Yu-Chu Su1, Horng-Yih Ou1, Hung-Tsung Wu1, Pensee Wu1, Yi-Cheng Chen1, Bing-Hua Su1, Ai-Li Shiau1, Chih-Jen Chang1, Chao-Liang Wu1. 1. Institute of Basic Medical Sciences (Y.-C.S., Y.-C.C., A.-L.S., C.-L.W.) and Departments of Biochemistry and Molecular Biology (H.-T.W., B.-H.S., C.-L.W.) and Microbiology and Immunology (A.-L.S.), College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan; Division of Endocrinology and Metabolism (H.-Y.O.), Department of Internal Medicine, and Department of Family Medicine (C.-J.C.), National Cheng Kung University Hospital, Tainan 70403, Taiwan; and Institute of Science and Technology in Medicine (P.W.), Keele University, Keele ST5 5BG, United Kingdom.
Abstract
CONTEXT: Prothymosin-α (ProT) is involved in oxidative stress, inflammation, cell proliferation, and apoptosis. Increased oxidative stress and chronic inflammation participate in the pathogenesis of diabetes. A recent study found that ProT is a ligand of toll-like receptor 4, which plays an important role in the development of insulin resistance. However, its physiological role remains poorly understood. OBJECTIVE: The objective was to investigate whether ProT contributes to the development of insulin resistance. DESIGN, SETTINGS, AND PATIENTS: A total of 185 subjects were recruited and classified into nondiabetes (n = 95) and newly diagnosed diabetes (n = 90) groups. Transgenic mice overexpressing ProT were used to investigate the role of ProT in the development of insulin resistance. Lentiviral vectors carrying short hairpin RNA specific for ProT were delivered via the portal vein to silence hepatic ProT expression in mice with high-fat diet-induced insulin resistance. Glucose uptake was determined in L6 myotubes. RESULTS: We show that the serum ProT levels of patients with type 2 diabetes were significantly higher than those of normal individuals (mean ± SEM, 419.8 ± 46.47 vs 246.4 ± 27.89 pg/mL; P < .001). Furthermore, ProT transgenic mice exhibited an insulin-resistant phenotype, whereas the silencing of hepatic ProT expression ameliorated high-fat diet-induced insulin resistance in C57BL/6 mice. In vitro studies reveal that ProT induced insulin resistance through a toll-like receptor 4-nuclear factor-κB-dependent pathway. CONCLUSIONS: Our results support the role for ProT in the development of insulin resistance. Therefore, ProT is a potential novel therapeutic target for type 2 diabetes.
CONTEXT: Prothymosin-α (ProT) is involved in oxidative stress, inflammation, cell proliferation, and apoptosis. Increased oxidative stress and chronic inflammation participate in the pathogenesis of diabetes. A recent study found that ProT is a ligand of toll-like receptor 4, which plays an important role in the development of insulin resistance. However, its physiological role remains poorly understood. OBJECTIVE: The objective was to investigate whether ProT contributes to the development of insulin resistance. DESIGN, SETTINGS, AND PATIENTS: A total of 185 subjects were recruited and classified into nondiabetes (n = 95) and newly diagnosed diabetes (n = 90) groups. Transgenic mice overexpressing ProT were used to investigate the role of ProT in the development of insulin resistance. Lentiviral vectors carrying short hairpin RNA specific for ProT were delivered via the portal vein to silence hepatic ProT expression in mice with high-fat diet-induced insulin resistance. Glucose uptake was determined in L6 myotubes. RESULTS: We show that the serum ProT levels of patients with type 2 diabetes were significantly higher than those of normal individuals (mean ± SEM, 419.8 ± 46.47 vs 246.4 ± 27.89 pg/mL; P < .001). Furthermore, ProT transgenic mice exhibited an insulin-resistant phenotype, whereas the silencing of hepatic ProT expression ameliorated high-fat diet-induced insulin resistance in C57BL/6 mice. In vitro studies reveal that ProT induced insulin resistance through a toll-like receptor 4-nuclear factor-κB-dependent pathway. CONCLUSIONS: Our results support the role for ProT in the development of insulin resistance. Therefore, ProT is a potential novel therapeutic target for type 2 diabetes.
Authors: Melis A Aksit; Rhonda G Pace; Briana Vecchio-Pagán; Hua Ling; Johanna M Rommens; Pierre-Yves Boelle; Loic Guillot; Karen S Raraigh; Elizabeth Pugh; Peng Zhang; Lisa J Strug; Mitch L Drumm; Michael R Knowles; Garry R Cutting; Harriet Corvol; Scott M Blackman Journal: J Clin Endocrinol Metab Date: 2020-05-01 Impact factor: 5.958