Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors
Nell Marty, … , Friedrich Beermann, Bernard Thorens
Nell Marty, … , Friedrich Beermann, Bernard Thorens
Published December 1, 2005
Citation Information: J Clin Invest. 2005;115(12):3545-3553. https://doi.org/10.1172/JCI26309.
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Research Article Metabolism

Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors

Abstract

Ripglut1;glut2–/– mice have no endogenous glucose transporter type 2 (glut2) gene expression but rescue glucose-regulated insulin secretion. Control of glucagon plasma levels is, however, abnormal, with fed hyperglucagonemia and insensitivity to physiological hypo- or hyperglycemia, indicating that GLUT2-dependent sensors control glucagon secretion. Here, we evaluated whether these sensors were located centrally and whether GLUT2 was expressed in glial cells or in neurons. We showed that ripglut1;glut2–/– mice failed to increase plasma glucagon levels following glucoprivation induced either by i.p. or intracerebroventricular 2-deoxy-D-glucose injections. This was accompanied by failure of 2-deoxy-D-glucose injections to activate c-Fos–like immunoreactivity in the nucleus of the tractus solitarius and the dorsal motor nucleus of the vagus. When glut2 was expressed by transgenesis in glial cells but not in neurons of ripglut1;glut2–/– mice, stimulated glucagon secretion was restored as was c-Fos–like immunoreactive labeling in the brainstem. When ripglut1;glut2–/– mice were backcrossed into the C57BL/6 genetic background, fed plasma glucagon levels were also elevated due to abnormal autonomic input to the α cells; glucagon secretion was, however, stimulated by hypoglycemic stimuli to levels similar to those in control mice. These studies identify the existence of central glucose sensors requiring glut2 expression in glial cells and therefore functional coupling between glial cells and neurons. These sensors may be activated at different glycemic levels depending on the genetic background.

Authors

Nell Marty, Michel Dallaporta, Marc Foretz, Martine Emery, David Tarussio, Isabelle Bady, Christophe Binnert, Friedrich Beermann, Bernard Thorens

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Abnormal glucagonemia in the fed state but normal glucagon secretion in ...
Abnormal glucagonemia in the fed state but normal glucagon secretion in response to hypoglycemia or 2-DG in ripglut1;glut2–/– mice in the C57BL/6 background. (A) Fed glucagon levels were approximately 2-fold higher in male ripglut1;glut2–/–(B6) than in C57BL/6 mice; (B) Fed glucagon levels were approximately 2-fold higher in female ripglut1;glut2–/–(B6) than in C57BL/6 mice. The fed hyperglucagonemia of mutant mice was reduced to the level found in control mice after ganglionic blockade with chlorisondamine (chlori). Chlorisondamine did not change the glucagonemia of control mice. (C) Plasma glucagon levels measured at the end of 3 hours of hypoglycemic (∼2.5 mM) or euglycemic (∼5.5 mM) clamps. Hypoglycemia induced an approximately 4-fold increase in glucagon plasma levels in control mice and an approximately 2-fold increase in mutant mice. (D) Plasma glucagon levels measured 60 minutes after i.p. injections of NaCl or 2-DG in C57Bl and ripglut1;glut2–/–(B6) mice. 2-DG induced a 5- and 3-fold increase in plasma glucagon in control and mutant mice, respectively. (E) Plasma glucagon levels measured 30 minutes after i.c.v. injection of NaCl or 2-DG. 2-DG induced a 5-fold increase in plasma glucagon in C57BL/6 mice and an approximately 3-fold increase in mutant mice. Data are indicated as mean ± SD; n = 6–8 for each data point. (C) Data are indicated as mean ± SEM of 3 experiments, each performed with 5–6 mice. **P < 0.01 and ***P < 0.005 for comparison between NaCl- and 2-DG–injected groups. #P < 0.05 and ##P < 0.01 for comparison between NaCl-injected control and ripglut1;glut2–/–(B6) groups (Student’s t test).