Regulation of hepatic glucose fluxes

描述（由申请人提供）：内源性葡萄糖生成（EGP）是在空腹条件下维持血糖水平的关键过程。虽然EGP受到葡萄糖和胰岛素的抑制，但它在2型糖尿病（T2DM）中不适当地升高，是这些个体高血糖的主要来源。虽然血糖和胰岛素升高会迅速抑制非糖尿病患者的EGP，但T2DM与血糖和胰岛素对EGP的抑制作用丧失有关。值得注意的是，最近的啮齿动物研究表明，由于胰岛素和葡萄糖激活下丘脑KATP通道，明显通过迷走神经传出信号抑制EGP和糖异生，肝脏葡萄糖通量受到集中调节。鉴于潜在的物种差异存在相当大的争议，确定这对人类正常葡萄糖稳态调节的重要性，以及这种中枢神经系统（CNS）调节是否在T2DM患者中受损，将是很重要的。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葡萄糖通量。我们将首先确定在固定激素条件下，KATP通道的激活是否以及如何影响非糖尿病受试者的肝糖通量，以及这种影响是否可以通过抑制KATP通道来消除。此外，我们将确定葡萄糖调节的中枢神经系统途径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，我们将检查这种调节是否在2型糖尿病患者中受损。由于我们的初步数据表明，中枢神经系统输入在人类肝脏葡萄糖通量的调节中起着关键作用，因此恢复这种调节可能是对患有糖尿病的个体进行干预的重要目标

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.