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J Proteome Res. 2016 Apr 1;15(4):1342-9. doi: 10.1021/acs.jproteome.6b00110. Epub 2016 Mar 16.

Post-Translational Regulation of the Glucose-6-Phosphatase Complex by Cyclic Adenosine Monophosphate Is a Crucial Determinant of Endogenous Glucose Production and Is Controlled by the Glucose-6-Phosphate Transporter.

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INSERM U1213, 7-11 rue Paradin, F-69008 Lyon, France.
Université de Lyon, 7-11 rue Paradin, F-69008 Lyon, France.
Université Lyon1, 43 Boulevard du 11 Novembre 1918, F-69622 Villeurbanne, France.
Institut Pluridisciplinaire Hubert Curien, Département Sciences Analytiques, CNRS UMR7178 , 25 rue Becquerel, 67087 Strasbourg Cedex 2, France.
Université de Strasbourg, 4 rue Blaise Pascal, F-67081 Strasbourg Cedex, France.


The excessive endogenous glucose production (EGP) induced by glucagon participates in the development of type 2 diabetes. To further understand this hormonal control, we studied the short-term regulation by cyclic adenosine monophosphate (cAMP) of the glucose-6-phosphatase (G6Pase) enzyme, which catalyzes the last reaction of EGP. In gluconeogenic cell models, a 1-h treatment by the adenylate cyclase activator forskolin increased G6Pase activity and glucose production independently of any change in enzyme protein amount or G6P content. Using specific inhibitors or protein overexpression, we showed that the stimulation of G6Pase activity involved the protein kinase A (PKA). Results of site-directed mutagenesis, mass spectrometry analyses, and in vitro phosphorylation experiments suggested that the PKA stimulation of G6Pase activity did not depend on a direct phosphorylation of the enzyme. However, the temperature-dependent induction of both G6Pase activity and glucose release suggested a membrane-based mechanism. G6Pase is composed of a G6P transporter (G6PT) and a catalytic unit (G6PC). Surprisingly, we demonstrated that the increase in G6PT activity was required for the stimulation of G6Pase activity by forskolin. Our data demonstrate the existence of a post-translational mechanism that regulates G6Pase activity and reveal the key role of G6PT in the hormonal regulation of G6Pase activity and of EGP.


Type 2 diabetes; glucagon; gluconeogenesis; glucose-6-phosphatase; glucose-6-phosphate transporter; post-translational modification (PTM); protein kinase A

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