title: Improving type 2 diabetes through a distinct adrenergic signaling pathway involving mTORC2 that mediates glucose uptake in skeletal muscle.
abstract: There is an increasing worldwide epidemic of type 2 diabetes that poses major health problems. We have identified a novel physiological system that increases glucose uptake in skeletal muscle but not in white adipocytes. Activation of this system improves glucose tolerance in Goto-Kakizaki rats or mice fed a high-fat diet, which are established models for type 2 diabetes. The pathway involves activation of β2-adrenoceptors that increase cAMP levels and activate cAMP-dependent protein kinase, which phosphorylates mammalian target of rapamycin complex 2 (mTORC2) at S2481. The active mTORC2 causes translocation of GLUT4 to the plasma membrane and glucose uptake without the involvement of Akt or AS160. Stimulation of glucose uptake into skeletal muscle after activation of the sympathetic nervous system is likely to be of high physiological relevance because mTORC2 activation was observed at the cellular, tissue, and whole-animal level in rodent and human systems. This signaling pathway provides new opportunities for the treatment of type 2 diabetes.
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden Department of Pharmacology, Monash University, Clayton, Victoria, Australia Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sato
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Nodi
authors.initials: N
authors.lastname: Dehvari
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Anette I
authors.initials: AI
authors.lastname: Oberg
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden Laboratory of Molecular Genetics, Howard Hughes Medical Institute, The Rockefeller University, New York, NY.
authors.forename: Olof S
authors.initials: OS
authors.lastname: Dallner
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Anna L
authors.initials: AL
authors.lastname: Sandström
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Olsen
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden.
authors.forename: Robert I
authors.initials: RI
authors.lastname: Csikasz
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Summers
authors.affiliation: Department of Pharmacology, Monash University, Clayton, Victoria, Australia Drug Discovery Biology Laboratory, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia.
authors.forename: Dana S
authors.initials: DS
authors.lastname: Hutchinson
authors.affiliation: Department of Molecular Biosciences, The Wenner-Gren Institute, Stockholm University, Stockholm, Sweden tore.bengtsson@su.se.
authors.forename: Tore
authors.initials: T
authors.lastname: Bengtsson
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D002478:Cells, Cultured; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000209:etiology / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D005951:Glucose Tolerance Test; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018343:Receptors, Adrenergic, beta-2 / Q000378:metabolism*; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
chemical_list: D001786:Blood Glucose; D051275:Glucose Transporter Type 4; D046912:Multiprotein Complexes; D018343:Receptors, Adrenergic, beta-2; D000076225:Mechanistic Target of Rapamycin Complex 2; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases