Toronto General Research Institute, University Health Network, Ontario, Canada.
Diabetes. 2011 Jan;60(1):107-13. doi: 10.2337/db10-0994. Epub 2010 Sep 24.
Hypothalamic nutrient sensing regulates glucose production, but the neuronal circuits involved remain largely unknown. Recent studies underscore the importance of N-methyl-d-aspartate (NMDA) receptors in the dorsal vagal complex in glucose regulation. These studies raise the possibility that hypothalamic nutrient sensing activates a forebrain-hindbrain NMDA-dependent circuit to regulate glucose production.
We implanted bilateral catheters targeting the mediobasal hypothalamus (MBH) (forebrain) and dorsal vagal complex (DVC) (hindbrain) and performed intravenous catheterizations to the same rat for infusion and sampling purposes. This model enabled concurrent selective activation of MBH nutrient sensing by either MBH delivery of lactate or an adenovirus expressing the dominant negative form of AMPK (Ad-DN AMPK α2 [D¹⁵⁷A]) and inhibition of DVC NMDA receptors by either DVC delivery of NMDA receptor blocker MK-801 or an adenovirus expressing the shRNA of NR1 subunit of NMDA receptors (Ad-shRNA NR1). Tracer-dilution methodology and the pancreatic euglycemic clamp technique were performed to assess changes in glucose kinetics in the same conscious, unrestrained rat in vivo.
MBH lactate or Ad-DN AMPK with DVC saline increased glucose infusion required to maintain euglycemia due to an inhibition of glucose production during the clamps. However, DVC MK-801 negated the ability of MBH lactate or Ad-DN AMPK to increase glucose infusion or lower glucose production. Molecular knockdown of DVC NR1 of NMDA receptor via Ad-shRNA NR1 injection also negated MBH Ad-DN AMPK to lower glucose production.
Molecular and pharmacological inhibition of DVC NMDA receptors negated hypothalamic nutrient sensing mechanisms activated by lactate metabolism or AMPK inhibition to lower glucose production. Thus, DVC NMDA receptor is required for hypothalamic nutrient sensing to lower glucose production and that hypothalamic nutrient sensing activates a forebrain-hindbrain circuit to lower glucose production.
下丘脑营养感应调节葡萄糖生成，但涉及的神经元回路在很大程度上仍然未知。最近的研究强调了 N-甲基-D-天冬氨酸 (NMDA) 受体在背侧迷走复合体 (DVC) 中在葡萄糖调节中的重要性。这些研究提出了一种可能性，即下丘脑营养感应激活了一个前脑-后脑 NMDA 依赖性回路，以调节葡萄糖生成。
我们将双侧导管植入靶向中脑基底部下丘脑 (MBH)（前脑）和背侧迷走复合体 (DVC)（后脑）的大鼠，并对同一大鼠进行静脉内导管插入术，用于输注和采样目的。这种模型使我们能够通过 MBH 给予乳酸或表达 AMPK 显性负形式的腺病毒 (Ad-DN AMPKα2[D¹⁵⁷A]) 选择性地激活 MBH 营养感应，同时通过 DVC 给予 NMDA 受体阻滞剂 MK-801 或表达 NMDA 受体 NR1 亚基的 shRNA 的腺病毒 (Ad-shRNA NR1) 抑制 DVC NMDA 受体，来抑制 DVC NMDA 受体。示踪剂稀释法和胰腺血糖钳夹技术用于评估同一清醒、不受约束的大鼠体内葡萄糖动力学的变化。
MBH 乳酸或 Ad-DN AMPK 联合 DVC 生理盐水增加了血糖钳夹期间葡萄糖生成所需的葡萄糖输注量，因为葡萄糖生成受到抑制。然而，DVC MK-801 否定了 MBH 乳酸或 Ad-DN AMPK 增加葡萄糖输注或降低葡萄糖生成的能力。通过 Ad-shRNA NR1 注射对 DVC NMDA 受体的分子敲低也否定了 MBH Ad-DN AMPK 降低葡萄糖生成的能力。
DVC NMDA 受体的分子和药理学抑制否定了由乳酸代谢或 AMPK 抑制激活的下丘脑营养感应机制来降低葡萄糖生成。因此，DVC NMDA 受体是下丘脑营养感应降低葡萄糖生成所必需的，并且下丘脑营养感应激活了一个前脑-后脑回路来降低葡萄糖生成。
