Effect of sitagliptin on serum levels of TNF-α, IL-1β and IL-10 in patients with type 2 diabetes mellitus

authors:

avatar Zahra Telikani , avatar Vida Sheikh , avatar Alireza zamani , avatar Shiva Borzouei , avatar Iraj Salehi , avatar Mohammad Ali Amirzargar , avatar Mahdi Alahgholi-Hajibehzad , *

Koomesh: Vol.22, issue 1; 71-77
published online: March 01, 2020
article type: Research Article
received: February 06, 2019
accepted: June 01, 2019

how to cite: Telikani Z, Sheikh V, zamani A, Borzouei S, Salehi I, et al. Effect of sitagliptin on serum levels of TNF-α, IL-1β and IL-10 in patients with type 2 diabetes mellitus. koomesh. 2020;22(1):e153151. 

Abstract

Introduction: Type 2 diabetes mellitus (T2DM) is an inflammatory disease with alterations in immune system. Remarkably, cytokine imbalance plays an important role in pathogenesis of T2DM. The purpose of this study was to determine the serum levels of TNF-α, IL-1β and IL-10 and the effects of sitagliptin on the level of these cytokines in patients with T2DM. Materials and Methods: Blood samples were collected from 60 T2DM patients and 30 healthy control subjects (HCs). T2DM patients were divided into two subgroups based on their treatment with sitagliptin treatment (100 mg/day, n=30) for 8 months and without sitagliptin treatment (n=30). The serum levels of TNF-α, IL-1β and IL-10 cytokines were assessed using ELISA method. ANOVA with posthoc Bonferroni were applied to statistical analysis. Results: The serum level of TNF-α was significantly higher in T2DM patients without sitagliptin compared to HCs (p=0.002). Whereas, the serum level of TNF-α was significantly lower in patients with sitagliptin compared to patients without sitagliptin (p=0.01). The serum level of IL-10 showed a significant reduction in patients without sitagliptin compared to HCs (p=0.003). On the other hand, a significant elevation was observed in serum level of IL-10 between T2DM patients with and without sitagliptin (p=0.002). Considerably, no significant difference was observed in serum level of IL-1β between T2DM patients with and without sitagliptin and also in comparison to HCs. Conclusion: Sitagliptin treatment significantly decreased the level of pro-inflammatory TNF-α and increased anti-inflammatory IL-10 in T2DM patients. It seems that sitagliptin had an anti-inflammatory effect on immune system of the patients.

References

  • 1.

    Sheikh V, Zamani A, Mahabadi-Ashtiyani E, Tarokhian H, Borzouei S, Alahgholi-Hajibehzad M. Decreased regulatory function of CD4(+)CD25(+)CD45RA(+) T cells and impaired IL-2 signalling pathway in patients with type 2 diabetes mellitus. Scand J Immunol 2018; 88: e12711.

  • 2.

    Borzouei S, Sheikh V, Ghasemi M, Zamani A, Telikani Z, Zareighane Z, et al. Anti-Inflammatory Effect of Combined Sitagliptin and Vitamin D3 on Cytokines Profile in Patients with Type 2 Diabetes Mellitus. J Interferon Cytokine Res 2019; 39: 293-301.

  • 3.

    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98-107.

  • 4.

    Wang C, Guan Y, Yang J. Cytokines in the Progression of Pancreatic beta-Cell Dysfunction. Int J Endocrinol 2010; 2010: 515136.

  • 5.

    Gregor MF, Hotamisligil GS. Inflammatory mechanisms in obesity. Ann Rev Immunol 2011; 29: 415-445.

  • 6.

    Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004; 27: 813-823.

  • 7.

    Navarro-Gonzalez JF, Mora-Fernandez C. The role of inflammatory cytokines in diabetic nephropathy. J Am Soc Nephrol 2008; 19: 433-442.

  • 8.

    Dinarello CA, Donath MY, Mandrup-Poulsen T. Role of IL-1beta in type 2 diabetes. Curr Opin Endoc Diabetes Obes 2010; 17: 314-321.

  • 9.

    Alahgholi-Hajibehzad M, Oflazer P, Aysal F, Durmus H, Gulsen-Parman Y, Marx A, et al. Regulatory function of CD4+CD25++ T cells in patients with myasthenia gravis is associated with phenotypic changes and STAT5 signaling: 1,25-Dihydroxyvitamin D3 modulates the suppressor activity. J Neuroimmunol 2015; 281: 51-60.

  • 10.

    Alahgholi-Hajibehzad M, Kasapoglu P, Jafari R, Rezaei N. The role of T regulatory cells in immunopathogenesis of myasthenia gravis: implications for therapeutics. Exp Rev Clin Immunol 2015; 11: 859-870.

  • 11.

    Alahgholi-Hajibehzad M, Durmus H, Aysal F, Gulsen-Parman Y, Oflazer P, Deymeer F, et al. The effect of interleukin (IL)-21 and CD4(+) CD25(++) T cells on cytokine production of CD4(+) responder T cells in patients with myasthenia gravis. Clin Exp Immunol 2017; 190: 201-207.

  • 12.

    Sheikh V, Kasapoglu P, Zamani A, Basiri Z, Tahamoli-Roudsari A, Alahgholi-Hajibehzad M. Vitamin D3 inhibits the proliferation of T helper cells, downregulate CD4(+) T cell cytokines and upregulate inhibitory markers. Human Immunol 2018; 79: 439-445.

  • 13.

    Gao M, Zhang C, Ma Y, Bu L, Yan L, Liu D. Hydrodynamic delivery of mIL10 gene protects mice from high-fat diet-induced obesity and glucose intolerance. Mol Ther 2013; 21: 1852-1861.

  • 14.

    Hong EG, Ko HJ, Cho YR, Kim HJ, Ma Z, Yu TY, et al. Interleukin-10 prevents diet-induced insulin resistance by attenuating macrophage and cytokine response in skeletal muscle. Diabetes 2009; 58: 2525-2535.

  • 15.

    Francisco CO, Catai AM, Moura-Tonello SC, Arruda LC, Lopes SL, Benze BG, et al. Cytokine profile and lymphocyte subsets in type 2 diabetes. Braz J Med Biol Res 2016; 49: e5062.

  • 16.

    Jagannathan-Bogdan M, McDonnell ME, Shin H, Rehman Q, Hasturk H, Apovian CM, et al. Elevated proinflammatory cytokine production by a skewed T cell compartment requires monocytes and promotes inflammation in type 2 diabetes. J Immunol 2011; 186: 1162-1172.

  • 17.

    Zeng C, Shi X, Zhang B, Liu H, Zhang L, Ding W, et al. The imbalance of Th17/Th1/Tregs in patients with type 2 diabetes: relationship with metabolic factors and complications. J Mol Med (Berlin, Germany) 2012; 90: 175-186.

  • 18.

    Correia S, Carvalho C, Santos MS, Seica R, Oliveira CR, Moreira PI. Mechanisms of action of metformin in type 2 diabetes and associated complications: an overview. Mini Rev Med Chem 2008; 8: 1343-1354.

  • 19.

    Plosker GL. Sitagliptin: a review of its use in patients with type 2 diabetes mellitus. Drugs 2014; 74: 223-242.

  • 20.

    Sromova L, Busek P, Posova H, Potockova J, Skrha P, Andel M, et al. The effect of dipeptidyl peptidase-IV inhibition on circulating T cell subpopulations in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2016; 118: 183-192.

  • 21.

    Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Couture P. Effects of sitagliptin therapy on markers of low-grade inflammation and cell adhesion molecules in patients with type 2 diabetes. Metabolism 2014; 63: 1141-1148.

  • 22.

    Telikani Z, Sheikh V, Zamani A, Borzouei S, Salehi I, Amirzargar MA, et al. Effects of sitagliptin and vitamin D3 on T helper cell transcription factors and cytokine production in clinical subgroups of type 2 diabetes mellitus: highlights upregulation of FOXP3 and IL-37. Immunopharmacol Immunotoxicol 2019; 41: 1-13.

  • 23.

    Barry JC, Shakibakho S, Durrer C, Simtchouk S, Jawanda KK, Cheung ST, et al. Hyporesponsiveness to the anti-inflammatory action of interleukin-10 in type 2 diabetes. Sci Rep 2016; 6: 21244.

  • 24.

    Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11: 98.

  • 25.

    Akash MSH, Rehman K, Liaqat A. Tumor Necrosis Factor-Alpha: Role in Development of Insulin Resistance and Pathogenesis of Type 2 Diabetes Mellitus. J Cell Biochem 2018; 119: 105-110.

  • 26.

    Tsiotra PC, Tsigos C, Yfanti E, Anastasiou E, Vikentiou M, Psarra K, et al. Visfatin, TNF-alpha and IL-6 mRNA expression is increased in mononuclear cells from type 2 diabetic women. Horm Metab Res 2007; 39: 758-763.

  • 27.

    Pickup JC, Chusney GD, Thomas SM, Burt D. Plasma interleukin-6, tumour necrosis factor and blood cytokine production in type 2 diabetes. Life Sci 2000; 67: 291-300.

  • 28.

    Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, et al. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine 2012; 57: 136-142.

  • 29.

    Satoh-Asahara N, Sasaki Y, Wada H, Tochiya M, Iguchi A, Nakagawachi R, et al. A dipeptidyl peptidase-4 inhibitor, sitagliptin, exerts anti-inflammatory effects in type 2 diabetic patients. Metabolism 2013; 62: 347-351.

  • 30.

    Sromova L, Busek P, Mareckova H, Andel M, Sedo A. The effect of dipeptidyl peptidase-IV inhibitor sitagliptin on the immune functions in patients with type 2 diabetes. Frontiers in Immunology 2013.02.00154.

  • 31.

    Maedler K, Sergeev P, Ris F, Oberholzer J, Joller-Jemelka HI, Spinas GA, et al. Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets. J Clin Invest 2002; 110: 851-860.

  • 32.

    Zhao G, Dharmadhikari G, Maedler K, Meyer-Hermann M. Possible Role of Interleukin-1 in Type 2 Diabetes Onset and Implications for Anti-inflammatory Therapy Strategies. PLoS Comput Biol 2014; 10: e1003798.

  • 33.

    Spranger J, Kroke A, Mohlig M, Hoffmann K, Bergmann MM, Ristow M, et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 2003; 52: 812-817.

  • 34.

    Kousathana F, Georgitsi M, Lambadiari V, Giamarellos-Bourboulis EJ, Dimitriadis G, Mouktaroudi M. Defective production of interleukin-1 beta in patients with type 2 diabetes mellitus: Restoration by proper glycemic control. Cytokine 2017; 90: 177-184.

  • 35.

    van Exel E, Gussekloo J, de Craen AJ, Frolich M, Bootsma-Van Der Wiel A, Westendorp RG. Low production capacity of interleukin-10 associates with the metabolic syndrome and type 2 diabetes: the Leiden 85-Plus Study. Diabetes 2002; 51: 1088-1092.

  • 36.

    Pinheiro MM, Stoppa CL, Valduga CJ, Okuyama CE, Gorjao R, Pereira RM, et al. Sitagliptin inhibit human lymphocytes proliferation and Th1/Th17 differentiation in vitro. Eur J Pharm Sci 2017; 100: 17-24.##.