SUMMARY
Insulin release from pancreatic β-cells is triggered by the metabolism-dependent closure of ATP-sensitive K+ (KATP) channels. Here, we used isoform-specific deletion of pyruvate kinase (PK) to identify the unique roles of PKm1 and PKm2 in the β-cell nutrient response. Both isoforms were found on the plasma membrane, where they endow KATP channels with nutrient sensitivity and specificity. Although PKm1 accounts for >90% of cellular activity, allosteric activation of the minor PKm2 isoform controls glucose-dependent KATP closure. Amino acids, which generate mitochondrial phosphoenolpyruvate (PEP) without allosterically activating PKm2, depend on PKm1 to raise ATP/ADP and close KATP channels. Shifting the β-cell from PKm2 to PKm1 correspondingly increased amino acid sensitivity and boosted secretory output. In addition to these membrane depolarizing “on-switches,” β-cell deletion of PCK2 exposed a mitochondrial PEP-dependent “off-switch” that facilitates Ca2+ extrusion. Restricting PCK2 prolonged Ca2+ influx and correspondingly increased insulin secretion. In summary, it is not the KATP channel alone, but the PK-KATP microcompartment that confers nutrient sensitivity to the β-cell plasma membrane. The differential response of the PK isoforms to the glycolytic and mitochondrial sources of PEP influences β-cell nutrient preference, and controls the oscillatory cycle regulating insulin secretion.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The authors have declared that no conflict of interest exists.