Purpose

Kv1.3 channel regulates the activity of lymphocytes, macrophages, or adipose tissue and its blockade reduces inflammatory cytokine secretion and improves insulin sensitivity in animals with metabolic syndrome and in genetically obese mice. Thus, Kv1.3 blockade could be a strategy for the treatment of type 2 diabetes. Elevated circulating levels of TNFα and IL-1b mediate the higher susceptibility to cardiac arrhythmia in type 2 diabetic rats. We hypothesized that Kv1.3 channel blockade with the psoralen PAP1 could have immunomodulatory properties that prevent QTc prolongation and reduce the risk of arrhythmia in type 2 diabetic rats.

Methods

Type 2 diabetes was induced to Sprague-Dawley rats by high-fat diet and streptozotocin injection. Diabetic animals were untreated, treated with metformin, or treated with PAP1 for 4 weeks. Plasma glucose, insulin, cholesterol, triglycerides, and cytokine levels were measured using commercial kits. ECG were recorded weekly, and an arrhythmia-inducing protocol was performed at the end of the experimental period. Action potentials were recorded in isolated ventricular cardiomyocytes.

Results

In diabetic animals, PAP1 normalized glycaemia, insulin resistance, adiposity, and lipid profile. In addition, PAP1 prevented the diabetes-induced repolarization defects through reducing the secretion of the inflammatory cytokines IL-10, IL-12p70, GM-CSF, IFNγ, and TNFα. Moreover, compared to diabetic untreated and metformin-treated animals, those treated with PAP1 had the lowest risk of developing the life-threatening arrhythmia Torsade de Pointes under cardiac challenge.

Conclusion

Kv1.3 inhibition improves diabetes and diabetes-associated low-grade inflammation and cardiac electrical remodeling, resulting in more protection against cardiac arrhythmia compared to metformin.

中文翻译：

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Kv1.3 通道阻断改善 2 型糖尿病大鼠的炎症特征，减少心脏电重构，并预防心律失常

目的

Kv1.3 通道调节淋巴细胞、巨噬细胞或脂肪组织的活性，其阻断作用可减少炎症细胞因子的分泌并改善患有代谢综合征的动物和遗传性肥胖小鼠的胰岛素敏感性。因此，Kv1.3 阻断可能是治疗 2 型糖尿病的一种策略。升高的 TNFα 和 IL-1b 循环水平介导 2 型糖尿病大鼠对心律失常的更高易感性。我们假设用补骨脂素 PAP1 阻断 Kv1.3 通道可能具有免疫调节特性，可防止 QTc 延长并降低 2 型糖尿病大鼠心律失常的风险。

方法

通过高脂饮食和链脲佐菌素注射诱导Sprague-Dawley大鼠患2型糖尿病。糖尿病动物未经治疗、用二甲双胍治疗或用 PAP1 治疗 4 周。使用商业试剂盒测量血浆葡萄糖、胰岛素、胆固醇、甘油三酯和细胞因子水平。每周记录心电图，并在实验期结束时执行心律失常诱导方案。在分离的心室心肌细胞中记录动作电位。

结果

在糖尿病动物中，PAP1 使血糖、胰岛素抵抗、肥胖和血脂正常化。此外，PAP1 通过减少炎性细胞因子 IL-10、IL-12p70、GM-CSF、IFNγ 和 TNFα 的分泌来预防糖尿病引起的复极化缺陷。此外，与未接受糖尿病治疗和接受二甲双胍治疗的动物相比，接受 PAP1 治疗的动物在心脏挑战下发生危及生命的尖端扭转型室性心律失常的风险最低。

结论

Kv1.3 抑制可改善糖尿病和糖尿病相关的低度炎症和心脏电重构，与二甲双胍相比，可更好地预防心律失常。