PMID- 36738300 OWN - NLM STAT- MEDLINE DCOM- 20230508 LR - 20230606 IS - 1520-7560 (Electronic) IS - 1520-7552 (Linking) VI - 39 IP - 4 DP - 2023 May TI - Th1 bias of liver mucosal-associated invariant T cells promotes hepatic gluconeogenesis in type 2 diabetes mellitus. PG - e3620 LID - 10.1002/dmrr.3620 [doi] AB - AIMS: 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. MATERIALS AND METHODS: 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. RESULTS: 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-gamma (IFN-gamma, 60.49% vs. 33.33%, p = 0.021) and tumour necrosis factor-alpha (TNF-alpha, 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-gamma(+) TNF-alpha(+) 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-gamma and TNF-alpha. CONCLUSIONS: 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. CLINICAL TRIAL REGISTRATION NUMBER: NCT03296605 (registered at www. CLINICALTRIALS: gov on 12 October 2018). CI - (c) 2023 John Wiley & Sons Ltd. FAU - Tang, Wenjuan AU - Tang W AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Ge, Kang AU - Ge K AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Shen, Lei AU - Shen L AD - Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China. FAU - Wang, Hongdong AU - Wang H AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Feng, Wenhuan AU - Feng W AUID- ORCID: 0000-0002-5145-127X AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Sun, Xitai AU - Sun X AD - Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Chu, Xuehui AU - Chu X AD - Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. FAU - Zhu, Dalong AU - Zhu D AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Yin, Hongli AU - Yin H AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. FAU - Bi, Yan AU - Bi Y AUID- ORCID: 0000-0003-3914-7854 AD - Department of Endocrinology, Endocrine and Metabolic Disease Medical Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. AD - Branch of National Clinical Research Center for Metabolic Diseases, Nanjing, China. LA - eng SI - ClinicalTrials.gov/NCT03296605 PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20230217 PL - England TA - Diabetes Metab Res Rev JT - Diabetes/metabolism research and reviews JID - 100883450 RN - 0 (Interleukin-17) RN - 0 (Tumor Necrosis Factor-alpha) SB - IM MH - Humans MH - *Mucosal-Associated Invariant T Cells/physiology MH - Interleukin-17 MH - Tumor Necrosis Factor-alpha MH - Gluconeogenesis MH - *Diabetes Mellitus, Type 2 MH - Liver OTO - NOTNLM OT - hepatic gluconeogenesis OT - interferon-gamma OT - mucosal-associated invariant T cells OT - tumour necrosis factor-alpha OT - type 2 diabetes mellitus EDAT- 2023/02/05 06:00 MHDA- 2023/05/08 06:42 CRDT- 2023/02/04 10:12 PHST- 2022/10/23 00:00 [revised] PHST- 2022/05/30 00:00 [received] PHST- 2023/01/23 00:00 [accepted] PHST- 2023/05/08 06:42 [medline] PHST- 2023/02/05 06:00 [pubmed] PHST- 2023/02/04 10:12 [entrez] AID - 10.1002/dmrr.3620 [doi] PST - ppublish SO - Diabetes Metab Res Rev. 2023 May;39(4):e3620. doi: 10.1002/dmrr.3620. Epub 2023 Feb 17.