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: 8391564
• 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 2013-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8391564
• 关键词: Acute; Adenoviruses; Adipose tissue; Affect; Amputation; Angiotensin II Receptor; Behavior Therapy; Binding; Burn Trauma; Burn injury; Cardiovascular Surgical Procedures; Chronic; Chronic Disease; Clinical Treatment; Complication; Critical Care; Critical Illness; Data; Defect; Development; Diabetes Mellitus; Diagnosis; Experimental Animal Model; Fatty acid glycerol esters; Genetically Modified Animals; Glucocorticoids; Glucose; Hemorrhage; Hepatic; Human; Hyperglycemia; Hyperinsulinism; Hypoglycemia; Incidence; Individual; Infection; Injury; Insulin; Insulin Receptor; Insulin Resistance; Intensive Care Units; Lead; Liver; Mediating; Metabolic; Metabolic Diseases; Metabolic syndrome; Morbidity - disease rate; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Operative Surgical Procedures; Outpatients; Pathway interactions; Patients; Peripheral; Play; Population; Prevalence; Progress Reports; Publishing; Reactive Oxygen Species; Renin-Angiotensin System; Risk Factors; Role; Sepsis; Signal Pathway; Signal Transduction Pathway; Skeletal Muscle; Time; Tissues; Trauma; Treatment Protocols; Tumor Necrosis Factor-alpha; Vascular Diseases; Work; adverse outcome; cytokine; glucose disposal; glucose metabolism; glucose output; glucose uptake; human TNF protein; in vivo; insulin signaling; mortality; prevent; protein expression; public health relevance; receptor; 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. The increased incidence of hypoglycemic incidents is 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 reduce insulin resistance more advantageous to the patient than intensive insulin therapy? And what tissue or tissues need to be targeted? Our recently published and preliminary data indicate that there are insulin receptor 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 the initial development of insulin resistance is unknown. Additional preliminary date 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. 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.

描述（由申请人提供）： 高血压和胰岛素抵抗在许多代谢紊乱中是常见的，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置减少，这主要发生在骨骼肌中。急性胰岛素抵抗和高血糖症的研究要少得多，但感染和损伤，如手术，烧伤，创伤和出血的特征性代谢反应。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病相关的发病率和死亡率。然而，关于强化胰岛素治疗的正确使用，以及在什么情况下它可以发挥最大的作用，或者相反，当它是不必要的或有害的时，存在一些争议。低血糖事件的发生率增加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广泛应用于ICU，但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是如何发展的，将是重要的，在确定强化胰岛素治疗的适当应用，最有利的时间开始后，不同的伤害，并可能建议新的治疗方案，以增加危重病人的生存。例如，降低胰岛素抵抗的治疗是否比强化胰岛素治疗对患者更有利？哪些组织或组织需要被靶向？我们最近发表的初步数据表明，手术创伤和出血后骨骼肌中胰岛素信号传导存在胰岛素受体和受体后缺陷。这些数据表明糖皮质激素和促炎细胞因子的重要作用，但它们如何相互作用导致胰岛素抵抗的初步发展尚不清楚。另外的初步数据表明，在三种主要的胰岛素靶组织（骨骼肌、肝脏和脂肪组织）中，胰岛素抵抗的发生机制是不同的。这使得有必要单独研究每个组织，以确定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。