New labdane diterpenoids from Alpinia galanga: A new type of GLP‐1 secretagogues targeting the PKA‐CREB and PI3K‐Akt signaling axes

• Published in: Archiv der Pharmazie (Weinheim) 2024-10, Vol.357 (10), p.e2400383-n/a
• Main Authors: Liu, Pei, Gongpan, Pianchou, Wu, Sheng‐Li, Li, Xin‐Yu, Huang, Xiao‐Yan, Ma, Yun‐Bao, Geng, Chang‐An
• Format: Article
• Language: English
• Subjects: Alpinia - chemistry; Alpinia galanga; Cyclic AMP Response Element-Binding Protein - metabolism; Cyclic AMP-Dependent Protein Kinases - metabolism; diabetes; Diterpenes - chemistry; Diterpenes - isolation & purification; Diterpenes - pharmacology; Dose-Response Relationship, Drug; Fruit - chemistry; GLP‐1 secretion; Glucagon-Like Peptide 1 - metabolism; Humans; labdane diterpenoids; Molecular Structure; network pharmacology; Phosphatidylinositol 3-Kinases - metabolism; Proto-Oncogene Proteins c-akt - antagonists & inhibitors; Proto-Oncogene Proteins c-akt - metabolism; Signal Transduction - drug effects; Structure-Activity Relationship
• ISSN: 0365-6233; 1521-4184; 1521-4184
• DOI: 10.1002/ardp.202400383

Glucagon‐like peptide‐1 (GLP‐1) secretagogues are fascinating pharmacotherapies to overcome the defects of GLP‐1 analogs and dipeptidyl peptidase‐4 (DPP‐4) inhibitors in treating diabetes and obesity. To discover new GLP‐1 secretagogues from natural sources, alpigalangols A‐Q (1–17), 17 new labdane diterpenoids including four unusual nor‐labdane and N‐containing ones, were isolated from the fruits of Alpinia galanga. Most of the isolates showed GLP‐1 promotive effects in NCl‐H716 cells, of which compounds 3, 4, 12, and 14–17 were revealed with high promoting rates of 246.0%–413.8% at 50 µM. A mechanistic study manifested that the most effective compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and the protein phosphorylation of PKA, CREB, and GSK3β, but was inactive on GPBAR and GPR119 receptors. Network pharmacology analysis indicated that the PI3K‐Akt pathway was involved in the GLP‐1 stimulation of 12, which was highly associated with AKT1, CASP3, PPARG, and ICAM1 proteins. This study suggests that A. galanga is rich in diverse labdane diterpenoids with GLP‐1 promoting effects, representing a new type of antidiabetic candidates from natural sources. Seventeen new labdane diterpenoids were isolated from the fruits of Alpinia galanga. Of these, compounds 3, 4, 12, and 14–17 showed obvious glucagon‐like peptide‐1 (GLP‐1) stimulation. Compound 12 upregulated the mRNA expression of Gcg and Pcsk1, and promoted GLP‐1 secretion via the PKA‐CREB and PI3K‐Akt signaling axes.