Lee Chien-Hsing, Chu Chih-Sheng, Tsai Han-Jie, Ke Liang-Yin, Lee Hsiang-Chun, Yeh Jwu-Lai, Chen Chu-Huang, Wu Bin-Nan
Department of Pharmacology, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Division of Cardiology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Lipid Science and Aging Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
Chem Biol Interact. 2018 Jan 5;279:171-176. doi: 10.1016/j.cbi.2017.11.017. Epub 2017 Nov 26.
Hyperglycemia-associated glucotoxicity induces β-cell dysfunction and a reduction in insulin secretion. Voltage-dependent K (Kv) channels in pancreatic β-cells play a key role in glucose-dependent insulin secretion. KMUP-1, a xanthine derivative, has been demonstrated to modulate Kv channel activity in smooth muscles; however, the role of KMUP-1 in glucotoxicity-activated Kv channels in pancreatic β-cells remains unclear. In this study we examined the mechanisms by which KMUP-1 could inhibit high glucose (25 mM) activated Kv currents (IKv) in pancreatic β-cells. Pancreatic β-cells were isolated from Wistar rats and IKv was monitored by perforated patch-clamp recording. The peak IKv in high glucose-treated β-cells was ∼1.4-fold greater than for normal glucose (5.6 mM). KMUP-1 (1, 10, 30 μM) prevented high glucose-stimulated IKv in a concentration-dependent manner. Reduction of high glucose-activated IKv was also found for protein kinase A (PKA) activator 8-Br-cAMP (100 μM). Additionally, KMUP-1 (30 μM) current inhibition was reversed by the PKA inhibitor H-89 (1 μM). Otherwise, pretreatment with the PKC activator or inhibitor had no effect on IKv in high glucose exposure. In conclusion, glucotoxicity-diminished insulin secretion was due to IKv activation. KMUP-1 attenuated high glucose-stimulated IKv via the PKA but not the PKC signaling pathway. This finding provides evidence that KMUP-1 might be a promising agent for treating hyperglycemia-induced insulin resistance.
高血糖相关的糖毒性会导致β细胞功能障碍并减少胰岛素分泌。胰腺β细胞中的电压依赖性钾（Kv）通道在葡萄糖依赖性胰岛素分泌中起关键作用。KMUP-1是一种黄嘌呤衍生物，已被证明可调节平滑肌中的Kv通道活性；然而，KMUP-1在胰腺β细胞中糖毒性激活的Kv通道中的作用仍不清楚。在本研究中，我们研究了KMUP-1抑制胰腺β细胞中高糖（25 mM）激活的Kv电流（IKv）的机制。从Wistar大鼠分离胰腺β细胞，并通过穿孔膜片钳记录监测IKv。高糖处理的β细胞中的IKv峰值比正常葡萄糖（5.6 mM）处理的细胞大约高1.4倍。KMUP-1（1、10、30 μM）以浓度依赖性方式阻止高糖刺激的IKv。蛋白激酶A（PKA）激活剂8-Br-cAMP（100 μM）也能降低高糖激活的IKv。此外，PKA抑制剂H-89（1 μM）可逆转KMUP-1（30 μM）对电流的抑制作用。否则，用PKC激活剂或抑制剂预处理对高糖暴露下的IKv没有影响。总之，糖毒性导致的胰岛素分泌减少是由于IKv激活。KMUP-1通过PKA信号通路而非PKC信号通路减弱高糖刺激的IKv。这一发现提供了证据，表明KMUP-1可能是治疗高血糖诱导的胰岛素抵抗的有前景的药物。
