Chemical Constituents from the Roots of Angelica reflexa That Improve Glucose-Stimulated Insulin Secretion by Regulating Pancreatic β-Cell Metabolism.

The aim of this study was to discover bioactive constituents of Angelica reflexa that improve glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells. Herein, three new compounds, namely, koseonolin A ( 1 ), koseonolin B ( 2 ), and isohydroxylomatin ( 3 ), along with 28 compounds ( 4 - 31 ) were isolated from the roots of A . reflexa by chromatographic methods. The chemical structures of new compounds ( 1 - 3 ) were elucidated through spectroscopic/spectrometric methods such as NMR and HRESIMS. In particular, the absolute configuration of the new compounds ( 1 and 3 ) was performed by electronic circular dichroism (ECD) studies. The effects of the root extract of A . reflexa (KH2E) and isolated compounds ( 1 - 31 ) on GSIS were detected by GSIS assay, ADP/ATP ratio assay, and Western blot assay. We observed that KH2E enhanced GSIS. Among the compounds 1 - 31 , isohydroxylomatin ( 3 ), (-)-marmesin ( 17 ), and marmesinin ( 19 ) increased GSIS. In particular, marmesinin ( 19 ) was the most effective; this effect was superior to treatment with gliclazide. GSI values were: 13.21 ± 0.12 and 7.02 ± 0.32 for marmesinin ( 19 ) and gliclazide at a same concentration of 10 μM, respectively. Gliclazide is often performed in patients with type 2 diabetes (T2D). KH2E and marmesinin ( 19 ) enhanced the protein expressions associated with pancreatic β-cell metabolism such as peroxisome proliferator-activated receptor γ, pancreatic and duodenal homeobox 1, and insulin receptor substrate-2. The effect of marmesinin ( 19 ) on GSIS was improved by an L-type Ca 2+ channel agonist and K+ channel blocker and was inhibited by an L-type Ca 2+ channel blocker and K + channel activator. Marmesinin ( 19 ) may improve hyperglycemia by enhancing GSIS in pancreatic β-cells. Thus, marmesinin ( 19 ) may have potential use in developing novel anti-T2D therapy. These findings promote the potential application of marmesinin ( 19 ) toward the management of hyperglycemia in T2D.