Affiliation:
1. Department of Endocrinology Endocrine and Metabolic Disease Medical Center Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing China
2. Branch of National Clinical Research Center for Metabolic Diseases Nanjing China
3. Shanghai Institute of Immunology Shanghai Jiao Tong University School of Medicine Shanghai China
4. Department of General Surgery Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School Nanjing China
Abstract
AbstractAimsIt 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.Materials and methodsFourteen 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.ResultsCompared 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.ConclusionsOur 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.Clinical trial registration numberNCT03296605 (registered at www.clinicaltrials.gov on 12 October 2018).
Funder
National Natural Science Foundation of China
Subject
Endocrinology,Endocrinology, Diabetes and Metabolism,Internal Medicine