1820-P: The Effect of Quinolines on KCNH6 Inhibition and Insulin Secretion

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Introduction and Objective: Quinoline drugs were used to treat malaria from as early as 17th century. However, aside from their potent anti-malarial effects, hypoglycemia was associated with the use of quinine during the treatment for malaria, which was attributed to the drug directly evoking insulin secretion through KATP channel inhibition. In this study, we aim to compare the effects of three quinoline drugs (quinine, quinidine and chloroquine) on insulin secretion and to investigate whether quinolines target KCNH6, a repolorizing Kv channel, to affect insulin secretion. Methods: we performed GSIS test with isolated mice islets and IPIRT/IPGTT test in mice. Ca2+ imaging was applied to detect the Ca2+ influx in dispersed mouse pancreatic β cells. we evaluated the inhibitory effect of drugs on KCNH6 channels by using patch clamp technique. Results: GSIS tests showed that quinine can directly evoke insulin secretion without glucose stimuli, but we did not observe chloroquine and quinidine inducing insulin secretion in low-glucose condition. In addition, all three quinolines inhibit KCNH6 channels at low micromolar concentrations, but only low-dose quinine potentiated insulin secretion in a high glucose-dependent way during GSIS test. Low-dose chloroquine even decreased Ca2+ influx and insulin secretion when compared with control. In vivo experiments showed that low-dose quinine improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout (βKO) mice. Conclusion: Our observation identified quinine as the most potent insulin secretagogue among three quinoline drugs and proved that KCNH6 plays a critical role in quinine-potentiated insulin secretion. Disclosure F. Xiong: None. J. Lu: None. J. Yang: None. Funding National Natural Science Foundation of China (81930019) to Jin-Kui Yang; National Natural Science Foundation of China (8247090082070890) to Jing Lu; Beijing Natural Science Foundation (7232230) to Jing Lu.

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