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Cited by 2Pancreatic function and diabetesIon channel regulation and functionDiabetes Treatment and Management

Low-dose quinine targets KCNH6 to potentiate glucose-induced insulin secretion

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Xiong, Feng-Ran, Zhu, Juan-Juan, Zhu, Xiao-Rong, Lu, Jing, Yang, Jin-Kui·2025·Journal of Molecular Cell Biology
DOI 10.1093/jmcb/mjae051PMC PMC12120441
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Abstract

Insulin secretion is mainly regulated by two electrophysiological events, depolarization initiated by the closure of adenosine triphosphate (ATP)-sensitive K+ (KATP) channels and repolarization mediated by K+ efflux. Quinine, a natural component commonly used for the treatment of malaria, has been reported to directly stimulate insulin release and lead to hypoglycemia in patients during treatment through inhibiting KATP channels. In this study, we verified the insulinotropic effect of quinine on the isolated mouse pancreatic islets. We also revealed that low-dose quinine (<20 μM) did not directly provoke Ca2+ spikes or insulin secretion under low-glucose conditions but potentiated Ca2+ influx and insulin secretion induced by high glucose, which cannot be explained by KATP inhibition. KCNH6 (hERG2) is a voltage-dependent K+ (Kv) channel that plays a critical role in the repolarization of pancreatic β cells. Patch clamp experiments showed that quinine inhibited hERG channels at low micromolar concentrations. However, whether quinine can target KCNH6 to potentiate glucose-induced insulin secretion remains unclear. Here, we showed that in vivo administration of low-dose quinine (25 mg/kg) improved glucose tolerance and increased glucose-induced insulin release in wild-type control mice but not in Kcnh6-β-cell-specific knockout (βKO) mice. Consistently, in vitro treatment of primary islet β cells with low-dose quinine (10 μM) prolonged action potential duration and augmented glucose-induced Ca2+ influx in the wild-type control group but not in the Kcnh6-βKO group. Our results demonstrate that KCNH6 plays an important role in low-dose quinine-potentiated insulin secretion and provide new insights into KCNH6-targeted drug development.

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  • Quinine causes hypoglycemia via β-cell KATP channel inhibition and voltage-dependent K channel inhibition, prolonging β-cell membrane depolarization.

    “β -cell K ATP channel inhibition Voltage-dependent K channels inhibition, prolonging β -cell membrane depolarization [110]”

    From Non-Diabetic Hypoglycemia: Evaluation and Management in Adults (2025) · cites this paper as [110]

    The Introduction links quinine-associated hypoglycemia mainly to KATP inhibition. The Results show that low-dose quinine inhibits β-cell voltage-dependent K+ currents and prolongs action potential duration, but the paper does not establish that this second mechanism causes hypoglycemia; it demonstrates potentiation of glucose-induced insulin secretion. (LLM, conf=0.83)

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Cited by

Sorted by citations

Authors
Xiong, F.-R., Zhu, J.-J., Zhu, X.-R., Lu, J., & Yang, J.-K.
Affiliations
  • Beijing Diabetes Institute, Beijing Key Laboratory of Diabetes Research and Care, Beijing Tongren Hospital, Capital Medical University Department of Endocrinology, , Beijing 100730 ,
  • Beijing Tongren Hospital (CN)
Corresponding author
Yang, Jin-Kui
ORCID
Yang, Jin-Kui
Venue
Journal of Molecular Cell Biology
Publisher
Oxford University Press (OUP)
Published
2024-11
Volume
16
Issue
11
ISSN
  • 1674-2788 (ISSN-L)
  • 1759-4685
DOI
10.1093/jmcb/mjae051
PMC
PMC12120441
OpenAlex
W4406746776
Cited by
2
References
1
Citations by year
2026: 1 · 2025: 1
FWCI
0.84
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Molecular Cell Biology (publishedVersion, cc-by-nc)
  • PubMed Central (publishedVersion, cc-by-nc)
  • PubMed (publishedVersion)
Funders
  • National Natural Science Foundation of China (82070890, 81930019)
  • Beijing Natural Science Foundation (7232230)
Topics
  • Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
Keywords
quinine, hERG, insulin secretion, pancreatic beta cells, glucose-induced insulin release, KATP channel inhibition, action potential duration, calcium influx, glucose tolerance, beta-cell-specific knockout mice
MeSH terms
Insulin Secretion, Animals, Calcium, Glucose, Insulin, Islets of Langerhans, Male, Mice, Inbred C57BL, Quinine, Mice, Knockout, Insulin-Secreting Cells, Mice, Ether-A-Go-Go Potassium Channels

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