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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 Article has an altmetric score of 3

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

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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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Figure 1

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Suppression of glucagon secretion in response to physiological hypoglyce...
Suppression of glucagon secretion in response to physiological hypoglycemia or cellular glucoprivation in ripglut1;glut2–/– mice. (A) Glycemic profiles during use of normoglycemic or hypoglycemic clamps in ripglut1;glut2+/– and ripglut1;glut2–/– mice. (B) Plasma glucagon levels measured at the end of the clamp experiment. Hypoglycemia induced an approximately 3-fold increase in plasma glucagon in control mice but no increase in ripglut1;glut2–/– mice. (C) Glucagon levels 30 minutes after i.p. injection of NaCl or 2-DG. 2-DG induced an approximately 1.7-fold increase in plasma glucagon in control mice but no increase in glut2-null mice. (D) Glucagon levels measured 30 minutes following i.c.v. injection of NaCl or 2-DG. 2-DG induced a 2.5-fold increase in plasma glucagon in control mice and no increase in ripglut1;glut2–/– mice. (B and D) Data are indicated as mean ± SD; n = 6–10 for each data point. (C) Data are indicated as mean ± SEM of 3 experiments, each performed with 6–8 mice. **P < 0.01 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–/– groups (Student’s t test).

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ISSN: 0021-9738 (print), 1558-8238 (online)

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