期刊
INTERNATIONAL JOURNAL OF BIOLOGICAL SCIENCES
卷 18, 期 5, 页码 1852-1864出版社
IVYSPRING INT PUBL
DOI: 10.7150/ijbs.66314
关键词
inflammation; lipid phosphatase; oxidative stress; type 2 diabetes; insulin resistance
资金
- Jane and Aatos Erkko Foundation
- European Foundation for the Study of Diabetes
- Academy of Finland [315762]
- Sigrid Juselius Foundation
- Paivikki and Sakari Sohlberg Foundation
- Diabetes Research Foundation
- Instrumentarium Science Foundation
- HiLife, Faculty of Medicine, University of Helsinki
- Japan Society for the Promotion of Science [KAKENHI JP19H05011, JP19K08997]
- Doctoral Programme in Biomedicine
- European Association for the Study of Diabetes Albert Renold travel grant
- Helsinki University Library
- Lilly European Diabetes Research Programme
- Academy of Finland (AKA) [315762, 315762] Funding Source: Academy of Finland (AKA)
Ebselen is a potential treatment for diabetes-related disorders. It inhibits SHIP2 to ameliorate insulin resistance and act as an antioxidant. Ebselen directly binds to and inhibits the activity of SHIP2, improving insulin sensitivity, protecting liver tissue, and improving glucose tolerance.
Ebselen, a multifunctional organoselenium compound, has been recognized as a potential treatment for diabetes-related disorders. However, the underlying mechanisms whereby ebselen regulates metabolic pathways remain elusive. We discovered that ebselen inhibits lipid phosphatase SHIP2 (Src homology 2 domain-containing inositol-5-phosphatase 2), an emerging drug target to ameliorate insulin resistance in diabetes. We found that ebselen directly binds to and inhibits the catalytic activity of the recombinant SHIP2 phosphatase domain and SHIP2 in cultured cells, the skeletal muscle and liver of the diabetic db/db mice, and the liver of the SHIP2 overexpressing (SHIP2-Tg) mice. Ebselen increased insulin-induced Akt phosphorylation in cultured myotubes, enhanced insulin sensitivity and protected liver tissue from lipid peroxidation and inflammation in the db/db mice, and improved glucose tolerance more efficiently than metformin in the SHIP2-Tg mice. SHIP2 overexpression abrogated the ability of ebselen to induce glucose uptake and reduce ROS production in myotubes and blunted the effect of ebselen to inhibit SHIP2 in the skeletal muscle of the SHIP2-Tg mice. Our data reveal ebselen as a potent SHIP2 inhibitor and demonstrate that the ability of ebselen to ameliorate insulin resistance and act as an antioxidant is at least in part mediated by the reduction of SHIP2 activity.
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