International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy.
International Center for T1D, Pediatric Clinical Research Center "Romeo ed Enrica Invernizzi", Department of Biomedical and Clinical Science L. Sacco, University of Milan, Milan, Italy; Nephrology Division, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Pharmacol Res. 2019 Oct;148:104405. doi: 10.1016/j.phrs.2019.104405. Epub 2019 Aug 20.
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 TNFa, 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 NFkB with antidiabetic agents. We conclude that Sitagliptin most effectively modulates beneficial immune-relevant pathways in a human beta cell line.
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 T2D 的当前金标准治疗方法；然而，目前的治疗方法只能延迟长期的糖尿病并发症，并且还可能与β细胞衰竭有关。虽然β细胞衰竭的机制已经得到很好的研究，但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β细胞系中免疫相关途径的影响。在受到上述抗糖尿病药物的挑战后，在不同时间点评估了共刺激分子表达、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类的表达，并上调免疫调节分子 PD-L1 和 CTLA4。二甲双胍和利拉鲁肽被证明会引起 TNFa、IL-6 和 GM-CSF 的释放显著增加，而西他列汀对促炎细胞因子的产生影响较小。基因表达分析证实了上述观察结果，并表明抗糖尿病药物可上调 NOS2、SIRT1、SITR3、POLRMT、MRPL43 和 NFkB。我们得出结论，西他列汀最有效地调节人β细胞系中有益的免疫相关途径。
