Hormonal Regulation of Glycogen Synthesis

毫无疑问，我们正处于世界范围内的糖尿病流行之中。 美国有近 1600 万人被认为患有此病，其中三分之一尚未确诊。胰岛素抵抗被认为是该疾病的一个特征，其定义是无法对正常的胰岛素循环水平做出反应。 这种状态的主要病变涉及肌肉和脂肪细胞中葡萄糖的摄取和储存缺陷。 针对这些缺陷是开发新治疗方法的关键。 然而，要了解导致 2 型糖尿病患者胰岛素抵抗的具体病变，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所涉及的分子事件，特别关注新描述的支架蛋白PTG在调节蛋白质去磷酸化中的作用。 在目标 I 中，将研究蛋白磷酸酶 1 (PP1) 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缺失和嵌合突变体进行分析。 随后将评估突变体对细胞模型和完整大鼠肝脏中糖原代谢的影响。 目标 2 将重点剖析信号通路，该信号通路介导胰岛素在糖原颗粒处激活 PP1，从而刺激糖原合成酶。 这种方法将追求两个新的假设，涉及识别可能作为磷酸化底物的调节蛋白。 目标 3 将通过对小鼠 PTG 基因进行有针对性的破坏来研究 PTG 的生理功能。 总之，这些方法将允许评估该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.