Development of a severe rat refeeding syndrome model and mathematical modeling of the associated hypophosphatemia

Refeeding syndrome (RFS) is a life-threatening metabolic complication caused by refeeding in malnourished patients and is a barrier to early nutritional supplementation. Hypophosphatemia is a hallmark of RFS; however, its detailed pathogenic mechanism remains unclear. In this study, we aimed to unravel the underlying mechanism by generating a novel rat model that exhibits a decrease in plasma inorganic phosphorus levels comparable to that in patients with severe RFS and developing a mathematical model that reproduces the results. Although insulin is believed to be implicated in hypophosphatemia, we found a crucial role of amino acids. Furthermore, we inferred the dynamics of associated factors that play important roles in the regulation of hypophosphatemia, such as phosphate diuretic hormones, intracellular phosphorus content, and mTOR signaling, and experimentally confirmed them. Our findings provide new insights into the mechanisms underlying hypophosphatemia in RFS and should contribute to advancements in the prevention and intervention of RFS.