Diffusion of metabolites across gap junctions mediates metabolic coordination of β-islet cells

Loss of oscillatory insulin secretion is an early marker of type II diabetes. In an individual beta-cell, insulin secretion is triggered by glucose metabolism, which leads to membrane depolarization and calcium influx. Islet {beta}-cells display coordinated secretion; however, it is unclear how the heterogeneous population of insulin-secreting beta cells coordinate their response to glucose. The mechanisms underlying both electrical and calcium synchronicity are well explored. Even so, the mechanism governing metabolic coordination is unclear given key glycolytic enzymes heterogeneous expression. To understand how islet cells coordinate their metabolic activity, a microfluidic applicator delivered glucose stimulation to spatially defined areas of isolated mouse islets. We measured metabolic responses using NADH/NADPH (or NAD(P)H) autofluorescence and calcium changes using Fluo-4 fluorescence. Glucose stimulated a rise in NAD(P)H even in islet areas unexposed to the treatment, suggesting metabolic coordination. A gap junction inhibitor blocked the coordinated NAD(P)H rise in the low-glucose areas. Additionally, metabolic communication did not occur in immortalized {beta}-cell clusters known to lack gap junctions, demonstrating their importance for metabolic coupling. Metabolic communication also preceded glucose-stimulated rises in intracellular calcium. Further, pharmacological blockade of calcium influx did not disrupt NAD(P)H rises in untreated regions. These data suggest that metabolic coordination between islet beta-cells relies on gap-junctional activity and precedes synchronous electrical and calcium activity.