SUN-652 Progesterone Receptor Membrane Component 1 Suppresses Type II Diabetes (T2D) Progression via Induced Insulin Signaling in Muscle

Type II diabetes (T2D) is characterized for insulin resistance in muscle, liver, and fat (1). Progesterone receptor membrane component 1 (Pgrmc1) is novel cell surface receptor which is associated with insulin receptor beta (IRβ) (2). Therefore, we speculated Pgrmc1 might be related to T2D. Using Pgrmc1 KO mice reported in our previous study (3), we observed the decrease of body weight (BW) and increase of muscle weight per body weight. When blood glucose level in post-prandial state was lower, Pgrmc1 KO mice showed improvements in glucose tolerance test (GTT) and insulin tolerance test (ITT). Though insulin level was low, insulin signaling genes were up-regulated in post-prandial Pgrmc1 KO mice, especially in muscle. Regulations of blood glucose level and insulin signaling gene levels by Pgrmc1 were also similarly observed in insulin-deficient state. To induce T2D, C57BL/6 mice were fed with high-fat diet for 8 weeks and injected by low dose of streptozotocin (30mg/kg). As a result, T2D-induced Pgrmc1 KO mice increased lean mass per BW, decreased the blood glucose level, and improved GTT and ITT. The insulin signaling genes were also up-regulated, while cytoplasmic GLUT4 was decreased, but membrane GLUT4 was increased in T2D-induced Pgrmc1 KO muscle. Glycolysis, TCA cycle, and oxidative phosphorylation genes were increased, suggesting energy metabolism was increased in T2D-induced Pgrmc1 KO muscle. Present study suggests that Pgrmc1 loss increases insulin signaling through induction of cytoplasmic IRβ and pAKT, and induces glucose uptake of muscle, thereby showing improvement in T2D progression. This has important clinical value because Pgrmc1 modulation will evade hypoglycemia caused by classic insulin therapy for T2D (4). References: (1) Fernandez, A. M., Kim, J. K., Yakar, S., Dupont, J., Hernandez-Sanchez, C., Castle, A. L., Filmore, J., Shulman, G. I., and Le Roith, D. (2001) Functional inactivation of the IGF-I and insulin receptors in skeletal muscle causes type 2 diabetes. Genes & development 15, 1926-1934. (2) Hampton, K. K., Anderson, K., Frazier, H., Thibault, O., and Craven, R. J. (2018) Insulin Receptor Plasma Membrane Levels Increased by the Progesterone Receptor Membrane Component 1. Mol Pharmacol 94, 665-673. (3) Lee, S. R., Kwon, S. W., Kaya, P., Lee, Y. H., Lee, J. G., Kim, G., Lee, G. S., Baek, I. J., and Hong, E. J. (2018) Loss of progesterone receptor membrane component 1 promotes hepatic steatosis via the induced de novo lipogenesis. Scientific reports 8, 15711. (4) Zammitt, N. N., and Frier, B. M. (2005) Hypoglycemia in type 2 diabetes: pathophysiology, frequency, and effects of different treatment modalities. Diabetes care 28, 2948-2961.