Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet β-cells
Inhibition by simvastatin, but not pravastatin, of glucose-induced cytosolic Ca2+ signalling and insulin secretion due to blockade of L-type Ca2+ channels in rat islet β-cells
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DOI：
10.1038/sj.bjp.0702397
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发表时间：
1999-03-01
影响因子：
7.3
通讯作者：
Kakei, M
中科院分区：
文献类型：
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作者：
Yada, T;Nakata, M;Kakei, M
1高胆固醇血症通常发生在2型糖尿病患者中，因此他们会遇到HMG-CoA还原酶抑制剂的给药。胰腺β细胞功能的改变导致对葡萄糖的胰岛素分泌反应受损，在2型糖尿病的发病机制中起着至关重要的作用。因此，重要的是要检查HMG-CoA还原酶抑制剂对β细胞功能的影响。2胞浆Ca 2+浓度（[Ca 2 +]（i））在β细胞功能的调节中起着核心作用。本研究检测了HMG-CoA还原酶抑制剂对大鼠胰岛β细胞中葡萄糖诱导的[Ca 2 +]（i）信号传导和胰岛素分泌的影响。3辛伐他汀是一种亲脂性HMG-CoA还原酶抑制剂，在0.1-3 μ g m（-1）浓度依赖性地抑制8.3 mM葡萄糖诱导的单个β细胞中[Ca 2 +]（i）的第一时相增加和振荡。亲脂性较低的抑制剂辛伐他汀酸抑制第一相[Ca 2 +]（i）的增加，但效力低两个数量级。亲水性抑制剂普伐他汀（100 μ g ml（-1））对[Ca 2 +]（i）无影响。4辛伐他汀（0.3 μ g ml（-1）），比辛伐他汀酸更有效（30 μ g ml（-1）），抑制葡萄糖诱导的胰岛素从胰岛分泌，而普伐他汀（100 μ g ml（-1））则没有作用。5全细胞膜片钳记录显示辛伐他汀对β细胞L型钙通道具有可逆性抑制作用，而普伐他汀则没有。辛伐他汀还通过L-精氨酸和KCl抑制[Ca 2 +]（i）增加，这些药物通过打开L型Ca 2+通道发挥作用。6总之，亲脂性HMG-CoA还原酶抑制剂可通过阻断β细胞中的L型Ca 2+通道抑制葡萄糖诱导的[Ca 2 +]（i）信号传导和胰岛素分泌，其抑制效力与其亲脂性平行。当HMG-CoA还原酶抑制剂用于临床时，尤其是用于2型糖尿病患者时，应注意这些发现。
1 Hypercholesterolaemia often occurs in patients with type 2 diabetes, who therefore encounter administration of HMG-CoA reductase inhibitors. Alteration of pancreatic beta-cell function leading to an impaired insulin secretory response to glucose plays a crucial role in the pathogenesis of type 2 diabetes. Therefore, it is important to examine the effects of HMG-CoA reductase inhibitors on beta-cell function.2 Cytosolic Ca2+ concentration ([Ca2+](i)) plays a central role in the regulation of beta-cell function. The present study examined the effects of HMG-CoA reductase inhibitors on the glucose-induced [Ca2+](i) signalling and insulin secretion in rat islet beta-cells.3 Simvastatin, a lipophilic HMG-CoA reductase inhibitor, at 0.1-3 mu g m(-1) concentration-dependently inhibited the first phase increase and oscillation of [Ca2+](i) induced by 8.3 mM glucose in single beta-cells. The less lipophilic inhibitor, simvastatin-acid, inhibited the first phase [Ca2+](i) increase but was two orders of magnitude less potent. The hydrophilic inhibitor, pravastatin (100 mu g ml(-1)), was without effect on [Ca2+](i).4 Simvastatin (0.3 mu g ml(-1)), more potently than simvastatin-acid (30 mu g ml(-1)), inhibited glucose-induced insulin secretion from islets, whereas pravastatin (100 mu g ml(-1)) had no effect.5 Whole-cell patch clamp recordings demonstrated a reversible inhibition of the beta-cell L-type Ca2+ channels by simvastatin, but not by pravastatin. Simvastatin also inhibited the [Ca2+](i) increases by L-arginine and KCl, agents that act via opening of L-type Ca2+ channels.6 In conclusion, lipophilic HMG-CoA reductase inhibitors can inhibit glucose-induced [Ca2+](i) signalling and insulin secretion by blocking L-type Ca2+ channels in beta-cells, and their inhibitory potencies parallel their lipophilicities. Precaution should be paid to these findings when HMG-CoA reductase inhibitors are used clinically, particularly in patients with type 2 diabetes.