There is little doubt that we are in the midst of a worldwide epidemic of diabetes. 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 nonoxidative metabolism of glucose, expressed as glycogen accumulation in muscle and liver, and may also involve changes in the branching structure of glycogen. Moreover, glycogen storage diseases involve aberrations in glycogen synthesis, degradation, branching and debranching. We have studied glycogen scaffolding proteins that target enzymes involved in glycogen metabolism, and uncovered a role in controlling glycogen debranching.
In Aim 1, we will study the signaling pathways involved in glycogen debranching, focusing on the regulation of the debranching enzyme AGL. We will investigate how hormones or glucose deprivation might influence the phosphorylation state and activity of this enzyme.
In Aim 2, we will evaluate how the glycogen targeting protein PTG influences glycogen metabolism via AGL. PTG can interact directly with AGL, and we will explore the regulatory significance of this interaction, evaluating the control of localization and activity in detail. Finally, in Aim 3, we will evaluate the role of a dual specificity protein phosphatase called Laforin in regulating glycogen metabolism and branching. Laforin dynamically regulates AGL along with PTG. The protein is encoded by the gene that causes Lafora's disease, a genetic disease in which unbranched glycogen accumulates, thus providing important hints into how this process is regulated in normal tissues. We will search for additional substrates of Laforin to explore other ways in which this protein regulates glycogen synthesis. Together, these approaches will allow for the evaluation of how glycogen metabolism is regulated in liver and muscle, setting the stage for future investigations into its potential role in the development of diabetes and other disorders of energy metabolism.
