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The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism.
J Transl Med. 2016 07 30; 14(1):229.JT

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.

Authors+Show Affiliations

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.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.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.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.Department of Medicine Endocrinology Unit, Ospedale San Raffaele, Milan, Italy.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.Department of Medical and Surgical Sciences, University of Catanzaro "Magna-Graecia", Catanzaro, Italy.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.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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

27473212

Citation

Andreozzi, Francesco, et al. "The GLP-1 Receptor Agonists Exenatide and Liraglutide Activate Glucose Transport By an AMPK-dependent Mechanism." Journal of Translational Medicine, vol. 14, no. 1, 2016, p. 229.
Andreozzi F, Raciti GA, Nigro C, et al. The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. J Transl Med. 2016;14(1):229.
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
Andreozzi F, et al. The GLP-1 Receptor Agonists Exenatide and Liraglutide Activate Glucose Transport By an AMPK-dependent Mechanism. J Transl Med. 2016 07 30;14(1):229. PubMed PMID: 27473212.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The GLP-1 receptor agonists exenatide and liraglutide activate Glucose transport by an AMPK-dependent mechanism. AU - Andreozzi,Francesco, AU - Raciti,Gregory Alexander, AU - Nigro,Cecilia, AU - Mannino,Gaia Chiara, AU - Procopio,Teresa, AU - Davalli,Alberto M, AU - Beguinot,Francesco, AU - Sesti,Giorgio, AU - Miele,Claudia, AU - Folli,Franco, Y1 - 2016/07/30/ PY - 2016/01/06/received PY - 2016/07/20/accepted PY - 2016/7/31/entrez PY - 2016/7/31/pubmed PY - 2017/10/17/medline KW - AMPK KW - Exenatide KW - Glucose uptake KW - Insulin signaling KW - Liraglutide KW - Skeletal muscle cells SP - 229 EP - 229 JF - Journal of translational medicine JO - J Transl Med VL - 14 IS - 1 N2 - 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. SN - 1479-5876 UR - https://www.unboundmedicine.com/medline/citation/27473212/The_GLP_1_receptor_agonists_exenatide_and_liraglutide_activate_Glucose_transport_by_an_AMPK_dependent_mechanism_ L2 - https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-016-0985-7 DB - PRIME DP - Unbound Medicine ER -