Berberine is an insulin secretagogue targeting the KCNH6 potassium channel

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.

INSULIN SECRETAGOGUE EFFECT OF ROOTS OF RAVENALA MADAGASCARIENSIS SONN. - AN IN VITRO STUDY

Objective: The objective of this study was to establish the cytotoxicity profile and to evaluate the insulin secretagogue effect of ethanolic root extract of Ravenala madagascariensis Sonn. Methods: The cell viability of rat insulinoma 5F (RIN5F) cell lines over the treatment of plant extract was assessed by 3-(4,5-dimethyl-2-thiazolyl)- 2,5-diphenyltetrazolium bromide assay. The insulin-releasing effect was evaluated by insulin secretion assay over RIN5F cell lines by enzyme-linked immunosorbent assay. Results: The ethanolic extract of the roots of R. madagascariensis Sonn. showed negligible cytotoxicity at 20–40 μg/ml, and hence, concentrations up to 40 μg/ml were used in insulin secretion assay. The ethanolic root extract at 20 and 40 μg/ml significantly (p<0.05 compared to control) stimulated the insulin release in a dose-dependent manner even in the presence of glucose at lower and higher concentrations (5 and 10 mM). Conclusion: Thus, our results validate its traditional claim in the treatment of diabetes by stimulating the secretion of insulin, thereby suggesting a possible mechanism of its antidiabetic effect.