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Effects of crocin and voluntary exercise, alone or combined, on heart VEGF-A and HOMA-IR of HFD/STZ induced type 2 diabetic rats

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Abstract

Background

Hyperglycemia is the main risk factor for microvascular complications in type 2 diabetes. Crocin and voluntary exercise have anti-hyperglycemic effects in diabetes. In this research, we evaluated the effects of crocin and voluntary exercise alone or combined on glycemia control and heart level of VEGF-A.

Materials and methods

Animals were divided into eight groups as: control (con), diabetes (Dia), crocin (Cro), voluntary exercise (Exe), crocin and voluntary exercise (Cro-Exe), diabetic–crocin (Dia-Cro), diabetic–voluntary exercise (Dia-Exe), diabetic–crocin–voluntary exercise (Dia-Cro-Exe). Type 2 diabetes was induced by a high-fat diet (4 weeks) and injection of streptozotocin (STZ) (i.p, 35 mg/kg). Animals received oral administration of crocin (50 mg/kg) or performed voluntary exercise alone or together for 8 weeks. Oral glucose tolerance test (OGTT) was performed on overnight fasted control, diabetic and treated rats after 8 weeks of treatment. Then, serum insulin and heart VEGF-A protein levels were measured.

Results

Crocin combined with voluntary exercise significantly decreased blood glucose levels (p < 0.001) and insulin resistance (HOMA-IR) (p < 0.001) compared to diabetic group. VEGF-A level was significantly (p < 0.01) lower in Dia group compared to control group. The combination of crocin and voluntary exercise significantly enhanced VEGF-A protein levels in Dia-Cro-Exe and Cro-Exe group compared to diabetic and control groups, respectively; p < 0.001 and p < 0.05.

Discussion

Crocin combined with voluntary exercise improved insulin resistance (HOMA-IR) and reduced glucose levels in diabetic rats. Since both crocin and voluntary exercise can increase VEGF-A protein expression in heart tissue, they probably are able to increase angiogenesis in diabetic animals.

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References

  1. DeFronzo RA (2009) From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes 58(4):773–795

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Grundy SM, Benjamin IJ, Burke GL, Chait A, Eckel RH, Howard BV, Mitch W, Smith SC, Sowers JR (1999) Diabetes and cardiovascular disease a statement for healthcare professionals from the American Heart Association. Circulation 100(10):1134–1146

    Article  CAS  PubMed  Google Scholar 

  3. Turner R, Holman R, Matthews D, Bassett P, Coster R, Stratton I, Cull C, Peto R, Frighi V, Kennedy I (1993) Hypertension in diabetes study (Hds). 1. Prevalence of hypertension in newly presenting Type-2 diabetic-patients and the association with risk-factors for cardiovascular and diabetic complications. J Hypertens 11(3):309–317

    Article  Google Scholar 

  4. Heller GV (2005) Evaluation of the patient with diabetes mellitus and suspected coronary artery disease. Am J Med Suppl 118:9–14

    Article  Google Scholar 

  5. Bernatchez PN, Soker S, Sirois MG (1999) Vascular endothelial growth factor effect on endothelial cell proliferation, migration, and platelet-activating factor synthesis is Flk-1-dependent. J Biol Chem 274(43):31047–31054

    Article  CAS  PubMed  Google Scholar 

  6. Ferrara N, Gerber H-P, LeCouter J (2003) The biology of VEGF and its receptors. Nat Med 9(6):669–676

    Article  CAS  PubMed  Google Scholar 

  7. Dvorak HF (2002) Vascular permeability factor/vascular endothelial growth factor: a critical cytokine in tumor angiogenesis and a potential target for diagnosis and therapy. J Clin Oncol 20(21):4368–4380

    Article  CAS  PubMed  Google Scholar 

  8. Stefansson E (2004) Diabetic retinopathy. New England J Med 350(24):2525–2526. doi:10.1056/NEJM200406103502421 (author reply 2525–2526)

    Article  CAS  Google Scholar 

  9. Chou E, Suzuma I, Way KJ, Opland D, Clermont AC, Naruse K, Suzuma K, Bowling NL, Vlahos CJ, Aiello LP (2002) Decreased cardiac expression of vascular endothelial growth factor and its receptors in insulin-resistant and diabetic states a possible explanation for impaired collateral formation in cardiac tissue. Circulation 105(3):373–379

    Article  CAS  PubMed  Google Scholar 

  10. Kivelä R, Silvennoinen M, Touvra A-M, Lehti TM, Kainulainen H, Vihko V (2006) Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. FASEB J 20(9):1570–1572

    Article  PubMed  Google Scholar 

  11. Lee S, Park Y, Zhang C (2011) Exercise training prevents coronary endothelial dysfunction in type 2 diabetic mice. Am J Biomed Sci 3(4):241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Erekat NS, Al-Jarrah MD, Al Khatib AJ (2014) Treadmill exercise training improves vascular endothelial growth Factor expression in the cardiac muscle of type I diabetic rats. Cardiol Res 5(1):23–29

    Google Scholar 

  13. Uysal N, Kiray M, Sisman A, Camsari U, Gencoglu C, Baykara B, Cetinkaya C, Aksu I (2015) Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotech Histochem 90(1):55–68. doi:10.3109/10520295.2014.946968

    Article  CAS  PubMed  Google Scholar 

  14. Ke Z, Yip SP, Li L, Zheng XX, Tong KY (2011) The effects of voluntary, involuntary, and forced exercises on brain-derived neurotrophic factor and motor function recovery: a rat brain ischemia model. PLoS One 6(2):e16643. doi:10.1371/journal.pone.0016643

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Lee I-A, Lee JH, Baek N-I, Kim D-H (2005) Antihyperlipidemic effect of crocin isolated from the fructus of Gardenia jasminoides and its metabolite crocetin. Biol Pharm Bull 28(11):2106–2110

    Article  CAS  PubMed  Google Scholar 

  16. Soeda S, Ochiai T, Paopong L, Tanaka H, Shoyama Y, Shimeno H (2001) Crocin suppresses tumor necrosis factor-α-induced cell death of neuronally differentiated PC-12 cells. Life Sci 69(24):2887–2898

    Article  CAS  PubMed  Google Scholar 

  17. Zheng Y-Q, Liu J-X, Wang J-N, Xu L (2007) Effects of crocin on reperfusion-induced oxidative/nitrative injury to cerebral microvessels after global cerebral ischemia. Brain Res 1138:86–94

    Article  CAS  PubMed  Google Scholar 

  18. Pitsikas N, Zisopoulou S, Tarantilis PA, Kanakis CD, Polissiou MG, Sakellaridis N (2007) Effects of the active constituents of Crocus sativus L., crocins on recognition and spatial rats’ memory. Behav Brain Res 183(2):141–146

    Article  CAS  PubMed  Google Scholar 

  19. Chen Y, Yang T, Huang J, TIAN X, ZHAO C, CAI L, FENG L-j, ZHANG H (2010) Comparative evaluation of the antioxidant capacity of crocetin and crocin in vivo. Chinese Pharm Bull 2:029

    Google Scholar 

  20. Naghizadeh B, Boroushaki MT, Vahdati Mashhadian N, Mansouri SMT (2008) Protective effects of crocin against cisplatin-induced acute renal failure and oxidative stress in rats. Iranian Biomed J 12(2):93–100

    CAS  Google Scholar 

  21. Wu Y, Pan R, Geng P (2010) [The effect of Crocin against hypoxia damage of myocardial cell and its mechanism]. Zhongguo ying yong sheng li xue za zhi = Zhongguo yingyong shenglixue zazhi. Chinese J Appl Physiol 26(4):453–457

    Google Scholar 

  22. Tsalouhidou S, Petridou A, Mougios V (2009) Effect of chronic exercise on DNA fragmentation and on lipid profiles in rat skeletal muscle. Exp Physiol 94(3):362–370

    Article  CAS  PubMed  Google Scholar 

  23. Zhang M, Lv X-Y, Li J, Xu Z-G, Chen L (2008) The characterization of high-fat diet and multiple low-dose streptozotocin induced type 2 diabetes rat model. Exp Diab Res 704045:1–9

  24. Qian C, Zhu C, Yu W, Jiang X, Zhang F (2015) High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells. PLoS One 10(8):e0136390

    Article  PubMed  PubMed Central  Google Scholar 

  25. Algandaby MM, Alghamdi HA, Ashour OM, Abdel-Naim AB, Ghareib SA, Abdel-Sattar EA, Hajar AS (2010) Mechanisms of the antihyperglycemic activity of Retama raetam in streptozotocin-induced diabetic rats. Food Chem Toxicol 48(8):2448–2453

    Article  CAS  PubMed  Google Scholar 

  26. Zong H, Wang C-C, Vaitheesvaran B, Kurland IJ, Hong W, Pessin JE (2011) Enhanced energy expenditure, glucose utilization, and insulin sensitivity in VAMP8 null mice. Diabetes 60(1):30–38

    Article  CAS  PubMed  Google Scholar 

  27. Matthews D, Hosker J, Rudenski A, Naylor B, Treacher D, Turner R (1985) Homeostasis model assessment: insulin resistance and β-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28(7):412–419

    Article  CAS  PubMed  Google Scholar 

  28. Katz A, Nambi SS, Mather K, Baron AD, Follmann DA, Sullivan G, Quon MJ (2000) Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans. J Clin Endocrinol Metab 85(7):2402–2410

    Article  CAS  PubMed  Google Scholar 

  29. Abacı A, Oğuzhan A, Kahraman S, Eryol NK, Ünal Ş, Arınç H, Ergin A (1999) Effect of diabetes mellitus on formation of coronary collateral vessels. Circulation 99(17):2239–2242

    Article  PubMed  Google Scholar 

  30. Jesmin S, Zaedi S, Shimojo N, Iemitsu M, Masuzawa K, Yamaguchi N, Mowa CN, Maeda S, Hattori Y, Miyauchi T (2007) Endothelin antagonism normalizes VEGF signaling and cardiac function in STZ-induced diabetic rat hearts. Am J Physiol Endocrinol Metab 292(4):E1030–E1040. doi:10.1152/ajpendo.00517.2006

    Article  CAS  PubMed  Google Scholar 

  31. Jesmin S, Zaedi S, Yamaguchi N, Maeda S, Shimojo N, Masuzawa K, Yamaguchi I, Goto K, Miyauchi T (2006) Differential effects of selective endothelin type a receptor antagonist on the gene expression of vascular endothelial growth factor and its receptors in streptozotocin-induced diabetic heart. Exp Biol Med 231(6):902–906

    CAS  Google Scholar 

  32. Srinivasan K, Viswanad B, Asrat L, Kaul C, 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

    Article  CAS  PubMed  Google Scholar 

  33. Armoni M, Harel C, Bar-Yoseph F, Milo S, Karnieli E (2005) Free fatty acids repress the GLUT4 gene expression in cardiac muscle via novel response elements. J Biol Chem 280(41):34786–34795

    Article  CAS  PubMed  Google Scholar 

  34. Tanaka S, Hayashi T, Toyoda T, Hamada T, Shimizu Y, Hirata M, Ebihara K, Masuzaki H, Hosoda K, Fushiki T (2007) High-fat diet impairs the effects of a single bout of endurance exercise on glucose transport and insulin sensitivity in rat skeletal muscle. Metab Clin Exp 56(12):1719–1728

    Article  CAS  PubMed  Google Scholar 

  35. Bie X, Chen Y, Zheng X, Dai H (2011) The role of crocetin in protection following cerebral contusion and in the enhancement of angiogenesis in rats. Fitoterapia 82(7):997–1002

    Article  CAS  PubMed  Google Scholar 

  36. He S-Y, Qian Z-Y, Tang F-T, Wen N, Xu G-L, Sheng L (2005) Effect of crocin on experimental atherosclerosis in quails and its mechanisms. Life Sci 77(8):907–921

    Article  CAS  PubMed  Google Scholar 

  37. Sheng L, Qian Z, Zheng S, Xi L (2006) Mechanism of hypolipidemic effect of crocin in rats: crocin inhibits pancreatic lipase. Eur J Pharmacol 543(1):116–122

    Article  CAS  PubMed  Google Scholar 

  38. Evans JL (2007) Antioxidants: do they have a role in the treatment of insulin resistance? Indian J Med Res 125(3):355

    CAS  PubMed  Google Scholar 

  39. Ochiai T, Ohno S, Soeda S, Tanaka H, Shoyama Y, Shimeno H (2004) Crocin prevents the death of rat pheochromocytoma (PC-12) cells by its antioxidant effects stronger than those of α-tocopherol. Neurosci Lett 362(1):61–64

    Article  CAS  PubMed  Google Scholar 

  40. Mohajeri D, Mousavi G, Doustar Y (2009) Antihyperglycemic and pancreas-protective effects of Crocus sativus L. (Saffron) stigma ethanolic extract on rats with alloxan-induced diabetes. J Biol Sci 9(4):302–310

    Article  Google Scholar 

  41. Xi L, Qian Z, Xu G, Zhou C, Sun S (2007) Crocetin attenuates palmitate-induced insulin insensitivity and disordered tumor necrosis factor-α and adiponectin expression in rat adipocytes. Br J Pharmacol 151(5):610–617

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yang Y-C, Hwang J-H, Hong S-J, Hsu H-K (2003) Enhancement of glucose uptake in 3T3-L1 adipocytes by Toona sinensis leaf extract. Kaohsiung J Med Sci 19(7):327–332

    Article  CAS  PubMed  Google Scholar 

  43. Youn J-Y, Park H-Y, Cho K-H (2004) Anti-hyperglycemic activity of Commelina communis L.: inhibition of α-glucosidase. Diab Res Clin Pract 66:S149–S155

    Article  Google Scholar 

  44. Voulgari C, Pagoni S, Vinik A, Poirier P (2013) Exercise improves cardiac autonomic function in obesity and diabetes. Metabolism 62(5):609–621

    Article  CAS  PubMed  Google Scholar 

  45. Srinivasan K, Patole P, Kaul C, Ramarao P (2004) Reversal of glucose intolerance by pioglitazone in high fat diet-fed rats. Methods Find Exp Clin Pharmacol 26(5):327–333

    Article  CAS  PubMed  Google Scholar 

  46. Habibuddin M, Daghriri HA, Humaira T, Al Qahtani MS, Hefzi AAH (2008) Antidiabetic effect of alcoholic extract of Caralluma sinaica L. on streptozotocin-induced diabetic rabbits. J Ethnopharmacol 117(2):215–220

    Article  CAS  PubMed  Google Scholar 

  47. Delghingaro-Augusto V, Decary S, Peyot ML, Latour MG, Lamontagne J, Paradis-Isler N, Lacharite-Lemieux M, Akakpo H, Birot O, Nolan CJ, Prentki M, Bergeron R (2012) Voluntary running exercise prevents beta-cell failure in susceptible islets of the Zucker diabetic fatty rat. Am J physiol Endocrinol Metab 302(2):E254–E264. doi:10.1152/ajpendo.00360.2011

    Article  CAS  PubMed  Google Scholar 

  48. Pold R, Jensen LS, Jessen N, Buhl ES, Schmitz O, Flyvbjerg A, Fujii N, Goodyear LJ, Gotfredsen CF, Brand CL, Lund S (2005) Long-term sAICAR administration and exercise prevents diabetes in ZDF rats. Diabetes 54(4):928–934

    Article  CAS  PubMed  Google Scholar 

  49. Miele C, Rochford JJ, Filippa N, Giorgetti-Peraldi S, Van Obberghen E (2000) Insulin and insulin-like growth factor-I induce vascular endothelial growth factor mRNA expression via different signaling pathways. J Biol Chem 275(28):21695–21702

    Article  CAS  PubMed  Google Scholar 

  50. Fujio Y, Walsh K (1999) Akt mediates cytoprotection of endothelial cells by vascular endothelial growth factor in an anchorage-dependent manner. J Biol Chem 274(23):16349–16354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tesfamariam B, Brown ML, Deykin D, Cohen RA (1990) Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta. J Clin Invest 85(3):929

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Uysal N, Kiray M, Sisman AR, Camsari UM, Gencoglu C, Baykara B, Cetinkaya C, Aksu I (2015) Effects of voluntary and involuntary exercise on cognitive functions, and VEGF and BDNF levels in adolescent rats. Biotechnic Histochem Off Publ Biol Stain Comm 90(1):55–68. doi:10.3109/10520295.2014.946968

    Article  CAS  Google Scholar 

  53. Ebrahimian TG, Heymes C, You D, Blanc-Brude O, Mees B, Waeckel L, Duriez M, Vilar J, Brandes RP, Levy BI (2006) NADPH oxidase-derived overproduction of reactive oxygen species impairs postischemic neovascularization in mice with type 1 diabetes. Am J Pathol 169(2):719–728

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Tavakkol-Afshari J, Brook A, Mousavi SH (2008) Study of cytotoxic and apoptogenic properties of saffron extract in human cancer cell lines. Food Chem Toxicol 46(11):3443–3447

    Article  CAS  PubMed  Google Scholar 

  55. Kivela R, Silvennoinen M, Touvra AM, Lehti TM, Kainulainen H, Vihko V (2006) Effects of experimental type 1 diabetes and exercise training on angiogenic gene expression and capillarization in skeletal muscle. FASEB J Off Publ Fed Am Soc Exp Biol 20(9):1570–1572. doi:10.1096/fj.05-4780fje

    CAS  Google Scholar 

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Correspondence to G. Mohaddes.

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This study was supported by Applied Drug Research Center, Tabriz University of medical Science, Tabriz, Iran. The authors have reported no conflicts of interest.

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All of the procedures were carried out under the ethical guidelines of the Tabriz University of Medical Sciences and the study received approval from the Ethics Committee of the Tabriz University of Medical Sciences, according to the guide for the care and use of laboratory animals.

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Ghorbanzadeh, V., Mohammadi, M., Dariushnejad, H. et al. Effects of crocin and voluntary exercise, alone or combined, on heart VEGF-A and HOMA-IR of HFD/STZ induced type 2 diabetic rats. J Endocrinol Invest 39, 1179–1186 (2016). https://doi.org/10.1007/s40618-016-0456-2

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  • DOI: https://doi.org/10.1007/s40618-016-0456-2

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