title: “Deletion of both Rab-GTPase–activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport [corrected].
abstract: The Rab-GTPase–activating proteins TBC1D1 and TBC1D4 (AS160) were previously shown to regulate GLUT4 translocation in response to activation of AKT and AMP-dependent kinase [corrected]. However, knockout mice lacking either Tbc1d1 or Tbc1d4 displayed only partially impaired insulin-stimulated glucose uptake in fat and muscle tissue. The aim of this study was to determine the impact of the combined inactivation of Tbc1d1 and Tbc1d4 on glucose metabolism in double-deficient (D1/4KO) mice. D1/4KO mice displayed normal fasting glucose concentrations but had reduced tolerance to intraperitoneally administered glucose, insulin, and AICAR. D1/4KO mice showed reduced respiratory quotient, indicating increased use of lipids as fuel. These mice also consistently showed elevated fatty acid oxidation in isolated skeletal muscle, whereas insulin-stimulated glucose uptake in muscle and adipose cells was almost completely abolished. In skeletal muscle and white adipose tissue, the abundance of GLUT4 protein, but not GLUT4 mRNA, was substantially reduced. Cell surface labeling of GLUTs indicated that RabGAP deficiency impairs retention of GLUT4 in intracellular vesicles in the basal state. Our results show that TBC1D1 and TBC1D4 together play essential roles in insulin-stimulated glucose uptake and substrate preference in skeletal muscle and adipose cells.
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany German Center for Diabetes Research (DZD), Düsseldorf, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Chadt
authors.affiliation: German Institute for Human Nutrition, Potsdam, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Immisch
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: de Wendt
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Springer
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Zhou
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany.
authors.forename: Torben
authors.initials: T
authors.lastname: Stermann
authors.affiliation: Department of Biology and Biochemistry, University of Bath, Bath, U.K.
authors.forename: Geoffrey D
authors.initials: GD
authors.lastname: Holman
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Dominique
authors.initials: D
authors.lastname: Loffing-Cueni
authors.affiliation: Institute of Anatomy, University of Zurich, Zurich, Switzerland.
authors.forename: Johannes
authors.initials: J
authors.lastname: Loffing
authors.affiliation: German Center for Diabetes Research (DZD), Düsseldorf, Germany German Institute for Human Nutrition, Potsdam, Germany.
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Joost
authors.affiliation: German Diabetes Center, Leibniz Center for Diabetes Research, Heinrich-Heine-University, Düsseldorf, Germany German Center for Diabetes Research (DZD), Düsseldorf, Germany hadi.al-hasani@ddz.uni-duesseldorf.de.
authors.forename: Hadi
authors.initials: H
authors.lastname: Al-Hasani
mesh_terms: D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001692:Biological Transport / Q000187:drug effects*; D001823:Body Composition / Q000502:physiology; D001835:Body Weight / Q000502:physiology; D002153:Calorimetry, Indirect; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D060005:Genotyping Techniques; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012265:Ribonucleotides / Q000494:pharmacology*
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; D009687:Nuclear Proteins; D012265:Ribonucleotides; C095906:Tbc1d1 protein, mouse; C505647:Tbc1d4 protein, mouse; D000620:Aminoimidazole Carboxamide; C031143:AICA ribonucleotide; D005947:Glucose