The aglycone of ginsenoside Rg3 enables glucagon-like peptide-1 secretion in enteroendocrine cells and alleviates hyperglycemia in type 2 diabetic mice

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.

Activation of intestinal olfactory receptor stimulates glucagon-like peptide-1 secretion in enteroendocrine cells and attenuates hyperglycemia in type 2 diabetic mice

“…Culturing the cells on the matrigel-precoated culture dishes causes the cells to exhibit the properties of enteroendocrine L cell, including their chromogranin and proglucagon expressions 15 , 16 . NCI-H716 cells secrete GLP-1 in response to a number of neurotransmitters, nutrients and secretagogues, as described in numerous studies 7 – 9 , 16 In the endocrine-differentiated NCI-H716 cells, geraniol, a monoterpene alcohol abundant in geraniums, grapes, lemons, and roses, exhibited the most significant GLP-1 stimulatory effect (Fig. 1a ).…”

“…The negative control siRNA did not affect the OR1A1 , OR1G1 , GNAL , CNGA2 , and GNAT3 expression levels in differentiated NCI-H716 cells. Endocrine-differentiated NCI-H716 cells were transfected with the siRNA duplexes using Lipofectamine RNAiMAX reagent (Invitrogen, Carlsbad, CA, USA) as previously described 9 .…”

“…We previously investigated taste receptors expressed in the gut and their activation via tastant binding, which leads to the secretion of glucagon-like peptide-1 (GLP-1), an incretin hormone that induces a decrease in blood glucose levels by stimulating insulin secretion 7 – 9 . We also found that the mRNA signals for several ORs in human enteroendocrine NCI-H716 cells are upregulated by the bitter tastant quinine as well as herbal extracts 10 – 12 .…”

Review of Ginseng Anti-Diabetic Studies

“…Kim et al screened the GLP-1 release ability of 15 ginsenosides and found that Rg3 showed the strongest GLP-1 secretion (about 27 pM/mg) effect in NCI-H716 cells. In this in vivo trial, 10 µM Rg3 significantly raised production of GLP-1 and insulin to reduce blood glucose in db/db mice [33]. In mouse islet cells, insulin secretion was significant: 2.3 times higher in the 4 µM Rg3 treatment group compared to control group [34].…”

The anti-hyperglycemic efficacy of a lipid-lowering drug Daming capsule and the underlying signaling mechanisms in a rat model of diabetes mellitus

“…Together the above results, it appears that DMC elicited its anti-hyperglycemic effects by enhancing GSK-3β activity and upregulating β-catenin expression, which in turn transactivated TCF7L2 that subsequently stimulated the secretion of GLP-1 and GIP leading to hypoglycemia. To further test this notion, we employed pharmacological tools and looked at the changes of these components in enteroendocrine cell line NCI-H716 cell, which is commonly used for measuring GLP-1 secretion 30 31 . Rheum Emodin is the main component of DMC (see Fig.…”