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诱发β细胞功能障碍和胰岛素分泌减少。电压依赖性K ⁺胰岛β细胞中的（Kv）通道在葡萄糖依赖性胰岛素分泌中起关键作用。黄嘌呤衍生物KMUP-1已被证明可调节平滑肌的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。在这项研究中，我们研究了KMUP-1抑制胰腺β细胞中高葡萄糖（25 mM）激活的Kv电流（IKv）的机制。从Wistar大鼠中分离出胰腺β细胞，并通过穿孔膜片钳记录监测IKv。高葡萄糖处理的β细胞中的IKv峰值约为正常葡萄糖（5.6 mM）的1.4倍。KMUP-1（1、10、30μM）以浓度依赖的方式阻止了高葡萄糖刺激的IKv。还发现蛋白激酶A（PKA）激活剂8-Br-cAMP（100μM）的高葡萄糖激活IKv降低。此外，PKA抑制剂H-89（1μM）逆转了KMUP-1（30μM）的电流抑制作用。否则，在高葡萄糖暴露下，用PKC激活剂或抑制剂进行预处理对IKv无影响。总之，葡萄糖毒性降低的胰岛素分泌归因于IKv激活。KMUP-1通过PKA减弱了高葡萄糖刺激的IKv，但未通过PKC信号传导途径。该发现提供了证据，表明KMUP-1可能是治疗高血糖诱导的胰岛素抵抗的有前途的药物。糖毒性降低的胰岛素分泌是由于IKv激活所致。KMUP-1通过PKA减弱了高葡萄糖刺激的IKv，但未通过PKC信号传导途径。该发现提供了证据，表明KMUP-1可能是治疗高血糖诱导的胰岛素抵抗的有前途的药物。糖毒性降低的胰岛素分泌是由于IKv激活所致。KMUP-1通过PKA减弱了高葡萄糖刺激的IKv，但未通过PKC信号传导途径。该发现提供了证据，表明KMUP-1可能是治疗高血糖诱导的胰岛素抵抗的有前途的药物。