Exploring the Phytochemicals from Gardenia jasminoides Ellis with GLP-1 Receptor Activation

Background: Type 2 diabetes mellitus (T2DM), which accounts for about 90% of cases of diabetes is characterized by hyperglycemia due to peripheral tissue resistance to insulin and progressive loss of insulin secreting pancreatic β-cells. T2DM remains a major health burden due to rapid increase in prevalence especially in middle and low-income countries. Glucagon like peptide-1 (GLP-1), an incretin hormone released from enteroendocrine cells of intestine after food intake, plays a crucial role in maintaining glucose homeostasis. The molecular mechanisms include stimulating glucose dependent insulin secretion from β-cells of pancreas, delaying gastric emptying and promoting satiety. GLP-1 receptor, a seven trans-membrane G protein coupled receptor, has evolved as a promising therapeutic target in treating T2DM and obesity. Understanding the physiology of incretin system enabled the development of GLP-1 receptor agonists that effectively mimic endogenous GLP-1 and maintain strict glycemic control. Despite advancements in GLP-1 based therapies, natural products that are potential GLP-1 activators and GLP-1 receptor modulators remain under-explored. Objective: This study aims to explore GLP-1 receptor modulating activity of compounds extracted from Gardenia jasminoides Ellis (GJE), a Traditional Chinese Medicinal plant with anti-diabetic properties. Methods: We used in-silico molecular docking approach to evaluate the interaction of compounds of GJE with GLP-1 receptor and GLP-1. Eighteen natural compounds of GJE (GJE 1-18) with anti-diabetic properties were retrieved from PubChem database. 3D cryo-electron microscopic structure of GLP-1 receptor (6X18) was procured from RSBC Protein Data Base. Molecular docking was performed using CB Dock 2 and each of these ligand receptor complexes were analyzed to identify interactions with key residues involved in receptor modulation. Results: Docking results revealed that most of these phytochemicals/ligands demonstrated favorable binding energies with the receptor, ranging from -9.6 kcal/mol to -5.9 kcal/mol. These ligands were observed to bind to the trans-membrane domine, which is important for signal transmission across the cell membrane. Four of the ligands- GJE 6 (-9.6 kcal/mol), GJE 7 (-9.3 kcal/mol), GJE 8 (-9 kcal/mol), GJE 11 (-9 kcal/mol)-demonstrated high binding affinities and key interactions with the receptor, indicating potential modulation of GLP-1 receptor signaling. Remaining ligands displayed moderate to low binding affinities with the receptor. Conclusion: Overall, these findings suggest that GJE 6, GJE 7, GJE 8, GJE 11 may favorably modulate GLP-1 receptor signaling to influence insulin secretion, gastric emptying and satiety. Further experiments validating the proposed functions using both in-vivo and in-vitro models are underway. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.