title: Activation of G proteins by GIV-GEF is a pivot point for insulin resistance and sensitivity.
abstract: Insulin resistance (IR) is a metabolic disorder characterized by impaired insulin signaling and cellular glucose uptake. The current paradigm for insulin signaling centers upon the insulin receptor (InsR) and its substrate IRS1; the latter is believed to be the sole conduit for postreceptor signaling. Here we challenge that paradigm and show that GIV/Girdin, a guanidine exchange factor (GEF) for the trimeric G protein Gαi, is another major hierarchical conduit for the metabolic insulin response. By virtue of its ability to directly bind InsR, IRS1, and phosphoinositide 3-kinase, GIV serves as a key hub in the immediate postreceptor level, which coordinately enhances the metabolic insulin response and glucose uptake in myotubes via its GEF function. Site-directed mutagenesis or phosphoinhibition of GIV-GEF by the fatty acid/protein kinase C-theta pathway triggers IR. Insulin sensitizers reverse phosphoinhibition of GIV and reinstate insulin sensitivity. We also provide evidence for such reversible regulation of GIV-GEF in skeletal muscles from patients with IR. Thus GIV is an essential upstream component that couples InsR to G-protein signaling to enhance the metabolic insulin response, and impairment of such coupling triggers IR. We also provide evidence that GIV-GEF serves as therapeutic target for exogenous manipulation of physiological insulin response and reversal of IR in skeletal muscles.
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Gary S
authors.initials: GS
authors.lastname: Ma
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Lopez-Sanchez
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aznar
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kalogriopoulos
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Shabnam
authors.initials: S
authors.lastname: Pedram
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093.
authors.forename: Krishna
authors.initials: K
authors.lastname: Midde
authors.affiliation: Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161.
authors.forename: Theodore P
authors.initials: TP
authors.lastname: Ciaraldi
authors.affiliation: Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161.
authors.forename: Robert R
authors.initials: RR
authors.lastname: Henry
authors.affiliation: Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 Department of Veterans Affairs, VA San Diego Healthcare System, San Diego, CA 92161 Department of Cell and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093 prghosh@ucsd.edu.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020555:GTP-Binding Protein Regulators / Q000378:metabolism*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008840:Microfilament Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism; D015398:Signal Transduction; D033921:Vesicular Transport Proteins / Q000378:metabolism*
chemical_list: C502451:CCDC88A protein, human; D005227:Fatty Acids; D020555:GTP-Binding Protein Regulators; D020662:Guanine Nucleotide Exchange Factors; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D008840:Microfilament Proteins; D033921:Vesicular Transport Proteins; D058539:Phosphatidylinositol 3-Kinase; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D019206:GTP-Binding Protein alpha Subunits, Gi-Go