Vavaiya Kamlesh V, Paranjape Sachin A, Briski Karen P
Department of Basic Pharmaceutical Sciences, College of Pharmacy, University of Louisiana at Monroe, Monroe, LA 71209, USA.
J Mol Neurosci. 2007;31(1):37-46. doi: 10.1007/BF02686116.
Recurrent insulin-induced hypoglycemia (RIIH) impairs glucose counter-regulatory function in male humans and rodents and, in the latter, diminishes neuronal activation in CNS structures that monitor metabolic homeostasis, including the lateral hypothalamic area (LHA) and dorsal vagal complex (DVC). We investigated whether habituated neuronal reactivity in CNS sensing sites to hypoglycemia is correlated with modified monocarboxylate and/or glucose uptake by using quantitative real-time RT-PCR to analyze neuronal monocarboxylate transporter (MCT2) and glucose transporter variant (GLUT and GLUT4) gene expression profiles in the microdissected LHA, ventromedial nucleus hypothalamus (VMH), and DVC after one or multiple insulin injections. Because orchidectomy (ORDX) maintains uniform glycemic responses to RIIH in male rats, we also examined whether regional gene response patterns are testes dependent. In the intact male rat DVC, MCT2, GLUT3, and GLUT4 gene expression was not altered by acute hypoglycemia but was enhanced by RIIH. MCT2 and GLUT3 mRNA levels in the ORDX rat DVC did not differ among groups, but GLUT4 transcripts were progressively increased by acute and recurrent hypoglycemia. Precedent hypoglycemia decreased or increased basal MCT2 and GLUT4 gene expression, respectively, in the intact rat LHA; LHA GLUT3 transcription was augmented by RIIH in intact rats only. Acute hypoglycemia suppressed MCT2, GLUT3, and GLUT4 gene expression in the intact rat VMH, a response that was abolished by RIIH. In ORDX rats, VMH gene transcript levels were unchanged in response to one dose of insulin but were selectively diminished during RIIH. These data demonstrate site-specific, testes-dependent effects of acute and recurrent hypoglycemia on neuronal metabolic substrate transporter gene expression in characterized rat brain metabolic sensing loci and emphasize the need to assess the impact of potential alterations in glucose and lactate uptake during RIIH on general and specialized, e.g., metabolic monitoring, functions of neurons in those sites.
反复胰岛素诱导的低血糖症（RIIH）会损害男性人类和啮齿动物的葡萄糖反调节功能，在后者中，会减少监测代谢稳态的中枢神经系统（CNS）结构中的神经元激活，包括下丘脑外侧区（LHA）和迷走背核复合体（DVC）。我们通过定量实时逆转录聚合酶链反应（RT-PCR）分析在显微切割的LHA、下丘脑腹内侧核（VMH）和DVC中，神经元单羧酸转运体（MCT2）和葡萄糖转运体变体（GLUT和GLUT4）基因表达谱，研究中枢神经系统传感部位对低血糖的习惯性神经元反应性是否与单羧酸和/或葡萄糖摄取的改变相关。由于睾丸切除术（ORDX）能维持雄性大鼠对RIIH的均匀血糖反应，我们还研究了区域基因反应模式是否依赖于睾丸。在完整雄性大鼠的DVC中，急性低血糖不会改变MCT2、GLUT3和GLUT4基因表达，但RIIH会增强这些基因表达。ORDX大鼠DVC中的MCT2和GLUT3 mRNA水平在各组之间没有差异，但急性和反复低血糖会使GLUT4转录本逐渐增加。先前的低血糖分别降低或增加了完整大鼠LHA中的基础MCT2和GLUT4基因表达；仅在完整大鼠中，RIIH会增强LHA中GLUT3的转录。急性低血糖会抑制完整大鼠VMH中的MCT2、GLUT3和GLUT4基因表达，而RIIH会消除这种反应。在ORDX大鼠中，VMH基因转录水平对一剂胰岛素无变化，但在RIIH期间会选择性降低。这些数据表明急性和反复低血糖对特征化大鼠脑代谢传感位点中神经元代谢底物转运体基因表达具有位点特异性、睾丸依赖性影响，并强调需要评估RIIH期间葡萄糖和乳酸摄取的潜在改变对这些位点中神经元的一般和特殊功能（如代谢监测）的影响。
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