Journal Article

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

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

2016

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: AMP-Activated Protein Kinases - metabolism / Analysis / Animals / Biological Transport - drug effects / Biomedical and Life Sciences / Biomedicine / Care and treatment / Cell Line / Deoxyglucose - metabolism / Dosage and administration / Enzyme Activation - drug effects / Gene Expression Profiling / Gene Silencing - drug effects / Glucagon-Like Peptide-1 Receptor - agonists / Glucagon-Like Peptide-1 Receptor - metabolism / Glucose - metabolism / Health aspects / Humans / Insulin Resistance / Liraglutide / Liraglutide - pharmacology / Medicine/Public Health / Mice / Muscle Fibers, Skeletal - drug effects / Muscle Fibers, Skeletal - enzymology / Muscle Fibers, Skeletal - metabolism / Muscles / Nutrition & metabolism / Papio / Peptides - pharmacology / Phosphorylation - drug effects / Proto-Oncogene Proteins c-akt - metabolism / Pyruvaldehyde - pharmacology / Rats / Signal Transduction - drug effects / Time Factors / Type 2 diabetes / Tyrosine / Venoms - pharmacology