Beta‐Cell Ion Channels and Their Role in Regulating Insulin Secretion

The isoforms of pyruvate kinase act as nutrient sensors for the β-cell KATP channel

“…An amino acid-stimulated rise in ATP/ADP c was shown to be insufficient to close K ATP channels, ruling out a key aspect of the “canonical model” in which accelerated mitochondrial metabolism raises ATP/ADP c to close K ATP channels (Campbell and Newgard, 2021; Prentki et al, 2013; Thompson and Satin, 2021). In PKm1-deficient β-cells, amino acids increased ATP/ADP c similarly to control β-cells, but were unable to close K ATP channels.…”

“…Plasma membrane-localized pyruvate kinase (PK) plays a key role in this nutrient response by converting phosphoenolpyruvate (PEP) and ADP to pyruvate and ATP, locally raising the ATP/ADP ratio in the KATP channel microcompartment to depolarize the membrane and initiate insulin secretion 1 . This local mechanism of control obviates the "standard model" of β-cell fuel sensing in which mitochondrial oxidative phosphorylation raises the ATP/ADP ratio to close KATP channels [2][3][4] -a concept that conflicts with the thermodynamic principle of mitochondrial respiratory control 1,5,6 . As such, Lewandowski et al 1 recently proposed a revised model of β-cell fuel sensing, which we refer to here as the MitoCat-MitoOx model, that is relevant to human islets and the in vivo context 1,7 .…”

“…Following membrane depolarization, the increased workload (ATP hydrolysis) associated with Ca 2+ extrusion and exocytosis elevates ADP, which activates oxidative phosphorylation to sustain the secretory phase in a phase referred to as MitoOx. While the biochemical underpinnings of this new model are supported by many islet studies, over the course of decades [1][2][3][4] , the current lack of genetic evidence supporting the roles of PK and PCK2 in compartmentalized KATP closure may preclude its wide acceptance.…”

“…Insulin release is stimulated by the metabolism-dependent closure of ATPsensitive K + (KATP) channels (Ashcroft et al, 1984;Cook and Hales, 1984;Rorsman and Trube, 1985), which triggers Ca 2+ influx and exocytosis (Anderson and Long, 1947;Grodsky et al, 1963). Contrary to what is often believed, the glucose-induced signaling process in β-cells has not been largely solved, and the entrenched model (Campbell and Newgard, 2021;Prentki et al, 2013;Thompson and Satin, 2021) implicating a rise in mitochondrially-derived ATP driving KATP channel closure is likely wrong, the main reason being that it does not account for the thermodynamic principle of mitochondrial respiratory control (Corkey, 2020;Lewandowski et al, 2020;Nicholls, 2016). The recent discovery that pyruvate kinase (PK), which converts ADP and phosphoenolpyruvate (PEP) to ATP and pyruvate, is present on the plasma membrane and sufficient to close KATP channels (Lewandowski et al, 2020), provides a potential resolution to this decades-old problem.…”

Maintaining Effective Beta Cell Function in the Face of Metabolic Syndrome-Associated Glucolipotoxicity—Nutraceutical Options

“…The consequent increase in cytoplasmic ATP/ADP ratio inhibits ATP-sensitive potassium channels in the beta cell plasma membrane, such that plasma membrane potential declines. This in turn opens voltage-sensitive calcium channels, causing an influx of calcium that triggers increased exocytosis of beta cell insulin granules [ 7 , 8 ]. The resulting increase in plasma insulin promotes storage of the elevated plasma glucose, such that postprandial glucose eventually returns to its healthy baseline level.…”