Salk Institute for Biological Studies

Role of COP1-Mediated Ubiquitination of TORC2 in Hepatic Gluconeogenesis

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Type 2 Diabetes Mellitus (or Non-Insulin Dependent Diabetes Mellitus) is a major health concern in U.S. Untreated type 2 diabetes leads to several complications such as high blood glucose, lipids and pressure, which cause the consequent failure of major organs. The result from the United Kingdom Prospective Diabetes Study has showed that normalization of high glucose could prevent the majority of diabetes complications. Therefore, understanding the regulation of glucose metabolism is critical for identification of new therapies. Blood glucose levels are physiologically maintained by the balance between glucose production by the liver and glucose utilization by other tissues such as muscles. In type 2 diabetes, glucose production by the liver is often increased and contributes significantly to fasting high blood glucose in patients. A new key regulator for glucose production, called TORC2 was identified in the Montminy laboratory at the Salk Institute. Activation of TORC2 in fasting condition increases glucose production in the liver. The laboratory has evidence suggesting that TORC2 can be turned off by a switch named COP1. With the Hillblom Fellowship, Li Yiu proposed to study how COP1 regulates TORC2 shutdown, and consequently suppressing glucose production in diabetes animal models. The outcome of this study will enhance our knowledge on the control of glucose metabolism in the liver. Moreover, the COP1-TORC2 switch can become a new potential target of therapies for high glucose in type 2 diabetes.