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 uptake and storage of glucose in muscle and fat cells. Insulin stimulates glucose uptake in these cells by increasing the concentration of the facilitativ transporter Glut4 at the cell surface, and stimulates storage by increasing the conversion of glucose into lipid. The molecular events involved in this process will be investigated, with specia attention to the underlying basis for the specificity of actions of the hormone. We have learned that small G proteins coordinately integrate signals from the insulin receptor to control the trafficking of Glut4. Previous studies have revealed a central role for the G proteins TC10 and Rab5, which are activated in a cascade of events.
In Aim 1, we will study the molecular mechanisms underlying the production of two unique and important phospholipids, phosphatidylinositol 3 phosphate and 3,5 bisphosphate. We will identify the enzymes responsible for their synthesis and determine how they are regulated by insulin.
In Aim 2, we will study how Rab5 cooperates with phosphatidylinositol 3-phosphate to control the trafficking of Glut4 in fat cells, focusing on the regulation of the internalization of this important transport protein. Finally, in Aim 3, we will evaluate how the lipid phosphatidylinositol 3,4 bisphosphate works together with Rab5 to regulate the mTORC1 phosphorylation pathway. This pathway is essential for growth and metabolism, and we hypothesize that the phospholipid controls the localization of the kinase complex in cells, ensuring the substrate specificity and fidelity of the phosphorylation events. Together, these approaches will allow for the evaluation of the importance of these regulatory molecules in insulin action, setting the stage for future investigations into their potential role in the development of diabetes.
Insulin increases glucose transport and storage in muscle and fat cells through coordinated pathways that involve small G proteins. We will investigate the mechanisms of regulation of these G proteins by the hormone, and how they control signaling pathways through the generation of novel phospholipids called phosphoinositides. We will study mice in which genes encoding some of these pathways are disrupted, in attempts to learn how organisms adapt to energy needs.
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