Regulation of glucagon secretion by glucose transporter type 2 (glut2) and astrocytedependent glucose sensors

被引:192
作者
Marty, N
Dallaporta, M
Foretz, M
Emery, M
Tarussio, D
Bady, I
Binnert, C
Beermann, F
Thorens, B [1 ]
机构
[1] Ctr Integrat Gen, Inst Physiol, Lausanne, Switzerland
[2] Swiss Inst Expt Canc Res, CH-1066 Epalinges, Switzerland
关键词
D O I
10.1172/JCI26309
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Ripglut1jglut2(-/-) 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.
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页码:3545 / 3553
页数:9
相关论文
共 58 条
[1]   NEUROPEPTIDERGIC VERSUS CHOLINERGIC AND ADRENERGIC REGULATION OF ISLET HORMONE-SECRETION [J].
AHREN, B ;
TABORSKY, GJ ;
PORTE, D .
DIABETOLOGIA, 1986, 29 (12) :827-836
[2]   Distribution and anatomical localization of the glucose transporter 2 (GLUT2) in the adult rat brain - an immunohistochemical study [J].
Arluison, M ;
Quignon, M ;
Nguyen, P ;
Thorens, B ;
Leloup, C ;
Penicaud, L .
JOURNAL OF CHEMICAL NEUROANATOMY, 2004, 28 (03) :117-136
[3]   Immunocytochemical localization of the glucose transporter 2 (GLUT2) in the adult rat brain. II. Electron microscopic study [J].
Arluison, M ;
Quignon, M ;
Thorens, B ;
Leloup, C ;
Penicaud, L .
JOURNAL OF CHEMICAL NEUROANATOMY, 2004, 28 (03) :137-146
[4]   Local ventromedial hypothalamus glucose perfusion blocks counterregulation during systemic hypoglycemia in awake rats [J].
Borg, MA ;
Sherwin, RS ;
Borg, WP ;
Tamborlane, WV ;
Shulman, GI .
JOURNAL OF CLINICAL INVESTIGATION, 1997, 99 (02) :361-365
[5]   LOCAL VENTROMEDIAL HYPOTHALAMUS GLUCOPENIA TRIGGERS COUNTERREGULATORY HORMONE-RELEASE [J].
BORG, WP ;
SHERWIN, RS ;
DURING, MJ ;
BORG, MA ;
SHULMAN, GI .
DIABETES, 1995, 44 (02) :180-184
[6]   Evidence that extrapancreatic GLUT2-Dependent glucose sensors control glucagon secretion [J].
Burcelin, R ;
Thorens, B .
DIABETES, 2001, 50 (06) :1282-1289
[7]  
CHOMCZYNSKI P, 1987, ANAL BIOCHEM, V162, P156, DOI 10.1016/0003-2697(87)90021-2
[8]   Hypoglycemia in diabetes [J].
Cryer, PE ;
Davis, SN ;
Shamoon, H .
DIABETES CARE, 2003, 26 (06) :1902-1912
[9]   Current concepts: Diverse causes of hypoglycemia-associated autonomic failure in diabetes [J].
Cryer, PE .
NEW ENGLAND JOURNAL OF MEDICINE, 2004, 350 (22) :2272-2279
[10]   Solitary tract nucleus sensitivity to moderate changes in glucose level [J].
Dallaporta, M ;
Himmi, T ;
Perrin, J ;
Orsini, JC .
NEUROREPORT, 1999, 10 (12) :2657-2660