Molecular Mechanisms of Burn Induced Insulin Resistance

烧伤所产生的胰岛素受体底物1(IRS-1)的磷酸化和/或降解的改变可能是烧伤诱导的胰岛素抵抗的部分原因。具体地说，烧伤后骨骼肌葡萄糖转运的减少可能继发于IRS-1的丰度和/或磷酸化的改变。我们认为，烧伤后IRS-1丝氨酸磷酸化的改变是由白介素6(IL-6)或肿瘤坏死因子[TNF]等细胞因子激活应激蛋白(p38、MAPK或SAPK中间通路)所介导的，通过多种机制下调IRS-1的功能。磷酸化可以改变IR/IRS1相互作用，也可以改变IRSI/PI 3-激酶相互作用。此外，IRS-1的丰度是胰岛素信号转导的主要决定因素，IRS-1的降解在一定程度上是通过改变IRS-1Ser/Thr的磷酸化来控制的，例如，通过依赖mTOR的途径。因此，我们认为烧伤可能增加IRS-1的周转。我们认为，进一步表征和探索与严重烧伤相关的糖耐量受损和“胰岛素抵抗”的代谢病因学的最好方法是通过一套完整的人类研究，并通过使用小鼠烧伤模型进行更具侵入性和机械重点的研究来补充和扩展这些研究。后者将被用来确定可能对临床环境中观察到的代谢变化和异常负有因果责任的胰岛素功能和作用的细胞基因座，并将作为合理设计干预措施的基础，旨在将糖代谢和体内平衡受损的不良后果降至最低。因此，本研究的具体目标是：(1)测定烧伤后胰岛素抵抗作用下体内骨骼肌葡萄糖转运/磷酸化和蛋白质合成/分解代谢；(2)测定应激反应。 (3)确定IRS-1上的磷酸化位点。

Alterations in the phosphorylation and/or degradation of insulin receptor substrate 1 (IRS-1) produced by burn injury may be responsible, in part, for burn-induced insulin resistance. Specifically, the reduction in glucose transport in skeletal muscle following burn injury may be secondary to altered abundance and/or phosphorylation of IRS-1. We propose that altered serine phosphorylation of IRS-1 following burn injury, mediated by the activation of the stress kinases (p38, MAPK, or SAPK intermediate pathways) by cytokines, such as interleukin-6 (IL-6) or Tumor Necrosis Factor [TNF], down-regulates IRS-1 functions through several mechanisms. Phosphorylation can alter IR/IRS1 interaction as well as IRSI/PI 3-kinase interaction. Moreover, the abundance of IRS-1 is a major determinant of insulin signaling, and the degradation of IRS-1 is controlled, in part, through altered IRS-1 ser/thr phosphorylation, e.g., by an mTOR-dependent pathway. Therefore, we propose that burn injury may increase the turnover of IRS-1. We believe that the best way to further characterize and explore the metabolic etiology of impaired glucose tolerance and the "insulin-resistance" associated with severe burn injury is via an integrated set of studies in human subjects that are complemented and extended by more invasive and mechanistically-focused investigations using murine burn models. The latter will be exploited to define possible cellular loci of insulin function and action that might be causally responsible for the metabolic alterations and abnormalities observed in the clinical setting and would serve as a basis for the rational design of interventions aimed at minimizing the untoward consequences of impaired glucose metabolism and homeostasis. Therefore, the specific aims are: (1) Determine in vivo skeletal muscle glucose transport/phosphorylation and protein synthesis/catabolism under the effects of insulin resistance of burn injury; (2) Determine stress kinase activities after injury; and (3) Determine the phosphorylation sites on IRS-1.