The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism

Francesco Andreozzi, Gregory Alexander Raciti, Cecilia Nigro, Gaia Chiara Mannino, Teresa Procopio, Alberto M. Davalli, Francesco Beguinot, Giorgio Sesti, Claudia Miele, Franco Folli

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22 Scopus citations

Abstract

Aims/hypothesis: 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. Methods: 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). Results: 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. Conclusions/interpretation: In L6 myotubes, EXE and liraglutide increase glucose uptake in an insulin-independent manner by activating AMPK.

Original languageEnglish (US)
Article number229
JournalJournal of Translational Medicine
Volume14
Issue number1
DOIs
StatePublished - Jul 30 2016

Keywords

  • AMPK
  • Exenatide
  • Glucose uptake
  • Insulin signaling
  • Liraglutide
  • Skeletal muscle cells

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Andreozzi, F., Raciti, G. A., Nigro, C., Mannino, G. C., Procopio, T., Davalli, A. M., Beguinot, F., Sesti, G., Miele, C., & Folli, F. (2016). The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. Journal of Translational Medicine, 14(1), [229]. https://doi.org/10.1186/s12967-016-0985-7