Control of hyperglycemia in male mice by leflunomide: mechanisms of action.

The Journal of Endocrinology
Junhong ChenXiulong Xu

Abstract

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 AKTS473/T308 and S6K1T389 phosphorylation but decreased S6S235/236 and IRS-1S1101 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 ob/ob and high-fat diet (HFD)-induced diabetes mouse models. Leflunomide treatment normalized blood glucose levels and overcame insulin resistance in glucose and i...Continue Reading

References

Feb 27, 1996·Transplantation·K F SiemaskoA Finnegan
Apr 29, 1998·The Journal of Clinical Investigation·M E PattiC R Kahn
Aug 15, 1998·The Journal of Biological Chemistry·K RückemannH A Simmonds
Oct 29, 2000·Annals of the Rheumatic Diseases·F C Breedveld, J M Dayer
May 16, 2001·Arthritis and Rheumatism·J S CoblynS Helfgott
Jun 3, 2004·Rheumatic Diseases Clinics of North America·Grant W Cannon, Joel M Kremer
Jun 7, 2006·Cell Metabolism·Sung Hee UmGeorge Thomas
Apr 25, 2007·Trends in Molecular Medicine·Stephen G DannGeorge Thomas
May 4, 2007·Scandinavian Journal of Rheumatology·A RosenvingeB K Pedersen
Aug 30, 2008·American Journal of Physiology. Endocrinology and Metabolism·Sigalit Boura-Halfon, Yehiel Zick
Oct 3, 2009·Science·Colin SelmanDominic J Withers
Dec 17, 2009·International Endodontic Journal·Y MalykN Ilie
Oct 12, 2010·The International Journal of Biochemistry & Cell Biology·Tim R Fenton, Ivan T Gout
Mar 20, 2012·Analytical Biochemistry·Katja ZebischMatthias Brandsch
Mar 14, 2014·The Lancet. Diabetes & Endocrinology·Paul Z ZimmetJonathan E Shaw
Jun 27, 2014·American Journal of Physiology. Regulatory, Integrative and Comparative Physiology·Christine E SchindlerSteven J Swoap
Aug 6, 2014·Autoimmunity Reviews·Mathilde VersiniYehuda Shoenfeld
Nov 8, 2014·Neoplasia : an International Journal for Oncology Research·Michelle E DoscasXiulong Xu
Jun 3, 2015·Current Diabetes Reviews·Herbert Sebastian Herlitz-CifuentesEnrique Alberto Guzman-Gutierrez
Sep 9, 2015·JAMA : the Journal of the American Medical Association·David M Nathan

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Citations

May 29, 2018·Clinical Science·Luciana A Pescatore, Francisco R M Laurindo
Apr 20, 2020·Rheumatology and Therapy·Giacomo Dal BelloGiampiero Girolomoni

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