Abstract
Ginsenosides can be classified on the basis of the skeleton of their aglycones. Here, we hypothesized that the sugar moieties attached to the dammarane backbone enable binding of the ginsenosides to the sweet taste receptor, eliciting glucagon-like peptide-1 (GLP-1) secretion in the enteroendocrine L cells. Using the human enteroendocrine NCI-H716 cells, we demonstrated that 15 ginsenosides stimulate GLP-1 secretion according to the position of their sugar moieties. Through a pharmacological approach and RNA interference technique to inhibit the cellular signal cascade and using the Gαgust−/− mice, we elucidated that GLP-1 secreting effect of Rg3 mediated by the sweet taste receptor mediated the signaling pathway. Rg3, a ginsenoside metabolite that transformed the structure through a steaming process, showed the strongest GLP-1 secreting effects in NCI-H716 cells and also showed an anti-hyperglycemic effect on a type 2 diabetic mouse model through increased plasma GLP-1 and plasma insulin levels during an oral glucose tolerance test. Our study reveals a novel mechanism where the sugar moieties of ginsenosides Rg3 stimulates GLP-1 secretion in enteroendocrine L cells through a sweet taste receptor-mediated signal transduction pathway and thus has an anti-hyperglycemic effect on the type 2 diabetic mouse model.
Highlights
GLP-1 is a potent anti-hyperglycemic agent, which induces glucose-dependent insulin secretion from pancreatic β cells, while suppresses glucagon secretion
We have reported that enteroendocrine L cells express taste receptors and their downstream signal elements, including a specific G protein, Gα -gustducin (Gα gust), and G protein-coupled sweet and bitter taste receptors, similar to their expression in the tongue[13,14]
We observed GLP-1 secretion in NCI-H716 cells treated with ginsenosides: Rb1, Rb2, Rd, Rg3, Rg5, Rk1, compound K (C-K), Re, and Rg1 (Fig. 1)
Summary
GLP-1 is a potent anti-hyperglycemic agent, which induces glucose-dependent insulin secretion from pancreatic β cells, while suppresses glucagon secretion. Previous reports suggest that the intracellular signal transduction pathway activated by sugar binding to taste receptors is mediated by the activation of Gα gust and a consequent signaling cascade including phospholipase Cβ 2 (PLCβ 2) and inositol 1,4,5-triphosphate (IP3)[16,17]. This Gβ γ -subunit mediating the signaling cascade elicits the release of Ca2+ from intracellular stores and subsequent Ca2+-dependent activation of a transient receptor potential channel M5 (TRPM5), leading to the membrane depolarization and further action potential generation in turn[18,19]. Using the cell line and Gα gust−/− mice, we investigated the cellular mechanism underlying the GLP-1 secreting effect of Rg3, and using db/db mice, we evaluated the possibility of exploiting the effect of Rg3 as a therapeutic agent for type 2 diabetes mellitus
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