The present data challenges the preconceptions that substrate oxidation is regulation at the substrate level by only two principles i.e. the glucose-fatty cycle described by Randle and the inverse Randle cycle [1], [2], [3] and [4]. Although they suffice at low-moderate substrate levels, two further principles determine substrate oxidation at higher substrate concentrations; first, anaplerosis of the tricarboxylic cycle through PC promoting complete and incomplete glucose oxidation and second, inhibition of complete PA oxidation with increasing incomplete PA oxidation mediated by high glucose and PA levels, respectively.