Prothymosin-α Overexpression Contributes to the Development of Insulin Resistance.
BACKGROUND
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.


METHODS
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.
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.
Yu-Chu
YC
Su
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.
Horng-Yih
HY
Ou
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.
Hung-Tsung
HT
Wu
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.
Pensee
P
Wu
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.
Yi-Cheng
YC
Chen
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.
Bing-Hua
BH
Su
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.
Ai-Li
AL
Shiau
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.
Chih-Jen
CJ
Chang
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.
Chao-Liang
CL
Wu
D000368:Aged; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D059305:Diet, High-Fat; D020868:Gene Silencing / Q000187:drug effects; D005822:Genetic Vectors; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology*; D016086:Lentivirus / Q000235:genetics; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D011498:Protein Precursors / Q000096:biosynthesis*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D013947:Thymosin / Q000031:analogs & derivatives* / Q000096:biosynthesis; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D016328:NF-kappa B; D011498:Protein Precursors; D034741:RNA, Small Interfering; D051197:Toll-Like Receptor 4; C040782:prothymosin alpha; D013947:Thymosin; D005947:Glucose