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Blocking IL-6 signaling improves glucose tolerance via SLC39A5-mediated suppression of glucagon secretion.
Chen, Wenli; Cui, Weiyi; Wu, Jianhong; Zheng, Wen; Sun, Xueting; Zhang, Jie; Shang, Haibao; Yuan, Ye; Li, Xue; Wang, Jue; Hu, Xinli; Chen, Liangyi; Zeng, Fanxin; Xiao, Rui-Ping; Zhang, Xiuqin.
Afiliação
  • Chen W; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Cui W; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Wu J; Department of Rheumatology and Immunology, Dazhou Central Hospital, Dazhou, China.
  • Zheng W; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Sun X; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Zhang J; Department of Clinical Research Center, Dazhou Central Hospital, Dazhou 635000, China.
  • Shang H; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Yuan Y; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Li X; Department of Clinical Research Center, Dazhou Central Hospital, Dazhou 635000, China.
  • Wang J; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Hu X; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China.
  • Chen L; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; National Biomedical Imaging Center, School of Future Technology, Peking University, Beijing
  • Zeng F; Department of Clinical Research Center, Dazhou Central Hospital, Dazhou 635000, China. Electronic address: zengfx@pku.edu.cn.
  • Xiao RP; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking-Tsinghua Center for
  • Zhang X; Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing 100871, China; National Biomedical Imaging Center, School of Future Technology, Peking University, Beijing
Metabolism ; 146: 155641, 2023 09.
Article em En | MEDLINE | ID: mdl-37380017
BACKGROUND AND AIMS: Hyperinsulinemia, hyperglucagonemia, and low-grade inflammation are frequently presented in obesity and type 2 diabetes (T2D). The pathogenic regulation between hyperinsulinemia/insulin resistance (IR) and low-grade inflammation is well documented in the development of diabetes. However, the cross-talk of hyperglucagonemia with low-grade inflammation during diabetes progression is poorly understood. In this study, we investigated the regulatory role of proinflammatory cytokine interleukin-6 (IL-6) on glucagon secretion. METHODS: The correlations between inflammatory cytokines and glucagon or insulin were analyzed in rhesus monkeys and humans. IL-6 signaling was blocked by IL-6 receptor-neutralizing antibody tocilizumab in obese or T2D rhesus monkeys, glucose tolerance was evaluated by intravenous glucose tolerance test (IVGTT). Glucagon and insulin secretion were measured in isolated islets from wild-type mouse, primary pancreatic α-cells and non-α-cells sorted from GluCre-ROSA26EYFP (GYY) mice, in which the enhanced yellow fluorescent protein (EYFP) was expressed under the proglucagon promoter, by fluorescence-activated cell sorting (FACS). Particularly, glucagon secretion in α-TC1 cells treated with IL-6 was measured, and RNA sequencing was used to screen the mediator underlying IL-6-induced glucagon secretion. SLC39A5 was knocking-down or overexpressed in α-TC1 cells to determine its impact in glucagon secretion and cytosolic zinc density. Dual luciferase and chromatin Immunoprecipitation were applied to analyze the signal transducer and activator of transcription 3 (STAT3) in the regulation of SLC39A5 transcription. RESULTS: Plasma IL-6 correlate positively with plasma glucagon levels, but not insulin, in rhesus monkeys and humans. Tocilizumab treatment reduced plasma glucagon, blood glucose and HbA1c in spontaneously obese or T2D rhesus monkeys. Tocilizumab treatment also decreased glucagon levels during IVGTT, and improved glucose tolerance. Moreover, IL-6 significantly increased glucagon secretion in isolated islets, primary pancreatic α-cells and α-TC1 cells. Mechanistically, we found that IL-6-activated STAT3 downregulated the zinc transporter SLC39A5, which in turn reduced cytosolic zinc concentration and ATP-sensitive potassium channel activity and augmented glucagon secretion. CONCLUSIONS: This study demonstrates that IL-6 increases glucagon secretion via the downregulation of zinc transporter SLC39A5. This result revealed the molecular mechanism underlying the pathogenesis of hyperglucagonemia and a previously unidentified function of IL-6 in the pathophysiology of T2D, providing a potential new therapeutic strategy of targeting IL-6/glucagon to preventing or treating T2D.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Proteínas de Transporte de Cátions / Diabetes Mellitus Tipo 2 / Células Secretoras de Glucagon Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Resistência à Insulina / Proteínas de Transporte de Cátions / Diabetes Mellitus Tipo 2 / Células Secretoras de Glucagon Limite: Animals / Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article