Enhanced insulin sensitivity in mice lacking ganglioside GM3
- Tadashi Yamashita*,
- Akira Hashiramoto*,
- Martin Haluzik†,
- Hiroki Mizukami*,
- Shoshannah Beck*,
- Aaron Norton*,
- Mari Kono*,
- Shuichi Tsuji‡,
- Jose Luis Daniotti§,
- Norbert Werth¶,
- Roger Sandhoff‖,
- Konrad Sandhoff¶, and
- Richard L. Proia*,**
- *Genetics of Development and Disease and †Diabetes Branches, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892; ‡Molecular Glycobiology, The Glycoscience Institute, Ochanomizu University, Otsuka, Bunkyo-ku, Tokyo 112-8610, Japan; §Centro de Investigaciones en Quimica Biologica de Cordoba, Departamento de Quimica Biologica, Facultad de Ciencias Quimicas, Universidad Nacional de Cordoba, Ciudad Universitaria, 5000 Cordoba, Argentina; ¶Kekulé-Institut für Organische Chemie und Biochemie, Universität Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany; and ‖Deutsches Krebsforschungszentrum Heidelberg, Abteilung für Zelluläre und Molekulare Pathologie, INF 280, 69120 Heidelberg, Germany
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Edited by Sen-itiroh Hakomori, Pacific Northwest Research Institute, Seattle, WA, and approved January 22, 2003 (received for review September 30, 2002)
Abstract
Gangliosides are sialic acid-containing glycosphingolipids that are present on all mammalian plasma membranes where they participate in recognition and signaling activities. We have established mutant mice that lack GM3 synthase (CMP-NeuAc:lactosylceramide α2,3-sialyltransferase; EC 2.4.99.-). These mutant mice were unable to synthesize GM3 ganglioside, a simple and widely distributed glycosphingolipid. The mutant mice were viable and appeared without major abnormalities but showed a heightened sensitivity to insulin. A basis for the increased insulin sensitivity in the mutant mice was found to be enhanced insulin receptor phosphorylation in skeletal muscle. Importantly, the mutant mice were protected from high-fat diet-induced insulin resistance. Our results show that GM3 ganglioside is a negative regulator of insulin signaling, making it a potential therapeutic target in type 2 diabetes.
Footnotes
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↵ ** To whom correspondence should be addressed at: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 10 Center Drive, MSC 1821, Building 10, Room 9N-314, Bethesda, MD 20892. E-mail: proia{at}nih.gov.
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This paper was submitted directly (Track II) to the PNAS office.
- Copyright © 2003, The National Academy of Sciences
