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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c-FLI cells in the NTS, the DMNX, and the VMH following 2-DG injections....
c-FLI cells in the NTS, the DMNX, and the VMH following 2-DG injections. Mice were injected i.p. with NaCl or 2-DG, and tissues were processed 2 hours later for c-FLI immunohistochemistry. (A) Representative photos from c-FLI–positive cells at 2 different levels of the NTS and DMNX of ripglut1;glut2+/– mice after i.p. injection of NaCl or 2-DG. The positions of the sections were between –7.64 and –7.48 mm relative to the bregma. Scale bars: 100 μm. AP, area postrema; cc, central canal. (B) c-FLI–positive cells in the NTS and DMNX of ripglut1;glut2+/–, ripglut1;glut2–/–, and pgfapglut2;ripglut1;glut2–/– mice after i.p. injection of NaCl or 2-DG. In glut2-null mice, there is no increase in the number of c-FLI–positive cells after 2-DG administration. Transgenic expression of GLUT2 in astrocytes restored the sensitivity of the NTS and DMNX to i.p. 2-DG. (C) c-FLI–positive cells in the VMH of control, ripglut1;glut2–/–, and pgfapglut2;ripglut1;glut2–/– mice after i.p. injection of NaCl or 2-DG. Data are indicated as mean ± SD; n = 6–8 mice for each data point. *P < 0.05, **P < 0.01 for comparison between NaCl- and 2-DG–injected groups (Student’s t test).