Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.
Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China.
Diabetes Metab Res Rev. 2023 May;39(4):e3620. doi: 10.1002/dmrr.3620. Epub 2023 Feb 17.
It is acknowledged that aberrant liver immunity contributes to the development of type 2 diabetes mellitus (T2DM). Mucosal-associated invariant T (MAIT) cells, an innate-like T-cell subset, are enriched in the human liver. Nevertheless, the characterisation and potential role of hepatic MAIT cells in T2DM remain unclear.
Fourteen newly diagnosed T2DM subjects and 15 controls received liver biopsy. The frequency and cytokine production of MAIT cells were analysed by flow cytometry. The expression of genes involved in glucose metabolism was determined in HepG2 cells co-cultured with hepatic MAIT cells.
Compared with controls, hepatic MAIT cell frequency was significantly increased in T2DM patients (24.66% vs. 14.61%, p = 0.001). There were more MAIT cells producing interferon-γ (IFN-γ, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-α (TNF-α, 46.84% vs. 5.91%, p = 0.021) in T2DM than in controls, whereas their production of interleukin 17 (IL-17) was comparable (15.25% vs. 4.55%, p = 0.054). Notably, an IFN-γ TNF-α IL-17 producing MAIT cell subset was focussed, which showed an elevated proportion in T2DM (42.66% vs. 5.85%, p = 0.021) and positively correlated with plasma glucose levels. A co-culture experiment further indicated that hepatic MAIT cells from T2DM upregulated the gene expression of pyruvate carboxylase, a key molecule involved in gluconeogenesis, in HepG2 cells, and this response was blocked with neutralising antibodies against IFN-γ and TNF-α.
Our data implicate an increased Th1-like MAIT cell subset in the liver of newly diagnosed T2DM subjects, which induces hyperglycaemia by promoting hepatic gluconeogenesis. It provides novel insights into the immune regulation of metabolic homoeostasis.
NCT03296605 (registered at www.
gov on 12 October 2018).
众所周知，肝脏免疫异常导致 2 型糖尿病（T2DM）的发生。黏膜相关不变 T（MAIT）细胞是一种固有样 T 细胞亚群，在人类肝脏中丰富存在。然而，肝 MAIT 细胞在 T2DM 中的特征和潜在作用尚不清楚。
14 例新诊断的 T2DM 患者和 15 例对照者接受了肝活检。通过流式细胞术分析 MAIT 细胞的频率和细胞因子产生。在与肝 MAIT 细胞共培养的 HepG2 细胞中，测定参与糖代谢的基因表达。
与对照组相比，T2DM 患者肝 MAIT 细胞频率明显升高（24.66% vs. 14.61%，p=0.001）。T2DM 患者 MAIT 细胞产生干扰素-γ（IFN-γ，60.49% vs. 33.33%，p=0.021）和肿瘤坏死因子-α（TNF-α，46.84% vs. 5.91%，p=0.021）的比例更高，而白细胞介素 17（IL-17）的产生则相当（15.25% vs. 4.55%，p=0.054）。值得注意的是，聚焦于 IFN-γ TNF-α IL-17 产生的 MAIT 细胞亚群在 T2DM 中比例升高（42.66% vs. 5.85%，p=0.021），并与血浆葡萄糖水平呈正相关。共培养实验进一步表明，来自 T2DM 的肝 MAIT 细胞上调了参与糖异生的关键分子丙酮酸羧化酶的基因表达，该反应被中和 IFN-γ 和 TNF-α 的抗体阻断。
我们的数据表明，新诊断的 T2DM 患者肝脏中 Th1 样 MAIT 细胞亚群增加，通过促进肝糖异生导致高血糖。这为代谢稳态的免疫调节提供了新的见解。
NCT03296605（于 2018 年 10 月 12 日在 www.clinicaltrials.gov 注册）。
