Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation
Brain GLUT4 Knockout Mice Have Impaired Glucose Tolerance, Decreased Insulin Sensitivity, and Impaired Hypoglycemic Counterregulation
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DOI：
10.2337/db16-0917
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发表时间：
2017-03-01
期刊：
影响因子：
7.7
通讯作者：
Fisher, Simon J.
中科院分区：
文献类型：
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作者：
Reno, Candace M.;Puente, Erwin C.;Fisher, Simon J.
肌肉和脂肪组织中的GLUT 4在维持葡萄糖稳态中是重要的。然而，胰岛素反应性GLUT 4在中枢神经系统中的作用尚未得到很好的表征。为了评估其重要性，通过将Nestin-Cre小鼠与GLUT 4-floxed小鼠杂交来产生脑GLUT 4的选择性敲除（BG 4KO）。BG 4 KO小鼠整个大脑的GLUT 4蛋白表达减少了99%。尽管正常进食和禁食，但BG 4KO小鼠葡萄糖不耐受，表现出肝脏胰岛素抵抗，并且脑中葡萄糖摄取减少。在低血糖反应中，BG 4 KO小鼠葡萄糖感知受损，表现为肾上腺素和胰高血糖素反应受损以及下丘脑室旁核c-fos激活受损。此外，在体外葡萄糖敏感的葡萄糖抑制神经元的腹内侧下丘脑受损的BG 4 KO小鼠。总之，BG 4KO小鼠是葡萄糖不耐受的、胰岛素抵抗的，并且具有受损的葡萄糖感知，表明脑GLUT 4在感知和响应血糖变化中的关键作用。
GLUT4 in muscle and adipose tissue is important in maintaining glucose homeostasis. However, the role of insulin-responsive GLUT4 in the central nervous system has not been well characterized. To assess its importance, a selective knockout of brain GLUT4 (BG4KO) was generated by crossing Nestin-Cre mice with GLUT4-floxed mice. BG4KO mice had a 99% reduction in GLUT4 protein expression throughout the brain. Despite normal feeding and fasting glycemia, BG4KO mice were glucose intolerant, demonstrated hepatic insulin resistance, and had reduced glucose uptake in the brain. In response to hypoglycemia, BG4KO mice had impaired glucose sensing, noted by impaired epinephrine and glucagon responses and impaired c-fos activation in the hypothalamic paraventricular nucleus. Moreover, in vitro glucose sensing of glucose-inhibitory neurons from the ventromedial hypothalamus was impaired in BG4KO mice. In summary, BG4KO mice are glucose intolerant, insulin resistant, and have impaired glucose sensing, indicating a critical role for brain GLUT4 in sensing and responding to changes in blood glucose.