The Magnesium Transporter NIPAL1 Is a Pancreatic Islet-Expressed Protein That Conditionally Impacts Insulin Secretion

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by pancreatic β-cell dysfunction and peripheral insulin resistance. Among individuals with T2D, approximately 30% exhibit hypomagnesemia. Hypomagnesemia has been linked to insulin resistance through reduced tyrosine kinase activity of the insulin receptor; however, its impact on pancreatic β-cell function is unknown. In this study, through analysis of several single-cell RNA-seq datasets in tandem with quantitative PCR validation in both murine and human islets, we identified NIPA-like domain containing 1 (NIPAL1) - encoding a magnesium influx transporter - as an islet-enriched gene. A series of immunofluorescence experiments confirmed NIPAL1's magnesium-dependent expression and that it specifically localizes to the Golgi in Min6-K8 cells, a pancreatic β-cell-like cell line. Under varying magnesium concentrations, NIPAL1 knockdown decreased both basal insulin secretion and total insulin content; in contrast, its over-expression increased total insulin content. Although the expression, distribution, and magnesium-responsiveness of NIPAL1 in α-TC6 glucagonoma cells (a pancreatic α-cell line) were similar to the observations in Min6-K8 cells, no effect was observed on glucagon secretion in α-TC6 cells under the conditions studied. Overall, these results suggest that NIPAL1 expression 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.

Keywords: NIPA-like domain containing 1 (NIPAL1); NIPA3; diabetes; glucagon; insulin; ion homeostasis; magnesium; pancreatic β-cell; single-cell RNA-seq; transcriptomics.