Evidence that extrapancreatic GLUT2-Dependent glucose sensors control glucagon secretion
Evidence that extrapancreatic GLUT2-Dependent glucose sensors control glucagon secretion
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DOI：
10.2337/diabetes.50.6.1282
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发表时间：
2001-06-01
期刊：
影响因子：
7.7
通讯作者：
Thorens, B
中科院分区：
文献类型：
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作者：
Burcelin, R;Thorens, B
在其β细胞中重新表达GLUT1或GLUT2的GLUT2(-/-)小鼠（RIPGLUT1 x GLUT2(-/-)或RIPGLUT2 x GLUT2(-/-)小鼠）具有几乎正常的葡萄糖刺激胰岛素分泌，但是；在进食状态下表现出高胰高血糖素血症。因为这表明胰高血糖素分泌的控制受损，所以我开始通过血糖浓度的变化直接评估对胰高血糖素血症的控制。使用禁食的 RIPGLUT1 x GLUT2(-/-) 小鼠，我们发现胰高血糖素血症不再因低血糖（2.5 mmol/l 葡萄糖）钳夹而增加，也不再因高血糖（10 和 20 mmol/l 葡萄糖）钳夹而抑制。然而，当血糖降低至小于或等于 1 mmol/l 时，可检测到血浆胰高血糖素水平增加，表明胰高血糖素分泌能力得以保留，但对血糖减少症的敏感性降低。为了评估高喂食的胰高血糖素血症是否可能是由于自主神经系统张力异常增加所致，给喂食的突变小鼠注射了神经节阻滞剂六甲铵和氯茚达明。这两种药物都会导致胰高血糖素血症迅速恢复到对照喂养小鼠的水平。我们的结论是：1）在缺乏 GLUT2 的情况下，低或高葡萄糖对胰高血糖素分泌的控制受损； 2) 这种胰高血糖素分泌活性受损不可能是由于α细胞缺乏GLUT2，因为这些细胞通常不表达这种转运蛋白； 3）这种失调可能是由于位于内分泌胰腺外部并控制胰高血糖素分泌的GLUT2依赖性葡萄糖传感器失活所致； 4)因为进食后的高胰高血糖素血症可以被神经节阻滞剂迅速逆转，这表明在缺乏GLUT2的情况下，在进食状态下刺激胰高血糖素分泌的自主神经系统的活动增加。
GLUT2(-/-) mice reexpressing GLUT1 or GLUT2 in their beta -cells (RIPGLUT1 x GLUT2(-/-) or RIPGLUT2 x GLUT2(-/-) mice) have nearly normal glucose-stimulated insulin secretion but; show high glucagonemia in the fed state. Because this suggested impaired control of glucagon secretion, me set out to directly evaluate the control of glucagonemia by variations in blood glucose concentrations. Using fasted RIPGLUT1 x GLUT2(-/-) mice, we showed that glucagonemia was no longer increased by hypoglycemic (2.5 mmol/l glucose) clamps or suppressed by hyperglycemic (10 and 20 mmol/l glucose) clamps. However, an increase in plasma glucagon levels mas detected when glycemia was decreased to less than or equal to1 mmol/l, indicating preserved glucagon secretory ability, but of reduced sensitivity to glucopenia. To evaluate whether the high-fed glucagonemia could be due to an abnormally increased tone of the autonomic nervous system, fed mutant mice were injected with the ganglionic blockers hexamethonium and chlorisondamine. Both drugs lead to a rapid return of glucagonemia to the levels found in control fed mice. We conclude that 1)in the absence of GLUT2, there is an impaired control of glucagon secretion by low or high glucose; 2) this impaired glucagon secretory activity cannot be due to absence of GLUT2 from alpha -cells because these cells do not normally express this transporter; 3) this dysregulation may be due to inactivation of GLUT2-dependent glucose sensors located outside the endocrine pancreas and controlling glucagon secretion; and 4) because fed hyperglucagonemia is rapidly reversed by ganglionic blockers, this suggests that in the absence of GLUT2, there is an increased activity of the autonomic nervous system stimulating glucagon secretion during the fed state.