We calculated the implications of diffusion for the phosphoenolpyruvate:glucose phosphotransferase system (glucose-PTS) of Escherichia coli in silicon cells of various magnitudes. For a cell of bacterial size, diffusion limitation of glucose influx was negligible. Nevertheless, a significant concentration gradient for one of the enzyme species, nonphosphorylated IIAGlc, was found. This should have consequences because the phosphorylation state of IIAGlc is an important intracellular signal. For mammalian cell sizes we found significant diffusion limitation, as well as strong concentration gradients in many PTS components, and strong effects on glucose and energy signaling. We calculated that the PTS may sense both extracellular glucose and the intracellular free-energy state. We discuss i), that the effects of diffusion on cell function should prevent this highly effective bacterial system from functioning in eukaryotic cells, ii), that in the larger eukaryotic cell any similar chain of mobile group-transfer proteins can neither sustain the same volumetric flux as in bacteria nor transmit a signal far into the cell, and iii), that systems such as these may exhibit spatial differentiation in their sensitivity to different signals.