A targetable mechanism in insulin-resistant diabetes

As of 2012, 9% of the US population had diabetes, making it the seventh leading cause of death. Kentucky recently ranked 7th in the nation for diabetes rate, and an estimated 8.5% of Kentuckians are diabetic. Insulin resistance is particularly challenging because of its insensitivity to therapeutics. Insulin resistance is classically associated with increased serine phosphorylation of a downstream insulin receptor effector protein, IRS-1, and with changes in gene expression. In adipocytes from insulin-resistant patients, the sigma-2 receptor (S2R), also called PGRMC1 (progesterone receptor membrane component 1), was down-regulated. S2R/PGRMC1 is a trafficking protein for plasma membrane receptors, and we provide preliminary data that S2R/PGRMC1 trafficks the insulin receptor (InsR) to the plasma membrane. S2R is particularly attractive as a therapeutic target in diabetes because it can be manipulated through a series of well characterized ligands. The hypothesis of the proposal is that S2R/PGRMC1 is essential for maintaining InsR signaling and trafficking in adipocytes and other tissues. The hypothesis is rooted in published evidence showing that S2R levels decrease during the onset of diabetes in model systems and in human subjects, as well as preliminary data linking S2R insulin receptor signaling. To test the hypothesis, we will perform the following specific aims. (1) Test the model that S2R suppresses signaling associated with insulin resistance. (2) Test the model that S2R levels correlate with insulin resistance and parameters of insulin signaling in adipocytes in clinical samples. Thus, the proposal is significant because it will test the model that S2R regulates key steps in insulin resistance.