Sitagliptin favorably modulates immune-relevant pathways in human beta cells
Sitagliptin favorably modulates immune-relevant pathways in human beta cells
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DOI：
10.1016/j.phrs.2019.104405
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发表时间：
2019-10-01
影响因子：
9.3
通讯作者：
Fiorina, Paolo
中科院分区：
文献类型：
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作者：
Malvandi, Amir Mohammad;Loretelli, Cristian;Fiorina, Paolo
2 型糖尿病 (T2D) 是一种以高血糖和慢性并发症为特征的疾病。抗糖尿病药物和生活方式干预是目前治疗 T2D 的金标准；然而，目前的疗法只能延缓长期糖尿病并发症，并且还可能与 β 细胞衰竭有关。虽然β细胞衰竭的机制已得到充分研究，但人们对与抗糖尿病药物相关的免疫和炎症事件知之甚少。在这里，我们研究了三种抗糖尿病药物（二甲双胍、西他列汀和利拉鲁肽）对人类 β 细胞系中免疫相关途径的影响。在用上述抗糖尿病药物攻击后的不同时间点评估共刺激分子表达、细胞因子分泌和基因表达谱。我们的结果表明，这三种抗糖尿病药物，特别是西他列汀，下调 HLA I 类和 II 类表达，并上调免疫调节分子 PD-L1 和 CTLA4。二甲双胍和利拉鲁肽可显着诱导更多的 TNF α、IL-6 和 GM-CSF 释放，而西他列汀对促炎细胞因子产生的影响较小。基因表达分析证实了上述观察结果，还证明了抗糖尿病药物对 NOS2、SIRT1、SITR3、POLRMT、MRPL43 和 NF kappa B 的上调。我们得出的结论是，西格列汀最有效地调节人类 β 细胞系中有益的免疫相关途径。
Type 2 diabetes (T2D) is a condition characterized by hyperglycemia and chronic complications. Antidiabetic drugs and lifestyle interventions are the current gold standard therapy for T2D; current therapies, however, can only delay long-term diabetic complications and can additionally be associated with beta cell failure. While the mechanism of beta cell failure is well-studied, little is known about the immunological and inflammatory events associated with antidiabetic agents. Here we studied the effects of three antidiabetic drugs (Metformin, Sitagliptin, and Liraglutide) on immune-relevant pathways in a human beta cell line. Costimulatory molecule expression, cytokine secretion, and gene expression profiles were evaluated at different time points following challenge with the aforementioned antidiabetic agents. Our results showed that these three antidiabetic agents, particularly Sitagliptin, downregulate HLA Class I and II expression and upregulate the immune-regulatory molecules PD-L1 and CTLA4. Metformin and Liraglutide were shown to elicit significantly greater release of TNF alpha, IL-6, and GM-CSF, while Sitagliptin had a lesser effect on pro-inflammatory cytokine production. Gene expression analysis confirmed the aforementioned observations and also demonstrated upregulation of NOS2, SIRT1, SITR3, POLRMT, MRPL43 and NF kappa B with antidiabetic agents. We conclude that Sitagliptin most effectively modulates beneficial immune-relevant pathways in a human beta cell line.