Diabetes is a metabolic disorder that is currently affecting as many as 350 million people worldwide. Its occurrence is on the rise, correlates with increase in obesity and is estimated to shorten human lifespan by the average of 10 years.
In a healthy human, energy storage and release is controlled by a peptide hormone insulin. Insulin is produced in pancreas and released in response to elevated blood glucose levels (mostly resulting from food consumption). It triggers a number of responses in cells, directing them to store glucose, reduce liver glucose production, and store fat instead of using it as energy source. Breakdown of pancreatic insulin-producing cells result in type I diabetes. Type 2 diabetes (T2D), which is the focus of this research and accounts for about 90% of patients, occurs in context of insulin resistance, when cells exhibit weakened response to insulin.
Insulin resistance may be caused by diverse hereditary and environmental factors. Existing treatments of type 2 diabetes target direct or indirect increase in available insulin or suppress release of glucose by liver. While effective, these therapies do not alleviate the insulin resistance itself, and ultimately fail to cure the underlying condition. The focus of our research is on developing molecular therapies for insulin resistance.
A central element of cellular insulin signaling network is a protein molecule called insulin receptor. It is embedded in cellular membrane, and the part of the molecule located outside of the cell binds insulin hormone. In response to insulin binding intracellular part of the receptor undergoes chemical changes that lead to a cascade of chemical reactions inside the cell. Among the number of cellular proteins that influence this process, we have identified a negative regulator of insulin receptor called GRB10. This adaptor protein was discovered in genome-wide association studies to be linked to diabetes. We and others have found that even modest reduction in cellular levels of GRB10 substantially increases response to insulin. It is known that GRB10 binds directly to the intracellular component of the insulin receptor and blocks it from activating insulin signaling cascade. Disrupting this interaction thus has potential of amplifying cellular response to insulin and alleviating insulin resistance under conditions of type 2 diabetes.