Alteration in Gene Expression of STAT4 and PIAS2 in Individuals with Type 2 Diabetes Mellitus Treated with the Dipeptidyl Peptidase 4 Inhibitor

Abstract

Objective: Impairment of immune cell signaling molecules is involved in diseases pathogenesis. The evaluation of signal transducer and activator of transcription (STAT) 4 and protein inhibitor of activated STAT (PIAS) 2 as well as immunoregulatory role of the dipeptidyl peptidase-4 inhibitor, sitagliptin were investigated in type 2 diabetes mellitus (T2DM). Materials and Methods: Peripheral blood mononuclear cells were purified from three study groups including healthy controls, T2DM patients with 6 months of sitagliptin treatment, and T2DM patients without sitagliptin. Expressions of STAT4 and PIAS2 were assessed with real-time polymerase chain reaction (qPCR). Results: The expression of STAT4 in patients without sitagliptin was higher than the healthy controls (p=0.001). Its expression was down-regulated in the sitagliptin treated patient group compared to those without sitagliptin (p=0.005). PIAS2 expression in patients without sitagliptin was lower than the healthy controls (p=0.009). PIAS2 was elevated in the sitagliptin treated group versus patients without sitagliptin (p=0.003). A negative correlation between STAT4 and PIAS2 was found in individuals without sitagliptin (p=0.01). In patients without sitagliptin, fasting plasma glucose was positively and negatively correlated with STAT4 and PIAS2, respectively (p=0.004 and p=0.001). Conclusion: Aberrant expression of STAT4 and reduced expression of PIAS2 were found in the T2DM patients. Sitagliptin may regulate the cell signaling pathways by elevating PIAS2 and reducing STAT4.

Keywords

• Type 2 diabetes mellitus
• STAT
• PIAS
• dipeptidyl peptidase 4 inhibitor

References

1. 1. Donath MY, Shoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol 2011; 11(2): 98-107. google scholar
2. 2. Liang Y, Pan HF, Ye DQ. Therapeutic potential of STAT4 in autoimmunity. Expert Opin Ther Targets 2014; 18(8): 945-60. google scholar
3. 3. Shuai K, Liu B. Regulation of gene-activation pathways by PIAS proteins in the immune system. Nat Rev Immunol 2005; 5(8): 593605. google scholar
4. 4. O’Shea JJ, Lahesmaa R, Vahedi G, Laurence A, Kanno Y. Genomic views of STAT function in CD4+ T helper cell differentiation. Nat Rev Immunol 2011; 11(4): 239-50. google scholar
5. 5. Yang C, Mai H, Peng J, Zhou B, Hou J, Jiang D. STAT4: an immunoregulator contributing to diverse human diseases. Int J Biol Sci 2020; 16(9): 1575-85. google scholar
6. 6. Magalhaes J, Tresse E, Ejlerskov P, Hu E, Liu Y, Marin A, et al. PIAS2-mediated blockade of IFN-beta signaling: a basis for sporadic Parkinson disease dementia. Mol Psychiatry 2021; 26(10): 608399. google scholar
7. 7. Xiao J, Cai X, Zhou W, Wang R, Ye Z. Curcumin relieved the rheumatoid arthritis progression via modulating the linc00052/ miR-126-5p/PIAS2 axis. Bioengineered 2022; 13(4): 10973-83. google scholar
8. 8. Ueno H. The IL-12-STAT4 axis in the pathogenesis of human systemic lupus erythematosus. Eur J Immunol 2020; 50(1): 10-6. google scholar

9. 9. Remmers EF, Plenge RM, Lee AT, Graham RR, Hom G, Behrens TW, et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N Engl J Med 2007; 357(10): 977-86. google scholar
10. 10. Lee M, Rhee MK. Sitagliptin for Type 2 diabetes: a 2015 update. Expert Rev Cardiovasc Ther 2015; 13(6): 597-610. google scholar
11. 11. Mahabadi-Ashtiyani E, Sheikh V, Borzouei S, Salehi I, Alahgholi-Hajibehzad M. The increased T helper cells proliferation and inflammatory responses in patients with type 2 diabetes mellitus is suppressed by sitagliptin and vitamin D3 in vitro. Inflamm Res 2019; 68(10): 857-66. google scholar
12. 12. Al-Rasheed NM, Al-Rasheed NM, Hasan IH, Al-Amin MA, Al-Ajmi HN, Mahmoud AM. Sitagliptin attenuates cardiomyopathy by modulating the JAK/STAT signaling pathway in experimental diabetic rats. Drug Des Devel Ther 2016; 10: 2095-107. google scholar
13. 13. 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(2): 299-311. google scholar
14. 14. 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(2): 201-7. google scholar
15. 15. Borzouei S, Gholamian-Hamadan M, Behzad M. Impact of interleukin-32alpha on T helper cell-related cytokines, transcription factors, and proliferation in patients with type 2 diabetes mellitus. Immunopharmacol Immunotoxicol 2023; 45(3): 268-76. google scholar
16. 16. Walker JG, Ahern MJ, Coleman M, Weedon H, Papangelis V, Beroukas D, et al. Characterisation of a dendritic cell subset in synovial tissue which strongly expresses Jak/STAT transcription factors from patients with rheumatoid arthritis. Ann Rheum Dis 2007; 66(8): 992-9. google scholar
17. 17. Lee PW, Smith AJ, Yang Y, Selhorst AJ, Liu Y, Racke MK, et al. IL-23R-activated STAT3/STAT4 is essential for Th1/Th17-mediated CNS autoimmunity. JCI Insight 2017; 2(17): e91663. google scholar
18. 18. Yang M, Tian M, Zhang X, Xu J, Yang B, Yu J, et al. Role of the JAK2/ STAT3 signaling pathway in the pathogenesis of type 2 diabetes mellitus with macrovascular complications. Oncotarget 2017; 8(57): 96958-69. google scholar
19. 19. Rezaeepoor M, Hoseini-Aghdam M, Sheikh V, Eftekharian MM, Behzad M. Evaluation of Interleukin-23 and JAKs/STATs/SOCSs/ ROR-gammat expression in type 2 diabetes mellitus patients treated with or without sitagliptin. J Interferon Cytokine Res 2020; 40(11): 515-23. google scholar
20. 20. Feng X, Tang H, Leng J, Jiang Q. Suppressors of cytokine signaling (SOCS) and type 2 diabetes. Mol Biol Rep 2014; 41(4): 2265-74. google scholar
21. 21. Chen H, Ren X, Liao N, Wen F. Th17 cell frequency and IL-17A concentrations in peripheral blood mononuclear cells and vitreous fluid from patients with diabetic retinopathy. J Int Med Res 2016; 44(6): 1403-13. google scholar
22. 22. Zhang H, Nair V, Saha J, Atkins KB, Hodgin JB, Saunders TL, et al. Podocyte-specific JAK2 overexpression worsens diabetic kidney disease in mice. Kidney Int 2017; 92(4): 909-21. google scholar