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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 HCO3- buffer, indicating that it does not result from an activation of this exchanger. In HEPES buffer, however, KIC strongly decreased pHi unless the rise in [Ca2+]i was prevented, in which case KIC increased pHi. When the HCO3-/Cl-exchanger was blocked by 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS), the effect of KIC in HCO3- buffer became similar to that in HEPES buffer without or with DIDS. The effects of leucine on pHi were similar to those of KIC. In conclusion, the effect of KIC and leucine on islet cell pHi, like that of glucose, is the complex result of an alkalinizing action of their metabolism and an acidifying action of the [Ca2+]i rise that they also produce. Compensation of this acidification is achieved by operation of the pHi-regulating exchangers, of which the HCO3-/Cl- exchanger plays a predominant role

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