Glycolytic activation of β-cell Na+/K+-ATPases containing β1-subunits accelerates Na+ extrusion, prolonging the duration of Ca2+ oscillations but decreasing insulin secretion Article Swipe

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Matthew T. Dickerson , Prasanna K. Dadi , Ross A. McDevitt , Jordyn R Dobson , Soma Behera , Spencer J. Peachee , SHANNON GIBSON , Tenzin Wangmo , David A. Jacobson ·

YOU? · · 2025 · Open Access · · DOI: https://doi.org/10.1016/j.molmet.2025.102296 · OA: W4416980796

Electrogenic Na+/K+ ATPases (NKAs) control β-cell Ca2+ influx and insulin secretion by integrating the signal strength of stimulatory G protein (Gs)-coupled ligands (e.g., GLP-1, glucagon) and inhibitory G protein (Gi)-coupled ligands (e.g., somatostatin, epinephrine). However, there is a significant gap in our understanding of how specific NKA subunits contribute to β-cell function. Here, we demonstrate that the NKA β1-subunit (NKAβ1) is highly expressed and functional at the plasma membrane of mouse and human β-cells. β-cell-specific NKAβ1 knockout improves glucose tolerance and hepatic insulin sensitivity, coinciding with enhanced first- and second-phase glucose-stimulated insulin secretion (GSIS). Electrophysiological studies reveal that β-cell NKAβ1 enhances somatostatin-induced NKA currents, increases action potential afterhyperpolarization amplitude, and accelerates action potential frequency. Loss of NKAβ1 delays glucose-stimulated Ca2+ entry by impairing glycolysis-dependent NKA activation and reduces Na+ clearance efficiency during Ca2+ oscillations, resulting in prolonged silent phases. Thus, glycolytic stimulation of Na+ influx dictates silent phase duration via the kinetics of Na+ clearance by NKA, which is diminished in β-cells without NKAβ1. Furthermore, NKAβ1 differentially modulates β-cell G protein-coupled receptor (GPCR) signaling by attenuating Gi-GPCR effects and augmenting Gs-coupled GLP-1 receptor-mediated cAMP production and Ca2+ entry. β-cell NKAβ1 knockdown in human pseudoislets led to tonically elevated intracellular Ca2+ and increased insulin secretion. These findings establish NKAβ1-containing NKA complexes as critical regulators of β-cell electrical activity, Ca2+ oscillations, and secretory patterns, with direct consequences for systemic glucose homeostasis.