{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:20:59Z","timestamp":1784557259911,"version":"3.55.0"},"reference-count":44,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["joe.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,4]]},"abstract":"<jats:p>\n                    p70 S6 kinase (S6K1) is a serine\/threonine kinase that phosphorylates the insulin receptor substrate-1 (IRS-1) at serine 1101 and desensitizes insulin receptor signaling. S6K1 hyperactivation due to overnutrition leads to hyperglycemia and type 2 diabetes. Our recent study showed that A77 1726, the active metabolite of the anti-rheumatoid arthritis (RA) drug leflunomide, is an inhibitor of S6K1. Whether leflunomide can control hyperglycemia and sensitize the insulin receptor has not been tested. Here we report that A77 1726 increased AKT\n                    <jats:sup>S473\/T308<\/jats:sup>\n                    and S6K1\n                    <jats:sup>T389<\/jats:sup>\n                    phosphorylation but decreased S6\n                    <jats:sup>S235\/236<\/jats:sup>\n                    and IRS-1\n                    <jats:sup>S1101<\/jats:sup>\n                    phosphorylation in 3T3-L1 adipocytes, C2C12 and L6 myotubes. A77 1726 increased insulin receptor tyrosine phosphorylation and binding of the p85 subunit of the PI-3 kinase to IRS-1. A77 1726 enhanced insulin-stimulated glucose uptake in L6 myotubes and 3T3-L1 adipocytes, and enhanced insulin-stimulated glucose transporter type 4 (GLUT4) translocation to the plasma membrane of L6 cells. Finally, we investigated the anti-hyperglycemic effect of leflunomide on\n                    <jats:italic>ob\/ob<\/jats:italic>\n                    and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and insulin tolerance tests in\n                    <jats:italic>ob\/ob<\/jats:italic>\n                    and HFD-fed mice but had no effect on mice fed a normal chow diet (NCD). Leflunomide treatment increased AKT\n                    <jats:sup>S473\/T308<\/jats:sup>\n                    phosphorylation in the fat and muscle of\n                    <jats:italic>ob\/ob<\/jats:italic>\n                    mice but not in normal mice. Our results suggest that leflunomide sensitizes the insulin receptor by inhibiting S6K1 activity\n                    <jats:italic>in vitro<\/jats:italic>\n                    , and that leflunomide could be potentially useful for treating patients with both RA and diabetes.\n                  <\/jats:p>","DOI":"10.1530\/joe-17-0536","type":"journal-article","created":{"date-parts":[[2018,3,1]],"date-time":"2018-03-01T20:45:27Z","timestamp":1519937127000},"page":"43-58","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-5","source":"Crossref","is-referenced-by-count":19,"title":["Control of hyperglycemia in male mice by leflunomide: mechanisms of action"],"prefix":"10.1530","volume":"237","author":[{"given":"Junhong","family":"Chen","sequence":"first","affiliation":[{"name":"1Institute of Comparative Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"},{"name":"2College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Sun","sequence":"additional","affiliation":[{"name":"1Institute of Comparative Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"},{"name":"2College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle E","family":"Doscas","sequence":"additional","affiliation":[{"name":"3Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Ye","sequence":"additional","affiliation":[{"name":"3Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ashley J","family":"Williamson","sequence":"additional","affiliation":[{"name":"4Rush Medical College, Rush University Medical Center, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanchun","family":"Li","sequence":"additional","affiliation":[{"name":"5Section of Endocrinology, Department of Medicine, University of Chicago, Chicago, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Li","sequence":"additional","affiliation":[{"name":"6Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A","family":"Prinz","sequence":"additional","affiliation":[{"name":"7Department of Surgery, NorthShore University Health System, Evanston, Illinois, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiulong","family":"Xu","sequence":"additional","affiliation":[{"name":"1Institute of Comparative Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"},{"name":"2College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, China"},{"name":"3Department of Cell and Molecular Medicine, Rush University Medical Center, Chicago, Illinois, USA"},{"name":"8Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","reference":[{"key":"ref201","doi-asserted-by":"crossref","first-page":"1052","DOI":"10.1001\/jama.2015.9536","article-title":"Diabetes: advances in diagnosis and treatment","volume":"314","year":"2015","journal-title":"JAMA"},{"key":"ref91","doi-asserted-by":"crossref","first-page":"2236","DOI":"10.1681\/ASN.2006030196","article-title":"Chronic inhibition of mammalian target of rapamycin signaling downregulates insulin receptor substrates 1 and 2 and AKT activation: a crossroad between cancer and diabetes?","volume":"17","year":"2006","journal-title":"Journal of the American Society of 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