The "protected" glucose transport through the astrocytic endoplasmic reticulum is too slow to serve as a quantitatively-important highway for nutrient delivery.

A novel mechanism involving "protected glucose trafficking" through the lumen of the astrocytic endoplasmic reticulum (ER) was proposed by Müller et al. (Current Biology 28:3481, 2018) and highlighted by Pellerin (Current Biology 28:R1258, 2018) as a potential route for astrocyte-neuron lactate shuttling. In their model, glucose is taken up from blood into astrocytic endfeet, phosphorylated, and some glucose-6-phosphate (Glc-6-P) is transported into the ER lumen where it is hydrolyzed by glucose-6-phosphatase-β to produce glucose. The glucose then diffuses within the ER lumen through peripheral astrocytic processes (PAPs) to regions in close proximity to synapses where it is released to cytoplasm and metabolized to lactate and neurotransmitter precursors that can be shuttled to neurons. Experimental evidence supports aspects of this model, but essential components were not established. This commentary critically evaluates the Müller et al. study and discusses its weaknesses and intriguing aspects. Most important, the rate-limiting step of the ER "protected highway," transport of Glc-6-P into the ER, is extremely slow, on the order of 550-3,700 times lower than glucose consumption by differentiated cultured astrocytes. Glucose diffusion through extracellular space to fuel neurons was not ruled out as an alternative mechanism. The ER glucose probes were not calibrated, and the ER luminal glucose reservoir size and flux of glucose through the ER are unknown. Effects of phosphatase knockdown are quite interesting and require further study. Glucose transport through a "protected intracellular highway" in the ER lumen is not quantitatively relevant to astrocytic glucose metabolism and is not energetically important.