MOLECULAR PHARMACOLOGY OF INSULIN RESISTANCE IN BURNS

烧伤与蛋白质、脂肪、 以及影响发病率和死亡率的碳水化合物。在生理状态下 在这种情况下，胰岛素会增加葡萄糖的摄取，延缓蛋白质的分解代谢。 烧伤后，胰岛素的这一关键作用就会失去敏感性。这 建议：(1)研究烧伤的分子机制 胰岛素抵抗与(2)明确治疗作用密切相关 多肽，胰岛素样生长因子-1(IGF-1)。 (1)β-肾上腺素能受体(beta-adrenoceptor，BetaAR)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信号转导缺陷与胰岛素抵抗之间的关系 是通过遗传分析确定的。此外，肿瘤坏死因子，其释放和 功能受β-AR控制，诱导胰岛素抵抗。这个 正在检验的假设是，烧伤的胰岛素抵抗与 β-AR信号的脱敏及其对增强表达和效应的影响 肿瘤坏死因子。体外脂肪分解和体内2-脱氧葡萄糖摄取联合应用 用生化方法测定βAR/G蛋白/腺苷环化酶/蛋白 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的胰岛素信号。肿瘤坏死因子的表达 也会在这些组织中进行分析。β-AR和胰岛素之间的联系 功能将通过给予特定的Beta2AR激动剂进行测试， 克伦特罗，并检测体内肌肉葡萄糖摄取(和 脂肪细胞)。将测试肿瘤坏死因子和胰岛素功能之间的联系。 在体内，通过在有或没有抗肿瘤坏死因子的情况下摄取葡萄糖 抗体。 (2)胰岛素样生长因子-1被证明可以促进胰岛素的细胞内信号传递。 并在许多病理状态下改善胰岛素抵抗。IGF-1， 应用于烧伤患者，可促进伤口愈合和 缩短住院时间。这些作用在烧伤中的分子机制 都不清楚。胰岛素样生长因子-1的有益作用是通过中介的假说 通过胰岛素样生长因子-1R增强胰岛素后受体信号转导 传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分析 行为。 这些研究将有助于分子的基础知识。 烧伤所致胰岛素抵抗的药理学基础及提供 胰岛素抵抗治疗操作的见解和理论基础。

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.