The magnesium transporter NIPAL1 is a pancreatic islet?expressed protein that conditionally impacts insulin secretion

Type 2 diabetes is a chronic metabolic disease characterized by pancreatic ?-cell dysfunction and peripheral insulin resistance. Among individuals with type 2 diabetes, ?30% exhibit hypomagnesemia. Hypomagnesemia has been linked to insulin resistance through reduced tyrosine kinase activity of the insulin receptor; however, its impact on pancreatic ?-cell function is unknown. In this study, through analysis of several single-cell RNA-sequencing data sets in tandem with quantitative PCR validation in both murine and human islets, we identifiedNIPAL1(NIPA-like domain containing 1), encoding a magnesium influx transporter, as an islet-enriched gene. A series of immunofluorescence experiments confirmedNIPAL1's magnesium-dependent expression and that it specifically localizes to the Golgi in Min6-K8 cells, a pancreatic ?-cell?like cell line (mouse insulinoma 6 clone K8). Under varying magnesium concentrations,NIPAL1knockdown decreased both basal insulin secretion and total insulin content; in contrast, its overexpression increased total insulin content. Although the expression, distribution, and magnesium responsiveness ofNIPAL1in ?-TC6 glucagonoma cells (a pancreatic ?-cell line) were similar to the observations in Min6-K8 cells, no effect was observed on glucagon secretion in ?-TC6 cells under the conditions studied. Overall, these results suggest thatNIPAL1expression is regulated by extracellular magnesium and that down-regulation of this transporter decreases glucose-stimulated insulin secretion and intracellular insulin content, particularly under conditions of hypomagnesemia.