Disruption of Adipose Rab10-Dependent Insulin Signaling Causes Hepatic Insulin Resistance.
Reema P Vazirani, Akanksha Verma, L Amanda Sadacca, Melanie S Buckman, Belen Picatoste, Muheeb Beg, Christopher Torsitano, Joanne H Bruno, Rajesh T Patel, Kotryna Simonyte, Joao P Camporez, Gabriela Moreira, Domenick J Falcone, Domenico Accili, Olivier Elemento, Gerald I Shulman, Barbara B Kahn, Timothy E McGraw
Author Information
Reema P Vazirani: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Akanksha Verma: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY.
L Amanda Sadacca: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Melanie S Buckman: Department of Cardiothoracic Surgery, Weill Cornell Medical College, New York, NY.
Belen Picatoste: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Muheeb Beg: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Christopher Torsitano: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Joanne H Bruno: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Rajesh T Patel: Department of Biochemistry, Weill Cornell Medical College, New York, NY.
Kotryna Simonyte: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Joao P Camporez: Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT.
Gabriela Moreira: Departments of Internal Medicine and Cellular & Molecular Physiology, Yale School of Medicine, Yale University, New Haven, CT.
Domenick J Falcone: Department of Pathology, Weill Cornell Medical College, New York, NY.
Domenico Accili: Department of Medicine and Naomi Berrie Diabetes Center, Columbia University, New York, NY.
Olivier Elemento: Department of Physiology and Biophysics, Weill Cornell Medical College, New York, NY.
Gerald I Shulman: Department of Pathology, Weill Cornell Medical College, New York, NY Howard Hughes Medical Institute, Yale University, New Haven, CT.
Barbara B Kahn: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
Timothy E McGraw: 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.
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.
