Muscle Fuel Utilization with Glycolysis Viewed Right Side Up

From contemporary studies of muscle and other tissues and whole-body metabolism, we now know that lactate is continuously produced under fully aerobic conditions in a variety of cells, tissues, and organs and serves at least three purposes-lactate is a preferred energy substrate, the major gluconeogenic precursor, and a signaling molecule. In sequence, from studies of exercise physiology, several lactate shuttles were discovered. These were the cell-cell and intracellular lactate shuttles with the astrocyte-neuron shuttles subsets of the former, and peroxisomal and cytosolic-mitochondrial lactate shuttles subsets of the latter. Most recently, with discovery of the postprandial lactate shuttle (PLS), we now realize that muscle, heart, brain, and liver lactate shuttle events are at either intermediate or terminal ends of carbohydrate carbon flow that commences when dietary carbohydrate enters the duodenum and is converted to lactate. There are two major phases of the PLS: enteric PLS (involving gut lactate production and lactate appearance in the systemic circulation) and the systemic PLS (involving hepatic glucose release, tissue glucose uptake and lactate production, and tissue lactate release). Hence, in terms of our understanding of body carbohydrate carbon flux, the gut is first and muscles are last (Matthew 20:16).