Berberine is an insulin secretagogue targeting the KCNH6 potassium channel

Miao-Miao Zhao, Jing Lu, Sen Li, Hao Wang, Xi Cao, Qi Li, Ting-Ting Shi, Kohichi Matsunaga, Chen Chen, Haixia Huang, Tetsuro Izumi and Jin-Kui Yang ()
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Miao-Miao Zhao: Beijing Tongren Hospital, Capital Medical University
Jing Lu: Beijing Tongren Hospital, Capital Medical University
Sen Li: Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute
Hao Wang: Beijing Tongren Hospital, Capital Medical University
Xi Cao: Beijing Tongren Hospital, Capital Medical University
Qi Li: Beijing Key Laboratory of Diabetes Research and Care, Beijing Diabetes Institute
Ting-Ting Shi: Beijing Tongren Hospital, Capital Medical University
Kohichi Matsunaga: Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University
Chen Chen: School of Biomedical Sciences, University of Queensland
Haixia Huang: School of Basic Medical Sciences, Capital Medical University
Tetsuro Izumi: Laboratory of Molecular Endocrinology and Metabolism, Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University
Jin-Kui Yang: Beijing Tongren Hospital, Capital Medical University

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: Abstract Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. However, its underlying mechanism remains poorly understood. Here, we report the effects of its main active component, berberine (BBR), on stimulating insulin secretion. In mice with hyperglycemia induced by a high-fat diet, BBR significantly increases insulin secretion and reduced blood glucose levels. However, in mice with hyperglycemia induced by global or pancreatic islet β-cell-specific Kcnh6 knockout, BBR does not exert beneficial effects. BBR directly binds KCNH6 potassium channels, significantly accelerates channel closure, and subsequently reduces KCNH6 currents. Consequently, blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. Finally, to assess the effect of BBR on insulin secretion in humans, a randomized, double-blind, placebo-controlled, two-period crossover, single-dose, phase 1 clinical trial (NCT03972215) including 15 healthy men receiving a 160-min hyperglycemic clamp experiment is performed. The pre-specified primary outcomes are assessment of the differences of serum insulin and C-peptide levels between BBR and placebo treatment groups during the hyperglycemic clamp study. BBR significantly promotes insulin secretion under hyperglycemic state comparing with placebo treatment, while does not affect basal insulin secretion in humans. All subjects tolerate BBR well, and we observe no side effects in the 14-day follow up period. In this study, we identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels.

Date: 2021
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DOI: 10.1038/s41467-021-25952-2

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