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: 7907741
• 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/7907741
• 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; Health; 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; receptor; response; study characteristics

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.

高血压和胰岛素抵抗常见于许多代谢紊乱， 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）。减少 对胰岛素的反应性导致胰岛素调节的葡萄糖处置减少， 主要发生在骨骼肌中。急性胰岛素抵抗和高血糖症要少得多 研究，但特征代谢反应感染和损伤，如手术， 烧伤创伤和出血 最近的数据表明，ICU患者的强化胰岛素治疗可能会减少这两种情况。 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，以及在什么条件下可以做到这一点。 最好的，或者相反，当它是不必要的或有害的。的发生率增加 低血糖事件是强化胰岛素治疗的主要并发症。即使 强化胰岛素治疗现在广泛用于ICU，但对胰岛素治疗的作用知之甚少。 胰岛素抵抗急性发作的潜在机制。例如， 发展，什么是致病因素，什么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， 在确定强化胰岛素治疗的正确应用方面，最重要的是 在不同的损伤后开始治疗的有利时间，并可能建议新的治疗方法 提高危重病人存活率的方案。比如说，减少胰岛素的治疗 胰岛素抵抗比强化胰岛素治疗对患者更有利？什么组织或者 组织需要靶向吗？ 我们最近发表的和初步的数据表明，有胰岛素受体， 手术后骨骼肌中胰岛素信号传导的受体后缺陷 创伤和出血这些数据表明糖皮质激素的重要作用， 促炎细胞因子，但它们如何相互作用，导致胰岛素的初步发展， 阻力未知。其他初步数据表明， 胰岛素抵抗的发展在三个主要的胰岛素靶组织（骨骼）中是不同的 肌肉肝脏和脂肪组织这使得有必要分别研究每个组织， 确定胰岛素抵抗是如何发生的。然而，这可能具有以下优点： 最终能够特异性地靶向个体组织， 强化胰岛素治疗导致低血糖事件。此外，了解 胰岛素抵抗的发展可能在确定胰岛素的适当应用方面是重要的。 强化胰岛素治疗，以及在什么情况下这种治疗可能最好。