Introduction: Aberrant angiogenesis in diabetes (DM) is caused by failure of local endothelial cells (ECs) to properly undergo VEGF-driven migration, and leads to a high propensity to develop critical limb ischemia. We recently showed that type 1 and 2 DM induce PGC-1α in ECs, which in turn strongly blocks EC migration and angiogenesis. Despite this therapeutic potential, PGC-1α may not be “druggable” due to the diverse distribution and functions in non-vascular tissues. Thus, understanding EC PGC-1α effectors is critical, which may involve bioenergetics since PGC-1α broadly induces mitochondrial OxPhos. Although ECs show high rate of glycolytic flux and synthesis of lactate, a burgeoning angiogenic mediator, this is blunted in DM via mechanisms still ill-defined. We hypothesized that a novel PGC-1α target in DM mediates blunted EC glycolysis and migration. Methods and Results: By leveraging NRF1/2-binding defective PGC-1α, we show that PGC-1α blocks glycolysis, through PPARgamma-driven Notch induction independent of mitochondrial activation, which fully accounts for PGC-1α inhibition of EC migration in DM. mRNA microarray identified ARHGAP6, a Rho-GAP and actin cytoskeletal modulator, as a DM-inducible main effector of PGC-1α axis to inhibit EC lactate synthesis and migration. Data suggest the causal role for ARHGAP6 in the reduced migration and glycolysis (Seahorse XF analyzer) of STZ-induced DM mouse ECs. Impaired migration of DM ECs and ECs overexpressing PPARgamma or ARHGAP6 was associated with decreased activity of Rac1 and rescued by addition of lactate. Reduced GTP-Rac1 in ECs overexpressing PGC-1α was restored by knockdown of ARHGAP6. Positive feedback loop between Rac1 and LDHA was demonstrated, suggesting a cytoskeletal-metabolic module to mediate EC migration and dysfunction. Conclusions: PGC-1α/ ARHGAP6 inhibition of EC glycolysis and lactate synthesis is a key mechanism of impaired EC migration in DM angiopathy. Our data provide important insights into the mechanistic link between EC actin cytoskeleton and bioenergetics mediated by ARHGAP6, and opportunities to restore diminished glycolysis in DM ECs by targeting PGC-1α axis component ARHGAP6 to develop safe and efficacious therapeutic since it is dispensable for health.