Hepatocyte Rap1a Contributes To Obesity- and Statin-Associated Hyperglycemia

Excessive hepatic glucose production contributes to the development of hyperglycemia and is a key feature of type 2 diabetes. Here, we report that activation of hepatic Rap1a suppresses gluconeogenic gene expression and glucose production, whereas Rap1a silencing stimulates them. Rap1a activation is suppressed in obese mouse liver and restoring its activity lowers blood glucose and improves glucose intolerance. As Rap1as membrane localization and activation depends on its geranylgeranylation, which is inhibited by statins, we found lower active-Rap1a levels in statin-treated hepatocytes and the human liver. Similar to Rap1a inhibition, statins stimulated hepatic gluconeogenesis and increased fasting blood glucose in obese mice. Geranylgeraniol treatment, which acts as the precursor for geranylgeranyl isoprenoids, restored Rap1a activity and improved statin-mediated glucose intolerance. Mechanistically, we show that Rap1a activation induces actin polymerization, which suppresses gluconeogenesis by Akt-mediated FoxO1 inhibition. Thus, Rap1a regulates hepatic glucose homeostasis, and blocking its activity, via lowering geranylgeranyl isoprenoids, contributes to statin-induced glucose intolerance.