Insulin Regulates Islet α-Cell Function by Reducing KATP Channel Sensitivity to Adenosine 5′-Triphosphate Inhibition

Glucose regulates pancreatic islet α-cell glucagon secretion directly by its metabolism to generate ATP in α-cells, and indirectly via stimulation of paracrine release of β-cell secretory products, particularly insulin. How the cellular substrates of these pathways converge in the α-cell is not well known. We recently reported the use of the MIP-GFP (mouse insulin promoter-green fluorescent protein) mouse to reliably identify islet α- (non-green cells) and β-cells (green cells), and characterized their ATP-sensitive K+ (KATP) channel properties, showing that α-cell KATP channels exhibited a 5-fold higher sensitivity to ATP inhibition than β-cell KATP channels. Here, we show that insulin exerted paracrine regulation of α-cells by markedly reducing the sensitivity of α-cell KATP channels to ATP (IC50 = 0.18 and 0.50 mm in absence and presence of insulin, respectively). Insulin also desensitized β-cell KATP channels to ATP inhibition (IC50 = 0.84 and 1.23 mm in absence and presence of insulin, respectively)....