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Abstract

Flavonoids are widely used phenolic compounds in traditional medicine due to their health-beneficial features. Quercetin is a remarkable member of flavonols, which is a sub-family of flavonoids, with its broad biological activity. Using flavonoids as adjuvant agents in the treatment of diabetes mellitus is frequently being debated. Inflammation, which is mentioned in the pathophysiology of diabetes, may be seen as a target for the adjuvant therapy. Thereby, in the present study, we aimed to investigate the effects of quercetin on the plasma inflammatory cytokines, namely interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in diabetic rats. Total six groups were assigned as controls and treatments (50 mg/kg and 100 mg/kg quercetin) in diabetic and non-diabetic main groups. We found that diabetes resulted in a significant increase of plasma IL-6 and TNF-α levels (respectively p=0,01 and p=0,01). Both doses of quercetin reduced plasma IL-6 and TNF-α to the levels that in non-diabetic animals (respectively p=0,01 and p=0,01). In terms of inflammatory cytokine levels, there was no significance between non-diabetic quercetin injected and control animals (p=0,99). Therefore, we assumed that quercetin acts as an immunomodulator rather than an immunosuppressant in diabetic rats

Keywords

• Quercetin, diabetes mellitus, inflammation, interleukin-6, tumor necrosis factor-α

DİYABETİK SIÇANLARDA IL-6 VE TNF-α SEVİYELERİ: KUERSETİNİN ETKİSİ

Öz

Flavonoidler sağlık açısından faydalarına istinaden geleneksel tıpta yaygın kullanılan fenolik bileşiklerdir. Flavonoidlerin alt ailesi olan flavonoller içerisinde kuersetin, yüksek biyolojik aktivitesi ile dikkat çekmektedir. Flavonoidlerin diyabetes mellitus tedavisinde destekleyici ajanlar olarak kullanılması sıkça tartışılmaktadır. Diyabet fizyopatogenezinde söz edilen inflamasyon, destekleyici tedavi açısından bir hedef olarak görülebilir. Buradan hareketle mevcut çalışmamızda diyabetik sıçanlarda kuersetinin plazma inflamatuar sitokinlerinden olan interlökin-6 (IL-6) ve tümör nekroz faktör-α (TNF-α) seviyelerine etkisinin araştırılması amaçlanmıştır. Diyabetik ve non-diyabetik iki ana grup içerisinde kontrol ve tedavi (50 mg/kg ve 100 mg/kg kuersetin) olmak üzere toplam altı alt grup oluşturulmuştur. Diyabetik hayvanlarda plazma IL-6 ve TNF-α seviyelerinde önemli düzeyde artış izlenmiştir (sırasıyla p=0,01 ve p=0,01). Her iki kuersetin dozu diyabetik hayvanlarda yükselen plazma IL-6 ve TNF-α seviyelerinin non-diyabetik hayvanlar düzeyine düşürülmesini sağlamıştır (sırasıyla p=0,01 ve p=0,01). İnflamatuar sitokin seviyeleri açısından diyabetik olmayan sıçanlarda kuersetin enjeksiyonu yapılan ve yapılmayan hayvanlar arasında farka rastlanmamıştır (p=0,99). Bu bulgular kuersetinin diyabetik sıçanlarda immünosupresandan ziyade immünomodülatör olarak davrandığını düşündürmektedir. Anahtar Kelimeler:

Anahtar Kelimeler

• Kuersetin, diyabetes mellitus, inflamasyon, interlökin-6, tümör nekroz faktör-α

References

1. International Diabetes Federation. IDF Diabetes Atlas, 6th
2. ed.th ed. 2013 [cited 2014 Feb 12]. Available from URL:
3. http://www.idf.org/diabetesatlas.
4. Bending D, Zaccone P, Cooke A. Inflammation and type one
5. diabetes. International Immunology. 2012;24(6); 339–346.
6. Kahn SE, Cooper ME, Del Prato S. Pathophysiology and
7. treatment of type 2 diabetes: perspectives on the past,
8. present, and future. The Lance. 2014;383(9922); 1068–1083.

9. Cade WT. Diabetes-related microvascular and
10. macrovascular diseases in the physical therapy setting.
11. Physical Therapy. 2008;88(11); 1322–1335.
12. Gabay C. Interleukin-6 and chronic inflammation. Arthritis
13. Research & Therapy. 2006;8 Suppl 2; S3.
14. Senn JJ, Klover PJ, Nowak IA, Mooney RA. Interleukin-6
15. Induces Cellular Insulin Resistance in Hepatocytes. Diabetes.
16. ;51(12); 3391–3399.
17. Rotter V, Nagaev I, Smith U. Interleukin-6 (IL-6) induces
18. insulin resistance in 3T3-L1 adipocytes and is, like IL-8 and
19. tumor necrosis factor-alpha, overexpressed in human fat cells
20. from insulin-resistant subjects. The Journal of Biological
21. Chemistry. 2003;278(46); 45777–45784.
22. Nieto-Vazquez I, Fernandez-Veledo S, Kramer DK, Vila-
23. Bedmar R, Garcia-Guerra L, Lorenzo M. Insulin resistance
24. associated to obesity: the link TNF-alpha. Archives of
25. Physiology and Biochemistry. 2008;114(3); 183–194.
26. Kumar S, Pandey AK. Chemistry and biological activities of
27. flavonoids: an overview. The Scientific World Journal.
28. ;2013; 162750.
29. Formica JV, Regelson W. Review of the biology of
30. Quercetin and related bioflavonoids. Food and Chemical
31. Toxicology. 1995;33(12); 1061–1080.
32. Kelly GS. Quercetin. Monograph. Alternative Medicine
33. Review. 2011;16(2); 172–194.
34. Kanter M. Protective effects of thymoquinone on
35. streptozotocin-induced diabetic nephropathy. Journal of
36. Molecular Histology. 2009;40(2); 107–115.
37. Akash, Muhammad Sajid Hamid, Rehman K, Chen S. Role
38. of inflammatory mechanisms in pathogenesis of type 2
39. diabetes mellitus. Journal of Cellular Biochemistry.
40. ;114(3); 525–531.
41. King GL. The role of inflammatory cytokines in diabetes
42. and its complications. Journal of Periodontology. 2008;79(8
43. Suppl); 1527–1534.
44. Bottino R, Lemarchand P, Trucco M, Giannoukakis N. Gene-
45. and cell-based therapeutics for type I diabetes mellitus.
46. Gene Therapy. 2003;10(10); 875–889.
47. Nicholas D, Odumosu O, Langridge, William H R.
48. Autoantigen based vaccines for type 1 diabetes. Discovery
49. Medicine. 2011;11(59); 293–301.
50. Phillips JM, Parish NM, Raine T, Bland C, Sawyer Y, De La
51. Peña, Hugo ve ark. Type 1 diabetes development requires
52. both CD4+ and CD8+ T cells and can be reversed by nondepleting
53. antibodies targeting both T cell populations. The
54. Review of Diabetic Studies 2009;6(2); 97–103.
55. Hamilton-Williams EE, Palmer SE, Charlton B, Slattery RM.
56. Beta cell MHC class I is a late requirement for diabetes.
57. Proceedings of the National Academy of Sciences.
58. ;100(11); 6688–6693.
59. Pinkse, Gabrielle G M, Tysma, Odette H M, Bergen, Cees A
60. M, Kester, Michel G D, Ossendorp F, van Veelen, Peter A ve
61. ark. Autoreactive CD8 T cells associated with beta cell
62. destruction in type 1 diabetes. Proceedings of the National
63. Academy of Sciences. 2005;102(51); 18425–18430.
64. Wedrychowicz A, Dziatkowiak H, Sztefko K. Interleukin-6
65. (IL-6) and IGF-IGFBP system in children and adolescents with
66. type 1 diabetes mellitus. Experimental and Clinical
67. Endocrinology & Diabetes. 2013;112(8); 435–439.
68. Snell-Bergeon JK, West NA, Mayer-Davis EJ, Liese AD,
69. Marcovina SM, D'Agostino, Ralph B Jr ve ark. Inflammatory
70. markers are increased in youth with type 1 diabetes: the
71. SEARCH Case-Control study. The Journal of Clinical
72. Endocrinology & Metabolism. 2010;95(6); 2868–2876.
73. Choi S, Choi K, Yoon I, Shin J, Kim J, Park W ve ark. IL-6
74. protects pancreatic islet beta cells from pro-inflammatory
75. cytokines-induced cell death and functional impairment in
76. vitro and in vivo. Transplant Immunology. 2004;13(1); 43–53.
77. Campbell IL, Hobbs MV, Dockter J, Oldstone MB, Allison J.
78. Islet inflammation and hyperplasia induced by the pancreatic
79. islet-specific overexpression of interleukin-6 in transgenic
80. mice. American Journal of Pathology. 1994;145(1); 157–166.
81. Wegner M, Araszkiewicz A, Piorunska-Stolzmann M,
82. Wierusz-Wysocka B, Zozulinska-Ziolkiewicz D. Association
83. Between IL-6 Concentration and Diabetes-Related Variables in
84. DM1 Patients with and without Microvascular Complications.
85. Inflammation. 2013;36(3); 723–728.
86. Lee L, Xu B, Michie SA, Beilhack GF, Warganich T, Turley S
87. ve ark. The role of TNF-alpha in the pathogenesis of type 1
88. diabetes in the nonobese diabetic mouse: analysis of dendritic
89. cell maturation. Proceedings of the National Academy of
90. Sciences. 2005;102(44); 15995–16000.
91. Koulmanda M, Bhasin M, Awdeh Z, Qipo A, Fan Z,
92. Hanidziar D ve ark. The role of TNF-α in mice with type 1- and
93. - diabetes. PLoS ONE. 2012;7(5); e33254.
94. Garber AJ. Obesity and type 2 diabetes: which patients are
95. at risk? Diabetes, Obesity and Metabolism. 2012;14(5); 399–
96. -
97. Yki-Järvinen H, Ryysy L, Kauppila M, Kujansuu E, Lahti J,
98. Marjanen T ve ark. Effect of obesity on the response to insulin
99. therapy in noninsulin-dependent diabetes mellitus. The
100. Journal of Clinical Endocrinology & Metabolism. 1997;82(12);
101. –4043.
102. Cruz NG, Sousa LP, Sousa MO, Pietrani NT, Fernandes AP,
103. Gomes KB. The linkage between inflammation and Type 2
104. diabetes mellitus. Diabetes Research and Clinical Practice.
105. ;99(2); 85–92.
106. Zozulinska D, Wierusz-Wysocka B. Type 2 diabetes
107. mellitus as inflammatory disease. Diabetes Research and
108. Clinical Practice. 2006;74(2); S12.
109. Rivera L, Morón R, Sánchez M, Zarzuelo A, Galisteo M.
110. Quercetin ameliorates metabolic syndrome and improves the
111. inflammatory status in obese Zucker rats. Obesity. 2008;16(9);
112. –2087.
113. Chuang C, Martinez K, Xie G, Kennedy A, Bumrungpert A,
114. Overman A ve ark. Quercetin is equally or more effective than
115. resveratrol in attenuating tumor necrosis factor- -mediated
116. inflammation and insulin resistance in primary human
117. adipocytes. American Journal of Clinical Nutrition. 2010;92(6);
118. –1521.
119. Zahedi M, Ghiasvand R, Feizi A, Asgari G, Darvish L. Does
120. Quercetin Improve Cardiovascular Risk factors and
121. Inflammatory Biomarkers in Women with Type 2 Diabetes: A
122. Double-blind Randomized Controlled Clinical Trial.
123. International Journal of Preventive Medicine. 2013;4(7); 777–
124. -
125. Egert S, Bosy-Westphal A, Seiberl J, Kürbitz C, Settler U,
126. Plachta-Danielzik S ve ark. Quercetin reduces systolic blood
127. pressure and plasma oxidised low-density lipoprotein
128. concentrations in overweight subjects with a highcardiovascular
129. disease risk phenotype: a double-blinded,
130. placebo-controlled cross-over study. British Journal of
131. Nutrition. 2009;102(7); 1065–1074.
132. Manach C, Williamson G, Morand C, Scalbert A, Remesy C.
133. Bioavailability and bioefficacy of polyphenols in humans. I.
134. Review of 97 bioavailability studies. The American Journal of
135. Clinical Nutrition. 2005;81(1 Suppl); 230S-242S.
136. . 2011; 112 (6): 318-22.
137. Noyan T, Balahoroğlu R, Kömüroğlu U. The Effects of Vitamin
138. A, E, and C Combined Insulin Treatments on the
139. Antioxidant Enzymes in the Diabetic Rats. Türk Klinik Biyokimya
140. Derg. 2004; 2(3): 113-119.