Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocyte-dependent glucose sensors.
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 alpha 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.
Marty
Nell
N
Institute of Physiology and Center for Integrative Genomics, Lausanne, Switzerland.
Dallaporta
Michel
M
Foretz
Marc
M
Emery
Martine
M
Tarussio
David
D
Bady
Isabelle
I
Binnert
Christophe
C
Beermann
Friedrich
F
Thorens
Bernard
B
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D001786:Blood Glucose / Q000378:metabolism; D015152:Blotting, Northern; D015139:Blotting, Southern; D015153:Blotting, Western; D018076:DNA, Complementary / Q000378:metabolism; D003847:Deoxyglucose / Q000737:chemistry; D005786:Gene Expression Regulation; D005934:Glucagon / Q000097:blood / Q000737:chemistry / Q000378:metabolism*; D050416:Glucagon-Secreting Cells / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051273:Glucose Transporter Type 2 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D007003:Hypoglycemia / Q000473:pathology; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D008957:Models, Genetic; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000378:metabolism; D016760:Proto-Oncogene Proteins c-fos / Q000378:metabolism; D013997:Time Factors; D019076:Transgenes
D001786:Blood Glucose; D018076:DNA, Complementary; D051273:Glucose Transporter Type 2; D007328:Insulin; D016760:Proto-Oncogene Proteins c-fos; C495682:Slc2a2 protein, mouse; D005934:Glucagon; D003847:Deoxyglucose; D005947:Glucose