Grant: Operating Grant

Metabolic diseases, including diabetes and obesity, are reaching epidemic levels in the Western world. Chronic activation of the glucocorticoid receptor signaling pathway by stress hormones can contribute to diabetes and metabolic dysfunction. Diabetes is characterized by elevated blood glucose levels (hyperglycemia) caused by the body's inability to properly secrete insulin and/or respond to increasing insulin levels. A known and preventable cause of hyperglycemia is the long-term therapeutic use of glucocorticoid drugs. Glucocorticoid drugs are widely prescribed for diseases in which their potent anti-inflammatory and immunosuppressive actions are desired including rheumatoid arthritis, asthma, certain types of cancers and organ transplants. However, the long-term use of glucocorticoid drugs is limited by undesirable side effects including obesity and type 2 diabetes. These negative side effects are due in part to the glucose production pathway being strongly induced by glucocorticoid drugs in the liver. We have a strong interest in understanding the molecular connections between stress hormones (glucocorticoids) and the ultimate response obtained in tissues such as the liver. We have identified new proteins that are important in selectively modulating the glucose metabolism pathway without affecting the anti-inflammatory effects of glucocorticoid signalling. In this proposal, we will use in vivo mouse models and in vitro primary cultures to uncover the different signalling mechanisms involved, and in the process identify new determinants of glucocorticoid specificity. This project has high public relevance because it will allow us to identify new drug targets to benefit the diabetic community and to create safer glucocorticoid drugs for the future.