Regulation of hepatic glucose fluxes

描述(由申请人提供)：内源性葡萄糖产生(EGP)是在禁食条件下维持血糖水平的关键过程。虽然EGP被葡萄糖和胰岛素抑制，但它在2型糖尿病(T2 DM)中不适当地升高，是这些人高血糖的主要来源。虽然在非糖尿病患者中，血糖和胰岛素的升高会迅速抑制EGP，但T2 DM与葡萄糖和胰岛素对EGP的这些抑制作用的丧失有关。值得注意的是，最近的啮齿动物研究表明，肝脏的葡萄糖流量是受中央调节的，因为胰岛素和葡萄糖激活下丘脑KATP通道抑制了EGP和糖异生，显然是通过迷走神经传出信号。鉴于潜在的物种差异存在相当大的争议，重要的是要确定这对人类葡萄糖稳态的正常调节有多重要，以及这种中枢神经系统(CNS)调节在T2 DM患者中是否受到损害。我们将在人类受试者中使用最先进的‘胰腺钳’研究来解决这些问题，并通过示踪剂方法量化肝脏葡萄糖流量。我们将首先确定在固定的激素条件下，KATP通道的激活是否以及如何影响非糖尿病受试者的肝脏葡萄糖流量，以及这种影响是否可以通过抑制KATP通道来消除。此外，我们还将确定中枢神经系统葡萄糖调节通路在多大程度上有助于葡萄糖和胰岛素对EGP的抑制作用。然后，我们将检查这一调节在T2 DM患者中是否受损。由于我们的初步数据表明，中枢神经系统的输入在人类肝脏葡萄糖流量的调节中起着关键作用，恢复这一调节可能是对患有糖尿病的患者进行干预的一个重要目标。 T2 DM。

DESCRIPTION (provided by applicant): Endogenous glucose production (EGP) is a critical process that maintains blood glucose levels under fasting conditions. While EGP is suppressed by both glucose and insulin, it is inappropriately elevated in type 2 diabetes mellitus (T2DM) and is the major source of hyperglycemia in these individuals. Although rises in plasma glucose and insulin rapidly inhibit EGP in nondiabetic individuals, T2DM is associated with loss of these suppressive effects of glucose and insulin on EGP. Of note, recent rodent studies suggest that hepatic glucose fluxes are centrally regulated, since activation of hypothalamic KATP channels by insulin and glucose suppresses EGP and gluconeogenesis, apparently via vagal efferent signals. Given considerable controversy about potential species differences, it will be important to establish how important this is to normal regulation of glucose homeostasis in humans, and whether this central nervous system (CNS) regulation is impaired in individuals with T2DM. We will address these questions in human subjects using state-of-the-art 'pancreatic clamp' studies, with quantification of hepatic glucose fluxes by tracer methodologies. We will first determine whether and how activation of KATP channels impacts hepatic glucose fluxes in nondiabetic subjects under fixed hormonal conditions, and whether this effect can be abolished by inhibiting KATP channels. Additionally, we will determine the extent to which CNS pathways of glucose regulation could contribute to the suppressive effects of glucose and insulin on EGP. We will then examine whether this regulation is impaired in individuals with T2DM. Since our preliminary data suggest that CNS inputs play a key role in the regulation of hepatic glucose fluxes in humans, restoring this regulation could be an important target for intervention in individuals with T2DM.