Expression of CD4+CD25+Foxp3+ Regulatory T Cells, Interleukin 10 and Transforming Growth Factor β in Newly Diagnosed Type 2 Diabetic Patients

Ning Yuan; Hai-feng Zhang; Qi Wei; Ping Wang; Wei-ying Guo

doi:10.1055/s-0043-113454

Experimental and Clinical Endocrinology & Diabetes, Table of Contents

Exp Clin Endocrinol Diabetes 2018; 126(02): 96-101
DOI: 10.1055/s-0043-113454

Article

Expression of CD4+CD25+Foxp3+ Regulatory T Cells, Interleukin 10 and Transforming Growth Factor β in Newly Diagnosed Type 2 Diabetic Patients

Ning Yuan

¹Endocrinology and Metabolic Department of the First Hospital of Jilin University, Changchun, Jilin, China

²Endocrinology Department of the Peking University International Hospital, Beijing, China

,

Hai-feng Zhang

¹Endocrinology and Metabolic Department of the First Hospital of Jilin University, Changchun, Jilin, China

,

Qi Wei

¹Endocrinology and Metabolic Department of the First Hospital of Jilin University, Changchun, Jilin, China

,

Ping Wang

¹Endocrinology and Metabolic Department of the First Hospital of Jilin University, Changchun, Jilin, China

,

Wei-ying Guo

¹Endocrinology and Metabolic Department of the First Hospital of Jilin University, Changchun, Jilin, China

› Author Affiliations

Abstract

Background Recent studies have shown that dysfunction and decrease of regulatory T cells (Tregs) correlates with insulin resistance (IR), one of the most significant mechanisms for type 2 diabetes mellitus (T2DM). To examine potential relationships among Tregs, IR, blood lipid content, and related cytokines, we investigated the frequency of CD4+CD25+Foxp3+ Tregs, as well as expression levels of interleukin 10 (IL-10) and transforming growth factor-β (TGF-β) in newly diagnosed T2DM patients.

Methods Fifty-one newly diagnosed T2DM patients and 55 control individuals were enrolled. According to body mass index (BMI), the T2DM patients were grouped into non-obese and obese groups. Blood was collected in ethylene diamine tetraacetic acid (EDTA) anticoagulant tubes for detection of CD4+CD25+Foxp3+ Tregs by flow cytometry. Serum was collected to quantify IL-10 and TGF-β levels by enzyme-linked immunosorbent assay (ELISA). By comparing percentages of Tregs between non-obese and obese groups, correlation with Treg frequency, homeostasis model assessment of insulin resistance (HOMA-IR), IL-10 and TGF-β was examined.

Results The percentage of CD4+CD25+Foxp3+ Tregs in the newly diagnosed T2DM group was significantly lower than in the control group (P<0.01). Further, levels of IL-10 and TGF-β were also lower in the T2DM group (P<0.05). The level of IL-10 was remarkably lower in the obese group than in the non-obese and the control groups (P<0.01), but there was no significant difference between non-obese group and the control group. The level of TGF-β was lower in obese group than in the control group (P<0.05). There was no significant difference between non-obese group and the control group. The frequency of CD4+CD25+Foxp3+ Tregs in the obese group was significantly lower than in the non-obese group (P<0.05). In the obese group, the percentage of Tregs negatively correlated with HOMA-IR and positively correlated with TGF-β (P<0.05). There was no obvious correlation between Treg and HOMA-IR in the non-obese group.

Conclusion The percentage of CD4+CD25+Foxp3+ Tregs and levels of related cytokines IL-10 and TGF-β were precipitously decreased in newly diagnosed T2DM patients. Therefore, the function of Tregs in limiting the proinflammatory milieu represents an important pathogenic mediator of the development of obesity-induced IR in newly diagnosed T2DM patients. Notably, TGF-β may play an important role in this process. Thus, enhancing expression of Tregs may improve IR in newly diagnosed T2DM patients with obesity.

Key words

Newly diagnosed type 2 diabetes - CD4+CD25+Foxp3+ regulatory T cells - Insulin resistance - IL-10 - TGF-β

Full Text

References

References
1 Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract 2010; 87: 4-14
2 Qiao YC, Shen J, He L. et al. Changes of Regulatory T Cells and of Proinflammatory and Immunosuppressive Cytokines in patients with type 2 diabetes mellitus: A systematic review and meta-analysis. J Diabetes Res 2016; 2016: 3694957
3 Yang TT, Song SJ, Xue HB. et al. Regulatory T cells in the pathogenesis of type 2 diabetes mellitus retinopathy by miR-155. Eur Rev Med Pharmacol Sci 2015; 19: 2010-2015
4 Harford KA, Reynolds CM, McGillicuddy FC. et al. Fats, inflammation and insulin resistance: insights to the role of macrophage and T-cell accumulation in adipose tissue. Proc Nutr Soc 2011; 70: 408-417
5 Josefowicz SZ, Lu LF, Rudensky AY. Regulatory T cells: mechanisms of differentiation and function. Annu Rev Immunol 2012; 30: 531-564
6 Deiuliis J, Shah Z, Shah N. et al. Visceral adipose inflammation in obesity is associated with critical alterations in tregulatory cell numbers. PLoS One 2011; 6: e16376
7 Winer S, Chan Y, Paltser G. et al. Normalization of obesity-associated insulin resistance through immunotherapy. Nat Med 2009; 15: 921-929
8 Feuerer M, Herrero L, Cipolletta D. et al. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med 2009; 15: 930-939
9 Eller K, Kirsch A, Wolf AM. et al. Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy. Diabetes 2011; 60: 2954-2962
10 Ilan Y, Maron R, Tukpah AM. et al. Induction of regulatory T cells decreases adipose inflammation and alleviates insulin resistance in ob/ob mice. Proc Natl Acad Sci USA 2010; 107: 9765-9770
11 Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol 2008; 8: 523-532
12 Hamaguchi M, Sakaguchi S. Regulatory T cells expressing PPAR-γ control inflammation in obesity. Cell Metab 2012; 16: 4-6
13 Matarese G, Procaccini C, Menale C. et al. Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses. Proc Natl Acad Sci U S A 2013; 110: 6193-6198
14 Procaccini C, De Rosa V, Galgani M. et al. An oscillatory switch in mTOR kinase activity sets regulatory T cell responsiveness. Immunity 2010; 33: 929-941
15 Xu J, Su HL, Wang JH. et al. Role of CD4+CD25+Foxp3+ regulatory T cells in type 2 diabetic nephropathy. Nan Fang Yi Ke Da Xue Xue Bao 2009; 29: 137-139
16 Afzal N, Javaid K, Zaman S. et al. Enumeration of CD4(+)CD25(+)T regulatory cells in Type-II diabetes retinopathy. Pak J Pharm Sci 2014; 27: 1191-1197
17 Yun JM, Jialal I, Devaraj S. Effects of epigallocatechin gallate on regulatory T cell number and function in obese v. lean volunteers. Br J Nutr 2010; 103: 1771-1777
18 Formoso G, Taraborrelli M, Guagnano MT. et al. Magnetic resonance imaging determined visceral fat reduction associates with enhanced IL-10 plasma levels in calorie restricted obese subjects. PLoS One 2012; 7: e52774
19 Han JM, Patterson SJ, Speck M. et al. Insulin inhibits IL-10-mediated regulatory T cell function: implications for obesity. J Immunol 2014; 192: 623-629
20 Vasanthakumar R, Mohan V, Anand G. et al. Serum IL-9, IL-17, and TGF-β levels in subjects with diabetic kidney disease (CURES-134). Cytokine 2015; 72: 109-112
21 Abbasi F, Amiri P, Sayahpour FA. et al. TGF-β and IL-23 gene expression in unstimulated PBMCs of patients with diabetes. Endocrine 2012; 41: 430-434
22 Genc H, Karadurmus N, Kisa U. et al. Transforming growth factor β (TGF-β) levels in otherwise healthy subjects with impaired glucose tolerance. Endokrynol Pol 2010; 61: 691-694
23 Maruyama T, Konkel JE, Zamarron BF. et al. The molecular mechanisms of Foxp3 gene regulation. Semin Immunol 2011; 23: 418-423
24 Wang X, Wang W, Xu J. et al. All-trans retinoid acid promotes allogeneic corneal graft survival in mice by regulating Treg-Th17 balance in the presence of TGF-β. BMC Immunol 2015; 16: 17
25 Shen Y, Wei Y, Wang Z. et al. TGF-β regulates hepatocellular carcinoma progression by inducing Treg cell polarization. Cell Physiol Biochem 2015; 35: 1623-1632