Ketoisocaproic acid and leucine increase cytoplasmic pH in mouse pancreatic B cells: role of cytoplasmic Ca2+ and pH-regulating exchangers

Endocrinology
R M ShepherdJ C Henquin

Abstract

The effects of nonglucose nutrient insulin secretagogues on cytoplasmic pH (pHi) in pancreatic B cells are unclear. These were studied with intact mouse islets loaded with BCECF and stimulated with ketoisocaproic acid (KIC) or leucine, which, unlike glucose, are exclusively metabolized in mitochondria. The changes in pHi were compared to those in cytoplasmic Ca2+ ([Ca2+]i; islets loaded with fura-2), metabolism [NAD(P)H fluorescence], and insulin release. In HCO3- buffer containing 3 mM glucose, 10 mM KIC produced a rapid and sustained increase in metabolism, [Ca2+]i, pHi, and insulin release. In HEPES buffer, the increase in metabolism, [Ca2+]i, and release were also rapid but not as sustained, whereas the alkalinization was delayed. The changes in release thus follow a time course more similar to that of [Ca2+]i and metabolism than to that of pHi. The role of [Ca2+]i in pHi changes was next examined. A similar rapid rise in pHi was produced by KIC in both HCO3- and HEPES buffers when its effects on [Ca2+]i were prevented, whether [Ca2+]i was kept low (4.8 mM KCl plus diazoxide) or high (30 mM KCl plus diazoxide). When the Na(+):H+ exchanger was blocked by dimethylamiloride, the alkalinizing effect of KIC was unaffected in HCO...Continue Reading

Citations

Apr 17, 2008·American Journal of Physiology. Endocrinology and Metabolism·Subhadra C GunawardanaDavid W Piston
Mar 20, 2003·American Journal of Physiology. Endocrinology and Metabolism·Kazuhiro EtoTakashi Kadowaki
Jun 19, 2002·The Journal of Biological Chemistry·Jonathan V RocheleauDavid W Piston

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