T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes
Yıl: 2020 Cilt: 24 Sayı: 3 Sayfa Aralığı: 177 - 183 Metin Dili: İngilizce DOI: 10.25179/tjem.2019-71070 İndeks Tarihi: 20-10-2020
T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes
Öz: Objective: In type 1 diabetes (T1D), T helper (Th) 1 cells affectβ cell functions significantly. This study aims to explorethe association between serum levels of Th1 cytokines [interferon-gamma (IFN-γ), interleukin (IL)-2 and tumor necrosisfactor-alpha (TNF-α)] and β cell function in T1D.Material and Methods: The study included 110 patientswith T1D (TIDPs) and 31 healthy controls. The β cell functionsin T1DPS were assessed by calculating mixed-meal stimulatedC-peptide levels. T1DPs were categorized into threegroups depending on results of this test (1a-lowest, 1b, 1chighest).Cytokine levels, IFN-γ/IL-2, and TNF-α/IL-2 ratiosin T1DPs were compared with that in controls. Correlationanalysis between cytokine levels and diabetes-related parameterswas then carried out. Results: IFN-γ, TNF-α, IL-2 levels,and TNF-α/IL-2 of T1DPs were higher (p=0.02, p=0.01,p=0.008, and p=0.01, respectively) than that of controls.The highest IFN-γ/IL-2 and TNF-α/IL-2 ratios were observedin group 1b (p=0.03 and p=0.04, respectively) while the lowestIFN-γ/IL-2 and TNF-α/IL-2 ratios were observed ingroup 1a (p=0.03 and p=0.04, respectively). The TNF-α levelswere found to be negatively correlated with fasting glucoselevels (r2=-0.003, p=0.031). However, after adjustmentfor age and gender, this correlation diminished (r2=-0.028,p=0.076). Conclusion: IFN-γ, IL-2, and TNF-α may exhibita triggering role in the pathogenesis of T1D. IFN-γ/IL-2 andTNF-α/IL-2 ratios possibly have more significant roles in theprogression of β cell dysfunction than other cytokines (ClinicalTrials.gov number: NCT02389335).
Anahtar Kelime: T Helper 1 Sitokinleri ve Tip 1 Diyabette Beta Hücre Fonksiyonu ile İlişkileri
Öz: Amaç: Tip 1 diyabette (T1D) T helper (Th) 1 hücrelerinin β hücre fonksiyonuna belirgin etkisi vardır. Bu çalışmada, T1D tanısı olan hastalarda serum Th1 sitokin [interferon-gama (IFN-γ), interlökin (IL)-2 ve tümör nekrozis faktör-alfa (TNF- α)] seviyeleri ile β hücre disfonksiyonu arasında bir ilişki saptanması amaçlandı. Gereç ve Yöntemler: Toplam 110 tip 1 diyabetli hasta (T1DH) ve 31 sağlıklı kontrol çalışmaya alındı. T1DH’lerin β hücre fonksiyonu, karışık öğün testi ile stimüle edilmiş C-peptit düzeyi ile ölçüldü. Hastalar, bu testin sonuçlarına göre üç gruba ayrıldı (1a- en düşük, 1b,1c- en yüksek). Sitokin seviyeleri ve IFN-γ/IL-2 ile TNF-α/IL-2 oranları kontroller ile karşılaştırıldı. Sitokin seviyeleri ile diyabet ilişkili parametreler arasında korelasyon analizi yapıldı. Bulgular: T1DH’lerin IFN-γ, TNF-α, IL-2 seviyeleri ve TNF-α/IL-2 oranı kontrollerden istatistiksel olarak anlamlı şekilde yüksekti (sırasıyla, p=0,02, p=0,01, p=0,008, p=0,01). En yüksek IFN-γ/IL-2 ve TNF-α/IL-2 oranı grup 1b’de gözlendi (sırasıyla, p=0,03, p=0,04) ve en düşük IFN-γ/IL-2 ve TNF- α/IL-2 oranı grup 1a’da görüldü (sırasıyla, p=0,03, p=0,04). TNF-α seviyesi, açlık glukoz seviyesi ile negative korele olarak saptandı (r2=-0,003, p=0,031). Ancak, yaş ve cinsiyete göre düzeltme yapıldığında bu korelasyon gözlenmedi (r2=- 0,028, p=0,076). Sonuç: IFN-γ, IL-2 ve TNF-α’nın T1D patogenezinde daha büyük rolü olabilir. IFN-γ/IL-2 ve TNF-α/IL-2 oranlarının β hücre disfonksiyonunun ilerlemesindeki rolü de diğer sitokinlerden fazla olabilir (Bu çalışmanın klinik araştırma kayıt numarası NCT02389335).
Anahtar Kelime: Belge Türü: Makale Makale Türü: Araştırma Makalesi Erişim Türü: Erişime Açık
- 1. Nunemaker CS. Considerations for defining cytokine dose, duration, and milieu that are appropriate for modeling chronic low-grade inflammation in type 2 diabetes. J Diabetes Res. 2016;2016:2846570. [Crossref] [PubMed] [PMC]
- 2. Ramadan JW, Steiner SR, O’Neill CM, Nunemaker CS. The central role of calcium in the effects of cytokines on beta-cell function: implications for type 1 and type 2 diabetes. Cell Calcium. 2011;50:481- 490. [Crossref] [PubMed] [PMC]
- 3. Hughson A, Bromberg I, Johnson B, Quataert S, Jospe N, Fowell DJ. Uncoupling of proliferation and cytokines from suppression within the CD4+ CD25+ Foxp3+ T-Cell compartment in the 1st year of human type 1 diabetes. Diabetes. 2011;60:2125- 2133. [Crossref] [PubMed] [PMC]
- 4. Karlsson FA, Bjork E. Beta-cell rest: a strategy for the prevention of autoimmune diabetes. Autoimmunity. 1997;26:117-122. [Crossref] [PubMed]
- 5. Mortensen HB, Swift PG, Holl RW, Hougaard P, Hansen L, Bjoerndalen H, de Beaufort CE, Knip M; Hvidoere Study Group on Childhood Diabetes. Multinational study in children and adolescents with newly diagnosed type 1diabetes: association of age, ketoacidosis, HLA status, and autoantibodies on residual beta- cell function and glycemic control 12 months after diagnosis. Pediatr Diabetes. 2010;1:218-226. [Crossref] [PubMed]
- 6. Lu J, Liu J, Li L, Lan Y, Liang Y. Cytokines in type 1 diabetes: mechanisms of action and immunotherapeutic targets. Clin Transl Immunology. 2020;16;9: e1122. [Crossref] [PubMed] [PMC]
- 7. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2019. Diabetes Care. 42(Supplement 1):S13-S28. [Crossref] [PubMed]
- 8. Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. New England Journal of Medicine. 1993;329: 977-986. [Crossref] [PubMed]
- 9. National Committee for Clinical Laboratory Standarts: Procedures for the collection of diagnostic blood specimens by venipuncture; approved standart. 4th ed. NCCLS document H3-A4. Wayne, PA: NCCLS, 1998.
- 10. CLSI. Protocols fort he Determination of Limits of Quantitation; Approved Guideline. CLSI document EP17-A. Vol 24. No:34. USA: CLSI; 2004.
- 11. Solidin OP, Dahlin JRB, Gresham EG, King J, Soldin SJ. Immulite 2000 age and sex-spesific reference intervals for alfa fetoprotein, homocysteine, insulin, insulin-like growth factor-1, insulin-like growth factor- 1 binding protein-3, C-peptide, immunoglibulin E and intact parathyroid hormone. Clin Biochem. 2008;41:937-942. [Crossref] [PubMed] [PMC]
- 12.Steffes MW, Sibley S, Jackson M, Thomas W. Beta- Cell function and the development of diabetes –related complications in the diabetes control and complications trial. Diabetes Care. 2003;26:832- 836. [Crossref] [PubMed]
- 13. Eizirik DL, Colli ML, Ortis, F. The role of inflammation in insulitis and beta-cell loss in type 1 diabetes. Nat Rev Endocrinol. 2009;5:219-226. [Crossref] [PubMed]
- 14.He JS, Xie PS, Luo Ds, Sun CJ, Zhang YG, Liu FX. Role of immune dysfunction in pathogenesis of type 1 diabetes mellitus in children. Asian Pac J Trop Med. 2014;7:823-826. [Crossref]
- 15.Foulis AK, McGill M, Farquharson MA. Insulitis in type 1 (insulin-dependent) diabetes mellitus in manmacrophages, lymphocytes, and interferon-γ containing cells. The Journal of Pathology. 1991;165: 97-103. [Crossref] [PubMed]
- 16. Bazzaz JT, Amoli MM, Taheri Z, Larijani B, Pravica V, Hutchinson IV. TNF-α and IFN-γ gene variation and genetic susceptibility to type 1 diabetes and its microangiopathic complications. J Diabetes Metab Disord. 2014;13:46. [Crossref] [PubMed] [PMC]
- 17.Stanley WJ, Trivedi PM, Sutherland AP, Thomas HE, Gurzov EN. Differential regulation of pro-inflammatory cytokine signalling by protein tyrosine phosphatases in pancreatic β-cells. J Mol Endocrinol. 2017;59:325-337. [Crossref] [PubMed]
- 18.Schloot NC, Hanifi-Moghaddam P, Aabenhus-Andersen N, Alizadeh BZ, Saha MT, Knip M, Devendra D, Wilkin T, Bonifacio E, Roep BO, Kolb H, Mandrup-Poulsen T. Association of immune mediators at diagnosis of Type 1 diabetes with later clinical remission. Diabetic Med. 2007;24:512-520. [Crossref] [PubMed]
- 19.Kaas A, Pfleger C, Kharagjitsingh AV, Schloot NC, Hansen L, Buschard K, Koeleman BPC, Roep BO, Mortensen HB, Alizadeh BZ: on behalf of the Hvidoere Study Group on Childhood Diabetes. Association between age, IL-10, IFN-γ, stimulated C-peptide and disease progression in children with newly diagnosed type 1 diabetes. Diabet Med. 2012;29:734-741. [Crossref] [PubMed]
- 20.El Samahy MH, Adly AA, Ismail EA, Salah NY. Regulatory T cells with CD62L or TNFR2 expression in young type 1diabetic patients: relation to inflammation, glycemic control and micro-vascular complications. J Diabetes Complications. 2015;29: 120-126. [Crossref] [PubMed]
- 21. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care. 2004;27(3):813-823. [Crossref] [PubMed]
- 22. Hotamisligil GS, Peraldi P, Budavari A, Ellis R, White MF, Spiegelman BM. IRS-1-mediated inhibitionof insulin receptor thyrosine kinase activity in TNF alpha- and obesity- induced insulin resistance. Science. 1996;2;271:665-668. [Crossref] [PubMed]
- 23. Qiao YC, Chen YL, Pan YH, Tian F, Xu Y, Zhang XX, Zhao HL. The change of serum tumor necrosis factor alpha in patients with type 1 diabetes mellitus: a systematic review and meta-analysis. PloS one. 2017;20;12:e0176157. [Crossref] [PubMed] [PMC]
- 24.Buzzetti R, Zampetti S, Pozzilli P. Impact of obesity on the increasing incidence of type 1 diabetes. Diabetes, Obesity & Metabolism. 2020;10. [Crossref] [PubMed]
- 25. Li CR, Mueller EE, Bradley LM. Islet antigen-spesific Th17 cells can induce TNF-α-dependent autoimmune diabetes. J Immunol. 2014;15;192:1425- 1432. [Crossref] [PubMed] [PMC]
- 26.Hartemann A, Bourron O. Interleukin-2 and type 1 diabetes: New therapeutic perspectives. Diabetes & Metabolism. 2012;38:387-391. [Crossref] [PubMed]
- 27.Chan SH, Perussia B, Gupta JW, Kobayashi M, Pospísil M, Young HA, Wolf SF, Young D, Clark SC, Trinchieri G. Induction of interferon gamma production by natural killer cell stimulatory factor: characterization of the responder cells and synergy with other inducers. J Exp Med. 1991;1;173:869-879. [Crossref] [PubMed] [PMC]
- 28. Balkwill F. Tumor Necrosis factor or tumor promoting factor? Cytokine Growth Factor Rev. 2002;13: 135-141. [Crossref]
| APA | Tamer G, Basok B, Dogan B, Telci Caklili O, Köstek O (2020). T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. , 177 - 183. 10.25179/tjem.2019-71070 |
| Chicago | Tamer Gonca,Basok Banu Isbılen,Dogan Burcu,Telci Caklili Ozge,Köstek Osman T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. (2020): 177 - 183. 10.25179/tjem.2019-71070 |
| MLA | Tamer Gonca,Basok Banu Isbılen,Dogan Burcu,Telci Caklili Ozge,Köstek Osman T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. , 2020, ss.177 - 183. 10.25179/tjem.2019-71070 |
| AMA | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. . 2020; 177 - 183. 10.25179/tjem.2019-71070 |
| Vancouver | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. . 2020; 177 - 183. 10.25179/tjem.2019-71070 |
| IEEE | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O "T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes." , ss.177 - 183, 2020. 10.25179/tjem.2019-71070 |
| ISNAD | Tamer, Gonca vd. "T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes". (2020), 177-183. https://doi.org/10.25179/tjem.2019-71070 |
| APA | Tamer G, Basok B, Dogan B, Telci Caklili O, Köstek O (2020). T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism, 24(3), 177 - 183. 10.25179/tjem.2019-71070 |
| Chicago | Tamer Gonca,Basok Banu Isbılen,Dogan Burcu,Telci Caklili Ozge,Köstek Osman T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism 24, no.3 (2020): 177 - 183. 10.25179/tjem.2019-71070 |
| MLA | Tamer Gonca,Basok Banu Isbılen,Dogan Burcu,Telci Caklili Ozge,Köstek Osman T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism, vol.24, no.3, 2020, ss.177 - 183. 10.25179/tjem.2019-71070 |
| AMA | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism. 2020; 24(3): 177 - 183. 10.25179/tjem.2019-71070 |
| Vancouver | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes. Turkish Journal of Endocrinology and Metabolism. 2020; 24(3): 177 - 183. 10.25179/tjem.2019-71070 |
| IEEE | Tamer G,Basok B,Dogan B,Telci Caklili O,Köstek O "T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes." Turkish Journal of Endocrinology and Metabolism, 24, ss.177 - 183, 2020. 10.25179/tjem.2019-71070 |
| ISNAD | Tamer, Gonca vd. "T Helper 1 Cytokines and Their Relationship with Beta Cell Function in Type 1 Diabetes". Turkish Journal of Endocrinology and Metabolism 24/3 (2020), 177-183. https://doi.org/10.25179/tjem.2019-71070 |
