Hepatic Insulin Resistance Following Hemorrhage

出血后肝胰岛素抵抗

基本信息

批准号：
7984813
负责人：
Joseph Louis Messina
金额：
$ 36.63万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
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/7984813
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

项目摘要

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 Grant DK62071的竞争更新，标题为“出血后肝胰岛素抵抗”，它重点研究受伤后胰岛素抵抗的急性发展。在过去的五年中，我们研究了导致动物中发生急性胰岛素耐药性状态的机制和致病因素，例如人类，受伤，感染或危重疾病。胰岛素抵抗和高血糖是对感染和损伤的特征代谢反应，例如手术，烧伤，创伤和出血。至少在某些情况下，对手术ICU患者的强化胰岛素治疗降低了与危重疾病相关的发病率和死亡率。但是，强化胰岛素治疗增加了有害降血糖事件的可能性。胰岛素是肝葡萄糖输出的主要调节剂，但几乎不知道肝胰岛素抵抗在损伤后的高血糖发展中的作用。因此，重要的是要了解导致肝胰岛素抵抗的原因。胰岛素抵抗可以通过胰岛素受体数量或其活性或后受体缺陷的变化来解释。最近发表的和初步的数据表明，仅手术创伤后，胰岛素信号中有胰岛素受体和受体后缺陷，并且在创伤和出血的结合之后，肝脏中会发展出胰岛素受体和受体缺陷。我们最近的初步数据还表明，肝胰岛素抵抗的初始发展不取决于促炎细胞因子。其他初步数据表明，在三个主要的胰岛素靶组织，肝脏，骨骼肌和脂肪组织中，胰岛素抵抗发展的机制不同。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。但是，这可能是最终能够特异性靶向单个组织的可能优势，与强化胰岛素治疗有关引起降血糖事件的治疗可能性较小。此外，了解胰岛素抵抗的发展对于确定强化胰岛素疗法的适当应用可能很重要，在哪些条件下，该疗法可能最有效。因此，在本应用中提出了研究，以确定肝脏急性胰岛素抵抗的发展机制。探索了潜在的临床治疗方法，可以扭转重症监护环境中与高血糖和胰岛素抵抗相关的死亡率和发病率。这些研究对于理解胰岛素抵抗在受伤，感染和危重疾病后的发病率和死亡率中的作用很重要。公共卫生相关性：重症监护病房中的患者通常具有高血糖水平以及高胰岛素水平，这种症状类似于2型糖尿病的胰岛素抵抗，即使没有糖尿病的先前症状。然而，几乎不知道这种胰岛素抵抗的基本原因以及对这种胰岛素抵抗的机制和病因因素的理解将使我们能够为许多在ICU和紧急情况下为许多葡萄糖代谢的患者开发集中的治疗方法。