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.
Highlights
Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years
We find that blockade of KCNH6 channels by BBR increases insulin secretion in a high-glucose-dependent manner or only under hyperglycemic conditions, suggesting that BBR is a glucose-dependent insulin secretagogue for the treatment of diabetes that does not cause hypoglycemia
BBR is a plant alkaloid isolated from the Coptidis rhizoma, the dried rhizome of Coptis chinensis (Fig. 1a)
Summary
Coptis chinensis is an ancient Chinese herb treating diabetes in China for thousands of years. Blocking KCNH6 currents prolongs high glucose-dependent cell membrane depolarization and increases insulin secretion. We identify BBR as a glucose-dependent insulin secretagogue for treating diabetes without causing hypoglycemia that targets KCNH6 channels. Glucose-stimulated insulin secretion (GSIS) from pancreatic islet β-cells is regulated by the electrogenic pathway associated with ATP-sensitive K+ (KATP) channels. Over the past half century, these drugs have been used as the main oral antidiabetic drugs to promote insulin secretion in patients These agents directly block KATP channels and stimulate insulin secretion in a high-glucose-independent manner, which can cause lifethreatening hypoglycemia[5]. We find that blockade of KCNH6 channels by BBR increases insulin secretion in a high-glucose-dependent manner or only under hyperglycemic conditions, suggesting that BBR is a glucose-dependent insulin secretagogue for the treatment of diabetes that does not cause hypoglycemia
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