Role of Hepatic Fat Metabolism in Glucose Effectiveness

描述(申请人提供)：内源性葡萄糖产生(EGP)在2型糖尿病(T2 DM)中升高，是空腹高血糖的主要原因。在非糖尿病患者中，升高的血糖水平主要通过抑制糖原分解来迅速抑制EGP。T2 DM患者的高血糖恶化与葡萄糖对EGP的抑制作用丧失有关。尽管它对代谢控制的恶化有重要贡献，但人们对T2 DM‘葡萄糖有效性’丧失的发病机制知之甚少。虽然已知T2 DM与糖异生增加和糖原分解减少有关，但高血糖对这些途径的影响从未在T2 DM受试者中被研究过。我们将使用最先进的胰腺钳研究技术，放射性标记和稳定的同位素示踪剂，以及核磁共振波谱来研究高血糖对肝脏葡萄糖流量的影响。将使用两种方法：a)比较控制不良的T2 DM患者与年龄和SMI匹配的非糖尿病受试者的这些反应，以及b)前瞻性地确定血糖控制正常化的影响。值得注意的是，我们已经表明，仅72小时的强化胰岛素治疗完全恢复了T2 DM患者的血糖有效性，同时使FFA水平正常化。事实上，T2 DM患者长期升高的游离脂肪酸(FFA)水平可能会损害肝脏的葡萄糖有效性。我们将对比非糖尿病受试者升高FFA水平与T2 DM患者降低FFA水平对肝脏葡萄糖流量调节的急性影响。虽然FFA的增加已知会刺激糖异生，但这一途径的增加是否或如何影响葡萄糖的有效性尚不清楚。由于葡萄糖和基础胰岛素都抑制非糖尿病患者的脂解作用，我们将确定这些抑制作用在T2 DM患者中是否受损，以及是否通过纠正代谢缺陷来恢复这些抑制作用。鉴于肝脏“葡萄糖效应”的丧失对T2 DM患者高血糖恶化的重要性，阐明这些关系将具有相当大的治疗意义。

DESCRIPTION (provided by applicant): Endogenous glucose production (EGP) is elevated in type 2 diabetes mellitus (T2DM), and is the main cause of fasting hyperglycemia. Rising glucose levels rapidly suppress EGP in nondiabetic individuals, mainly by inhibiting glycogenolysis. Worsening hyperglycemia in T2DM is associated with loss of the suppressive effects of glucose on EGP. Little is known about the pathogenesis of this loss of 'glucose effectiveness' in T2DM, despite its important contribution to worsening metabolic control. Although T2DM is known to be associated with increased gluconeogenesis and decreased glycogenolysis, the impact of hyperglycemia on these pathways has never been examined in T2DM subjects. We will use 'state-of-the-art' techniques of pancreatic clamp studies, radiolabeled and stable isotope tracers, and NMR spectroscopy to study the impact of hyperglycemia on hepatic glucose fluxes. Two approaches will be used: a) comparing these responses in poorly controlled T2DM individuals versus age- and SMI-matched non-diabetic subjects, and b) prospectively determining the impact of normalizing glycemic control. Of note, we have shown that intensive insulinization for only 72 hours completely restores glucose effectiveness in T2DM along with normalizing FFA levels. Indeed, the chronically elevated free fatty acid (FFA) levels in T2DM may impair hepatic glucose effectiveness. We will contrast the acute effects of raising FFA levels in nondiabetic subjects vs. lowering FFA levels in T2DM on the regulation of hepatic glucose fluxes. While increased FFA are known to stimulate gluconeogenesis, it is not known whether or how an increase in this pathway would impact glucose effectiveness. Since glucose and basal insulin both inhibit lipolysis in nondiabetic individuals, we will determine whether these inhibitory effects are impaired in T2DM and whether they are restored by correcting the metabolic defects. Given the importance of the loss of hepatic 'glucose effectiveness' to worsening hyperglycemia in T2DM, elucidating these relationships would be of considerable therapeutic relevance.