SUMMARY
As nutrient sensors for the organism, pancreatic β-cells use metabolism as a signaling pathway to elicit insulin secretion. Phosphoenolpyruvate (PEP), the substrate for pyruvate kinase (PK), may be a critical signaling intermediate based on its ability to locally control ATP-sensitive K+ (KATP) channels on the plasma membrane. Using isoform-specific deletion, we show that constitutively-active PKm1 is sufficient for KATP closure. Yet, it is the minor but allosterically-tunable PKm2 isoform that enables glucose-dependent regulation of the KATP channel microcompartment. In contrast to glucose, PKm1 and PKm2 have non-overlapping responses to amino acids, which generate PEP via the mitochondrial PCK2 enzyme. β-cell deletion of PCK2 blocked amino acid regulation of KATP and impacted Ca2+ influx (via PKm1) and extrusion (via PKm2). Shifting the β-cell from PKm2 to PKm1 correspondingly increased secretory output. Together, these three knockout models indicate that the source of PEP and the isoforms of PK are key determinants of the β-cell nutrient response.
Competing Interest Statement
The authors have declared no competing interest.