Hepatic Insulin Resistance Following Hemorrhage

出血后肝胰岛素抵抗

• 批准号: 8089345
• 负责人: Joseph Louis Messina
• 金额: $ 30.09万
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8089345
• 关键词: Acute; Adenoviruses; Adipose tissue; Animals; Behavior Therapy; Binding; Blood Glucose; Burn Trauma; Burn injury; Cellular Stress; Characteristics; Clinical Treatment; Complication; Critical Care; Critical Illness; Data; Defect; Development; Diabetes Mellitus; Emergency Situation; Energy Metabolism; Experimental Animal Model; Fatty acid glycerol esters; Future; Genetically Modified Animals; Grant; Hemorrhage; Hepatic; Human; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Incidence; Individual; Infection; Injury; Insulin; Insulin Receptor; Insulin Resistance; Insulin Signaling Pathway; Intensive Care Units; Liver; MAPK8 gene; Mediating; Metabolic; Morbidity - disease rate; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Operative Surgical Procedures; Patients; Peripheral; Progress Reports; Publishing; Renin-Angiotensin System; Role; Sepsis; Signal Pathway; Skeletal Muscle; Surgical Intensive Care; Symptoms; Tissues; Trauma; Treatment Protocols; United States National Institutes of Health; Work; adverse outcome; cytokine; design; glucose metabolism; glucose output; in vivo; insulin signaling; mortality; protein expression; public health relevance; receptor; response

DESCRIPTION (provided by applicant): This is a competitive renewal of NIH grant DK62071 entitled "Hepatic Insulin Resistance Following Hemorrhage" which focuses on studying the acute development of insulin resistance following injury. Over the past 5 years we have studied the mechanisms and causative factors that result in an acute insulin resistant state that occurs in animals, as in humans, after injury, infection or critical illness. Insulin resistance and hyperglycemia are characteristic metabolic responses to infections and injury such as surgery, burns, trauma and hemorrhage. Intensive insulin treatment of patients in the surgical ICU reduces both morbidity and mortality associated with critical illness, at least in some situations. However, intensive insulin therapy increases the likelihood of deleterious hypoglycemic incidents. Insulin is a primary modulator of hepatic glucose output, but little is known concerning the role of hepatic insulin resistance in the development of hyperglycemia following injury. Thus, it is important to understand what causes hepatic insulin resistance. Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post- receptor defect. Recently published and preliminary data indicate that there are insulin receptor and post-receptor defects in insulin signaling that develop in the liver following surgical trauma alone, and to an even greater degree following the combination of trauma and hemorrhage. Our recent preliminary data also indicates that the initial development of hepatic insulin resistance is not dependent upon proinflammatory cytokines. Additional preliminary data indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, liver, skeletal muscle and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. However, this has a possible advantage of eventually being able to specifically target individual tissues, with treatments less likely than intensive insulin therapy to cause hypoglycemic incidents. In addition, understanding the development of insulin resistance may be important in determining the proper application of intensive insulin therapy, and under what conditions this therapy might do the most good. Thus, studies are proposed in this application to determine the mechanism(s) of the development of acute insulin resistance in liver. Potential clinical treatments are explored that may work to reverse the mortality and morbidity related to hyperglycemia and insulin resistance in the critical care setting. These studies are important in understanding the role of insulin resistance in the morbidity and mortality following injury, infection and critical illness. PUBLIC HEALTH RELEVANCE: Patients in intensive care units often have high blood glucose levels, as well as high insulin levels, a symptom similar to the insulin resistance of Type 2 diabetes, even with no preexisting symptoms of diabetes. However, little is known as to the basic reasons of this insulin resistance and an understanding of the mechanisms and causative factors of this insulin resistance will allow us to develop focused treatments for the many patients with deranged glucose metabolism in the ICU and emergency setting.

描述（由申请人提供）：这是NIH资助DK62071的竞争性更新，标题为“出血后肝胰岛素抵抗”，重点研究损伤后胰岛素抵抗的急性发展。在过去的5年里，我们研究了导致动物（如人类）在受伤、感染或重症后出现急性胰岛素抵抗状态的机制和致病因素。胰岛素抵抗和高血糖症是对感染和损伤如手术、烧伤、创伤和出血的特征性代谢反应。外科ICU患者的强化胰岛素治疗至少在某些情况下降低了与危重病相关的发病率和死亡率。然而，强化胰岛素治疗增加了有害的低血糖事件的可能性。胰岛素是肝脏葡萄糖输出的主要调节剂，但关于肝脏胰岛素抵抗在损伤后高血糖发展中的作用知之甚少。因此，重要的是要了解是什么原因导致肝脏胰岛素抵抗。 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。最近发表的和初步的数据表明，在胰岛素信号传导中存在胰岛素受体和受体后缺陷，其在单独的手术创伤后在肝脏中发展，并且在创伤和出血的组合后发展到甚至更大的程度。我们最近的初步数据也表明，肝脏胰岛素抵抗的最初发展并不依赖于促炎细胞因子。另外的初步数据表明，在三种主要的胰岛素靶组织（肝脏、骨骼肌和脂肪组织）中，胰岛素抵抗的发展机制是不同的。这使得有必要分别研究每个组织，以确定这种胰岛素抵抗是如何发生的。然而，这具有最终能够特异性靶向个体组织的可能优势，治疗不太可能比强化胰岛素治疗引起低血糖事件。此外，了解胰岛素抵抗的发展可能对确定强化胰岛素治疗的正确应用以及在何种条件下这种治疗可能最有效很重要。 因此，在本申请中提出了研究以确定肝脏中急性胰岛素抵抗的发展机制。潜在的临床治疗进行了探讨，可能会工作，以扭转死亡率和发病率相关的高血糖症和胰岛素抵抗的重症监护设置。这些研究对于了解胰岛素抵抗在损伤、感染和危重病后发病率和死亡率中的作用具有重要意义。 公共卫生相关性：重症监护病房的患者通常具有高血糖水平以及高胰岛素水平，这是一种类似于2型糖尿病的胰岛素抵抗的症状，即使没有预先存在的糖尿病症状。然而，很少有人知道这种胰岛素抵抗的基本原因，了解这种胰岛素抵抗的机制和致病因素将使我们能够为ICU和急诊环境中的许多葡萄糖代谢紊乱的患者开发有针对性的治疗方法。