Hormonal Regulation of Glycogen Synthesis

毫无疑问，我们正处于糖尿病的全球流行之中。据认为，美国有近1600万人患有这种疾病，其中三分之一未被诊断出来。胰岛素抵抗被认为是该疾病的一个特征，其特征是无法对正常循环水平的胰岛素做出反应。这种状态下的原发性病变包括肌肉和脂肪细胞对葡萄糖的摄取和储存缺陷。针对这些缺陷是开发新的治疗方法的关键。然而，要了解导致2型糖尿病患者胰岛素抵抗的特定病变，首先需要更好地掌握胰岛素作用的细胞生物学。为此，将研究胰岛素调节糖原合成的分子事件，特别关注一种新描述的支架蛋白PTG在调节蛋白质去磷酸化中的作用。在Aim 1中，将研究蛋白磷酸酶1 （PP1）的多个支架蛋白存在的分子基础，评估该家族的每个成员在信号转导中具有明确的单独功能的假设。这些分子的结构/功能关系将通过一系列的缺失和嵌合突变来分析。接下来将在细胞模型和完整大鼠肝脏中评估突变体对糖原代谢的影响。Aim 2将重点剖析胰岛素在糖原颗粒处激活PP1的信号通路，从而刺激糖原合成酶。这种方法将追求两个新的假设，涉及鉴定可能是磷酸化底物的调节蛋白。PTG的生理功能将在Aim 3中通过靶向破坏小鼠PTG基因来研究。总之，这些方法将允许评估这一途径在胰岛素作用中的重要性，为未来研究其在糖尿病发展中的潜在作用奠定基础。

There is little doubt that we are in the midst of a worldwide epidemic of diabetes. Almost 16 million people in the US are thought to be afflicted, a third of whom are undiagnosed. Insulin resistance is recognized as a characteristic trait of the disease, defined by the inability to respond to normal circulating levels of insulin. The primary lesion in this state involves defects in the uptake and storage of glucose in muscle and fat cells. Targeting these defects holds the key to the development of new therapeutic approaches. However, understanding the specific lesions that cause insulin resistance in patients with type 2 diabetes will first require a better grasp of the cell biology of insulin action. To this end, the molecular events involved in the regulation of glycogen synthesis by insulin will be investigated, with special attention to the role of a newly described scaffolding protein, PTG, in the regulation of protein dephosphorylation. In Aim l, the molecular basis for the existence of multiple scaffolding proteins for protein phosphatase 1 (PP1) will be investigated, evaluating the hypothesis that each member of this family has a defined separate function in signal transduction. The structure/function relationships of these molecules will be analyzed by a series of deletion and chimeric mutants. This will be followed by evaluation of the effects of the mutants on glycogen metabolism in cell models, and in intact rat liver. Aim 2 will focus on dissecting the signaling pathway that mediates the activation of PP1 by insulin at the glycogen pellet, resulting in the stimulation of glycogen synthase. This approach will pursue two novel hypotheses involving the identification of regulatory proteins that might be substrates for phosphorylation. The physiological function of PTG will be investigated in Aim 3, by the targeted disruption of the PTG gene in mice. Together, these approaches will allow for the evaluation of the importance of this pathway in insulin action, setting the stage for future investigations into its potential role in the development of diabetes.