A considerable portion of post-prandial glucose clearance occurs in response to glucose itself. In the insulin-resistant state up to 83% of glucose is cleared independent of the insulin response; this can rise to 99% in Type 2 diabetics. Although mechanistically not understood, this is an important process, particularly in the face of defective insulin action. GLUT proteins exhibit specific tissue expression reflecting their roles in glucose metabolism. GLUT12 is expressed in skeletal muscle, thus we hypothesised that GLUT12-mediated glucose transport could be important for post-prandial glucose disposal. We have now identified a novel, insulin independent pathway that responds directly to dietary nutrients to regulate glucose uptake into cells. By developing a knockout mouse model we show this process is delineated in skeletal muscle by GLUT12. Acute activation of GLUT12-mediated glucose transport is induced by glucose and amino acid regulated mTOR stimulation, independent of de novo protein synthesis. Insulin, AICAR and contraction stimulated glucose uptake are normal in EDL muscle lacking GLUT12, suggesting GLUT12 function does not overlap with that of GLUT4. Although body mass and activity levels did not differ, total food intake, respiratory exchange ratios and energy turnover were reduced in GLUT12 null mice. Significantly, GLUT12 null mice are lean but are hyperglycaemic and exhibit glucose intolerance and secondary insulin resistance. Our findings reveal a new paradigm in which GLUT12 is critical for regulating not only nutrient responsive glucose uptake into muscle but also whole body insulin sensitivity. Central to the underlying mechanism is rapid, nutrient stimulated mTOR activation, the absolute requirement for both glucose and amino acids and of GLUT12, providing a critical link between dietary nutrients and whole body glucose homeostasis.