title: The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism.
abstract: Potentiation of glucose-induced insulin secretion is the main mechanism of exenatide (EXE) antidiabetic action, however, increased glucose utilization by peripheral tissues has been also reported. We here studied the effect of EXE on glucose uptake by skeletal muscle cells.
  
  
  
  2-deoxy-glucose (2DG) uptake and intracellular signal pathways were measured in rat L6 skeletal muscle myotubes exposed to 100 nmol/l EXE for up to 48 h. Mechanisms of EXE action were explored by inhibiting AMPK activity with compound C (CC, 40 μmol/l) or siRNAs (2 μmol/l).
  
  
  
  Time course experiments show that EXE increases glucose uptake up to 48 h achieving its maximal effect, similar to that induced by insulin, after 20 min (2- vs 2.5-fold-increase, respectively). Differently from insulin, EXE does not stimulate: (i) IR β-subunit- and IRS1 tyrosine phosphorylation and binding to p85 regulatory subunit of PI-3kinase; (ii) AKT activation; and (iii) ERK1/2 and JNK1/2 phosphorylation. Conversely, EXE increases phosphorylation of α-subunit of AMPK at Thr172 by 2.5-fold (p < 0.01). Co-incubation of EXE and insulin does not induce additive effects on 2DG-uptake. Inhibition of AMPK with CC, and reduction of AMPK protein expression by siRNA, completely abolish EXE-induced 2DG-uptake. Liraglutide, another GLP-1 receptor agonist, also stimulates AMPK phosphorylation and 2DG-uptake. Moreover, EXE stimulates 2DG-uptake also by L6 myotubes rendered insulin-resistant with methylglyoxal. Finally, EXE also induces glucose transporter Glut-4 translocation to the plasma membrane.
  
  
  
  In L6 myotubes, EXE and liraglutide increase glucose uptake in an insulin-independent manner by activating AMPK.
authors.affiliation: Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy. andreozzif@unicz.it.|Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA. andreozzif@unicz.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Andreozzi
authors.affiliation: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.|Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.
authors.forename: Gregory Alexander
authors.initials: GA
authors.lastname: Raciti
authors.affiliation: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.|Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Nigro
authors.affiliation: Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy.
authors.forename: Gaia Chiara
authors.initials: GC
authors.lastname: Mannino
authors.affiliation: Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Procopio
authors.affiliation: Department of Medicine Endocrinology Unit, Ospedale San Raffaele, Milan, Italy.
authors.forename: Alberto M
authors.initials: AM
authors.lastname: Davalli
authors.affiliation: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.|Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Beguinot
authors.affiliation: Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Sesti
authors.affiliation: Institute of Experimental Endocrinology and Oncology "G. Salvatore", National Council of Research, Naples, Italy.|Department of Translational Medical Sciences, University of Naples "Federico II", Naples, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Miele
authors.affiliation: Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA. folli@uthscsa.edu.|Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil. folli@uthscsa.edu.
authors.forename: Franco
authors.identifier: 0000-0001-9824-5222
authors.initials: F
authors.lastname: Folli
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D003847:Deoxyglucose / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D000077270:Exenatide; D020869:Gene Expression Profiling; D020868:Gene Silencing / Q000187:drug effects; D000067757:Glucagon-Like Peptide-1 Receptor / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007333:Insulin Resistance; D000069450:Liraglutide / Q000494:pharmacology*; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D010215:Papio; D010455:Peptides / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014688:Venoms / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D014688:Venoms; D011765:Pyruvaldehyde; D000069450:Liraglutide; D003847:Deoxyglucose; D000077270:Exenatide; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: AMPK; Exenatide; Glucose uptake; Insulin signaling; Liraglutide; Skeletal muscle cells