Restoring Central Regulation of Glucose Production in Type 2 Diabetes

项目摘要/摘要 内源性葡萄糖的产生(Egp)是维持血液的一个重要过程。 在禁食条件下的血糖水平，通常被葡萄糖和 胰岛素。不适当的高EGP是个体高血糖的主要来源 患有2型糖尿病(T2D)，并极大地增加了糖尿病并发症。我们的 研究小组正在进行的研究表明，中枢神经系统(CNS)信号在 在调节EGP方面发挥重要作用。三磷酸腺苷敏感钾(KATP)通道 下丘脑腹内侧核(VMH)似乎介导了某些抑制效应 循环胰岛素和葡萄糖对EGP的影响，但这一调节在T2D和 糖尿病啮齿动物。我们观察到，完全降低游离脂肪酸(FFA)水平 通过激活中枢KATP通道恢复对EGP的调节。因此，我们 假设慢性脂质过载可能导致中枢信号转导缺陷 T2D。因此，通过对人类和啮齿动物的互补研究，我们建议扩大 我们对特定的中枢神经系统信号通路如何通过 以下具体目标：1)确定是否可以对EGP进行中央调控 通过降低T2D患者的FFA水平恢复，2)确定是否完整 EGP降压后中枢调节的恢复需要肝神经支配 T2D患者的FFA，以及3)确定中枢调节是否受损 T2D中EGP的表达是由KATP通道激活的神经元特异性缺陷所介导的 VMH。此外，我们将确定降低FFA水平是否有助于 通过减少内质网恢复葡萄糖产生的中枢调节 (Er)特定葡萄糖感觉神经元的应激反应。总的来说，这些研究应该 T2D中EGP中枢调节受损的机制解释(S) 并帮助指出新的治疗靶点。

Project Summary/Abstract Endogenous glucose production (EGP) is a crucial process that maintains blood glucose levels under fasting conditions and is normally inhibited by both glucose and insulin. Inappropriately high EGP is the major source of hyperglycemia in individuals with type 2 diabetes (T2D) and contributes significantly to diabetes complications. Our groups’ ongoing work suggests that central nervous system (CNS) signals play an important role in regulating EGP. ATP-sensitive potassium (KATP) channels in the ventromedial hypothalamus (VMH) appear to mediate some of the suppressive effects of circulating insulin and glucose on EGP, but this regulation is impaired in T2D and diabetic rodents. We have observed that lowering free fatty acid (FFA) levels completely restored the regulation of EGP by central KATP channel activation. Therefore, we hypothesize that chronic lipid overload may contribute to the central signaling defects in T2D. Thus, through complementary human and rodent studies we propose to expand our understanding of how specific CNS signaling pathways regulate EGP through the following specific aims: 1) To establish whether central regulation of EGP can be restored by lowering FFA levels in patients with T2D, 2) To determine whether intact hepatic innervation is required for restoration of central regulation of EGP upon lowering FFA in individuals with T2D, and 3) To establish whether the impaired central regulation of EGP in T2D is mediated by neuron-specific defects in KATP channel activation within the VMH. Furthermore, we will determine whether lowering FFA levels contributes to restoring central regulation of glucose production by reducing endoplasmic reticulum (ER) stress in specific glucose-sensing neurons. Collectively, these studies should provide mechanistic explanation(s) for the impaired central regulation of EGP in T2D and help point toward novel therapeutic targets.