Weinhaus Anthony J, Tabiin Muhammad T, Poronnik Philip, Palma Catalina A, Cook David I, Tuch Bernard E
Department of Medicine, University of Sydney, NSW 2006, Australia.
J Clin Endocrinol Metab. 2003 Jun;88(6):2753-9. doi: 10.1210/jc.2002-021542.
Fetal pancreatic beta-cells release insulin poorly in response to glucose; however, the cellular mechanism for this is unknown. By using fura-2 to measure changes in the cytoplasmic free Ca(2+) concentration in beta-cells, we examined human/porcine fetal islet-like cell clusters (ICCs) and human adult islets for the presence of functional K(+)(ATP) and voltage-activated Ca(2+) ion channels. The effects of glucose, glyceraldehyde, leucine, KCl, and the channel effectors glipizide and BAY K8644 were studied. In fetal human/porcine ICCs and adult islets, KCl, glipizide, and BAY K8644 increased Ca(2+). Both glucose and glyceraldehyde increased Ca(2+) in islets but had no effect on ICCs. Leucine increased Ca(2+) in islets and porcine but not human ICCs. We hypothesize that the beneficial effect of leucine in fetal porcine, but not human ICCs, is attributable to time-dependent maturation of the beta-cells, because porcine ICCs examined were at 87% of the gestational period, and human ICCs were at 42%. Our data demonstrate that both K(+)(ATP) and voltage-activated Ca(2+) channels, required for glucose-stimulated increase in Ca(2+), are functional early in gestation. This suggests that the cause of the immaturity of fetal human/porcine beta-cells is at a more proximal step of glucose-induced metabolism than the channels on the cell surface.
胎儿胰腺β细胞对葡萄糖刺激的胰岛素释放功能较差；然而，其细胞机制尚不清楚。通过使用fura-2测量β细胞胞质游离Ca(2+)浓度的变化，我们检测了人/猪胎儿胰岛样细胞簇（ICCs）和成人胰岛中功能性K(+)(ATP)和电压激活Ca(2+)离子通道的存在情况。研究了葡萄糖、甘油醛、亮氨酸、KCl以及通道效应剂格列吡嗪和BAY K8644的作用。在胎儿人/猪ICCs和成人胰岛中，KCl、格列吡嗪和BAY K8644均可增加Ca(2+)。葡萄糖和甘油醛均可增加胰岛中的Ca(2+)，但对ICCs无影响。亮氨酸可增加胰岛和猪ICCs中的Ca(2+)，但对人ICCs无影响。我们推测，亮氨酸对猪胎儿而非人ICCs有有益作用，这归因于β细胞的时间依赖性成熟，因为所检测的猪ICCs处于妊娠期的87%，而人ICCs处于42%。我们的数据表明，葡萄糖刺激Ca(2+)增加所需的K(+)(ATP)和电压激活Ca(2+)通道在妊娠早期就已发挥功能。这表明，胎儿人/猪β细胞不成熟的原因在于葡萄糖诱导代谢的更近端步骤，而非细胞表面的通道。
