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

Departments of ¹Metabolic Diseases and ²Pharmacology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655; ³CREST of Japan Science and Technology Corporation, Saitama 332-0012; ⁴Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005, Japan; and ⁵Department of Biochemistry, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, United Kingdom

Submitted 13 December 2002 ; accepted in final form 10 March 2003

We studied acute changes of secretory vesicle pH in pancreatic -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 -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.

glutamate metabolism; alkalinization of vesicular pH; regulation of insulin secretion

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