Role of synaptic plasticity and EphA5-ephrinA5 interaction within the ventromedial hypothalamus in response to recurrent hypoglycemia.
Role of synaptic plasticity and EphA5-ephrinA5 interaction within the ventromedial hypothalamus in response to recurrent hypoglycemia.
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突触可塑性和 EphA5-ephrinA5 相互作用在下丘脑腹内侧对反复低血糖的反应中的作用。
DOI：
10.2337/db13-1259
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发表时间：
2014-03
期刊：
影响因子：
7.7
通讯作者：
Sherwin RS
中科院分区：
文献类型：
--
作者：
Szepietowska B;Horvath TL;Sherwin RS
低血糖刺激反调节激素释放以恢复正常。这种保护性反应会因反复发生的低血糖而减弱，从而限制了糖尿病患者强化胰岛素治疗的益处。我们以前报道，EphA 5受体ephrinA 5腹内侧下丘脑（VMH）内的相互作用的影响，在非糖尿病大鼠急性低血糖的反调节激素反应。在这项研究中，我们研究了是否经常性低血糖改变ephrinA 5配体激活VMH EphA 5受体的能力，如果是这样的话，这些变化是否可能有助于发病机制的缺陷葡萄糖反调节在一个标准的低血糖刺激。在VMH中ephrinA 5的表达，而不是EphA 5受体，被先前的复发性低血糖降低。此外，突触连接的数量增加，星形胶质细胞突触覆盖减少。在高胰岛素低血糖钳夹研究之前，通过靶向微量注射ephrinA 5-Fc激活VMH EphA 5受体，导致暴露于复发性低血糖的非糖尿病大鼠的葡萄糖输注速率降低。对胰岛素诱导的低血糖的反调节反应的增加与胰高血糖素释放增加150%相关（P < 0.001）。这些数据表明，ephrinA 5/EphA 5相互作用和VMH内的突触可塑性的变化，在大脑中的关键葡萄糖敏感区域，可能有助于胰高血糖素分泌和反调节反应的损害引起的复发性低血糖症。
Hypoglycemia stimulates counterregulatory hormone release to restore euglycemia. This protective response is diminished by recurrent hypoglycemia, limiting the benefits of intensive insulin treatment in patients with diabetes. We previously reported that EphA5 receptor-ephrinA5 interactions within the ventromedial hypothalamus (VMH) influence counterregulatory hormone responses during acute hypoglycemia in nondiabetic rats. In this study, we examined whether recurrent hypoglycemia alters the capacity of the ephrinA5 ligand to activate VMH EphA5 receptors, and if so, whether these changes could contribute to pathogenesis of defective glucose counterregulation in response to a standard hypoglycemic stimulus. The expression of ephrinA5, but not EphA5 receptors within the VMH, was reduced by antecedent recurrent hypoglycemia. In addition, the number of synaptic connections was increased and astroglial synaptic coverage was reduced. Activation of VMH EphA5 receptors via targeted microinjection of ephrinA5-Fc before a hyperinsulinemic hypoglycemic clamp study caused a reduction in the glucose infusion rate in nondiabetic rats exposed to recurrent hypoglycemia. The increase in the counterregulatory response to insulin-induced hypoglycemia was associated with a 150% increase in glucagon release (P < 0.001). These data suggest that changes in ephrinA5/EphA5 interactions and synaptic plasticity within the VMH, a key glucose-sensing region in the brain, may contribute to the impairment in glucagon secretion and counterregulatory responses caused by recurrent hypoglycemia.
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