Grant: CIHR New Investigator

Metabolic diseases, including diabetes and obesity, are reaching epidemic levels in the Western world. Diabetes is characterized by elevated blood glucose levels (hyperglycemia) caused by the body's inability to properly secrete insulin 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. Therefore, there is extensive interest in generating new and improved "dissociated" glucocorticoid drugs that retain anti-inflammatory and immunosuppressive effects without the undesirable side effects. We have identified the liver X receptor beta (LXRbeta), a nuclear hormone receptor that is responsive to cholesterol metabolites, as a novel factor important in selectively modulating the hyperglycemic and not the immunosuppressive effects of glucocorticoid signalling. In this proposal, we will take the unique approach of using the liver X receptor beta knockout mice to uncover the signalling mechanism 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.