title: Enhanced insulin sensitivity in mice lacking ganglioside GM3.
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 alpha2,3-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.
authors.affiliation: Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Building 10, 10 Center Drive, Bethesda, MD 20892, USA.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yamashita
authors.forename: Akira
authors.initials: A
authors.lastname: Hashiramoto
authors.forename: Martin
authors.initials: M
authors.lastname: Haluzik
authors.forename: Hiroki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Shoshannah
authors.initials: S
authors.lastname: Beck
authors.forename: Aaron
authors.initials: A
authors.lastname: Norton
authors.forename: Mari
authors.initials: M
authors.lastname: Kono
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsuji
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: Daniotti
authors.forename: Norbert
authors.initials: N
authors.lastname: Werth
authors.forename: Roger
authors.initials: R
authors.lastname: Sandhoff
authors.forename: Konrad
authors.initials: K
authors.lastname: Sandhoff
authors.forename: Richard L
authors.initials: RL
authors.lastname: Proia
mesh_terms: D000818:Animals; D004041:Dietary Fats / Q000008:administration & dosage; D005679:G(M3) Ganglioside / Q000172:deficiency*; D018390:Gene Targeting; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010766:Phosphorylation; D011972:Receptor, Insulin / Q000378:metabolism; D012799:Sialyltransferases / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction
chemical_list: D004041:Dietary Fats; D005679:G(M3) Ganglioside; D012799:Sialyltransferases; C021343:haematoside synthetase; D011972:Receptor, Insulin