Hepatic Insulin Resistance Following Hemorrhage

出血后肝胰岛素抵抗

• 批准号: 7245931
• 负责人: Joseph Louis Messina
• 金额: $ 30.25万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7245931
• 关键词: Antibiotics; Applications Grants; Burn Trauma; Burn injury; Characteristics; Clinical; Critical Illness; Critical Illness Polyneuropathy; Data; Defect; Development; Energy Metabolism; Erythrocytes; Fatty acid glycerol esters; Glucose; Hemorrhage; Hepatic; Hyperglycemia; Hyperinsulinism; Immunologics; Individual; Infection; Inflammation; Injury; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Interleukin-6; Kidney Failure; Liver; Mechanical ventilation; Metabolic; Modeling; Morbidity - disease rate; Multiple Organ Failure; Muscle; Neurologic; Numbers; Operative Surgical Procedures; Outcome; Patients; Peripheral; Physiological; Play; Resistance; Role; Sepsis; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Skeletal Muscle; Tissues; Transfusion; Trauma; Work; cytokine; glucose output; glucose uptake; insight; insulin signaling; mortality; prevent; receptor; research study; resistance factors; resistance mechanism; response; response to injury; wasting

DESCRIPTION (provided by applicant): Insulin resistance and hyperglycemia are characteristic metabolic responses to infections (sepsis) and injury such as surger, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of patients reduces both morbidity and mortality associated with critical illness. However, little is known concerning the role of insulin resistance in the liver and the importance of this resistance in the physiological responses to injury. The liver plays a central role in the development of hyperglycemia and insulin is a primary modulator of hepatic glucose output. Thus, it is important to understand what causes hepatic insulin resistance, and the role this resistance plays in mortality following injury. The few research studies performed to date have focused on changes in insulin signaling in skeletal muscle following different kinds of injury or hemorrhage. Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post-receptor defect. Little is known about the cellular mechanisms by which the liver becomes resistant to insulin and the mechanisms and potential reversibility of trauma and hemorrhage-induced insulin resistance in the liver is the subject of this proposal. Preliminary studies suggest that hepatic insulin resistance develops rapidly following surgical trauma and hemorrhage. Proinflammatory cytokines may be involved in the development of this insulin resistance, and there is a defect in at least one insulin regulated signaling pathway. The aims of this proposal are to characterize the effects of experimental trauma (surgery) and hemorrhage on the development of hepatic insulin resistance, to investigate the mechanisms and causative factors leading to the insulin resistance and to determine whether insulin sensitizing agents can reverse or prevent the development of hepatic insulin resistance following trauma and hemorrhage. These studies are important in understanding the role of insulin resistance in the morbidity and mortality following various types of infections, surgery, burns, trauma and hemorrhage.

描述（由申请人提供）： 胰岛素抵抗和高血糖是对感染（败血症）和损伤（如手术、烧伤、创伤和出血）的典型代谢反应。最近的数据表明，对患者进行强化胰岛素治疗可降低与危重疾病相关的发病率和死亡率。然而，人们对胰岛素抵抗在肝脏中的作用以及这种抵抗在损伤生理反应中的重要性知之甚少。肝脏在高血糖的发生中起着核心作用，而胰岛素是肝葡萄糖输出的主要调节剂。因此，了解导致肝脏胰岛素抵抗的原因以及这种抵抗在损伤后死亡率中所起的作用非常重要。迄今为止进行的少数研究主要集中在不同类型的损伤或出血后骨骼肌中胰岛素信号的变化。胰岛素抵抗可以通过胰岛素受体数量或其活性的变化或受体后缺陷来解释。关于肝脏对胰岛素产生抵抗的细胞机制知之甚少，而肝脏中创伤和出血引起的胰岛素抵抗的机制和潜在可逆性是该提案的主题。初步研究表明，手术创伤和出血后肝脏胰岛素抵抗迅速发展。促炎细胞因子可能参与这种胰岛素抵抗的发展，并且至少一种胰岛素调节信号通路存在缺陷。该提案的目的是表征实验性创伤（手术）和出血对肝脏胰岛素抵抗发展的影响，研究导致胰岛素抵抗的机制和致病因素，并确定胰岛素增敏剂是否可以逆转或预防创伤和出血后肝脏胰岛素抵抗的发展。这些研究对于了解胰岛素抵抗在各种类型的感染、手术、烧伤、创伤和出血后的发病率和死亡率中的作用非常重要。