Mevalonate pathway orchestrates insulin signaling via RAB14 geranylgeranylation-mediated phosphorylation of AKT to regulate hepatic glucose metabolism

Statin use accompanies with increased risk of new onset of type 2 diabetes, however, the underlying mechanisms remain not be fully understood and effective prevention strategies are still lacking. Herein, we find that both pharmacological and genetic inhibition of GGTase II mimic the disruption of simvastatin on hepatic insulin signaling and glucose metabolism in vitro. AAV8-mediated knockdown of liver RABGGTA, the specific subunit of GGTase II, triggers systemic glucose metabolism disorders in vivo. By adopting a small-scale siRNA screening, we identify RAB14 as a regulator of hepatic insulin signaling and glucose metabolism. Geranylgeranylation deficiency of RAB14 inhibits the phosphorylation of AKT (Ser473) and disrupts hepatic insulin signaling and glucose metabolism possibly via impeding mTORC2 complex assembly. Finally, geranylgeranyl pyrophosphate (GGPP) supplementation is sufficient to prevent simvastatin-caused disruption of hepatic insulin signaling and glucose metabolism in vitro. Geranylgeraniol (GGOH), a precursor of GGPP, is able to ameliorate simvastatin-induced systemic glucose metabolism disorders in vivo. In conclusion, our data indicate that statins-targeted mevalonate pathway regulates hepatic insulin signaling and glucose metabolism via geranylgeranylation of RAB14. GGPP/GGOH supplementation might be an effective strategy for the prevention of the diabetic effects of statins. •Statin-targeted mevalonate pathway modulates hepatic insulin sensitivity;•RAB14 geranylgeranylation regulates the phosphorylation of AKT (Ser473) via modulating mTORC2 complex assembly;•GGOH supplementation might be a therapeutic strategy for statin-induced hepatic insulin resistance.