Free Fatty Acids and Hepatic Insulin Resistance

游离脂肪酸和肝胰岛素抵抗

• 批准号: 7009244
• 负责人: Guenther Boden
• 金额: $ 32.33万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7009244
• 关键词: adult human (21+); calorimetry; clinical research; diabetes mellitus; diacylglycerols; fatty acids; gluconeogenesis; glucose metabolism; glycogenolysis; human subject; insulin sensitivity /resistance; laboratory rat; liver; phosphorylation; polymerase chain reaction; protein kinase C; tyrosine; western blottings

DESCRIPTION (provided by applicant): Hepatic insulin resistance resuIting in increased endogenous glucose production (EGP) is a major factor in the pathogenesis of type 2 diabetes (T2DM) Increased plasma levels of free fatty acids (FFAs) which are characteristically seen in obese individuals, have been established to cause peripheral (muscle) as well as hepatic insulin resistance. Most of the research efforts in recent years have focused on peripheral insulin resistance. Mainly due to methodological problems, hepatic insulin resistance has not received much attention. Recently, however, several methods have become available which allow non-invasive measurement of in vivo rates of gluconeogenesis (GNG) and glycogenolysis (GL), the two components of EGP. Using the 2H2O method, we have recently shown in healthy volunteers that acute elevations of plasma FFAs cause hepatic insulin resistance through inhibition of insulin suppression of GL. In the current application, we plan to expand these findings. In Specific Aim 1, we propose to assess dose dependency, duration and possible gender differences of the effects of acute elevation of plasma FFAs on insulin suppression of GL/EGP in healthy subjects and in patients with mild and severe T2DM. These studies will involve measurements of rates of GL, GNG and EGP during euglycemic-hyperinsulinemic clamping (in normal controls) or during isoglycemic-hyperinsulinemic clamping (in patients with T2DM) with and without simultaneous infusion of heparinized lipid (at different rates of infusion) to acutely raise plasma FFAs to different levels. In Specific Aim 2, we propose to evaluate effects of prolonged elevation of plasma FFAs on hepatic insulin sensitivity. The experimental approach will be to lower plasma FFAs overnight (12 h) with Niaspan (a nicotinic acid analog) and to measure insulin suppression of GL/EGP the next morning (during hyperinsulinemic clamping) in obese patients with mild or severe T2DM. In Specific Aim 3, we will address the mechanism by which elevated FFAs cause hepatic insulin resistance. Specifically, we will test the hypothesis that FFA mediated hepatic insulin resistance is associated with intrahepatic accumulation of diacylglycerol (DAG), activation of protein kinase C (PKC), with increased serine and decreased tyrosine phosphorylation of IRS-1/2, and a decrease in PI3 kinase responses to insulin. The experimental approach will be to sacrifice rats at various time intervals during hyperinsulinemic-euglycemic clamping performed with and without lipid/heparin infusions and determine hepatic concentrations of DAG, PKC activity and isoforms, IRS-1/2, tyrosine phosphorylation and PI3 kinase activity. These studies will hopefully provide much needed information relative to important details and mechanisms of FFA induced hepatic insulin resistance.

描述（由申请人提供）：在增加内源性葡萄糖产生（EGP）中抑制肝胰岛素抵抗，是2型糖尿病（T2DM）发病机理的主要因素，增加了在肥胖个体中具有特征性的自由脂肪酸（FFA）的血浆水平，从而导致肥胖个体有特征性地观察到的是跨性别的（均可引起彼得（Muscle）（肌肉）（肌肉）。近年来，大多数研究工作都集中在外围胰岛素抵抗上。主要是由于方法论问题，肝胰岛素抵抗并没有得到太多关注。然而，最近，已经获得了几种方法，这些方法允许对体内糖生成速率（GNG）和糖原分解（GL）（EGP的两个成分）进行非侵入性测量。使用2H2O方法，我们最近在健康志愿者中表明，血浆FFA的急性升高通过抑制GL胰岛素抑制而导致肝胰岛素抵抗。在当前的应用程序中，我们计划扩展这些发现。在特定目标1中，我们建议评估血浆FFA急性升高对健康受试者胰岛素抑制GL/EGP急性升高以及轻度和重度T2DM患者GL/EGP抑制GL/EGP的影响的剂量依赖性差异。这些研究将涉及测量在渗透性 - 高血糖 - 血肿胰岛素夹紧（在正常对照组中）或在同时输注肝素的脂质速率（以不同的水平）中，以使Plassma的水平不同。在特定目标2中，我们建议评估血浆FFA延长升高对肝胰岛素敏感性的影响。实验方法是用Niaspan（一种烟酸类似物）降低血浆FFA过夜（12小时），并在轻度或重度T2DM的肥胖患者中第二天早晨（在高胰岛素夹夹期间）测量GL/EGP的胰岛素抑制。在特定目标3中，我们将解决升高的FFA引起肝胰岛素抵抗的机制。具体而言，我们将检验以下假设：FFA介导的肝胰岛素抵抗与肝内二酰基甘油（DAG）的积累有关，丝氨酸蛋白激酶C（PKC）的激活，丝氨酸增加和降低IRS-1/2的酪氨酸磷酸化，以及PI3 KINase Respees to Insululin for Insululin sos inINase to inInsion sose in IRS-1/2的磷酸化。实验方法将是在有或没有脂质/肝素输注的高胰岛素 - 毛囊夹紧中以各种时间间隔牺牲大鼠，并确定DAG的肝浓度，PKC活性和同型，IRS-1/2，IRS-1/2，酪氨酸磷酸化和PI3激酶活性。这些研究将有望提供相对于FFA诱导的肝胰岛素抵抗的重要细节和机制的急需信息。