Levi E, Fadda G Z, Ozbasli C, Massry S G
Department of Medicine, University of Southern California School of Medicine, Los Angeles 90033.
Endocrinology. 1992 Nov;131(5):2182-8. doi: 10.1210/endo.131.5.1330495.
Phosphate depletion (PD) causes a rise in basal level of cytosolic calcium ([Ca2+]i) of pancreatic islets, a decrease in their basal and stimulated ATP content, a reduction in the maximum velocity (Vmax) of Ca2+ adenosine triphosphatase (ATPase) and Na(+)-K+ ATPase, impaired glucose-induced calcium signal and decreased glucose-induced insulin secretion. The sequence of events that lead to these derangements during the evolution of PD are not defined. The present study examined this issue by measuring the metabolic and functional profile of pancreatic islets weekly during the evolution of PD over a period of 6 weeks, and whether phosphate repletion reverses these abnormalities. The results show that initial abnormalities are a rise in Vmax of Ca2+ ATPase and modest rise in basal [Ca2+]i. This was followed by a fall in basal and stimulated ATP content. With the fall in ATP content, the Vmax of Ca2+ ATPase and Na(+)-K+ ATPase decreases and the rise in [Ca2+]i becomes more pronounced. A decrease in glucose-induced insulin secretion becomes evident with the fall in ATP, the decrease in glucose-induced calcium signal, and/or delta[Ca2+]i/basal[Ca2+]i. All functional and metabolic derangements of the pancreatic islets returned to normal after phosphate repletion. Taken together, our data are consistent with the notion that PD is associated with an initial increase in calcium influx into the islets. This is followed by modest but significant rise in [Ca2+]i which, in turn, would inhibit mitochondrial oxidation and ATP generation leading to a decrease in ATP content. The latter compromises the activity of Ca2+ ATPase and Na(+)-K+ ATPase which are involved, directly or indirectly, in calcium extrusion out of the islets. The increased influx of calcium combined with decreased calcium extrusion is followed by a further rise in basal levels of [Ca2+]i. This sequence of events continues until a steady state is reached and is characterized by reduced basal and stimulated ATP content, reduced Vmax of Ca2+ ATPase and Na(+)-K+ ATPase and elevated basal level of [Ca2+]i. Phosphate repletion reverses all these abnormalities.
磷酸盐耗竭（PD）会导致胰岛细胞质钙（[Ca2+]i）的基础水平升高，基础和刺激状态下的ATP含量降低，Ca2+三磷酸腺苷酶（ATPase）和Na(+)-K+ ATPase的最大速度（Vmax）降低，葡萄糖诱导的钙信号受损以及葡萄糖诱导的胰岛素分泌减少。在PD发展过程中导致这些紊乱的事件顺序尚不明确。本研究通过在6周的PD发展过程中每周测量胰岛的代谢和功能概况，以及磷酸盐补充是否能逆转这些异常来研究这个问题。结果表明，最初的异常是Ca2+ ATPase的Vmax升高和基础[Ca2+]i适度升高。随后基础和刺激状态下的ATP含量下降。随着ATP含量的下降，Ca2+ ATPase和Na(+)-K+ ATPase的Vmax降低，[Ca2+]i的升高变得更加明显。随着ATP的下降、葡萄糖诱导的钙信号降低和/或δ[Ca2+]i/基础[Ca2+]i降低，葡萄糖诱导的胰岛素分泌减少变得明显。磷酸盐补充后，胰岛的所有功能和代谢紊乱都恢复正常。综上所述，我们的数据与以下观点一致，即PD与最初进入胰岛的钙流入增加有关。随后[Ca2+]i适度但显著升高，这反过来又会抑制线粒体氧化和ATP生成，导致ATP含量降低。后者会损害直接或间接参与将钙挤出胰岛的Ca2+ ATPase和Na(+)-K+ ATPase的活性。钙流入增加与钙挤出减少相结合，随后基础[Ca2+]i水平进一步升高。这一系列事件持续进行，直到达到稳定状态，其特征是基础和刺激状态下的ATP含量降低、Ca2+ ATPase和Na(+)-K+ ATPase的Vmax降低以及基础[Ca2+]i水平升高。磷酸盐补充可逆转所有这些异常。
