Glucose metabolism and glutamate analog acutely alkalinize pH of insulin secretory vesicles of pancreatic β-cells

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Abstract
We studied acute changes of secretory vesicle pH in pancreatic β-cells with a fluorescent pH indicator, lysosensor green DND-189. Fluorescence was decreased by 0.66 ± 0.10% at 149 ± 16 s with 22.2 mM glucose stimulation, indicating that vesicular pH was alkalinized by ∼0.016 unit. Glucose-responsive pH increase was observed when cytosolic Ca2+influx was blocked but disappeared when an inhibitor of glycolysis or mitochondrial ATP synthase was present. Glutamate dimethyl ester (GME), a plasma membrane-permeable analog of glutamate, potentiated glucose-stimulated insulin secretion at 5 mM without changing cellular ATP content or cytosolic Ca2+concentration ([Ca2+]). Application of GME at basal glucose concentration decreased DND-189 fluorescence by 0.83 ± 0.19% at 38 ± 2 s. These results indicated that the acutely alkalinizing effect of glucose on β-cell secretory vesicle pH was dependent on glucose metabolism but independent of modulations of cytosolic [Ca2+]. Moreover, glutamate derived from glucose may be one of the mediators of this alkalinizing effect of glucose, which may have potential relevance to the alteration of secretory function by glutamate.

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