Roe M W, Worley J F, Tokuyama Y, Philipson L H, Sturis J, Tang J, Dukes I D, Bell G I, Polonsky K S
Department of Medicine, University of Chicago, Illinois 60637; USA.
Am J Physiol. 1996 Jan;270(1 Pt 1):E133-40. doi: 10.1152/ajpendo.1996.270.1.E133.
Development of non-insulin-dependent diabetes mellitus (NIDDM) is associated with defects in glucose-stimulated insulin secretion. We have investigated Zucker diabetic fatty rats (ZDF), an animal model of NIDDM, and found that, compared with control islets, the expression of mRNA encoding C- and D-isoforms of alpha 1-subunits of beta-cell L-type voltage-dependent Ca2+ channels (VDCC) was significantly reduced in islets isolated from ZDF rats. This correlated with a substantial reduction of L-type Ca2+ currents (ICa) in ZDF beta-cells. Intracellular Ca2+ concentration responses in ZDF islets after glucose, KCI, or BAY K 8644 stimulation were markedly attenuated, whereas responses evoked by carbachol were unimpaired, consistent with a specific decrease in ICa in the diabetic islets. This reduction was accompanied by loss of pulsatile insulin secretion from ZDF islets treated with oscillatory increases of external glucose concentration. Our findings suggest that the attenuation of ICa in diabetic islets may contribute to the abnormal glucose-dependent insulin secretory responses associated with NIDDM and indicate that this defect is caused by decreased expression of genes encoding beta-cell VDCC alpha 1-subunits.
非胰岛素依赖型糖尿病（NIDDM）的发生与葡萄糖刺激的胰岛素分泌缺陷有关。我们研究了NIDDM动物模型——Zucker糖尿病脂肪大鼠（ZDF），发现与对照胰岛相比，从ZDF大鼠分离的胰岛中，编码β细胞L型电压依赖性Ca2+通道（VDCC）α1亚基C和D亚型的mRNA表达显著降低。这与ZDFβ细胞中L型Ca2+电流（ICa）的大幅减少相关。葡萄糖、KCI或BAY K 8644刺激后，ZDF胰岛中的细胞内Ca2+浓度反应明显减弱，而卡巴胆碱引起的反应未受影响，这与糖尿病胰岛中ICa的特异性降低一致。这种降低伴随着用外部葡萄糖浓度振荡增加处理的ZDF胰岛中脉冲式胰岛素分泌的丧失。我们的研究结果表明，糖尿病胰岛中ICa的减弱可能导致与NIDDM相关的异常葡萄糖依赖性胰岛素分泌反应，并表明这种缺陷是由编码β细胞VDCCα1亚基的基因表达减少引起的。
