Trauma and Hemorrhage-Induced Skeletal Muscle Insulin Resistance

创伤和出血引起的骨骼肌胰岛素抵抗

• 批准号: 8920784
• 负责人: Joseph Louis Messina
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-10-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920784
• 关键词: Accidental Injury; Acute; Adipose tissue; Affect; Binding; Biological; Blood Glucose; Burn Trauma; Burn injury; Cells; Chronic; Chronic Disease; Clinical Treatment; Complication; Critical Care; Critical Illness; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Energy Metabolism; Fatty acid glycerol esters; Functional disorder; Genetically Modified Animals; Glucocorticoids; Glucose; Hemorrhage; Hepatic; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Imaging Techniques; Incidence; Individual; Infection; Injury; Insulin; Insulin Receptor; Insulin Resistance; Intensive Care Units; Interleukin-6; Liver; Metabolic; Metabolic Diseases; Metabolic syndrome; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Patients; Peripheral; Play; Population; Progress Reports; Publishing; Reactive Oxygen Species; Recovery; Renin-Angiotensin System; Resuscitation; Risk Factors; Role; Sepsis; Signal Pathway; Skeletal Muscle; Source; Symptoms; Time; Tissues; Trauma; Trauma patient; Treatment Protocols; Tumor Necrosis Factor-alpha; Work; adverse outcome; cytokine; design; glucose disposal; glucose metabolism; glucose output; glucose uptake; insulin sensitivity; insulin signaling; mortality; prevent; public health relevance; receptor; resistance mechanism; response; study characteristics

 DESCRIPTION (provided by applicant): Hyperglycemia and insulin resistance are common in many metabolic disorders such Type 2 diabetes, obesity, and metabolic syndrome. In these chronic conditions, there is a decreased responsiveness to endogenous insulin (insulin resistance). The decreased responsiveness to insulin results in a reduction in insulin- regulated glucose disposal, which occurs mostly in skeletal muscle. Acute insulin resistance and hyperglycemia are much less studied, but are characteristic metabolic responses to infections and injuries such as surgery, burns, trauma and hemorrhage. Recent data suggests that intensive insulin treatment of ICU patients may reduce both morbidity and mortality associated with critical illness. However, there is some controversy concerning the proper use of intensive insulin therapy, and under what conditions it can do the most good, or conversely when it is unnecessary or harmful. Intensive insulin therapy increases the likelihood of deleterious hypoglycemic incidents, a major complication of intensive insulin therapy. Even though intensive insulin therapy is now extensively used in the ICU, little is known about the mechanisms underlying the acute onset of insulin resistance. For instance, how quickly it develops, what are the causative factors, what intracellular signaling pathways are affected, and what tissues are involved. An understanding of how this insulin resistance develops will be important in determining the proper application of intensive insulin therapy, the most advantageous time for initiation following different injuries, and may suggest new treatment protocols to increase survival of critically ill patients. For instance, is therapy to reuce insulin resistance more advantageous to the patient than intensive insulin therapy? And what tissue or tissues need to be targeted? Insulin resistance can be explained by changes in the number of insulin receptors or their activity, or a post- receptor defect. Our recently published and preliminary data indicate that there are insulin receptors and post-receptor defects in insulin signaling that develop in skeletal muscle following surgical trauma and hemorrhage. The data suggests an important role for the glucocorticoids and proinflammatory cytokines, but how they interact to cause the initial development of insulin resistance is unknown. Additional preliminary data indicate that the mechanisms of the development of insulin resistance are different in the three main insulin target tissues, skeletal muscle, liver, and adipose tissue. This makes it necessary to study each tissue separately, to determine how this insulin resistance occurs. In addition, there are time-dependent changes in the factors that maintain the insulin resistant state. We have also found these to be tissue dependent. These results may be clinically advantageous, allowing us to specifically target individual tissues with treatments less likely tha intensive insulin therapy to cause hypoglycemic incidents, and more likely to achieve the proper range of blood glucose levels in patients in the ICU. Thus, studies are proposed in this application to determine the mechanism(s) of the development of acute insulin resistance in skeletal muscle. Also, much of this application is designed to study the mechanisms of recovery of insulin sensitivity following resuscitation. 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 following injury, infection and critical illness.

 描述(由申请人提供)： 高血糖和胰岛素抵抗在许多代谢紊乱中很常见，如2型糖尿病、肥胖症和代谢综合征。在这些慢性疾病中，对内源性胰岛素的反应性降低(胰岛素抵抗)。对胰岛素的反应性降低导致胰岛素调节的葡萄糖处置减少，这主要发生在骨骼肌中。急性胰岛素抵抗和高血糖的研究要少得多，但它们是对感染和损伤(如手术、烧伤、创伤和出血)的典型代谢反应。最近的数据表明，ICU患者的强化胰岛素治疗可能会降低与危重疾病相关的发病率和死亡率。然而，对于胰岛素强化治疗的正确使用，以及在什么情况下可以起到最大的作用，或者相反，当它是不必要的或有害的，仍存在一些争议。强化胰岛素治疗增加了有害低血糖事件的可能性，这是强化胰岛素治疗的主要并发症。尽管强化胰岛素治疗现在在ICU中得到了广泛的应用，但人们对胰岛素抵抗急性发作的机制知之甚少。例如，它的发展速度有多快，致病因素是什么，细胞内的哪些信号通路受到影响，以及涉及哪些组织。了解胰岛素抵抗是如何发生的，对于确定胰岛素强化治疗的正确应用具有重要意义，强化胰岛素治疗是在不同创伤后开始治疗的最有利时机，并可能建议新的治疗方案以提高危重患者的存活率。例如，减轻胰岛素抵抗的治疗是否比强化胰岛素治疗更有利于患者？哪些组织或组织需要作为目标？胰岛素抵抗可以通过胰岛素受体数量或活性的变化或受体后缺陷来解释。我们最近发表的初步数据表明，胰岛素中存在胰岛素受体和受体后缺陷。 在手术创伤和出血后在骨骼肌中发展的信号。这些数据表明糖皮质激素和促炎细胞因子发挥了重要作用，但它们如何相互作用导致胰岛素抵抗的初始发展尚不清楚。更多的初步数据表明，胰岛素抵抗的发生机制在三个主要的胰岛素靶组织中是不同的，即骨骼肌、肝脏和脂肪组织。这使得有必要单独研究每个组织，以确定这种胰岛素抵抗是如何发生的。此外，维持胰岛素抵抗状态的因素存在时间依赖性变化。我们还发现这些都是组织依赖的。这些结果可能在临床上是有利的，使我们能够针对个别组织进行特定的治疗，这些治疗比强化胰岛素治疗更不可能导致低血糖事件，而更有可能达到ICU患者的适当范围的血糖水平。因此，建议在这一应用中进行研究，以确定骨骼肌急性胰岛素抵抗的发生机制(S)。此外，这种应用的大部分是为了研究复苏后胰岛素敏感性恢复的机制。探索了潜在的临床治疗方法，可能 努力扭转与受伤、感染和危重疾病后的重症监护环境中的高血糖和胰岛素抵抗有关的死亡率和发病率。