Project 454772

It is now estimated that one-third of Canadians are living with diabetes or prediabetes and approximately 90% of these individuals are diagnosed with type 2 diabetes (T2D), the vast majority of which is due to underlying obesity. Even though several new drugs for T2D have been approved in the last decade, these treatments are not a cure, and most diabetics often end up requiring a combination of drugs to properly control their elevated blood sugar. Thus, the continued discovery of new drugs is critical. As such, we have recently identified a protein which is a key regulator in the metabolism of ketones (an energy source made during fasting) that is exclusively increased in the skeletal muscles of obese/diabetic mice. Using genetically modified mice, we deleted the gene that encodes for this protein only in skeletal muscle, and we observed that these animals did not develop T2D. Based on these findings, we concluded that a drug capable of interfering with this enzyme could lead to revolutionizing therapy for T2D. To find such a compound, we used computers to search for potential drugs that could block the function of this protein. Of interest, we identified that an old antipsychotic drug (pimozide) could theoretically interfere with SCOT function. We next confirmed that pimozide improves high blood sugar levels in diabetic animals. However, pimozide also enters the brain and interferes with brain ketone metabolism (brain relies heavily on ketones during fasting) and produces unwanted side-effects (drowsiness). Therefore, we are using computer modeling to design new drugs that selectively interfere with SCOT with no antipsychotic effects. These compounds will be designed in a way so that they cannot penetrate the brain, allowing the brain access to ketones as a fuel source. Taken together, these drugs we develop could become an important and exciting medication for improving blood sugar control and the overall quality of life for people living with T2D.