Investigating the Role of the O-GlcNAc Post-Translational Modification in the Development of Type II Diabetes and Alzheimer's Disease

There is a growing prevalence of type 2 diabetes. It has been estimated that more than 20 million people have the disease in the United States alone. Type 2 diabetes is a disease characterized by resistance of our bodies to insulin, a hormone needed for normal metabolism of carbohydrates, fats, and proteins. This resistance leads to prolonged elevation of blood sugar levels, eventually giving rise to the diseased state. Understanding what events lead to insulin resistance is an intense topic of research. Nevertheless, the precise molecular mechanisms by which insulin resistance arises still require delineation in order to fully understand the disease Building on his MSFHR-funded Master’s research, Matthew Macauley is investigating what the role of proteins modified by a sugar known as GIcNAc have in causing insulin resistance. One hypothesis is that high levels of glucose over a long time period may increase GlcNAc modification and that this in turn results in insulin resistance. Macauley is using an enzyme inhibitor of O-GlcNAcase to artificially create elevated levels of GlcNAc in animal models to determine if insulin resistance and type 2 diabetes ensue. Using this same enzyme inhibitor, Macauley is also conducting a separate study to increase GIcNAc attached to tau, a key protein involved in the development of Alzheimer’s disease. The goal of this study is to determine if the inhibitor can prevent or delay the onset of Alzheimer’s in an animal model.