title: Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.
abstract: Insulin controls glucose uptake into adipose and muscle cells by regulating the amount of GLUT4 in the plasma membrane. The effect of insulin is to promote the translocation of intracellular GLUT4 to the plasma membrane. The small Rab GTPase, Rab10, is required for insulin-stimulated GLUT4 translocation in cultured 3T3-L1 adipocytes. Here we demonstrate that both insulin-stimulated glucose uptake and GLUT4 translocation to the plasma membrane are reduced by about half in adipocytes from adipose-specific Rab10 knockout (KO) mice. These data demonstrate that the full effect of insulin on adipose glucose uptake is the integrated effect of Rab10-dependent and Rab10-independent pathways, establishing a divergence in insulin signal transduction to the regulation of GLUT4 trafficking. In adipose-specific Rab10 KO female mice, the partial inhibition of stimulated glucose uptake in adipocytes induces insulin resistance independent of diet challenge. During euglycemic-hyperinsulinemic clamp, there is no suppression of hepatic glucose production despite normal insulin suppression of plasma free fatty acids. The impact of incomplete disruption of stimulated adipocyte GLUT4 translocation on whole-body glucose homeostasis is driven by a near complete failure of insulin to suppress hepatic glucose production rather than a significant inhibition in muscle glucose uptake. These data underscore the physiological significance of the precise control of insulin-regulated trafficking in adipocytes.
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Reema P
authors.initials: RP
authors.lastname: Vazirani
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY.
authors.forename: Akanksha
authors.initials: A
authors.lastname: Verma
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: L Amanda
authors.initials: LA
authors.lastname: Sadacca
authors.affiliation: Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY.
authors.forename: Melanie S
authors.initials: MS
authors.lastname: Buckman
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Belen
authors.initials: B
authors.lastname: Picatoste
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Muheeb
authors.initials: M
authors.lastname: Beg
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Christopher
authors.initials: C
authors.lastname: Torsitano
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Joanne H
authors.initials: JH
authors.lastname: Bruno
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
authors.forename: Rajesh T
authors.initials: RT
authors.lastname: Patel
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Kotryna
authors.initials: K
authors.lastname: Simonyte
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT.
authors.forename: Joao P
authors.initials: JP
authors.lastname: Camporez
authors.affiliation: Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Moreira
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, NY.
authors.forename: Domenick J
authors.initials: DJ
authors.lastname: Falcone
authors.affiliation: Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY.
authors.forename: Domenico
authors.initials: D
authors.lastname: Accili
authors.affiliation: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY.
authors.forename: Olivier
authors.initials: O
authors.lastname: Elemento
authors.affiliation: Department of Pathology, Weill Cornell Medical College, New York, NY Howard Hughes Medical Institute, Yale University, New Haven, CT.
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
authors.forename: Barbara B
authors.initials: BB
authors.lastname: Kahn
authors.affiliation: Department of Biochemistry, Weill Cornell Medical College, New York, NY Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY temcgraw@med.cornell.edu.
authors.forename: Timothy E
authors.initials: TE
authors.lastname: McGraw
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism*; D000818:Animals; D002462:Cell Membrane / Q000378:metabolism; D005260:Female; D005947:Glucose / Q000096:biosynthesis; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism; D021381:Protein Transport; D015398:Signal Transduction; D020691:rab GTP-Binding Proteins / Q000172:deficiency*
chemical_list: D051275:Glucose Transporter Type 4; D007328:Insulin; C520736:Rab10 protein, mouse; D020691:rab GTP-Binding Proteins; D005947:Glucose