Salazar MP et al (2004) Calcitriol improves streptozotocin-induced diabetes and recovers bone mineral density in diabetic rats. Calcif Tissue Int 75:526–532. doi:10.1007/s00223-004-0118-9

    CAS  PubMed  Google Scholar 

  28. Carr ME (2001) Diabetes mellitus: a hypercoagulable state. J Diabetes Complicat 15:44–54

    CAS  PubMed  Google Scholar 

  29. Bours MJ, Swennen EL, Di Virgilio F et al (2006) Adenosine 5′-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther 112:358–404. doi:10.1016/j.pharmthera.2005.04.013

    CAS  PubMed  Google Scholar 

  30. Rutkiewicz J, Gorski J (1990) On the role of insulin in regulation of adenosine deaminase activity in rat tissues. FEBS Lett 271:79–80

    CAS  PubMed  Google Scholar 

  31. Kurtul N, Pence S, Akarsu E et al (2004) Adenosine deaminase activity in the serum of type 2 diabetic patients. Acta Medica (Hradec Kralove) 47:33–35

    CAS  Google Scholar 

  32. Matsuno H, Tokuda H, Ishisaki A et al (2005) P2Y12 receptors play a significant role in the development of platelet microaggregation in patients with diabetes. J Clin Endocrinol Metab 90:920–927. doi:10.1210/jc.2004-0137

    CAS  PubMed  Google Scholar 

  33. Soslau G, McKenzie RJ, Brodsky I et al (1995) Extracellular ATP inhibits agonist-induced mobilization of internal calcium in human platelets. Biochim Biophys Acta 1268:73–80

    PubMed  Google Scholar 

  34. Soslau G, Youngprapakorn D (1997) A possible dual physiological role of extracellular ATP in the modulation of platelet aggregation. Biochim Biophys Acta 1355:131–140

    CAS  PubMed  Google Scholar 

  35. Bodin P, Burnstock G (1996) ATP-stimulated release of ATP by human endothelial cells. J Cardiovasc Pharmacol 27:872–875

    CAS  PubMed  Google Scholar 

  36. Redegeld FA, Caldwell CC, Sitkovsky MV (1999) Ecto-protein kinases: ecto-domain phosphorylation as a novel target for pharmacological manipulation? Trends Pharmacol Sci 20:453–459

    CAS  PubMed  Google Scholar 

  37. Furstenau CR, Spier AP, Rucker B et al (2004) The effect of ebselen on adenine nucleotide hydrolysis by platelets from adult rats. Chem Biol Interact 148:93–99. doi:10.1016/j.cbi.2004.04.003

    PubMed  Google Scholar 

  38. Mamputu JC, Wiernsperger NF, Renier G (2003) Antiatherogenic properties of metformin: the experimental evidence. Diabetes Metab 29:6S71–6S76

    CAS  PubMed  Google Scholar 

  39. Winocour PD, Laimins M, Colwell JA (1984) Platelet survival in streptozotocin-induced diabetic rats. Thromb Haemost 51:307–312

    CAS  PubMed  Google Scholar 

  40. Martin FJ, Miguez JM, Aldegunde M et al (1995) Platelet serotonin transport is altered in streptozotocin-induced diabetic rats. Life Sci 56:1807–1815

    CAS  PubMed  Google Scholar 

  41. James J, Padayatti P, Paul T et al (1997) Platelet monoamine changes in diabetic patients and streptozotocin-induced diabetic rats. Curr Sci 72:137–139

    CAS  Google Scholar 

  42. Paton RC (1979) Platelet survival in diabetes mellitus using an aspirin-labelling technique. Thromb Res 15:793–802

    CAS  PubMed  Google Scholar 

  43. Leytin V, Freedman J (2003) Platelet apoptosis in stored platelet concentrates and other models. Transfus Apher Sci 28:285–295. doi:10.1016/S1473-0502(03)00048-X

    PubMed  Google Scholar 

  44. Pilo R, Aharony D, Raz A (1981) Testosterone potentiation of ionophore and ADP induced platelet aggregation: relationship to arachidonic acid metabolism. Thromb Haemost 46:538–542

    CAS  PubMed  Google Scholar 

  45. Khetawat G, Faraday N, Nealen ML et al (2000) Human megakaryocytes and platelets contain the estrogen receptor beta and androgen receptor (AR): testosterone regulates AR expression. Blood 95:2289–2296

    CAS  PubMed  Google Scholar 

  46. Bockow B, Kaplan TB (2013) Refractory immune thrombocytopenia successfully treated with high-dose vitamin D supplementation and hydroxychloroquine: two case reports. J Med Case Rep. doi:10.1186/1752-1947-7-91

    PubMed Central  PubMed  Google Scholar 

  47. Silvagno F, De Vivo E, Attanasio A et al (2010) Mitochondrial localization of vitamin D receptor in human platelets and differentiated megakaryocytes. PLoS One 5:e8670. doi:10.1371/journal.pone.0008670

    Article  PubMed Central  PubMed  Google Scholar 

  48. Song LN, Cheng T (1993) Glucocorticoid-induced growth inhibition and differentiation of a human megakaryoblastic leukemia cell line: involvement of glucocorticoid receptor. Stem Cells 11:312–318. doi:10.1002/stem.5530110409

    Article  CAS  PubMed  Google Scholar 

  49. Michno A, Bielarczyk H, Pawelczyk T et al (2007) Alterations of adenine nucleotide metabolism and function of blood platelets in patients with diabetes. Diabetes 56:462–467. doi:10.2337/db06-0390

    Article  CAS  PubMed  Google Scholar 

  50. Grundy SM (2006) Diabetes and coronary risk equivalency: what does it mean? Diabetes Care 29:457–460

    Article  PubMed  Google Scholar 

  51. Chahil TJ, Ginsberg HN (2006) Diabetic dyslipidemia. Endocrinol Metab Clin North Am 35(491–510):vii–viii. doi:10.1016/j.ecl.2006.06.002

    Google Scholar 

  52. Jaiswal M, Schinske A, Pop-Busui R (2014) Lipids and lipid management in diabetes. Best Pract Res Clin Endocrinol Metab 28:325–338. doi:10.1016/j.beem.2013.12.001

    CAS  PubMed  Google Scholar 

  53. Maahs DM, Dabelea D, D’Agostino RB Jr et al (2013) Glucose control predicts 2-year change in lipid profile in youth with type 1 diabetes. J Pediatr 162(101–107):e101. doi:10.1016/j.jpeds.2012.06.006

    Google Scholar 

  54. Valdivielso P, Sanchez-Chaparro MA, Calvo-Bonacho E et al (2009) Association of moderate and severe hypertriglyceridemia with obesity, diabetes mellitus and vascular disease in the Spanish working population: results of the ICARIA study. Atherosclerosis 207:573–578. doi:10.1016/j.atherosclerosis.2009.05.024

    Article  CAS  PubMed  Google Scholar 

  55. Hamzah RU, Odetola AA, Erukainure OL et al (2012) Peperomia pellucida in diets modulates hyperglyceamia, oxidative stress and dyslipidemia in diabetic rats. J Acute Dis 1(2):135–140

    Google Scholar 

  56. Gonçalves AESS, Lellis-Santos C, Curi R et al (2014) Frozen pulp extracts of camu-camu(Myrciaria dubia McVaugh) attenuate the hyperlipidemia and lipid peroxidation of Type 1 diabetic rats. Food Res Int 64:1–8

    Google Scholar 

  57. Pillai SI, Subramanian SP, Kandaswamy M (2014) Antidyslipidemic effect of a novel vanadium-3-hydroxy flavone complex in streptozotocin-induced experimental diabetes in rats. Biomed Prev Nut 4:189–193

    Google Scholar 

  58. Ugochukwu NH, Figgers CL (2007) Attenuation of plasma dyslipidemia and oxidative damage by dietary caloric restriction in streptozotocin-induced diabetic rats. Chem Biol Interact 169:32–41. doi:10.1016/j.cbi.2007.05.002

    CAS  PubMed  Google Scholar 

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Conflict of interests

The authors declare that they have no Conflict of interests.

Compliance with ethical standards

This study was carried out in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Committee on the Ethics of Animal Experiments of the Federal University of Santa Maria (protocol under number: 23/2012). All efforts were made to minimize suffering.

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Authors and Affiliations

  1. Programa de Pós-Graduação em Ciências Biológicas: Bioquímica Toxicológica, Centro de Ciências Naturais e Exatas, Universidade Federal de Santa Maria, Santa Maria, RS, Brazil

    Nicéia Spanholi Calgaroto, Pauline da Costa, Andréia Machado Cardoso, Juliano Marchi Vieira, Diéssica Dalenogare, Luana Paula Pelinson, Jucimara Baldissarelli, Vera Maria Morsch & Maria Rosa Chitolina Schetinger

  2. Instituto Federal de Educação, Ciência e Tecnologia de Mato Grosso, Campo Novo do Parecis, MT, Brazil

    Luciane Belmonte Pereira

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  1. Nicéia Spanholi Calgaroto
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  2. Pauline da Costa
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  3. Andréia Machado Cardoso
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  4. Luciane Belmonte Pereira
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  9. Vera Maria Morsch
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Correspondence to Nicéia Spanholi Calgaroto.

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Calgaroto, N.S., da Costa, P., Cardoso, A.M. et al. Vitamin D3 prevents the increase in ectonucleotidase activities and ameliorates lipid profile in type 1 diabetic rats. Mol Cell Biochem 405, 11–21 (2015). https://doi.org/10.1007/s11010-015-2390-6

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