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

Journal of Translational Medicine

Research

Giorgio Sesti¹  Teresa Procopio¹  Gaia Chiara Mannino¹  Francesco Andreozzi²  Alberto M. Davalli³  Franco Folli⁴  Francesco Beguinot⁵  Cecilia Nigro⁵  Gregory Alexander Raciti⁵  Claudia Miele⁵ 

[1] Department of Medical and Surgical Sciences, University of Catanzaro “Magna-Graecia”, Catanzaro, Italy;Department of Medical and Surgical Sciences, University of Catanzaro “Magna-Graecia”, Catanzaro, Italy;Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA;Department of Medicine Endocrinology Unit, Ospedale San Raffaele, Milan, Italy;Division of Diabetes, Department of Medicine, University of Texas Health Science Center, San Antonio, TX, USA;Department of Internal Medicine, University of Campinas, Campinas, SP, Brazil;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;

关键词: Exenatide;    Liraglutide;    Glucose uptake;    AMPK;    Skeletal muscle cells;    Insulin signaling;   

DOI  :  10.1186/s12967-016-0985-7

 received in 2016-01-06, accepted in 2016-07-20,  发布年份 2016

来源: Springer

【 摘 要 】

Aims/hypothesisPotentiation 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.Methods2-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).ResultsTime 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/interpretationIn L6 myotubes, EXE and liraglutide increase glucose uptake in an insulin-independent manner by activating AMPK.

【 授权许可】

CC BY   
© The Author(s) 2016