Lifting the Veil on the “Phosphate Flush,” a Cryptic Phenomenon of Experimental Pancreatic Islet Physiology

Abstract

The original encounter of the “phosphate flush” in isolated pancreatic islets by Norbert Freinkel (1,2) is steeped in the history of research into the complexities of “stimulus secretion coupling” in cells and organs of the body (3), in particular of the discovery of the “phosphoinositide effect” in studies by Mabel and Lowell Hokin (4). The publication by Berggren and colleagues discussed here (5) can be traced to and must be understood on this pioneering background. The discovery of the phosphate efflux channel XPR1 in pancreatic β-cells and first success of describing its regulation provide new fundamental insights into the role of cellular phosphate and inositol-phosphate metabolism in pancreatic islet physiology. The “phosphate flush” is a large efflux of inorganic phosphate (i.e., ∼50% of the cellular content) within a 10-min period induced by high glucose or other suitable fuel stimuli (e.g., leucine) under highly specific experimental conditions. The phenomenon can be dissociated from stimulation of insulin release (1). It is demonstrable either by measuring release of radioactive phosphorous from prelabeled cells or by the net loss of inorganic phosphate (Pi) from cells using biochemical analytical methods (6,7). To observe it, isolated islets or suitable β-cell lines are preconditioned for extended periods at low glucose levels, most often 0.5 mmol/L but …