Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia.
Brain insulin action regulates hypothalamic glucose sensing and the counterregulatory response to hypoglycemia.
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作者：
Diggs-Andrews KA;Zhang X;Song Z;Daphna-Iken D;Routh VH;Fisher SJ
感知和适当应对胰岛素诱导的低血糖的能力受损是接受胰岛素治疗的糖尿病患者面临的常见和严重并发症。本研究验证了胰岛素直接在大脑中调节下丘脑中的关键葡萄糖敏感神经元以介导对低血糖的反调节反应的假设。为了描述脑中的胰岛素作用，对神经元特异性胰岛素受体敲除（NIRKO）小鼠和同窝对照进行分级的低血糖（100、70、50和30 mg/dl）高胰岛素血症（20 mU/kg/min）钳夹和非低血糖应激源（例如，约束、加热）。随后，测量反调节反应、下丘脑神经元激活（转录标记物c-fos）和局部脑葡萄糖摄取（通过14 C-2脱氧葡萄糖放射自显影）。此外，个别葡萄糖抑制神经元的电生理活性和下丘脑葡萄糖敏感蛋白的表达（GLUT，葡萄糖激酶）进行了测量。NIRKO小鼠表现出对低血糖的交感肾上腺反应的血糖依赖性损害，并表现出对低血糖反应的下丘脑c-fos激活显著降低（3倍），但对其他应激源无影响。NIRKO小鼠下丘脑腹内侧的葡萄糖抑制神经元显示出明显的葡萄糖反应性减弱（膜电位和输入电阻反应分别减弱66%和80%）。此外，下丘脑表达的胰岛素响应GLUT 4，但不是葡萄糖激酶，减少了30%，而区域脑葡萄糖摄取保持不变。长期而言，胰岛素通过直接改变下丘脑神经元的葡萄糖感知并改变引起正常交感肾上腺反应所需的血糖水平，在大脑中发挥作用，以调节对低血糖的反调节反应。
An impaired ability to sense and appropriately respond to insulin-induced hypoglycemia is a common and serious complication faced by insulin-treated diabetic patients. This study tests the hypothesis that insulin acts directly in the brain to regulate critical glucose-sensing neurons in the hypothalamus to mediate the counterregulatory response to hypoglycemia. To delineate insulin actions in the brain, neuron-specific insulin receptor knockout (NIRKO) mice and littermate controls were subjected to graded hypoglycemic (100, 70, 50, and 30 mg/dl) hyperinsulinemic (20 mU/kg/min) clamps and nonhypoglycemic stressors (e.g., restraint, heat). Subsequently, counterregulatory responses, hypothalamic neuronal activation (with transcriptional marker c-fos), and regional brain glucose uptake (via 14C-2deoxyglucose autoradiography) were measured. Additionally, electrophysiological activity of individual glucose-inhibited neurons and hypothalamic glucose sensing protein expression (GLUTs, glucokinase) were measured. NIRKO mice revealed a glycemia-dependent impairment in the sympathoadrenal response to hypoglycemia and demonstrated markedly reduced (3-fold) hypothalamic c-fos activation in response to hypoglycemia but not other stressors. Glucose-inhibited neurons in the ventromedial hypothalamus of NIRKO mice displayed significantly blunted glucose responsiveness (membrane potential and input resistance responses were blunted 66 and 80%, respectively). Further, hypothalamic expression of the insulin-responsive GLUT 4, but not glucokinase, was reduced by 30% in NIRKO mice while regional brain glucose uptake remained unaltered. Chronically, insulin acts in the brain to regulate the counterregulatory response to hypoglycemia by directly altering glucose sensing in hypothalamic neurons and shifting the glycemic levels necessary to elicit a normal sympathoadrenal response.
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影响因子：
2.9
作者：
Grillo, C. A.;Tamashiro, K. L.;Reagan, L. P.
通讯作者：
Reagan, L. P.
影响因子：
168.9
作者：
Turner, RC;Holman, RR;Ward, JD
通讯作者：
Ward, JD
影响因子：
5.9
作者：
通讯作者：
--
影响因子：
7.7
作者：
Chan, O;Chan, S;Vranic, M
通讯作者：
Vranic, M
DOI：
10.1152/ajpendo.1997.272.4.e567
发表时间：
1997-04-01
影响因子：
5.1
作者：
Davis, SN;Dunham, B;Cherrington, AD
通讯作者：
Cherrington, AD