Partial blockade of Kv2.1 channel potentiates GLP-1's insulinotropic effects in islets and reduces its dose required for improving glucose tolerance in type 2 diabetic male mice.
Partial blockade of Kv2.1 channel potentiates GLP-1's insulinotropic effects in islets and reduces its dose required for improving glucose tolerance in type 2 diabetic male mice.
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DOI：
10.1210/en.2014-1728
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发表时间：
2015
期刊：
影响因子：
4.8
通讯作者：
Rauza Sukma Rita;K. Dezaki;Tomoyuki Kurashina;M. Kakei;T. Yada
中科院分区：
文献类型：
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作者：
Rauza Sukma Rita;K. Dezaki;Tomoyuki Kurashina;M. Kakei;T. Yada
基于胰高血糖素样肽-1 (GLP-1) 的药物最近被广泛用于治疗 2 型糖尿病患者，但恶心和呕吐的不良反应已有记录。抑制胰腺 β 细胞中的电压门控 K(+) 通道亚型 Kv2.1 有助于轻度去极化和促进胰岛素释放。本研究旨在确定 Kv2.1 通道的阻断是否会增强 GLP-1 激动剂的促胰岛素作用。 Kv2.1 通道阻滞剂 guangxitoxin-1E (GxTx) 和 GLP-1 激动剂 exendin-4 在阈值以下浓度联合使用时，以葡萄糖依赖性方式显着增加小鼠胰岛和 β 细胞中的胰岛素释放和胞质 Ca(2+) 浓度 ([Ca(2+)]i)。单独使用阈下浓度的 Exendin-4 可增加 Kv2.1(+/-) 小鼠的胰岛胰岛素释放和 β 细胞 [Ca(2+)]i。蛋白激酶A抑制剂H-89预处理减弱了[Ca(2+)]i对阈下exendin-4和GxTx组合的反应，表明协同效应依赖于蛋白激酶A。此外，阈下剂量的 GxTx 和 GLP-1 激动剂利拉鲁肽联合使用可显着增加糖尿病 db/db 小鼠和 NSY 小鼠的血浆胰岛素并改善葡萄糖耐量。这些结果表明，适度抑制 Kv2.1 通道可显着提高基于 GLP-1 的药物的促胰岛素效力，这为减少其剂量和相关不良反应开辟了一条新途径，同时在 2 型糖尿病中实现相同的血糖控制。
Glucagon-like peptide-1 (GLP-1)-based medicines have recently been widely used to treat type 2 diabetic patients, whereas adverse effects of nausea and vomiting have been documented. Inhibition of voltage-gated K(+) channel subtype Kv2.1 in pancreatic β-cells has been suggested to contribute to mild depolarization and promotion of insulin release. This study aimed to determine whether the blockade of Kv2.1 channels potentiates the insulinotropic effect of GLP-1 agonists. Kv2.1 channel blocker guangxitoxin-1E (GxTx) and GLP-1 agonist exendin-4 at subthreshold concentrations, when combined, markedly increased the insulin release and cytosolic Ca(2+) concentration ([Ca(2+)]i) in a glucose-dependent manner in mouse islets and β-cells. Exendin-4 at subthreshold concentration alone increased islet insulin release and β-cell [Ca(2+)]i in Kv2.1(+/-) mice. The [Ca(2+)]i response to subthreshold exendin-4 and GxTx in combination was attenuated by pretreatment with protein kinase A inhibitor H-89, indicating the protein kinase A dependency of the cooperative effect. Furthermore, subthreshold doses of GxTx and GLP-1 agonist liraglutide in combination markedly increased plasma insulin and improved glucose tolerance in diabetic db/db mice and NSY mice. These results demonstrate that a modest suppression of Kv2.1 channels dramatically raises insulinotropic potency of GLP-1-based drugs, which opens a new avenue to reduce their doses and associated adverse effects while achieving the same glycemic control in type 2 diabetes.