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性疾病中很常见，例如 2 型糖尿病、肥胖和代谢综合征。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理减少，这主要发生在骨骼肌中。急性胰岛素抵抗和高血糖的研究较少，但它们是对手术、烧伤、外伤和出血等感染和损伤的典型代谢反应。 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，关于正确使用强化胰岛素治疗以及在什么情况下它可以发挥最大作用，或者在什么情况下没有必要或有害时则相反，存在一些争议。强化胰岛素治疗会增加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 中广泛使用，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，哪些细胞内信号通路受到影响，以及涉及哪些组织。了解这种胰岛素抵抗如何发展对于确定强化胰岛素治疗的正确应用、不同损伤后开始治疗的最有利时间非常重要，并且可能会提出新的治疗方案以提高危重患者的生存率。例如，减少胰岛素抵抗的治疗是否比强化胰岛素治疗对患者更有利？需要针对哪些组织或哪些组织？ 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。我们最近发表的初步数据表明，胰岛素存在胰岛素受体和受体后缺陷 手术创伤和出血后骨骼肌中产生的信号。数据表明糖皮质激素和促炎细胞因子具有重要作用，但它们如何相互作用导致胰岛素抵抗的最初发展尚不清楚。其他初步数据表明，胰岛素抵抗的发展机制在骨骼肌、肝脏和脂肪组织这三个主要胰岛素靶组织中是不同的。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。此外，维持胰岛素抵抗状态的因素也存在随时间变化的变化。我们还发现这些是组织依赖性的。这些结果可能在临床上是有利的，使我们能够专门针对个体组织进行治疗，这种治疗比强化胰岛素治疗不太可能引起低血糖事件，并且更有可能使 ICU 患者的血糖水平达到适当的范围。 因此，在本申请中提出了研究以确定骨骼肌中急性胰岛素抵抗的发展机制。此外，该应用的大部分目的是研究复苏后胰岛素敏感性恢复的机制。探索潜在的临床治疗方法 致力于扭转受伤、感染和危重病后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。