P-Rex1 limits glucose clearance and suppresses hepatocyte glucose uptake and mitochondrial metabolism independently of its Rac-GEF activity.

We investigated the roles of Rac guanine-nucleotide exchange factor (Rac-GEF) P-Rex1 in glucose homeostasis using Prex1^-/- and catalytically inactive Prex1^GD mice. P-Rex1 maintains fasting blood glucose levels and insulin sensitivity through its Rac-GEF activity but limits glucose clearance independently of its catalytic activity, throughout aging. Prex1^-/- mice on a high-fat diet are protected from diabetes. The increased glucose clearance in Prex1^-/- mice may stem in part from constitutively enhanced hepatic glucose uptake. P-Rex1 controls Glut2 surface levels and mitochondrial morphology, membrane potential, and ATP production in hepatocytes, independently of its catalytic activity. The inverse agonist GRA2 showed that P-Rex1 suppresses glucose uptake and mitochondrial ATP production in hepatocytes through the orphan GPCR Gpr21. Cell fractionation showed that P-Rex1 controls Gpr21 trafficking, independently of its catalytic activity. We propose that P-Rex1 limits hepatocyte glucose uptake by retaining Gpr21 at the plasma membrane. These findings delineate new strategies for controlling glucose homeostasis.