MOLECULAR PHARMACOLOGY OF INSULIN RESISTANCE IN BURNS

烧伤与蛋白质，脂肪， 和碳水化合物影响发病率和死亡率。在生理 在某些条件下，胰岛素增强葡萄糖摄取并延缓蛋白质分解。 胰岛素的这一关键作用在烧伤后被脱敏。这 本研究旨在（1）探讨烧伤诱导的分子机制， 胰岛素抵抗和（2）定义密切相关的治疗作用 肽，胰岛素样生长因子-1（IGF-1）。 (1)β-肾上腺素受体（β AR）信号系统在 烧伤后的心肌和脂肪组织。最近，一个明确的联系 β-AR信号缺陷与胰岛素抵抗之间的联系 通过基因分析。此外，TNF，其释放和 功能由β AR控制，诱导胰岛素抵抗。的 正在检验的假设是，烧伤的胰岛素抵抗与 β AR信号转导的脱敏以及增强的表达和作用 的TNF。体外脂肪分解和体内2-脱氧葡萄糖摄取联合 β AR/G蛋白/腺苷酸环化酶/蛋白的生化测定 激酶A系统和胰岛素受体/胰岛素受体底物- 1/磷脂酰肌醇3-激酶系统将研究β AR和 烧伤大鼠脂肪细胞和肌肉中胰岛素信号的变化TNF表达 也将在这些组织中进行分析。β AR和胰岛素之间的联系 通过施用特异性β 2 AR激动剂来测试功能， 克伦特罗，并检查在体内葡萄糖摄取的肌肉（和 脂肪细胞）。将检验TNF和胰岛素功能之间的关联 在体内，通过在存在和不存在抗TNF的情况下的葡萄糖摄取 抗体的 (2)已显示IGF-1促进胰岛素的细胞内信号传导 并改善许多病理状态下的胰岛素抵抗。IGF-1， 施用给烧伤患者，导致增强的伤口愈合， 缩短住院时间。烧伤中这些作用的分子机制 不清楚。假设IGF-1的有益作用是由 通过IGF-1 R增强胰岛素后受体的信号传导 转导分子将在脂肪细胞和肌肉中进行测试，使用 上述用于评估胰岛素的相同技术和测定 行动 这些研究将有助于分子生物学的基础知识 烧伤诱导的胰岛素抵抗的药理学基础，并提供 对胰岛素抵抗治疗操作的见解和基本原理。

Burn injury is associated with uncontrolled catabolism of proteins, fats, and carbohydrates affecting morbidity and mortality. Under physiological conditions, insulin enhances glucose uptake and retards protein catabolism. This pivotal action of insulin is desensitized following burns. This proposal aims to (1) investigate the molecular mechanism of burn-induced insulin resistance and (2) define the therapeutic role of a closely-related peptide, insulin-like growth factor-1 (IGF-1). (1) Beta-adrenoceptor (betaAR) signaling system is desensitized in myocardial and adipose tissues after burns. Recently, a definitive link between defective betaAR signaling and insulin resistance has been established by genetic analyses. Furthermore, TNF, whose release and function are controlled by betaAR, induces insulin resistance. The hypothesis being tested is, that insulin resistance of burns is related to desensitization of betaAR signaling and to enhanced expression and effects of TNF. Lipolysis in vitro and 2-Deoxy -glucose uptake in vivo combined with biochemical assays of betaAR/G-protein/adenylate cyclase/protein kinase A systems and of insulin receptor/insulin receptor substrate- 1/phosphatidylinositol 3-kinase systems will investigate the betaAR and insulin signaling in adipocytes and muscles of burned rats. TNF expression will also be analyzed in those tissues. The link between betaAR and insulin function will be tested by administration of specific beta2AR agonist, clenbuterol, and examining in vivo glucose uptake in muscle (and adipocyte). The association between TNF and insulin function will be tested in vivo, by glucose uptake in the presence and absence of anti-TNF antibodies. (2) IGF-1 has been shown to facilitate intracellular signaling of insulin and improve insulin resistance in many pathological states. IGF-1, administered to burned patients, results in enhanced wound healing and shorter hospital stay. The molecular mechanisms of these actions in burns are unclear. The hypothesis that beneficial effects of IGF-1 are mediated through IGF-1R which enhances signaling via post insulin receptor transducing molecules will be tested in adipocytes and muscle, using the same techniques and assays described above for assessment of insulin actions. These studies will contribute to the fundamental knowledge of the molecular pharmacological bases of burn-induced insulin resistance and provide insights and rationale for therapeutic manipulation of insulin resistance.